Clinical trial NCT03305419
Conditions: Autoimmune Diseases
Keywords: Crossover Sequential GSK2982772 Safety Pharmacokinetics Healthy subjects
Sponsor: GlaxoSmithKline
Start date: 2017-10-11; Completion date: 2018-10-15
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is designed to evaluate the safety, tolerability and PK of GSK2982772, in repeat oral doses in healthy subjects. This study is being conducted to support administration of higher dose levels of GSK2982772 than initially studied in the First Time in Human (FTiH) study. This study will also assess the impact of food during the repeat doses of GSK2982772. This will be a two part study; Part A and Part B. Part A (cohort 1) - single ascending dose, randomized, placebo-controlled, 3-way crossover. Part B (cohorts 2, 3, 4 and 5) - repeat dose, randomized, placebo-controlled, sequential-group. Subjects will be randomized in 3:1 ratio to receive GSK2982772 or placebo in crossover manner on Day 1 of each of the three periods in Part A. Subjects will be randomized in 3:1 ratio to receive GSK2982772 or placebo in sequential groups for 14 days in cohort 2 of Part B and in 9:5 ratio to receive GSK2982772 or placebo in sequential groups for 14 days in cohorts 3, 4 and 5 of Part B. Approximately 66 subjects will be included in this study. The study duration, including screening and follow-up, will not be expected to exceed 13 weeks for Part A and 8 weeks for Part B.

Detailed description:

Arms: arm 1: Eligible subjects will be randomized to receive treatment sequence ABC in Part A; A= GSK2982772 120 mg TID, B= GSK2982772 240 mg TID, and C= GSK2982772 360 mg BID. Subjects will receive oral capsule of GSK2982772 or placebo on Day 1 in each of the 3 treatment periods followed by a wash-out period of at least 7 days between dosing regimens. arm 2: Eligible subjects will be randomized to receive treatment sequence ABP in Part A; A= GSK2982772 120 mg TID, B= GSK2982772 240 mg TID, and P= Placebo. Subjects will receive oral capsule of GSK2982772 or placebo on Day 1 in each of the 3 treatment periods followed by a wash-out period of at least 7 days between dosing regimens. arm 3: Eligible subjects will be randomized to receive treatment sequence APC in Part A; A= GSK2982772 120 mg TID, P= Placebo and C= GSK2982772 360 mg BID. Subjects will receive oral capsule of GSK2982772 or placebo on Day 1 in each of the 3 treatment periods followed by a wash-out period of at least 7 days between dosing regimens. arm 4: Eligible subjects will be randomized to receive treatment sequence PBC in Part A; P= Placebo, B= GSK2982772 240 mg TID and C= GSK2982772 360 mg BID. Subjects will receive oral capsule of GSK2982772 or placebo on Day 1 in each of the 3 treatment periods followed by a wash-out period of at least 7 days between dosing regimens. arm 5: Eligible subjects will receive GSK2982772 oral capsule with a dose of 120 mg TID for 14 days in Part B. arm 6: Eligible subjects will receive GSK2982772 oral capsule with a dose of 120 mg TID for 14 days in Part B. arm 7: Eligible subjects will receive GSK2982772 oral capsule with a dose of 240 mg TID for 14 days in Part B. arm 8: Eligible subjects will receive GSK2982772 oral capsule with a dose of 360 mg BID for 14 days in Part B. arm 9: Subjects will receive placebo oral capsule for 14 days in Part B. arm 10: Subjects will receive placebo oral capsule for 14 days in Part B. arm 11: Subjects will receive placebo oral capsule for 14 days in Part B. arm 12: Subjects will receive placebo oral capsule for 14 days in Part B.
Interventions: intervention 1: GSK2982772 capsule intervention 2: Placebo capsule
Intervention descriptions: intervention 1: GSK2982772 will be available as size 00, white, opaque capsule containing white to almost white Solid (120 mg maximum fill per capsule). It will be administered orally with water to receive total dose of 120 mg, 240 mg or 360 mg per randomization. intervention 2: Placebo will be available as size 00, white, opaque capsule containing white to almost white Solid. It will be administered orally with water.

Protocol documents:
Prot_000.pdf: 
2017N326600_00 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
205184 
 
1 
 
TITLE PAGE 
Protocol Title: A single-centre, randomized, double-blind (sponsor-unblinded), placebo-
controlled study to evaluate the safety, tolerability and pharmacokinetics of GSK2982772 
in repeat oral doses in healthy subjects. 
Protocol Number: 205184 
Short Title: GSK2982772 high dose safety and PK study in healthy volunteers. 
Compound Number: GSK2982772  
 
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 
Regulatory Agency Identifying Number(s):  EudraCT 2017-002662-45 
Approval Date: 31-JUL-2017 
 
 
 
 
 
 
 
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


PPD
PPD


2017N326600_00
CONFIDENTIAL
205184
3
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205184........................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................10
2.1.
Time and Events Table – Part A (Cohort 1) ................................................11
2.2.
Time and Events Table – Part B (Cohorts 2-4) ...........................................13
3.
INTRODUCTION....................................................................................................18
3.1.
Study Rationale ..........................................................................................18
3.2.
Background ................................................................................................18
3.3.
Benefit/Risk Assessment ............................................................................18
3.3.1.
Risk Assessment .........................................................................19
3.3.2.
Benefit Assessment.....................................................................25
3.3.3.
Overall Benefit:Risk Conclusion...................................................25
4.
OBJECTIVES AND ENDPOINTS...........................................................................26
5.
STUDY DESIGN ....................................................................................................27
5.1.
Overall Design ............................................................................................27
5.2.
Number of Participants ...............................................................................28
5.3.
Sentinel Dosing...........................................................................................28
5.4.
Dose Escalation Decisions .........................................................................28
5.5.
Participant and Study Completion...............................................................28
5.6.
Scientific Rationale for Study Design ..........................................................29
5.7.
Dose Justification........................................................................................29
6.
STUDY POPULATION...........................................................................................32
6.1.
Inclusion Criteria.........................................................................................32
6.2.
Exclusion Criteria........................................................................................33
6.3.
Lifestyle Restrictions...................................................................................35
6.3.1.
Meals and Dietary Restrictions ....................................................35
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................36
6.3.3.
Activity .........................................................................................36
6.4.
Screen Failures...........................................................................................36
7.
TREATMENTS.......................................................................................................37
7.1.
Treatments Administered............................................................................37
7.2.
Method of Treatment Assignment ...............................................................37
7.3.
Blinding.......................................................................................................38
7.4.
Preparation/Handling/Storage/Accountability..............................................39
7.5.
Treatment Compliance................................................................................39
7.6.
Concomitant Therapy..................................................................................39
7.7.
Treatment after the End of the Study ..........................................................40
8.
DISCONTINUATION CRITERIA.............................................................................41
8.1.
Discontinuation of Study Treatment ............................................................41
8.1.1.
Dose Modification/Stopping Criteria.............................................41
8.1.2.
Pharmacokinetic Dose Modification or Stopping Criteria..............41
8.1.3.
Liver Chemistry Stopping Criteria ................................................42
8.1.4.
QTc Stopping Criteria ..................................................................42


2017N326600_00
CONFIDENTIAL
205184
4
8.1.5.
Individual Safety Stopping Criteria ...............................................43
8.1.6.
Group Safety Stopping Criteria ....................................................43
8.1.7.
Nervous System Stopping Criteria ...............................................43
8.1.8.
Rechallenge.................................................................................44
8.1.8.1.
Study Treatment Restart or Rechallenge....................44
8.2.
Withdrawal from the Study..........................................................................44
8.3.
Lost to Follow Up........................................................................................44
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................46
9.1.
Adverse Events...........................................................................................46
9.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................46
9.1.2.
Method of Detecting AEs and SAEs.............................................47
9.1.3.
Follow-up of AEs and SAEs.........................................................47
9.1.4.
Regulatory Reporting Requirements for SAEs .............................47
9.1.5.
Pregnancy ...................................................................................48
9.2.
Treatment of Overdose...............................................................................48
9.3.
Safety Assessments ...................................................................................48
9.3.1.
Physical Examinations.................................................................48
9.3.2.
Neurological Exams.....................................................................49
9.3.3.
Vital Signs....................................................................................49
9.3.4.
Electrocardiograms......................................................................49
9.3.5.
Clinical Safety Laboratory Assessments ......................................50
9.3.6.
Suicidal Risk Monitoring...............................................................50
9.4.
Pharmacokinetics .......................................................................................51
9.4.1.
Blood Sample Collection..............................................................51
9.4.2.
Sample Analysis ..........................................................................51
9.4.3.
Plasma Sample for CYP3A4 Enzyme Activity ..............................52
9.5.
Pharmacodynamics ....................................................................................52
9.6.
Pharmacological Biomarkers ......................................................................52
10. STATISTICAL CONSIDERATIONS........................................................................52
10.1.
Sample Size Determination ........................................................................52
10.2.
Sample Size Sensitivity...............................................................................53
10.3.
Populations for Analyses ............................................................................55
10.4.
Statistical Analyses.....................................................................................55
10.4.1.
Safety Analyses...........................................................................55
10.4.2.
PK Analyses ................................................................................55
10.4.3.
Other Analyses ............................................................................56
10.4.4.
Interim Analyses ..........................................................................56
10.5.
Dose Escalation Committee........................................................................56
11. REFERENCES.......................................................................................................58
12. APPENDICES........................................................................................................59
12.1.
Appendix 1: Abbreviations and Trademarks................................................59
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................62
12.3.
Appendix 3: Study Governance Considerations..........................................64
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................68
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................73


2017N326600_00
CONFIDENTIAL
205184
5
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................77
12.7.
Appendix 7:  Nervous System Adverse Events (CTCAE Criteria) ...............79


2017N326600_00
CONFIDENTIAL
205184
6
1.
PROTOCOL SYNOPSIS FOR STUDY 205184
Protocol Title: A single-centre, randomized, double-blind (sponsor-unblinded), placebo-
controlled study to evaluate the safety, tolerability and pharmacokinetics of GSK2982772 
in repeat oral doses in healthy subjects.
Short Title: GSK2982772 high dose safety and PK study in healthy volunteers.
Rationale: The purpose of this study is to evaluate the safety, tolerability and 
pharmacokinetics (PK) of repeat oral doses of GSK2982772 (TID and BID, if required) 
in healthy subjects. TID dosing will be administered as a 7hr, 7hr, 10hr dosing interval 
and BID as a 12hr dosing interval. 
Objectives and Endpoints:
Objective
Endpoint
Primary

To investigate the safety and tolerability of 
repeat doses of GSK2982772 in healthy 
subjects.

Adverse events.

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature).

Physical examinations.

12-Lead ECG monitoring.
Secondary

To characterise the PK profile of repeat 
doses of GSK2982772 in healthy subjects.

A 24 hr profile to be collected on Day 1 of 
Part A and Day 14 of Part B. On Day 1 of 
Part B, the PK profile will be evaluated 
following the first dose only. Derived PK 
parameters for GSK2982772, including area 
under the plasma drug concentration versus 
time curve over 24 hr (AUC(0-24)) and AUC 
over each dose interval (i.e. AUC(0-7), AUC(7-
14) and AUC(14-24) for TID and AUC(0-12) and 
AUC(12-24) for BID). Maximum observed 
plasma drug concentration (Cmax) following
each dose, time to maximum observed 
plasma drug concentration (Tmax) following 
each dose, observed trough plasma drug 
concentrations (C0, C7, C14 and C24 for TID
dosing and C0, C12 and C24 for BID dosing).

To assess the impact of food on the PK of 
repeat doses of GSK2982772 in healthy 
subjects at steady state

Derived PK parameters for GSK2982772, 
including AUC(0-7), AUC(7-14), Cmax, after 1st
dose of day and Tmax after 1st dose of day.


2017N326600_00
CONFIDENTIAL
205184
7
Objective
Endpoint

To assess potential effect of repeat doses 
of GSK2982772 on CYP3A4 enzyme 
activity.

Plasma 4β-hydroxycholesterol to 
cholesterol ratio pre-treatment and following 
14 days of repeat dosing of GSK2982772.
Exploratory

To investigate the levels of circulating 
glucuronide metabolite (M8; GSK3562183)
and desmethyl metabolite (M9; 
GSK2997852) in healthy subjects after 
repeat dosing of GSK2982772.

Quantify M8 (GSK3562183) and M9 
(GSK2997852) in select plasma PK 
samples at pre-dose and 2 hr following Day 
14 of repeat dosing of GSK2982772.
Overall Design:
This is a single-centre, randomized, double-blind (sponsor-unblinded), placebo-controlled 
study to evaluate the safety, tolerability and pharmacokinetics of GSK2982772, in repeat 
oral doses in healthy subjects. The study design schematic is depicted in the Figure
below:
Study Design
*With Food Effect Treatment
Part A - Single-Day Ascending Doses
1 Day
3:1 Randomized 
GSK2982772:Placebo
Part B – Repeat Doses 
14 Days
3:1 Randomized 
GSK2982772:Placebo
Cohort 1
N=12
120 mg TID (1 Day) followed by,
240 mg TID (1 Day) followed by,
360 mg BID (1 Day)
Cohort 2
N=12
120 mg TID
14 Days *
Cohort 3
N=12
240 mg TID
14 Days *
Cohort 4
N=12
360 mg BID
14 Days


2017N326600_00
CONFIDENTIAL
205184
8
Type and Number of Participants:
Healthy volunteer subjects will be enrolled, such that up to approximately 12 subjects (9 
active, 3 placebo) in each Cohort (up to approximately 48 in total) complete dosing and 
critical assessments. A subject is defined to have completed the study when he/she has 
attended all study visits.
Sentinel dosing will be employed within each Cohort for both Part A and Part B of the 
study. The doses in the single-ascending dose portion of the study (Part A) will be 
staggered such that for each of the three treatment periods, on Day 1, two of the 12 
subjects will be randomized to treatment (one subject will receive GSK2982772 and one 
subject will receive matched-placebo). Assuming 2 subjects are dosed on Day 1 and 
assuming adequate safety in the judgment of the Principal Investigator (e.g., vital signs, 
ECGs, and adverse events) through approximately 24 hours after their last dose on Day 1, 
the remaining subjects may be randomized to dosing in that period. The doses in the 
repeat dose portion of the study (Part B) will be staggered such that for each treatment 
period on Day 1, two of the 12 subjects will be randomized to treatment (one subject will 
receive GSK2982772 and one subject will receive matched-placebo) and dosed for at 
least 7 days before the rest of the cohort is randomized. Assuming 2 subjects are dosed on 
Day 1 to 7 and assuming adequate safety in the judgment of the Principal Investigator 
(e.g., vital signs, ECGs, and adverse events) through approximately Day 7, the remaining 
subjects may be randomized to dosing.
If subjects prematurely discontinue the study, additional replacement subjects may be 
randomized in order to guarantee that sufficient subjects are treated with GSK2982772 at 
any given dose before escalating to the following dose. Replacement subjects will be 
assigned to the same treatment sequence (Cohort 1) or treatment (Cohorts 2-4) and start 
from the period to be replaced at the discretion of the Sponsor and in consultation with 
the Principal Investigator.
Treatment Groups and Duration:
The study duration, including screening and follow-up, is not expected to exceed 
13 weeks for Part A and 8 weeks for Part B of the study.
Study Duration – Cohort 1
Screening
Approximately 28 days.
Number of Subjects
One Cohort of 12 subjects (N=12).
Treatment Period
Cohort 1 will comprise of three treatment periods, investigating three dosing regimens. 
Each dose regimen consists of 1 day treatment duration, with subjects in house for 4
nights (through at least 48 hours post-last dose). Subjects will be admitted to the unit 
the day before dosing, will remain in the unit overnight, and will be released following 
completion of the assessments on Day 4 of each treatment period, provided there are 
no safety concerns.
Washout Period 
Will be at least 7 days between dose regimens for an individual subject.
Follow-up
At least 7 days and no greater than 14 days after last study drug administration. If 
warranted, additional follow-up visits may be scheduled.


2017N326600_00
CONFIDENTIAL
205184
9
Study Duration – Cohorts 2-4
Screening
Approximately 28 days.
Number of Subjects
Three Cohorts of 12 subjects each (N=36).
Treatment Period
The treatment duration will be 14 days. Subjects will be admitted to the unit the day 
before dosing, will remain in the unit overnight and will be released following 
completion of the assessments on Day 17, provided there are no safety concerns.
Follow-up
At least 7 days and no greater than 14 days after last study drug administration. If 
warranted, additional follow-up visits may be scheduled.


2017N326600_00
CONFIDENTIAL
205184
10
2.
SCHEDULE OF ACTIVITIES (SOA)
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Activities (SoA) tables (Section 2.1 and Section 2.2), are 
essential and required for study conduct.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the Study Reference Manual (SRM). The SRM will provide the site 
personnel with administrative and detailed technical information that does not impact 
subject safety.
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the SoA tables (Section 2.1 and Section 2.2).
The following points must be noted:

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-Lead ECG
2. Vital Signs
3. Blood Draws
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, or other 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.

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File, which is approved by the relevant GSK 
study team member and then archived in the study sponsor and site study files, 
but this will not constitute a protocol amendment.

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.

The Institutional Review Board/Independent Ethics Committee (IRB/IEC) will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form.
A table defining the allowed variance in timings of assessments without being considered 
a protocol deviation will be included in the SRM.


2017N326600_00
CONFIDENTIAL
205184
11
2.1.
Time and Events Table – Part A (Cohort 1)
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up  
(No more 
than 14 days 
post last 
dose)
Notes
-1
1
2
3
4
Outpatient Visit
X
X
Admission to Clinical Unit
X
Inpatient Stay at Clinical Unit
==X==
Discharge from Clinical Unit
X
Following completion of all assessments.
Informed Consent
X
Inclusion and Exclusion Criteria
X
Demography
X
Full Physical Examination
X
Additional exams/screens may be performed, or brief exams made full exams, by the Investigator, as 
deemed necessary (e.g. where safety or laboratory findings indicate). Tests will be conducted within 
site specified standards.
Brief Physical Examination
X
X
X
Height
X
Weight
X
Drug/Alcohol/Cotinine Screen
X
X
Tests include alcohol breath test, cotinine breath test and urine drug screen.
Medical/Medication/Drug/Alcohol 
History
X
HIV, Hepatitis B and C Screening
X
Tuberculosis Test
X
Conducted at the standard practice of the site.
Serum Pregnancy Test (WOCBP only)
X
X
Urine Pregnancy Test (WOCBP only)
X
X
Meals
X
Xa
X
X
X
a On Day 1, subjects will fast 8hr overnight prior to dose 1. A breakfast will be served approximately 2hr 
after dose 1. 
TID dosing: On Day 1, lunch and dinner will be served between 2 to 3hr prior to doses 2 and 3, 
respectively. 
BID dosing: On Day 1, lunch will be served approximately 4 to 5hr after dose 1. Dinner will be served 
between 2 to 3hr prior to dose 2. A snack may be consumed approximately 2 to 3hr after dose 2.
Water is permitted with dosing and at all times. Subjects will receive standardized meals scheduled at 
the same time in each period.
Haem/Chem/Urinalysis Test 
(Include Liver Chemistries)
X
X
X
X
X
X
Non-fasted samples can be collected on Day -1.


2017N326600_00
CONFIDENTIAL
205184
12
Procedure
Screening
(U t 28
Study Period (Days)
Follow-Up  
(N
Notes
PK Blood Sampling
X
X
TID Dosing: PK samples to be taken pre-dose on Day 1 and then at the following time points post first-
dose: 20min, 40min, 1hr, 1hr 30min, 2hr, 3hr, 5hr, 7hr, 7hr 20min, 7hr 40 min, 8hr, 8hr 30min, 9hr, 
10hr, 12hr, 14hr, 14hr 20min, 14hr 40 min, 15hr, 15hr 30min, 16hr, 19hr, 22hr, 24hr.
BID Dosing: PK samples to be taken pre-dose on Day 1 and then at the following time points post first-
dose: 20min, 40min, 1hr, 1hr 30min, 2hr, 3hr, 4hr, 6hr, 8hr, 10hr, 12hr, 12hr 20min, 12hr 40min, 13hr, 
13hr 30min, 14hr, 15hr, 16hr, 19hr, 22hr, 24hr.
Neuro. Examination
X
X
X
TID Dosing: Neurological examinations to be conducted either on Day -1 or pre-dose Day 1 and then 
at the subsequent time points post first-dose on Day 1: 2hr, 9hr, 16hr, 24hr and 48hr. Then 24 and 48hr
after the last dose administered on Day 1.
BID Dosing: Neurological examinations to be conducted either on Day -1 or pre-dose Day 1 and then 
at the subsequent time points post first-dose: 2hr, 14hr, 24hr and 48hr. Then 24 and 48 hr after the last 
dose administered on Day 1.
Telemetry
X
Continuous at least 24hr post-evening dose. Initiate at least 15 min. prior to dosing.
12-Lead ECG
X
X
T
X
X
Vital signs to include HR, BP, temperature and respiration rate. 
TID Dosing: 12-Lead ECG and Vital Signs to be conducted on Day -1 and pre-dose on Day 1 and 
then at the subsequent time points post first-dose: 40min, 2hr, 4hr, 7hr (pre-2nd dose), 9hr, 14hr (pre-3rd
dose), 16hr, 24hr and 48hr. Then 24 and 48hr after the last dose administered on Day 1.
BID Dosing: 12-Lead ECG and Vital Signs to be conducted on Day -1 and pre-dose on Day 1 and then 
at the subsequent time points post first-dose: 40 min, 2hr, 4hr, pre-2nd dose, 12hr 20 min, 14hr, 24hr 
and 48 hr. Then 24 and 48hr after the last dose administered on Day 1.
T = Triplicate.
Vital Signs
X
X
T
X
X
X
Randomization
X
Study Treatment
Xb
b TID dosing: GSK2982772 or placebo will be administered using a 7hr, 7hr and 10hr dosing interval.
BID dosing: GSK2982772 or placebo will be administered using a 12hr dosing interval.
AE Review
========X=======
X
SAE Review
========X=======
X
Concomitant Medication Review
X
========X=======
X


2017N326600_00
CONFIDENTIAL
205184
13
2.2.
Time and Events Table – Part B (Cohorts 2-4)
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more than 
14 days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Outpatient Visit
X
X
Admission to Clinical Unit
X
Inpatient Stay at Clinical Unit
===================================X==================================
Discharge from Clinical Unit
X
Following completion of all assessments.
Informed Consent
X
Inclusion and Exclusion Criteria
X
Demography
X
Full Physical Examination
X
X
Additional exams/screens may be 
performed, or brief exams made full 
exams, by the Investigator, as deemed 
necessary (e.g. where safety or laboratory 
findings indicate). Tests will be conducted 
within site specified standards.
Brief Physical Examination
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
Drug/Alcohol/Cotinine Screen
X
X
Tests include alcohol breath test, cotinine
breath test and urine drug screen.
Medical/Medication/Drug/Alcohol 
History
X
HIV, Hepatitis B and C Screening
X
Tuberculosis Test
X
Anti-Nuclear Antibody
X
X
X
Serum Pregnancy Test (WOCBP 
only)
X
X
Urine Pregnancy Test (WOCBP 
only)
X
X
C-SSRS
X
X
X
X
Xc
May be completed on either Day -1 or 
Day 1, but no later than 1hr prior to 
dosing. To be completed pre-dose on Day 
7.


2017N326600_00
CONFIDENTIAL
205184
14
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more than 
14 days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
c C-SSRS to be conducted on follow-up 
only in the instance that a subject 
withdraws from the study.
Meals
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TID Dosing: On Day 1 through 14
subjects will fast 8hr overnight. Breakfast 
will be served approximately 2hr after 
dosing on Days 1-8, 10, 12 and 13 and 
2hr after dosing on Day 14. A “standard” 
and a “high fat” breakfast will be served 
approximately 30 minutes prior to dosing 
on Day 9 and Day 11, respectively. On all 
study days, lunch and dinner will be 
served between 2 to 3hr prior to dose 2 
and dose 3, respectively.     
BID Dosing: On Day 1, subjects will fast 
8hr overnight prior to dose 1. A breakfast 
will be served approximately 2hr after 
dose 1. Lunch will be served 
approximately 4-5hr after dose 1. Dinner 
will be served between 2-3hr prior to dose 
2. A snack may be consumed 
approximately 2-3hr after dose 2.
Water is permitted with dosing and at all 
times. Subjects will receive standardized 
meals scheduled at the same time in each 
period.
Haem/Chem/Urinalysis Test 
(Include Liver Chemistries and 
fasting lipid panel)
X
X
X
X
X
X
X
X
X
May be completed on either Day -1 or 
Day 1, but no later than 1hr prior to 
dosing. To be drawn pre-dose on Days 2, 
4, 7 and 10.
Telemetry
X
X
X
Continuous at least 24 hr post-evening 
dose. Initiate at least 15 min. prior to 
dosing.
PK blood sampling
Xd,g
Xe
Xe
Xe
Xe
Xe
Xf
Xf
Xg
dOn Day 1, PK samples will be collected
pre-dose and at the following time points 
post first-dose: 20min, 40min, 1hr, 1hr 


2017N326600_00
CONFIDENTIAL
205184
15
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more than 
14 days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
30min, 2hr, 3hr, 5hr and 7hr.
eOnDays 2,3 4, 5 and 7 pre-dose 
samples only .
f Days 9, and 11: Cohort 2 and Cohort 3
PK sampling at the following time points 
post first-dose: 20min, 40min, 1hr, 1hr 
30min, 2hr, 3hr, 5hr, 7hr (prior to 2nd
dose) 7hr 20min, 7hr 40 min, 8hr, 8hr 
30min, 9hr, 10hr, 12hr. Cohort 4 is 
currently not planned to have PK 
assessment but may be included 
depending on outcome of food effect in 
Cohorts 2 and 3.
g Day 14 sampling for Cohorts 2, 3 and 4
will be over 24hr according to the 
following schedules:
For TID Dosing: PK samples to be taken 
pre-dose and then at the following time 
points post first-dose: 20min, 40min, 1hr, 
1hr 30min, 2hr, 3hr, 5hr, 7hr (pre-2nd
dose) 7hr 20min, 7hr 40 min, 8hr, 8hr 
30min, 9hr, 10hr, 12hr, 14hr (pre 3rd
dose), 14hr 20min, 14hr 40 min, 15hr, 
15hr 30min, 16hr, 19hr, 22hr, 24hr.
For BID Dosing: PK samples to be taken 
pre-dose on Day 1 and then at the 
subsequent time points post first-dose: 
20min, 40min, 1hr, 1hr 30min, 2hr, 3hr, 
4hr, 6hr, 8hr, 10hr, 12hr (pre 2nd dose), 
12hr 20min, 12hr 40min, 13hr, 13hr 
30min, 14hr, 15hr, 16hr, 19hr, 22hr, 24hr.
Metabolite sampling
Xh
hMetabolite sampling will be conducted 
pre-dose and 2hr post first dose on Day 
14 only.
4β-hydroxycholesterol sampling
Xi
Xj
iSample to be taken pre-dose on either 
Day-1 or Day 1.


2017N326600_00
CONFIDENTIAL
205184
16
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more than 
14 days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
jSample to be taken at 24hr post first 
dose on Day 14.
Neuro. examination
X
X
X
X
X
TID Dosing: Neurological examinations 
to be conducted either on Day-1 or pre-
dose Day 1 and then at the subsequent 
time points post first dose: 2hr, 9hr, 16hr, 
24hr and 48hr. To be completed pre-dose
on Day 7 and then 48 hr post-last dose on 
Day 14.
BID Dosing: Neurological examinations 
to be conducted pre-dose either on Day-1 
or Day 1 and then at the subsequent time 
points post first dose: 2hr, 14hr, 24hr and 
48hr. To be completed pre-dose on Day 7 
and then 48hr post-last dose on Day 14.
12-Lead ECG
X
X
T
X
X
X
X
X
Vital signs to include HR, BP, temperature 
and respiration rate. 
On Day 1:
TID Dosing: 12-Lead ECG and Vital 
Signs to be conducted on Day-1 and pre-
dose Day 1 and then at the subsequent 
time points post first-dose: 40min, 2hr, 
4hr, 7hr (pre-2nd dose), 9hr, 14hr (pre-3rd
dose), 16hr, 24hr, 48hr. Then 24 and 48hr 
after the first dose and last dose 
administered on Day 14.
BID Dosing: 12-Lead ECG and Vital 
Signs to be conducted pre-dose either on 
Day-1 or Day 1 and then at the 
subsequent time points post first-dose: 40 
min, 2hr, 4hr, 12hr (pre-2nd dose), 14hr, 
24hr, 48hr. Then 24 and 48hr after the 
first and last dose administered on Day 
14.
OnDays 3 to 14,  pre-dose samples only.
T = Triplicate.
Vital signs
X
X
T
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


2017N326600_00
CONFIDENTIAL
205184
17
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more than 
14 days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Randomization
X
Study Treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TID dosing: GSK2982772 or placebo will 
be administered using a 7hr, 7hr and 10hr 
dosing interval.
BID dosing: GSK2982772 or placebo will 
be administered using a 12hr dosing 
interval.
AE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

The timing and number of planned study assessments, including safety, pharmacokinetic or other 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 informed consent form (ICF).


2017N326600_00
CONFIDENTIAL
205184
18
3.
INTRODUCTION
3.1.
Study Rationale
The current study is being conducted to support administration of higher dose levels than 
initially studied in the First Time in Human (FTiH) study - 200975. The dose in the FTiH 
study was capped at 120 mg BID based on exposure margins with the no observable 
adverse effect limit (NOAEL) in the 28-day monkey toxicology study (10 mg/kg/day). 
Subsequently, a 13-week toxicity study in monkeys has completed which increased the 
NOAEL to 30 mg/kg/day which will allow for an approximate 4-fold increase in the 
safety margins, in terms of systemic exposure to GSK2982772. The current study is 
being conducted to explore administration of higher dose levels than achieved in the 
FTiH study to support subsequent Phase 2a Proof of Concept (PoC) studies and Phase 2b 
dose range studies in subjects with psoriasis (PsO), rheumatoid arthritis (RA) and 
ulcerative colitis (UC).    
3.2.
Background
GSK2982772 is a first-in-class, highly selective, small molecule inhibitor of receptor-
interacting serine/threonine protein-1 (RIP1) kinase. RIP1 is a member of the receptor-
interacting serine/threonine kinase family containing an amino-terminal kinase domain, 
an intermediate domain and a carboxy-terminal death domain. RIP1 regulates 
inflammatory signalling in response to stimuli such as tumour necrosis factor (TNF) and 
ligands of the Toll-like receptor family in both kinase-dependent and -independent 
manners [Ofengeim, 2013]. Upon binding to its receptor, tumour necrosis factor receptor-
1 (TNFR1), TNFα triggers one of three distinct cellular fates; NFκB activation, apoptosis, 
or the more recently identified programmed necrosis [Ofengeim, 2013]. In addition, 
recent studies have shown that the programmed necrosis signalling complex also 
regulates the induction of certain cytokines. Although RIP1 serves as a key decision 
checkpoint for all three of these pathways, its kinase activity is only requisite for the 
initiation of programmed necrosis and pro-inflammatory cytokine production [Berger, 
2014]. The discovery of this newly defined inflammatory, programmed necrotic pathway 
calls into question the major contributor to human disease downstream of the TNFR1. As 
such, a RIP1 kinase inhibitor represents a novel, selective mechanism for the treatment of 
inflammatory conditions such as Crohn’s Disease, Plaque Psoriasis, and Rheumatoid 
Arthritis through multiple mechanisms, including the blockade of cell death, danger 
associated molecular pattern (DAMP)-driven inflammation and pro-inflammatory 
cytokine production.
3.3.
Benefit/Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2982772 can be found in the Investigator’s Brochure (IB). The following section 
outlines the risk assessment and mitigation strategy for this protocol:


2017N326600_00
CONFIDENTIAL
205184
19
3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Investigational Product (IP) GSK2982772
Central Nervous System (CNS) Effects
Non-Clinical Data:
In the 4-week GLP toxicology study, CNS 
findings were observed in 2/12 monkeys which 
were administered 100 or 300 mg/kg/day. CNS 
findings included uncoordination, irregular gait, 
trembling, hunched appearance and decreased 
activity. The NOAEL for this study was 
determined at 10 mg/kg/day.
In the 13-week GLP toxicology study, there were 
no CNS findings observed in monkeys 
administered 10, 30 or 100 mg/kg/day. The 
NOAEL for this study was determined at 30 
mg/kg/day.
Clinical Data:
A FTiH study with single ascending and multiple 
ascending dose study has been performed in 67 
healthy male volunteers to date (see IB 
[GlaxoSmithKline Document Number 
2014N204126_02]). No drug-associated CNS 
adverse events (AEs) were identified and no 
Serious AEs (SAEs) were reported.
Subject Selection:
Subjects with known history of significant 
neurologic disorders including but not limited to 
progressive multiple sclerosis (MS), Amyotrophic
lateral sclerosis (ALS), Alzheimer’s and dementia 
will be excluded. 
Individuals with potentially increased 
susceptibility for neurologic effects will be 
excluded based on medical history at screening.
Subject Monitoring:
Subjects will be monitored for standard CNS-
related AEs.


2017N326600_00
CONFIDENTIAL
205184
20
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Immunosuppression
The possibility of immunosuppression, including 
an increase in the frequency and/or severity of 
infection, may result from the intended 
pharmacologic effect of GSK2982772. This may
be enhanced in subjects taking other 
immunomodulating drugs or corticosteroids.
Clinical Data:
In the FTiH study, no SAEs were reported. One 
subject experienced an Adverse Event (AE) 
herpes zoster approximately 27 days after 
receiving his last dose with GSK2982772 or 
placebo. The blinded investigator determined this 
to be potentially drug-related.
Subject Selection:
Subjects with recurrent, chronic or active 
infections will be excluded from the study.
Subjects will be screened for TB, HIV, Hepatitis 
B and C, and excluded from the study if positive.
Investigators are expected to follow local and/or 
national guidelines with respect to vaccinations, 
including against influenza and pneumococcus.
Subject Monitoring:
Subjects will be monitored for signs of infection.
See Individual Safety Stopping Criteria for 
atypical or opportunistic infections (Section 
8.1.5).
Vaccinations
There is a theoretical risk that GSK2982772 
could decrease an individual’s immune response 
to vaccines or allow symptoms to develop 
following vaccination with a live vaccine when 
administered while on therapy.
Subject Selection:
Attenuated or live vaccines should not be 
administered to subjects from 30 days prior to 
the first dose of GSK2982772, during the study 
and for 5 half-lives plus 30 days (total 32 days) 
after GSK2982772 is discontinued.


2017N326600_00
CONFIDENTIAL
205184
21
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
If indicated, non-live vaccines (e.g. inactivated 
influenza vaccines) may be administered while 
receiving GSK2982772 based on a treating 
physician assessment of the benefit: risk (e.g., 
risk of theoretical decreased responsiveness).
Investigators will be expected to have followed 
local and/or national guidelines with respect to 
vaccinations, including against influenza and 
pneumococcus.
Respiratory
Non-clinical data:
In the single-dose Safety Cardiovascular and 
Respiratory Study in monkeys, a decrease in 
minute volume (MV) and respiratory rate was 
observed at all doses (10, 100, and 300 mg/kg).  
These findings were noted to be reversible and 
mild in severity.
In a 14-day repeat dose Safety Respiratory 
Study in monkeys, no respiratory effects on total 
pulmonary ventilation (MV) or respiratory rate 
were observed at doses of 1 or 10 mg/kg/day. 
See IB for GSK2982772 [GlaxoSmithKline 
Document Number 2014N204126_02].
Subject Monitoring:
Subjects should be monitored for standard 
respiratory-related AEs.
Vital signs will be monitored during study visits.


2017N326600_00
CONFIDENTIAL
205184
22
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Clinical data:
In the FTiH study, repeat doses of GSK2982772 
up to 120 mg BID were administered x 14 days 
in 48 healthy male volunteers. Extensive 
respiratory monitoring with end-tidal CO2 
(ETCO2), oxygen saturation (SpO2) and 
nocturnal respiratory rate monitoring was 
performed.   No SAEs occurred, and no drug-
associated respiratory-related AEs were 
identified.
Suicidality
GSK2982772 is considered to be a CNS-active 
drug based on pre-clinical studies.
Clinical Data:
In the FTiH study, there have been some reports 
of lethargy, abnormal dreams and depressed 
mood. No events of suicidal ideation or 
behaviour or changes in behaviour were 
reported.
Subject Selection:
Subjects with a current history of Suicidal 
Ideation Behaviour (SIB) as measured using the 
Columbia Suicide Severity Rating Scale (C-
SSRS) or a history of attempted suicide will be 
excluded from the study.
Subject Monitoring:
Subjects should be monitored appropriately and 
observed closely for suicidal ideation and 
behaviour or any other unusual changes in 
behaviour.
Baseline and treatment emergent assessment of 


2017N326600_00
CONFIDENTIAL
205184
23
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
suicidality will be conducted by trained site 
personnel using the C-SSRS in all subjects.
Reproductive Toxicity
Non-Clinical Data:
In the rat embryofetal development study, there 
were no maternal or developmental toxicity at 
doses ≤200 mg/kg/day.
In the rabbit embryofetal development study, 
GSK2982772 was administered at doses of 0, 
10, 100, 300 or 600 mg/kg/day on gestation day 
7 to 19. No developmental toxicity was evident at 
doses up to 300 mg/kg/day.
Subject Selection:
Male and female subjects of childbearing 
potential will be included in this study only if they 
agree to use highly effective methods of 
contraception and avoid conception for defined 
periods of time before first administration of 
study drug until 30 days (females) and 90 days 
(males) after the last administration of study 
drug.
Females of childbearing potential will undergo 
serum pregnancy test at screening and then 
urine pregnancy testing at regular intervals 
during the study.
Pregnant and lactating females are not eligible 
for inclusion in the study.
Withdrawal Criteria:
If a female subject should become pregnant 
during the study, study medication should be 
discontinued. The subject will be followed to 
determine the outcome of the pregnancy. Any 


2017N326600_00
CONFIDENTIAL
205184
24
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
pregnancy complication or elective termination of 
a pregnancy will be reported as an AE or SAE.
Drug Interaction
Non-Clinical Data:
In vitro studies with GSK2982772 assessing 
potential drug-drug interactions with Cytochrome 
P450 3A4 (CYP3A4) substrates and P-
glycoprotein (Pgp) inhibitors were completed. To 
date, formal drug interaction studies in humans 
have not been performed with GSK2982772.
There is a low risk that GSK2982772 could be an 
inducer of CYP3A4 and therefore may lower 
circulating levels of concomitant medications that 
are metabolised by CYP3A4 when co-
administered with GSK2982772.
GSK2982772 is a Pgp substrate and therefore 
co-administration with concomitant medications 
that are Pgp inhibitors could increase circulating 
levels of GSK2982772.  See Section 4.3.6 of 
GSK2982772 IB [GlaxoSmithKline Document 
Number 2014N204126_02].
Subject Selection:
Subjects who are taking concomitant 
medications known to inhibit Pgp or are CYP3A4 
narrow therapeutic index (NTI) substrates will be 
excluded from the study.
Subject Monitoring:
Subjects’ concomitant medication usage will be 
reviewed prior to inclusion and monitored 
throughout the study.
Subjects should be monitored throughout the 
study for potential effects of interaction between 
GSK2982772 and other concomitant 
medications.


2017N326600_00
CONFIDENTIAL
205184
25
3.3.2.
Benefit Assessment
The proposed study with GSK2982772 will be conducted in healthy volunteers; no 
medical benefit will be derived by volunteers’ participation. Subjects will indirectly gain 
through their contribution to the process of developing new therapies in an area of unmet 
need.
3.3.3.
Overall Benefit:Risk Conclusion
The known risks associated with GSK2982772 can be appropriately mitigated by the 
careful selection of study participants and the proposed safety monitoring procedures. As 
such, the risk to potential subjects is considered low. Routine safety and tolerability will 
be evaluated from reported AEs, scheduled physical examinations, vital sign 
measurements, cardiac rhythm monitoring, 12-lead ECGs, and clinical laboratory test 
results as well as continued observation by clinical staff.
The study will be conducted in a hospital-based unit or unit with immediate access to 
hospital facilities for the treatment of medical emergencies. The in-house periods as 
detailed in the SoA (Section 2) will allow for continuous medical monitoring for all 
subjects following the first dose in each treatment group. Subjects will only be discharged 
from the unit 48 hours post-dose if the Investigator deems it safe to do so.
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with GSK2982772 are justified by the 
anticipated benefits that may be afforded by the future development of a new therapy in 
an area of unmet need.


2017N326600_00
CONFIDENTIAL
205184
26
4.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary

To investigate the safety and tolerability of 
repeat doses of GSK2982772 in healthy 
subjects.

Adverse events.

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature).

Physical examinations.

12-Lead ECG monitoring.
Secondary

To characterise the pharmacokinetic (PK)
profile of repeat doses of GSK2982772 in 
healthy subjects.

A 24 hr profile to be collected on Day 1 of 
Part A and Day 14 of Part B. On Day 1 of 
Part B, the PK profile will be evaluated 
following the first dose only. Derived PK 
parameters for GSK2982772, including area 
under the plasma drug concentration versus 
time curve over 24 hr (AUC(0-24)) and AUC 
over each dose interval (i.e. AUC(0-7), AUC(7-
14) and AUC(14-24) for TID and AUC(0-12) and 
AUC(12-24) for BID). Maximum observed 
plasma drug concentration (Cmax) following
each dose, time to maximum observed 
plasma drug concentration (Tmax) following 
each dose, observed trough plasma drug 
concentrations (C0, C7, C14 and C24 for TID
dosing and C0, C12 and C24 for BID dosing).

To assess the impact of food on the PK of 
repeat doses of GSK2982772 in healthy 
subjects at steady state 

Derived PK parameters for GSK2982772, 
including AUC(0-7), AUC(7-14), Cmax, after 1st
dose of day and Tmax after 1st dose of day.

To assess potential effect of repeat doses 
of GSK2982772 on CYP3A4 enzyme 
activity.

Plasma 4β-hydroxycholesterol to 
cholesterol ratio pre-treatment and following 
14 days of repeat dosing of GSK2982772.
Exploratory

To investigate the levels of circulating 
glucuronide metabolite (M8; GSK3562183) 
and desmethyl metabolite (M9; 
GSK2997852) in healthy subjects after 
repeat dosing of GSK2982772.

Quantify M8 (GSK3562183) and M9 
(GSK2997852) in select plasma PK 
samples at pre-dose and 2 hr following Day 
14 of repeat dosing of GSK2982772.


2017N326600_00
CONFIDENTIAL
205184
27
5.
STUDY DESIGN
5.1.
Overall Design
This is a single-centre, randomized, double-blind (sponsor-unblinded), placebo-controlled 
study to evaluate the safety, tolerability and pharmacokinetics of GSK2982772, in repeat 
oral doses in healthy subjects. The study design schematic is depicted in Figure 1.
Figure 1
Study Design
*With Food Effect Treatment
This study is planned to include approximately 48 subjects and consists of 2 parts:

Part A (Cohort 1) – single ascending dose, randomized, placebo-controlled, 3-way 
crossover.  

Part B (Cohorts 2, 3 and 4) – repeat dose, randomized, placebo-controlled, 
sequential-group.
For TID dosing, GSK2982772 or placebo will be administered using a 7hr, 7hr and 10hr
dosing interval. For BID dosing, GSK2982772 or placebo will be administered using a 
12hr dosing interval. 
The impact of food on the PK of GSK2982772 will be investigated during the 14 Day 
repeat dose phase of the study (Part B) in Cohorts 2 and 3. On Days 1 to 14, subjects will 
fast for 8hr overnight. Breakfast will be served 2hr after dosing on Days 1 through 8, 10, 
Part A - Single-Day Ascending Doses
1 Day
3:1 Randomized 
GSK2982772:Placebo
Part B – Repeat Doses 
14 Days
3:1 Randomized 
GSK2982772:Placebo
Cohort 1
N=12
120 mg TID (1 Day) followed by,
240 mg TID (1 Day) followed by,
360 mg BID (1 Day)
Cohort 2
N=12
120 mg TID
14 Days *
Cohort 3
N=12
240 mg TID
14 Days *
Cohort 4
N=12
360 mg BID
14 Days


2017N326600_00
CONFIDENTIAL
205184
28
12 and 14. A standard breakfast will be served 30 minutes prior to dosing on Day 9, and a
high fat breakfast will be served 30 minutes prior to dosing on Day 11. 
All of the Cohorts in this study will be double-blind with respect to the subjects, 
investigator and site staff (with the exception of the site pharmacist). The Sponsor, the 
GSK study team, will be unblinded throughout.
5.2.
Number of Participants
Sufficient number of healthy subjects will be enrolled, such that approximately 12 
subjects in each Cohort complete dosing and critical assessments. If subjects prematurely 
discontinue the study, additional replacement subjects may be randomized in order to 
guarantee that sufficient subjects are treated with GSK2982772 at any given dose before 
escalating to the following dose. Subjects that participate in Part A of the study cannot 
participate in Part B.
5.3.
Sentinel Dosing
Sentinel dosing will be employed within each dosing period in Part A of the study. The 
doses in the single-ascending dose portion of the study (Part A) will be staggered such 
that for each of the three treatment periods, on Day 1, two of the 12 subjects will be 
randomized to treatment (one subject will receive GSK2982772 and one subject will 
receive matched-placebo). Assuming 2 subjects are dosed on Day 1 and assuming 
adequate safety in the judgment of the Principal Investigator (e.g., vital signs, ECGs, and 
AEs) through approximately 24 hours after their last dose on Day 1, the remaining 
subjects may be randomized to dosing in that period. The doses in the repeat dose portion 
of the study (Part B) will be staggered such that for each treatment period on Day 1, two 
of the 12 subjects will be randomized to treatment (one subject will receive GSK2982772 
and one subject will receive matched-placebo) and dosed for at least 7 days before the 
rest of the cohort is randomized. If participants prematurely discontinue the study, 
additional replacement participants may be recruited and assigned to the same treatment 
sequence, at the discretion of the Sponsor in consultation with the investigator.
5.4.
Dose Escalation Decisions
The decision to proceed to the next dose level of GSK2982772 within the study will be 
made by a Dose Escalation Committee (DEC) consisting of Principal Investigator, or 
delegate, and other relevant GSK clinical staff (See Section 10.5).
5.5.
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 scheduled procedure shown in the SoA (Section 2).
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA for the last participant in the trial 
globally.


2017N326600_00
CONFIDENTIAL
205184
29
5.6.
Scientific Rationale for Study Design
In Part A, each cohort will initially evaluate the safety, tolerability and PK of 
GSK2982772 administered for 1 day as a TID or BID dosing regimen (Cohort 1). 
In Part B, the 14-day TID or BID repeat dosing (Cohort 2, 3 and 4) was chosen since it 
will provide sufficient safety and tolerability data to bridge to longer duration studies 
with the recently achieved safety margins from the 13-week toxicology study in 
monkeys. In the previous FTiH study (200975), GSK2982772 was administered up to 
120 mg BID for 14 days and was well tolerated with no safety concerns identified. Please 
see GSK2982772 IB [GlaxoSmithKline Document Number 2014N204126_02].
Cohort 4, 360 mg BID dosing regimen, may only be evaluated if the results of a modified 
release (MR) formulation study (205017) being conducted in parallel with the current 
study indicate that a MR formulation is not feasible for GSK2982772. In which case a 
BID regimen using the current immediate release formulation may be taken forward in to
Phase 2a PoC studies. Additionally, Cohort 4 dose may be modified to include the 
repetition of a previous or lower TID or BID dose based on the results of the safety and 
tolerability review or if further characterization of the safety profile at a previously tested
dose is required.     
In the previous FTiH (Study 200975), the impact of a high-fat meal on the absorption of 
GSK2982772 was investigated following single dose administration of GSK2982772 at a 
dose of 40 mg. The rate and extent of absorption was similar in the fed state as compared 
to the fasted state, although there was evidence of a time lag in the absorption in the fed 
state, probably as a result of delayed gastric emptying. It is likely that higher doses to be 
used in this study will have a similar food effect to that observed at 40 mg. Therefore,
this study plans to evaluate the impact of food during the repeat dose phase in Cohorts 2 
and 3 rather than conducting a standalone single dose food effect PK study.
5.7.
Dose Justification
An adaptive dose-escalation approach, guided by the observed safety, tolerability and 
plasma PK exposure will be taken to allow an efficient evaluation of a range of doses 
above the 120 mg BID dose that was evaluated in the FTiH study.    
The initial starting dose planned is 120 mg TID and the maximum daily dose is 
anticipated to be approximately 720 mg administered as 240 mg TID and 360 mg BID.  
For doses of up to 120 mg BID, the pharmacokinetics of GSK2982772 are approximately 
linear. Please see GSK2982772 IB [GlaxoSmithKline Document Number 
2014N204126_02]. After attainment of  Cmax, at approximately 2 hours post-dose, 
GSK2982772 concentrations decline rapidly until about 12 hours post-dose, with a t1/2 of 
approximately 2 to 3 hours. The majority of the systemic exposure to GSK2982772 is 
observed within the first 12 hours after administration. Following repeat dosing of 
GSK2982772, there is no evidence of drug accumulation for either a QD or BID dosing 
regimen. The major circulating metabolite is an N-glucuronide which accounts for 
approximately 70% of drug related material in plasma. Since glucuronidation is a high 


2017N326600_00
CONFIDENTIAL
205184
30
capacity clearance mechanism it is unlikely that the kinetics of GSK2982772 will become 
saturable with more frequent dosing nor at the higher doses planned in the current study.   
Due to the short half-life of GSK2982772 (~2-3 hr), it is expected that steady-state will 
be achieved by Day 2 of dosing and that negligible accumulation will be observed. 
Therefore, the PK safety margins described for Day 1 and for Day 14 of dosing will be
similar. 
The predicted mean AUC(0-24) for the highest planned doses of 240 mg TID and 360 mg 
BID (40.2 μg*h/mL) approximates parity with the mean AUC(0-24) observed at the 
NOAEL (30 mg/kg/day) in the 13-week monkey toxicology study (48.4 μg*h/ml). Mean 
Cmax values for the 240 mg TID (3.21 μg/mL) and 360 mg BID (4.31 μg/mL) doses are 
predicted to be 1/4th and 1/3rd respectively, of the Cmax observed at the NOAEL (12.3 
μg/mL). The doses for Cohorts 2 and 3 may be adjusted based on PK/safety data from 
previous treatment periods. It is planned that the 95th percentile for the predicted 
AUC(0-24) values will not exceed the maximum AUC(0-24) value observed at the NOAEL
and for Cmax the 95th percentile will not exceed the mean Cmax and the NOAEL. The 
current predicted 5th -95th percentiles for AUC(0-24) and Cmax values using repeat dose PK 
data from FTiH study and mean/individual AUC(0-24) and Cmax values from the 13-week 
Monkey Study at 30 mg/kg/day (NOAEL) and 100 mg/kg/day are shown in Figure 2 and 
Figure 3, respectively.
Figure 2
Mean and 95% Prediction Interval for Human AUC(0-24) Values 
versus Mean and Individual Monkey Cmax Values at Week 13


2017N326600_00
CONFIDENTIAL
205184
31
Figure 3
Mean and 95% Prediction Interval for Human Cmax values Versus 
Mean and Individual Monkey Cmax values at Week 13


2017N326600_00
CONFIDENTIAL
205184
32
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1.
Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2.
Healthy as determined by the Investigator or medically qualified designee based on a 
medical evaluation including medical history, physical examination, neurological 
examination, laboratory tests and cardiac monitoring.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the Investigator in 
consultation with the Medical Monitor (if required) agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures.
Note: Screened subjects with laboratory values outside of the normal range may be 
repeated once for inclusion into the study at the discretion of the Investigator.
WEIGHT
3.
Body weight 50 kg and body mass index (BMI) within the range 19 - 30 kg/m2
(inclusive).
SEX
4.
Male and/or Female Subjects
a. Male participants:
A male participant must agree to use contraception as detailed in Appendix 5 of this 
clinical study proposal during the treatment period and for at least 90 days after the 
last dose of study treatment and refrain from donating sperm during this period.
b. 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:


2017N326600_00
CONFIDENTIAL
205184
33
i.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
ii. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
during the treatment period and for at least 30 days corresponding to time 
needed to eliminate study treatment after the last dose of study treatment.
INFORMED CONSENT
5.
Capable of giving signed informed consent as described in Appendix 3 which
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
MEDICAL CONDITIONS
1.
History or presence of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; 
constituting a risk when taking the study treatment; or interfering with the 
interpretation of data.
2.
History of herpes zoster (shingles) reactivation.
3.
Evidence of active or latent tuberculosis (TB) as documented by medical history and 
examination, chest x-rays (posterior anterior and lateral), and TB testing: either a 
positive tuberculin skin test (TST; defined as a skin induration <5 mm at 48 to 72 
hours, regardless of Bacillus Calmette-Guerin (BCG) or other vaccination history) or 
a positive (not indeterminate) QuantiFERON-TB Gold test.
NOTE: The choice to perform a TST or a QuantiFERON-TB Gold test will be made 
by the investigator according to local licensing and standard of care. The 
QuantiFERON-TB Gold test can only be used in countries where it is licensed, and 
the use of this test is dependent on previous treatment(s). This test may not be 
suitable if previous treatment(s) produced significant immunosuppression.
4.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).
5.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
6.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
7.
QTc >450 msec
NOTES:

The QTc is the QT interval corrected for heart rate according to Bazett’s 


2017N326600_00
CONFIDENTIAL
205184
34
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-
read or manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to initiation 
of the study. In other words, several different formulae cannot be used to 
calculate the QTc for an individual subject and then the lowest QTc value used 
to include or discontinue the subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).
8.
History of serious or recurrent infections or has had an active infection within 14 
days of receiving study medication.
9.
History of diagnosis of obstructive sleep apnoea or significant respiratory disorder.  
Childhood asthma that has fully resolved is permitted.
10. Part A: History of active SIB within the past 6 months or any history of attempted 
suicide in a participant’s lifetime.
11. History of current evidence of febrile seizures, epilepsy, convulsions, significant 
head injury, or other significant neurologic conditions.
PRIOR/CONCOMITANT THERAPY
12. Past or intended use of over-the-counter or prescription medication, including herbal 
medications, within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 
half-lives (whichever is the longest) prior to dosing. Specific medications listed in 
Section 7.6 may be allowed.
13. Subject received a vaccine (either live attenuated or now-live) within 30 days prior to 
randomisation, or plans to receive a live attenuated vaccine within 30 days + 5 half-
lives (32 days) of the last dose of study medication.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
14. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within a 56-day period.
15. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.


2017N326600_00
CONFIDENTIAL
205184
35
DIAGNOSTIC ASSESSMENTS 
16. Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C 
antibody test result at screening.
17. Positive pre-study drug/alcohol screen.
18. Positive human immunodeficiency virus (HIV1 and 2) antibody test.
19. Regular use of known drugs of abuse.
20. Subjects with impaired renal function defined as Chronic Kidney Disease 
Epidemiology Collaboration (CKS-EPI) Creatinine > 1.6mg/dL with an age 
appropriate GFR mL/min/1.73 m2) estimated by the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation [Snyder, 2009 and Levey, 2010].
21. An elevated C-reactive protein (CRP) outside of the normal reference range.
OTHER EXCLUSIONS
22. Regular alcohol consumption within 6 months prior to the study defined as: 

For UK - an average weekly intake of >14 units for males and females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 
mL) of wine or 1 (25 mL) measure of spirits. 
23. Cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 6 months prior to screening.
24. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study
25. Unwilling or unable to swallow multiple size 00 capsules as part of study 
participation.
PART B SPECIFIC CRITERIA
26. History of SIB as measured using the C-SSRS or a history of attempted suicide.
27. A positive anti-nuclear antibody (ANA) outside of the normal reference range.
28. Total cholesterol 300 mg/dL or triglycerides 250 mg/dL.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice, 
pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days prior to
each first dose of study treatment in Part A up until discharge from the unit. In Part B, 
subjects must refrain from consumption of red wine, Seville oranges, grapefruit or 
grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 
days prior to the first dose of study treatment until after the final dose.


2017N326600_00
CONFIDENTIAL
205184
36
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 
hours before the start of dosing until after collection of the final PK sample.

During each dosing period, participants will abstain from alcohol for 24 hours before 
the start of dosing until after collection of the final PK sample.

Use of tobacco products will not be allowed from 6 months prior to 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 studies (e.g., watching television, reading).

Participants will abstain from travelling to regions of high endemic infection, as 
determined by the investigator, for the duration of the study.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. 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 SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened only on approval of the GSK Medical Monitor. Rescreened 
participants should be assigned the same participation number as for the initial screening.


2017N326600_00
CONFIDENTIAL
205184
37
7.
TREATMENTS
The term study treatment is used throughout the protocol and 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.
7.1.
Treatments Administered
Study Treatment
Product name:
GSK2982772
Placebo
Formulation description
API filled capsule
Placebo blend filled capsule
Dosage form:
HPMC capsule
HPMC capsule
Unite dose strength(s)/Dosage level(s):
120 mg maximum fill per capsule 
NA
Route of administration:
For oral use only
For oral use only
Dosing instructions:
Dose with water
Dose with water
Physical description:
Size 00, white, opaque capsule 
containing white to almost white 
solid
Size 00, white, opaque capsule 
containing white to almost white 
solid
Source of procurement
Study medication is supplied by 
GlaxoSmithKline
Study medication is supplied by 
GlaxoSmithKline
Method for individualizing dosage:
Site to assemble
Site to assemble
7.2.
Method of Treatment Assignment
On Day 1 participants will be assigned a unique number (randomization number) in 
ascending numerical order. The randomization number encodes the participant’s 
assignment to either GSK2982772 or placebo, according to the randomization schedule 
generated prior to the study by the Statistics Department at GSK, using validated internal 
software. 
All participants will be centrally randomized using an Interactive Voice/Web Response 
System (IVRS/IWRS). Before the study is initiated, the telephone number and call-in 
directions for the IVRS and/or the log in information & directions for the IWRS will be 
provided to the site.
Study treatment will be dispensed at the study visits summarized in SoA. Each participant 
will be dispensed blinded study treatment, labelled with his/her unique randomization 
number, throughout the study. Returned study treatment should not be re-dispensed to the 
participants
In all four cohorts, subjects will be randomized in a 3:1 ratio to either GSK2982772 or 
placebo. In Cohort 1, the subjects will be randomized to one of three sequences (ABP, 
APC, PBC), where the treatments are:
A
120 mg TID
B
240 mg TID


2017N326600_00
CONFIDENTIAL
205184
38
C
360 mg BID
P
Placebo
The planned dose levels are defined in Section 5.1.
The randomisation will reflect the fact that at least 2 of the 12 subjects (one subject will 
receive GSK2928772 and one subject will receive matched-placebo) will be dosed first 
(on Day 1) in each part to enable dose staggering. 
Once a treatment allocation number has been assigned to a subject, it cannot be 
reassigned to any other subject.
7.3.
Blinding
This will be a double blind (sponsor-unblinded) study and the following will apply:

The Investigator or treating physician will remain blinded to each participant’s 
assigned study treatment throughout the course of the study. In order to maintain 
this blind, an otherwise uninvolved 3rd party will be responsible for the 
reconstitution and dispensation of all study treatment and will endeavour to 
ensure that there are no differences in time taken to dispense following 
randomization

This 3rd party will instruct the participant to avoid discussing the taste, dosing 
frequency, or packaging of the study treatment with the investigator

Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) 
will be allowed access to un-blinded study treatment records at the site(s) to 
verify that randomization/dispensing has been done accurately.

The IVRS/IWRS will be programmed with blind-breaking instructions.

In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a participant’s treatment assignment is 
warranted. Participant safety must always be the first consideration in making 
such a determination.

If the investigator decides that unblinding is warranted, the investigator should 
make every effort to contact GSK prior to unblinding a participant’s treatment 
assignment unless this could delay emergency treatment of the participant.

If a participant’s treatment assignment is unblinded, GSK must be notified 
within 24 hours after breaking the blind.

The date and reason that the blind was broken must be recorded in the source 
documentation and Case Report Form (CRF), as applicable.

A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the 
event or condition which led to the unblinding) will be recorded in the CRF.


2017N326600_00
CONFIDENTIAL
205184
39

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of 
the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.
7.4.
Preparation/Handling/Storage/Accountability

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.

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.

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).

Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.

Under normal conditions of handling and administration, study treatment is not
expected to pose significant safety risks to site staff.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.5.
Treatment Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

When 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.
7.6.
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:


2017N326600_00
CONFIDENTIAL
205184
40

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. 
Paracetamol at doses of 2 grams/day, is permitted for use any time during the study. 
Other concomitant medication may be considered on a case-by-case basis by the 
Investigator in consultation with the Medical Monitor if required.
7.7.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK, or with GSK2982772, after 
completion of the study because only healthy volunteers are eligible for study 
participation.


2017N326600_00
CONFIDENTIAL
205184
41
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Dose Modification/Stopping Criteria
This protocol allows some alteration from the currently outlined dosing schedule, but the 
maximum total daily dose will not intentionally exceed the 13-week NOAEL exposure in 
monkeys. Currently, the highest planned dose is 720 mg/day of GSK2982772.
The decision to proceed to the next dose level of GSK2982772 in each part of this study 
will be made by the DEC, including the Medical Monitor and the Investigator and 
relevant clinical site staff (see Section 10.5) based on safety, tolerability, and preliminary 
PK data obtained in at least 6 subjects (through at least 24 hours post-dose) with at least 6
subjects having received active treatment (GSK2982772) at the prior dose level.  The 
actual doses to be administered may be adjusted based on safety, tolerability and 
preliminary PK data at previous dose levels; these dose adjustments may involve either 
an increase or a decrease in the planned dose, but will not exceed the PK criteria defined 
in Section 8.1.2.  Planned doses may also be repeated.
The Principal Investigator and the GSK Medical Monitor will review the following and 
dosing will be halted and progression to the next higher dose level stopped if:

One (1) or more subjects experience a SAE which has a reasonable possibility of 
relation to study drug.

Two (2) or more subjects experience a severe or clinically significant non-serious 
AE (based upon investigator judgment) which has a reasonable possibility of relation 
to study drug.

Two (2) or more subjects in a Part A cohort or 3 or more subjects in a Part B cohort 
experience the same AE of moderate severity which has a reasonable possibility of 
relation to study drug.

Consistent Common Terminology Criteria for Adverse Events (CTCAE) Nervous 
System AEs of any grade occur across subjects that have a reasonable possibility of 
relation to study drug.
If dosing is halted and if deemed acceptable by GSK internal safety review to proceed 
with or modify dose escalation to further characterize the safety profile, a formal request 
with appropriate data and substantial amendment will be submitted to MHRA (Medicines 
and Healthcare Products Regulatory Agency) for approval.
8.1.2.
Pharmacokinetic Dose Modification or Stopping Criteria
The 240 mg TID dose and/or the 360 mg BID dose in Cohorts 1, 3 and 4 may be adjusted 
up or down based on PK data from previous treatment periods. It is planned that the 95th


2017N326600_00
CONFIDENTIAL
205184
42
percentile for the predicted AUC(0-24) values will not exceed the maximum AUC(0-24)
value observed at the NOAEL and for Cmax the 95th percentile will not exceed the mean 
Cmax and the NOAEL. 
8.1.3.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when:

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 I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
8.1.4.
QTc Stopping Criteria
A subject that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.  

QTcF > 500 msec,

Change from baseline: QTc > 60 msec

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study (i.e., QTcF in this study).  


2017N326600_00
CONFIDENTIAL
205184
43
This formula may not be changed or substituted once the participant has been 
enrolled.
For example, if a participant is eligible for the protocol based on QTcF, then QTcF
must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs are 
an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period. If an 
ECG demonstrates a prolonged QTc, obtain 2 more ECGs over a brief period (5-10 
minutes), and then use the averaged QTc values of the 3 ECGs to determine whether 
the subject should be discontinued from the study.
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
8.1.5.
Individual Safety Stopping Criteria

If a participant experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is possibly, probably or definitely related to investigational product.

The participant becomes pregnant.

The participant initiates treatment with any prohibited medications.

The participant develops a serious opportunistic or atypical infection.

If any of the liver chemistry stopping criteria (See Section 8.1.3) or QTc stopping 
criteria (see Section 8.1.4) are met.

The participant experiences any signs of suicidal ideation or behaviour (See 
Section 9.3.6).
8.1.6.
Group Safety Stopping Criteria
In addition to the criteria specified above, AEs, SAEs, laboratory abnormalities, ECG 
abnormalities and changes in vital signs occurring across all randomized subjects will be 
regulatory reviewed by the Sponsor Safety Review Team (SRT) in order to ensure 
appropriate subject safety. Any changes to the study due to safety reasons will be 
promptly communicated to the appropriate Regulatory Authorities.
8.1.7.
Nervous System Stopping Criteria
The CNS observations in the 4-week GLP toxicology study in monkeys were found to be 
random, diverse, and unpredictable in monkeys (see Section 3.3.1).  There were no 
similar findings observed in the 13-week GLP toxicology study in monkeys.  The 
CTCAE Nervous System is a monitoring tool which provides the Principal Investigator 


2017N326600_00
CONFIDENTIAL
205184
44
the appropriate guidance for grading of a neurological event.  The significance of any 
neurological event experienced by a subject will be determined based on clinical 
judgment, characteristics of the event and/or based upon changes from a baseline 
assessment.
The Principal Investigator and the GSK Medical Monitor will review all neurological 
events utilizing the CTCAE Nervous System criteria and dosing may be halted if and 
progression to the next higher dose level stopped as per Section 8.1.1.
A subject will be withdrawn from the study if:

A Grade 3 or greater CTCAE Nervous System finding is observed or a significant 
neurologic change from a subject’s baseline physical examination is observed.

Any adverse event included in the CTCAE for Nervous System, which is also 
considered to be clinically significant by the Principal Investigator, will be reviewed 
for potential subject withdrawal.
Note:  Appendix 7 (Section 12.7) provides Guidance for Grading Adverse Events that is 
taken from the CTCAE Version 4.03.
8.1.8.
Rechallenge
8.1.8.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
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. The reason for withdrawal 
should be documented in the CRF.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
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 study discontinuation and 
follow-up and for any further evaluations that need to be completed.
If a subject chooses to withdraw from the study after dosing, then the Investigator must 
make every effort to complete the follow-up assessments detailed in the SoA (Section 2).
8.3.
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. 


2017N326600_00
CONFIDENTIAL
205184
45
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

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 and, if necessary, a certified letter to the participant’s last known 
mailing address 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.


2017N326600_00
CONFIDENTIAL
205184
46
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should 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.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
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 the study treatment (see Section 8). 
9.1.1.
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 subject 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).


2017N326600_00
CONFIDENTIAL
205184
47

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 CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4. 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 4.
9.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.1.3.
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, and non-serious AEs of special 
interest (as defined in Section 3.3.1), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4.
9.1.4.
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 
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, 
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 


2017N326600_00
CONFIDENTIAL
205184
48
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.1.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study treatment and until 30 days 
after the last dose.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.
Treatment of Overdose
GSK does not recommend specific treatment for an overdose. The investigator will use 
clinical judgement to treat an overdose as and when they are made aware of this.
In the event of an overdose, the investigator or treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK2982772 can no longer be detected systemically (at least 2 days for 
GSK2982772).
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.
9.3.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.3.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.
Height (screening only) and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.


2017N326600_00
CONFIDENTIAL
205184
49
9.3.2.
Neurological Exams
Neurological examination will include, at a minimum, assessment of: mental status, gait, 
balance, coordination, cranial nerves, motor power, reflexes, and sensory system (light 
touch and pain). Assessments will be standardized across all scheduled time points (see 
SoA).  Significant changes from the baseline or any clinically significant changes will be 
noted as part of further scheduled examinations or unscheduled examinations (if needed).  
Clinically significant abnormalities or changes in status from baseline will be:

entered as an adverse event,

may trigger increased monitoring of the subject(s),

may result in withdrawal of the subject (see Section 8.2),

may result in referral to a specialist.
9.3.3.
Vital Signs

Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed in a supine or semi-
supine position with a completely automated device. Manual techniques will be 
used only if an automated device is not available.

Blood pressure and pulse measurements should 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 will be measured in a supine or semi-supine position after 5 minutes’
rest and will include temperature, systolic and diastolic blood pressure, and 
pulse and respiratory rate.

In Part A and B on Day 1, vital signs (to be taken before blood collection for 
laboratory tests) will consist of 3 pulse and 3 blood pressure measurements pre-
dose on Day 1 (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute). The average of the 3 blood pressure readings will 
be recorded on the CRF.
9.3.4.
Electrocardiograms

Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 2) 
using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. Refer to Section 8.1.4 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession with at least 2 
minutes but no more than 10 minutes apart. 

Continuous cardiac telemetry will be performed at time points indicated in the 
SoA (Section 2).  Full disclosures will be reviewed in detail and the review 
maintained as part of the subject’s source documents.


2017N326600_00
CONFIDENTIAL
205184
50
9.3.5.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 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 relevant 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 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 etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SRM and the SoA.
9.3.6.
Suicidal Risk Monitoring
GSK2982772 is considered to be a CNS-active drug.  There is some concern that some 
CNS-active drugs may be associated with an increased risk of suicidal thinking or 
behaviour when given to some subjects. Although this drug has not been shown to be 
associated with an increased risk of suicidal thinking or behaviour when given to healthy 
volunteers, GSK considers it important to monitor for such events before or during 
clinical studies with compounds such as this.
Participants being treated with GSK2982772 should be monitored appropriately and 
observed closely for suicidal ideation and behaviour or any other unusual changes in 
behaviour. All subjects who experience signs of suicidal ideation or behaviour must 
immediately be discontinued from study medication.
Families and caregivers of participants being treated with GSK2982772 should be alerted 
about the need to monitor participants for the emergence of unusual changes in 
behaviour, as well as the emergence of suicidal ideation and behaviour and to report such 
symptoms immediately to the study investigator.
At screening and baseline (pre-dose Day 1) in Part B only, the Baseline/Screening 
assessment of suicidal ideation and behaviour and treatment emergent suicidal ideation 
and behaviour will be monitored during study 205184 using C-SSRS. At Days 7 and 17 
of the study, the ‘Since Last Visit C-SSRS’ will be completed. Refer to Section 2, SoA,
for more information.
Subjects who answer ‘Yes’ to any suicidal behaviour or ‘Yes’ to suicidal ideation 
Questions 4 or 5 will be referred to their General Practitioner (GP) or appropriate 


2017N326600_00
CONFIDENTIAL
205184
51
psychiatric care. The medical monitor will be notified. If appropriate, an AE or SAE 
should be reported (see Section 9.1). In addition, the investigator should complete a 
Possible Suicidality Related Adverse Event (PSRAE) form to collect detailed information 
on the circumstances of the reported AEs which, in the investigator’s opinion, are 
possibly suicidality-related. These may include, but are not limited to, an event involving 
suicidal ideation, a preparatory act toward imminent suicidal behaviour, a suicide 
attempt, or a completed suicide.
9.4.
Pharmacokinetics
9.4.1.
Blood Sample Collection 
Blood will be collected into EDTA tubes and processed to plasma for PK analysis of 
GSK2982772 at the time points indicated in Section 2, SoA Tables. The actual date and 
time (24-hour clock time) of each blood sample collection will be recorded. The timing 
of PK samples may be altered and/or PK samples may be obtained at additional time 
points to ensure thorough PK monitoring.  
Blood will be collected into EDTA tubes and processed to plasma for PK analysis of M8 
(GSK3562183) and M9 (GSK2997852). This will be collected at the time points 
indicated in Section 2, SoA Tables. The actual date and time of each blood sample 
collection will be recorded. 
Blood will be collected into EDTA tubes and processed to plasma for
4β-hydroxycholesterol and cholesterol. This will be collected at the time points indicated 
in Section 2, SoA Tables. The actual date and time of each blood sample collection will 
be recorded. 
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the SRM. 
9.4.2.
Sample Analysis
Plasma analysis will be performed at a bioanalytical site (to be detailed in the SRM) 
under the control of Platform Technology and Science In Vitro/In Vivo Translation (PTS 
IVIVT) and Third Party Resource, GlaxoSmithKline. Concentrations of GSK2982772
will be determined in plasma samples, and concentrations of M8 (GSK3562183) and M9 
(GSK2997852) will be determined in select plasma samples, using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in 
the SRM).
Once the plasma sample has been analysed for GSK2982772 (or M8 [GSK3562183] and 
M9 [GSK2997852] as indicated above), any remaining plasma sample may be analysed
for other compound-related material and the results may be reported under a separate 
PTS-IVIVT, GlaxoSmithKline protocol.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.


2017N326600_00
CONFIDENTIAL
205184
52
9.4.3.
Plasma Sample for CYP3A4 Enzyme Activity
Plasma derived from select PK blood samples in Part B (as in the SoA Table), will be 
analyzed for 4β-hydroxycholesterol and cholesterol as a potential in vivo marker of 
CYP3A4 enzyme activity. Samples collected pre-treatment and at steady-state will be 
compared to evaluate this potential marker.
Details on CYP3A4 enzyme activity marker plasma sample collection, processing, 
storage and shipping procedures are provided in the SRM.
Baseline and Day 14, post-treatment plasma samples will be analyzed using a validated, 
specific, and sensitive liquid chromatography–mass spectrometry (LC-MS/MS) method 
to determine concentrations of 4β-hydroxycholesterol and total cholesterol.  A 
comparison will be made between the ratio of 4β-hydroxycholesterol : cholesterol at 
baseline and on Day 14 to assess potential changes in CYP3A4 enzyme activity 
following GSK2982772 treatment.
Analysis will be performed at a bioanalytical site (to be detailed in the SRM) under the 
control of PTS-IVIVT and Third Party Resource, GlaxoSmithKline.
9.5.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.6.
Pharmacological Biomarkers
Pharmacological biomarkers are not evaluated in this study.
10.
STATISTICAL CONSIDERATIONS
The objectives of this study are to assess the safety and tolerability of single and repeat 
ascending doses of GSK2982772. No formal hypotheses will be tested.  
An estimation approach will be used to describe PK of GSK2982772, where point 
estimates and corresponding 90% confidence intervals will be constructed.
10.1.
Sample Size Determination
No statistical techniques were used to calculate the sample size, and sample size is based 
on feasibility.
The primary objective of the study is safety, where the number of safety events are of 
interest.  A maximum of 9 subjects will receive each active dose and; therefore, if 0/9 of 
a particular safety event in the GSK2982772 group is observed, the upper limit of the 
exact 95% CI indicates that a true incidence rate of 33.6% could not be ruled out.  
Whereas if 1/9 of the same safety event in the GSK2982772 group is observed, the upper 
limit of the exact 95% CI indicates that a true incidence rate of 48.2% could not be ruled 
out.


2017N326600_00
CONFIDENTIAL
205184
53
Using a Bayesian approach to determine the confidence interval around an observed 
safety event, we would assume a flat Beta (1,1) prior, and if we were to observe one
safety event in 9 then the posterior distribution would be Beta (2, 9), as outlined below:
Bayesian Approach to Determine Confidence in a Safety Event.
Thus, we can be 95% certain that the true probability of the safety event lies between 
0.04 and 0.39.
Pharmacokinetic Parameters
To date the pharmacokinetics of GSK2982772 have been studied up to 120 mg BID. The 
maximum between-subject coefficient of variation (CVb) for AUC(0-τ) and Cmax observed 
in study 200975 was 27.1 and 36.1 respectively. 
Based on these estimates of variability, slightly more conservative for a cross-over study
and a sample size of 9 completers in Cohort 2, it is estimated that the lower and upper 
bounds of the 90% confidence interval for the means of AUC and Cmax will be within 
approximately 17.9% and 24.2% of the point estimate, respectively.
10.2.
Sample Size Sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint, to 
investigate different safety event rates. If the number of subjects who completed each 
active dose, then the true incidence rates of safety events that could not be ruled out (as 
outlined in Section 10.1 Sample Size Determination) would change.  These changes are 
outlined in Table 1:


2017N326600_00
CONFIDENTIAL
205184
54
Table 1
Safety Events - Sample Size Sensitivity
N Completing 
Cohort
Number of a particular safety event 
observed with GSK2982772
Upper limit of exact 95%CI indicating that a true 
incidence rate of x% could not be ruled out
9
2
60.0%
3
70.0%
4
78.8%
8
0
36.9%
1
52.7%
2
65.1%
3
75.5%
7
0
41.0%
1
57.8%
2
70.9%
3
81.6%
Pharmacokinetic Parameters
A sample size sensitivity analysis has also been conducted on the PK parameters to 
investigate the effect of fewer number of subjects, or 10% difference in the between-
subject coefficient of variation on the precision of the point estimate.  These changes are 
outlined in Table 2:
Table 2
Pharmacokinetic Parameters – Sample Size Sensitivity
Number of Subjects
CVb
Precision (%)
Cmax
6
26.1%
29.8
6
28.8%
33.4
6
31.5%
37.0
9
19.6%
21.7
9
21.7%
24.2
9
23.7%
26.7
AUC(0-tau)
6
19.7%
21.8
6
21.9%
24.5
6
24.0%
27.1
9
14.9%
16.1
9
16.5%
17.9
9
18.1%
19.8


2017N326600_00
CONFIDENTIAL
205184
55
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
PK
The ‘PK Population' is defined as subjects in the ‘Safety’ population 
for whom a PK sample was obtained and analyzed.
10.4.
Statistical Analyses
10.4.1.
Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarised 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Primary
All safety evaluations will be based on the Safety population.  Clinical 
interpretation will be based on the review and displays of adverse events, 
clinical laboratory values, vital sign measurements and 12-lead ECG 
monitoring.
10.4.2.
PK Analyses
Endpoint
Statistical Analysis Methods
Secondary
PK analyses will be described in the RAP. 
The PK of TID and BID dosing on Day 1 in Part A will be evaluated. In 
Part B the comparisons of interest will be:
The PK profile following the 1st dose of the day following administration 
in the fed state (standard meal on Day 9 and high fat meal on Day 11) or in 
the fasted state (Day 14).  
The pharmacokinetic profile following the 1st dose on Day 14 (fasted) and 
the 1st dose on Day 1 (fasted);  
Pharmacokinetic data will be listed and presented in graphical form and 
will be summarized descriptively. 
Statistical summaries of the PK parameter data will be the responsibility of 


2017N326600_00
CONFIDENTIAL
205184
56
Clinical Statistics, GlaxoSmithKline.
Descriptive statistics (n, arithmetic mean, standard deviation, 95% CI, 
minimum, median and maximum,) will be calculated for all 
pharmacokinetic parameters by treatment. In addition, for loge-transformed 
variables geometric mean, 95% confidence interval and %CVb (100 * √ 
(exp(SD2) -1)) will be provided, where the SD is the standard deviation of 
log-transformed data.
10.4.3.
Other Analyses
Descriptive statistics (n, arithmetic mean, standard deviation, 95% CI, minimum, median 
and maximum) of circulating glucuronide metabolite (M8; GSK3562183) and des-methyl 
metabolite will be investigated in healthy subjects after single and repeat dosing of 
GSK2982772. 
10.4.4.
Interim Analyses
An interim analysis may be performed during the study on completed cohorts in Part A 
and Part B of the study to aid internal decision making only. There will be no changes to 
the study design or planned number of subjects in future cohorts as a result of the interim 
analysis.
For Parts A and B of the study, interim PK analyses will be performed on plasma 
GSK2982772 concentration-time data generated during the conduct of this study.
The decision to proceed to higher dose strengths will be made by the DEC based on 
assessment of safety, tolerability and pharmacokinetic data at the preceding dose. The 
exception to this will be in Part A where only a safety assessment (not PK) for the 120 
mg TID dose will be performed. To date, the PK of GSK2982772 has been well-
characterised up to 120 mg BID in the FTiH study and the 120 mg TID for Part A 
represents a 50% increase in dose where PK simulations are predictable. This analysis 
can include review of individual subject data, summaries, graphical presentations and/or 
statistical analysis.
The RAP will describe the planned interim analyses in greater detail.
10.5.
Dose Escalation Committee
The decision to proceed to the next dose level of GSK2982772 in each Cohort will be 
made by a DEC consisting of the Principal Investigator (or appropriate designee), 
Medical Monitor, GSK Clinical Investigational lead and/or Study Team Leader, GSK 
Pharmacokineticist, a GSK GCSP representative and GSK Statistician. All GSK 
personnel including the GSK Statistician and the GSK Pharmacokineticist will remain 
unblinded throughout the course of the study. 
For Part A, dose escalation decisions will be based on data obtained from 6 or more 
subjects receiving GSK2982772 at the prior dose level. The review of the data set will 


2017N326600_00
CONFIDENTIAL
205184
57
consist at a minimum of: listings of all AEs, clinical laboratory results, flagged vital 
signs, flagged findings during continuous cardiac monitoring (telemetry), ECG and PK 
results derived from 24-hour plasma profiles.
The decision and selection of dose to proceed to Part B, will be made by the DEC based 
on safety, tolerability, and PK data from the same dose levels evaluated in Part A.  
For Part B, dose escalation decisions will be based on data obtained from 6 or more 
subjects receiving GSK2982772 at the prior dose level. The review of the data set will 
consist at a minimum of: listings of all AEs, clinical laboratory results, flagged vital 
signs, flagged findings during continuous cardiac monitoring (telemetry) and ECG 
findings through Day 16 of the previous cohorts(s) in Part B. Also included will be any 
PK results derived through at least Day 7 of the previous cohort(s).


2017N326600_00
CONFIDENTIAL
205184
58
11.
REFERENCES
Berger SB, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M, et al. Cutting edge: 
RIP1 kinase activity is dispensable for normal development but is a key regulator of 
inflammation in SHARPIN-deficient mice. J Immunol. 2014; 192(12):5476-80.
GlaxoSmithKline Document Number 2014N204126_02. GSK2982772 Investigator’s 
Brochure, Version 3. Effective Date: 27-January-2017.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos. 2009; 37:1779-1784.
Levey AS and Stevens LA. Estimating GFR Using the CKD Epidemiology Collaboration 
(CKD-EPI) Creatinine Equation: More Accurate GFR Estimates, Lower CKD Prevalence 
Estimates and Better Risk Predictions. Am J Kidney Dis. 2010; 55:622-627.
Ofengeim D and Yuan J. Regulation of RIP1 kinase signalling at the crossroads of 
inflammation and cell death. Nat Rev Mol Cell Biol. 2013; 14(11):727-736.
Snyder JJ, Foley RN, and Collins AJ. Prevalence of CKD in the United States: A 
Sensitivity Analysis Using the National Health and Nutrition Examination Survey 
(NHANES) 1999-2004. Am J Kidney Dis. 2009; 53(2):218-228.


2017N326600_00
CONFIDENTIAL
205184
59
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALS
Amyotrophic lateral sclerosis
ALT
Alanine aminotransferase
ANA
Anti-nuclear Antibody
API
Active Pharmaceutical Ingredient
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC(0-7)
Area under the concentration-time curve from time zero to 7 hours 
post first dose (TID dosing)
AUC(7-14)
Area under the concentration-time curve from 7 to 14 hours post 
first dose (TID dosing)
AUC(14-24)
Area under the concentration-time curve from 14 to 24 hours post 
first dose (TID dosing)
AUC(0-12)
Area under the concentration-time curve from 0 to 12 hours post 
first dose (BID dosing)
AUC(12-24)
Area under the concentration-time curve from 12 to 24 hours post 
first dose (BID dosing)
AUC(0-24)
Area under the concentration-time curve from time zero to 24 
hours post first dose
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) 
to last time of quantifiable concentration within a subject across all 
treatments
AUC(0-τ)
AUC from 0 hours to the time of next dosing.
BID
Twice a day
BMI
Body Mass Index
BP
Blood Pressure
CFR
Code of Federal Regulations
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum observed concentration
CNS
Central Nervous System
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CRF
Case Report Form
CRP
C-Reactive Protein
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CVb
Coefficient of Variation
CYP3A4
Cytochrome P450 3A4


2017N326600_00
CONFIDENTIAL
205184
60
DEC
Dose Escalation Committee
ECG
Electrocardiogram
eGFR
Estimated glomerular filtration rate
FSH
Follicle stimulating hormone
FTiH
First Time in Human
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance 
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HPLC
High performance liquid chromatography
HPMC
Hydroxypropylmethyl cellulose
HR
Heart Rate
HRT
Hormonal replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IgG
Immunoglobulin G
IP
Investigational Product
IRB/IEC
The Institutional Review Board/ Independent Ethics Committee
IUD
Intrauterine device
IUS 
Intrauterine hormone-releasing system
kg 
Kilogram
LDH
Lactate dehydrogenase
MCH
Mean corpuscular haemoglobin
MCV
Mean corpuscular volume
mg
Milligram
mL
Millilitre
MR
Modified Release
MS
Multiple Sclerosis
MSDS
Material Safety Data Sheet
NFκB
Nuclear factor kappa-light-chain-enhancer of activated B cells
NOAEL
No observable adverse effect limit
NTI
Narrow Therapeutic Index
Pgp
P-glycoprotein
PK
Pharmacokinetics
PoC
Proof of Concept
PsO
Psoriasis
PSRAE
Possible Suicidality Related Adverse Event
QTc
Electrocardiogram QT interval corrected for heart rate
QTcB
Electrocardiogram QT interval corrected for heart rate using 
Bazett’s formula
QTcF
Electrocardiogram QT interval corrected for heart rate using 


2017N326600_00
CONFIDENTIAL
205184
61
Fridericia’s formula
RA
Rheumatoid Arthritis
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RIP1
Receptor-interacting protein-1
SAE
Serious Adverse Event
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SIB
Suicidal Ideation Behaviour
SoA
Schedule of Activities
SOP
Standard Operating Procedure
SRM
Study Reference Manual
SRT
Safety Review Team
SUSAR
Suspected unexpected serious adverse events
TB
Tuberculosis
TID
Three times a day
Tmax
Time taken to maximum observed plasma drug concentration
TNF
Tumour Necrosis Factor
TNFR1
Tumour Necrosis Factor Receptor-1
UC
Ulcerative Colitis
μg
Microgram
UK
United Kingdom
ULN
Upper Limit of Normal
WOCBP
Woman of Child Bearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Quantiferon


2017N326600_00
CONFIDENTIAL
205184
62
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 3 will be performed by the Doctor’s 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 3
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Red Blood Cell (RBC)
Indices:
Mean Corpuscular 
Volume (MCV)
Mean corpuscular 
haemoglobin (MCH)
%Reticulocytes
White Blood Cell (WBC)
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose 
(Fasted)2
Calcium
Alkaline 
phosphatase
Albumin
Anti-nuclear 
antibody [(ANA), 
Part B only]
C-reactive protein 
(CRP)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Alcohol breath test and urine drug screen (to include at minimum: 


2017N326600_00
CONFIDENTIAL
205184
63
Laboratory 
Assessments
Parameters
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)]

Breath cotinine

Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential). To be done at screening and Day 17 of 
Part B.

Urine hCG pregnancy test (as needed for women of child bearing potential)3

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody)

Tuberculosis test

Total Cholesterol, Low-density lipoprotein, triglycerides (Part B only)

Estimated glomerular filtration rate (eGFR) will be calculated using the CKD-
EPI formula.
The results of each test must be entered into the CRF.
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 6 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).
2.
Non-fasted samples can be collected on Day -1.
3.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
Laboratory that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded.


2017N326600_00
CONFIDENTIAL
205184
64
12.3.
Appendix 3: 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 (e.g., 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 Code of Federal Regulations (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. 


2017N326600_00
CONFIDENTIAL
205184
65

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
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 centre. 

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. 

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with Standard Operating 
Procedure (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, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.


2017N326600_00
CONFIDENTIAL
205184
66
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.

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 subjects, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

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.
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 (e.g., 
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. 


2017N326600_00
CONFIDENTIAL
205184
67

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 
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.

A study specific source documentation list will be finalised by the sponsor 
before the start of the clinical phase of the study. The document will identify 
what data should be considered source data for this study.
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


2017N326600_00
CONFIDENTIAL
205184
68
12.4.
Appendix 4: 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 assessmentse.g.eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., 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.
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 


2017N326600_00
CONFIDENTIAL
205184
69
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 (e.g., 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.
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 (e.g., 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 


2017N326600_00
CONFIDENTIAL
205184
70
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.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., 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 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 


2017N326600_00
CONFIDENTIAL
205184
71
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
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 Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 


2017N326600_00
CONFIDENTIAL
205184
72
this information to the medical monitor or the SAE coordinator.

In rare circumstances and in the absence of facsimile equipment, 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 Study Reference Manual.


2017N326600_00
CONFIDENTIAL
205184
73
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy

Documented tubal ligation
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrolment.
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 during the protocol-defined 
time frame in Section 6.1: 

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 


2017N326600_00
CONFIDENTIAL
205184
74

Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 4 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 protocol-defined time frame

In addition, male participants must refrain from donating sperm for duration of 
study and for 90 days after study completion or from last dose
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 4. 
Table 4
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 ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

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 


2017N326600_00
CONFIDENTIAL
205184
75
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. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 7 days after the last dose of study treatment 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test 

Additional pregnancy testing at admission to each study period and at the follow-up 
visit.

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.

Pregnancy testing, with a sensitivity of 25 mIU/mL will be performed using the test 
kit approved by the sponsor and in accordance with instructions provided in its 
package insert.
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 
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. 


2017N326600_00
CONFIDENTIAL
205184
76
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

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 Appendix 4. 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 discontinue study 
treatment.


2017N326600_00
CONFIDENTIAL
205184
77
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
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 event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hr

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 24 hours of 
last dose4 

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

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
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 


2017N326600_00
CONFIDENTIAL
205184
78
Liver Chemistry Stopping Criteria 
liver event follow up assessments within 24-
72 hr

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects 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 forms.
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 subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen 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 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
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 subject’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. 


2017N326600_00
CONFIDENTIAL
205184
79
12.7.
Appendix 7:  Nervous System Adverse Events (CTCAE Criteria)
Taken from the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
The purpose of this Appendix is to provide guidance and is to be used in conjunction with the Investigator’s judgment.
Table 5
Guidance For Grading Adverse Events
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Abducens nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the abducens nerve (sixth cranial nerve).
Accessory nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the accessory nerve (eleventh cranial 
nerve).
Acoustic nerve disorder 
NOS
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the acoustic nerve (eighth cranial nerve).
Akathisia
Mild restlessness or 
increased motor activity
Moderate restlessness 
or increased motor 
activity; limiting 
instrumental ADL
Severe restlessness or 
increased motor 
activity; limiting self 
care ADL
-
-
A disorder characterized by an 
uncomfortable feeling of inner restlessness 
and inability to stay still; this is a side effect 
of some psychotropic drugs.
Amnesia
Mild; transient memory 
loss
Moderate; short term 
memory loss; limiting 
instrumental ADL
Severe; long term 
memory loss; limiting 
self care ADL
-
-
A disorder characterized by systematic and 
extensive loss of memory.


2017N326600_00
CONFIDENTIAL
205184
80
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Aphonia
-
-
Voicelessness; unable 
to speak
-
-
A disorder characterized by the inability to 
speak. It may result from injuries to the 
vocal cords or may be functional 
(psychogenic).
Arachnoiditis
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
of the arachnoid membrane and adjacent 
subarachnoid space.
Ataxia
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL; 
mechanical assistance 
indicated
-
-
A disorder characterized by lack of 
coordination of muscle movements 
resulting in the impairment or inability to 
perform voluntary activities.
Brachial plexopathy
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by regional 
paresthesia of the brachial plexus, marked 
discomfort and muscle weakness, and 
limited movement in the arm or hand.
Central nervous system 
necrosis
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
corticosteroids 
indicated
Severe symptoms; 
medical intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by a necrotic 
process occurring in the brain and/or spinal 
cord.
Cerebrospinal fluid 
leakage
Post-craniotomy: 
asymptomatic; Post-
lumbar puncture: 
transient headache; 
postural care indicated
Post-craniotomy: 
moderate symptoms; 
medical intervention 
indicated; Post-lumbar 
puncture: persistent 
moderate symptoms; 
blood patch indicated
Severe symptoms; 
medical intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by loss of 
cerebrospinal fluid into the surrounding 
tissues.


2017N326600_00
CONFIDENTIAL
205184
81
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Cognitive disturbance
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; 
specialized educational 
services/devices not 
indicated
Moderate cognitive 
disability; interfering 
with work/school/life 
performance but 
capable of 
independent living; 
specialized resources 
on part time basis 
indicated
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance
-
-
A disorder characterized by a conspicuous 
change in cognitive function.
Concentration 
impairment
Mild inattention or 
decreased level of 
concentration
Moderate impairment 
in attention or 
decreased level of 
concentration; limiting 
instrumental ADL
Severe impairment in 
attention or decreased 
level of concentration; 
limiting self care ADL
-
-
A disorder characterized by a deterioration 
in the ability to concentrate.
Depressed level of 
consciousness
Decreased level of 
alertness
Sedation; slow 
response to stimuli; 
limiting instrumental 
ADL
Difficult to arouse
Life-threatening 
consequences
Death
A disorder characterized by a decrease in 
ability to perceive and respond.
Dizziness
Mild unsteadiness or 
sensation of movement
Moderate 
unsteadiness or 
sensation of 
movement; limiting 
instrumental ADL
Severe unsteadiness 
or sensation of 
movement; limiting self 
care ADL
-
-
A disorder characterized by a disturbing 
sensation of lightheadedness, 
unsteadiness, giddiness, spinning or 
rocking.
Dysarthria
Mild slurred speech
Moderate impairment 
of articulation or 
slurred speech
Severe impairment of 
articulation or slurred 
speech
-
-
A disorder characterized by slow and 
slurred speech resulting from an inability to 
coordinate the muscles used in speech.
Dysesthesia
Mild sensory alteration
Moderate sensory 
alteration; limiting 
instrumental ADL
Severe sensory 
alteration; limiting self 
care ADL
-
-
A disorder characterized by distortion of 
sensory perception, resulting in an 
abnormal and unpleasant sensation.
Dysgeusia
Altered taste but no 
change in diet
Altered taste with 
change in diet (e.g., 
oral supplements); 
noxious or unpleasant 
taste; loss of taste
-
-
-
A disorder characterized by abnormal 
sensual experience with the taste of 
foodstuffs; it can be related to a decrease 
in the sense of smell.


2017N326600_00
CONFIDENTIAL
205184
82
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Dysphasia
Awareness of receptive 
or expressive 
characteristics; not 
impairing ability to 
communicate
Moderate receptive or 
expressive 
characteristics; 
impairing ability to 
communicate 
spontaneously
Severe receptive or 
expressive 
characteristics; 
impairing ability to 
read, write or 
communicate 
intelligibly
-
-
A disorder characterized by impairment of 
verbal communication skills, often resulting 
from brain damage.
Edema cerebral
-
-
-
Life-threatening 
consequences; 
urgent 
intervention 
indicated
A disorder characterized by swelling due to 
an excessive accumulation of fluid in the 
brain.
Encephalopathy
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by a pathologic 
process involving the brain.
Extrapyramidal disorder
Mild involuntary 
movements
Moderate involuntary 
movements; limiting 
instrumental ADL
Severe involuntary 
movements or 
torticollis; limiting self 
care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by abnormal, 
repetitive, involuntary muscle movements, 
frenzied speech and extreme restlessness.
Facial muscle weakness
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by a reduction in 
the strength of the facial muscles.
Facial nerve disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the facial nerve (seventh cranial nerve).


2017N326600_00
CONFIDENTIAL
205184
83
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Glossopharyngeal nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by involvement of 
the glossopharyngeal nerve (ninth cranial 
nerve).
Headache
Mild pain
Moderate pain; limiting 
instrumental ADL
Severe pain; limiting 
self care ADL
-
-
A disorder characterized by a sensation of 
marked discomfort in various parts of the 
head, not confined to the area of 
distribution of any nerve.
Hydrocephalus
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
intervention not 
indicated
Severe symptoms or 
neurological deficit; 
intervention indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by an abnormal 
increase of cerebrospinal fluid in the 
ventricles of the brain.
Hypersomnia
Mild increased need for 
sleep
Moderate increased 
need for sleep
Severe increased 
need for sleep
-
-
A disorder characterized by characterized 
by excessive sleepiness during the 
daytime.
Hypoglossal nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the hypoglossal nerve (twelfth cranial 
nerve).
Intracranial hemorrhage
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
medical intervention 
indicated
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or 
operative intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by bleeding from 
the cranium.
Ischemia 
cerebrovascular
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms
-
-
-
A disorder characterized by a decrease or 
absence of blood supply to the brain 
caused by obstruction (thrombosis or 
embolism) of an artery resulting in 
neurological damage.


2017N326600_00
CONFIDENTIAL
205184
84
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
IVth nerve disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the trochlear nerve (fourth cranial nerve).
Lethargy
Mild symptoms; reduced 
alertness and 
awareness
Moderate symptoms; 
limiting instrumental 
ADL
-
-
-
A disorder characterized by a decrease in 
consciousness characterized by mental 
and physical inertness.
Leukoencephalopathy
Asymptomatic; small 
focal T2/FLAIR 
hyperintensities; 
involving periventricular 
white matter or <1/3 of 
susceptible areas of 
cerebrum mild 
increase in 
subarachnoid space 
(SAS) and/or mild 
ventriculomegaly
Moderate symptoms; 
focal T2/FLAIR 
hyperintensities, 
involving 
periventricular white 
matter extending into 
centrum semiovale or 
involving 1/3 to 2/3 of 
susceptible areas of 
cerebrum moderate 
increase in SAS and/or 
moderate 
ventriculomegaly
Severe symptoms; 
extensive T2/FLAIR 
hyperintensities, 
involving 
periventricular white 
matter involving 2/3 or 
more of susceptible 
areas of cerebrum 
moderate to severe 
increase in SAS and/or 
moderate to severe 
ventriculomegaly
Life-threatening 
consequences; 
extensive 
T2/FLAIR 
hyperintensities, 
involving 
periventricular 
white matter 
involving most of 
susceptible 
areas of 
cerebrum 
moderate to 
severe increase 
in SAS and/or 
moderate to 
severe 
ventriculomegaly
Death
A disorder characterized by diffuse 
reactive astrocytosis with multiple areas of 
necrotic foci without inflammation.
Memory impairment
Mild memory impairment
Moderate memory 
impairment; limiting 
instrumental ADL
Severe memory 
impairment; limiting 
self care ADL
-
-
A disorder characterized by a deterioration 
in memory function.
Meningismus
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by neck stiffness, 
headache, and photophobia resulting from 
irritation of the cerebral meninges.


2017N326600_00
CONFIDENTIAL
205184
85
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Movements involuntary
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by uncontrolled 
and purposeless movements.
Myelitis
Asymptomatic; mild 
signs (e.g., Babinski's 
reflex or Lhermitte's 
sign)
Moderate weakness or 
sensory loss; limiting 
instrumental ADL
Severe weakness or 
sensory loss; limiting 
self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
involving the spinal cord. Symptoms 
include weakness, paresthesia, sensory 
loss, marked discomfort and incontinence.
Neuralgia
Mild pain
Moderate pain; limiting 
instrumental ADL
Severe pain; limiting 
self care ADL
-
-
A disorder characterized by intense painful 
sensation along a nerve or group of 
nerves.
Nystagmus
-
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involuntary 
movements of the eyeballs.
Oculomotor nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the oculomotor nerve (third cranial nerve).
Olfactory nerve disorder
-
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the olfactory nerve (first cranial nerve).
Paresthesia
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by functional 
disturbances of sensory neurons resulting 
in abnormal cutaneous sensations of 
tingling, numbness, pressure, cold, and 
warmth that are experienced in the 
absence of a stimulus.
Peripheral motor 
neuropathy
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL; 
assistive device 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
or degeneration of the peripheral motor 
nerves.


2017N326600_00
CONFIDENTIAL
205184
86
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Peripheral sensory 
neuropathy
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
or degeneration of the peripheral sensory 
nerves.
Phantom pain
Mild pain
Moderate pain; limiting 
instrumental ADL
Severe pain; limiting 
self care ADL
-
-
A disorder characterized by marked 
discomfort related to a limb or an organ 
that is removed from or is not physically 
part of the body.
Presyncope
-
Present (e.g., near 
fainting)
-
-
-
A disorder characterized by an episode of 
lightheadedness and dizziness which may 
precede an episode of syncope.
Pyramidal tract 
syndrome
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by dysfunction of 
the corticospinal (pyramidal) tracts of the 
spinal cord. Symptoms include  an 
increase in the muscle tone in the lower 
extremities, hyperreflexia, positive Babinski 
and a decrease in fine motor coordination.
Radiculitis
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL; medical 
intervention indicated
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
involving a nerve root. Patients experience 
marked discomfort radiating along a nerve 
path because of spinal pressure on the 
connecting nerve root.
Recurrent laryngeal 
nerve palsy
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms
Severe symptoms; 
medical intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection)
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by paralysis of 
the recurrent laryngeal nerve.


2017N326600_00
CONFIDENTIAL
205184
87
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Reversible posterior 
leukoencephalopathy 
syndrome
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
abnormal imaging 
studies; limiting 
instrumental ADL
Severe symptoms; 
very abnormal imaging 
studies; limiting self 
care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by headaches, 
mental status changes, visual 
disturbances, and seizures associated with 
imaging findings of posterior 
leukoencephalopathy. It has been 
observed in association with hypertensive 
encephalopathy, eclampsia, and 
immunosuppressive and cytotoxic drug 
treatment. It is an acute or subacute 
reversible condition.
Seizure
Brief partial seizure; no 
loss of consciousness
Brief generalized 
seizure
Multiple seizures 
despite medical 
intervention
Life-threatening; 
prolonged 
repetitive 
seizures
Death
A disorder characterized by a sudden, 
involuntary skeletal muscular contractions 
of cerebral or brain stem origin.
Sinus pain
Mild pain
Moderate pain; limiting 
instrumental ADL
Severe pain; limiting 
self care ADL
-
-
A disorder characterized by marked 
discomfort in the face, between the eyes, 
or upper teeth originating from the sinuses.
Somnolence
Mild but more than usual 
drowsiness or 
sleepiness
Moderate sedation; 
limiting instrumental 
ADL
Obtundation or stupor
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by characterized 
by excessive sleepiness and drowsiness.
Spasticity
Mild or slight increase in 
muscle tone
Moderate increase in 
muscle tone and 
increase in resistance 
through range of 
motion
Severe increase in 
muscle tone and 
increase in resistance 
through range of 
motion
Life-threatening; 
unable to move 
active or passive 
range of motion
Death
A disorder characterized by increased 
involuntary muscle tone that affects the 
regions interfering with voluntary 
movement. It results in gait, movement, 
and speech disturbances.
Stroke
Asymptomatic or mild 
neurologic deficit; 
radiographic findings 
only
Moderate neurologic 
deficit
Severe neurologic 
deficit
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by a sudden loss 
of sensory function due to an intracranial 
vascular event.
Syncope
-
-
Fainting; orthostatic 
collapse
-
-
A disorder characterized by spontaneous 
loss of consciousness caused by 
insufficient blood supply to the brain.


2017N326600_00
CONFIDENTIAL
205184
88
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Transient ischemic 
attacks
Mild neurologic deficit 
with or without imaging 
confirmation
Moderate neurologic 
deficit with or without 
imaging confirmation
-
-
-
A disorder characterized by a brief attack 
(less than 24 hours) of cerebral 
dysfunction of vascular origin, with no 
persistent neurological deficit.
Tremor
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms;
limiting self care ADL
-
-
A disorder characterized by the 
uncontrolled shaking movement of the 
whole body or individual parts.
Trigeminal nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the trigeminal nerve (fifth cranial nerve).
Vagus nerve disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by involvement of 
the vagus nerve (tenth cranial nerve).
Vasovagal reaction
-
-
Present
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by a sudden drop 
of the blood pressure, bradycardia, and 
peripheral vasodilation that may lead to 
loss of consciousness. It results from an 
increase in the stimulation of the vagus 
nerve.
Nervous system 
disorders - Other, 
specify
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations 
only; intervention not 
indicated
Moderate; minimal, 
local or noninvasive 
intervention indicated; 
limiting age-
appropriate 
instrumental ADL
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
existing hospitalization 
indicated; disabling;  
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
-


2017N326600_01
CONFIDENTIAL
GlaxoSmithKline group of companies
205184
1
TITLE PAGE
Protocol Title: A single-centre, randomized, double-blind (sponsor-unblinded), placebo-
controlled study to evaluate the safety, tolerability and pharmacokinetics of GSK2982772 
in repeat oral doses in healthy subjects.
Protocol Number: 205184/ Amendment 01
Short Title: GSK2982772 high dose safety and PK study in healthy volunteers.
Compound Number:
GSK2982772
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
Regulatory Agency Identifying Number(s):  EudraCT 2017-002662-45
Approval Date: 07-DEC-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


2017N326600_01
CONFIDENTIAL
205184
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 01
07-DEC-2017
Original Protocol
31-JUL-2017
Amendment 01 07-Dec-2017
Overall Rationale for the Amendment:
Clarification of the allowed contraception methods for female participants of child 
bearing potential and male participants with female partners of child bearing potential. 
Pharmacogenetic sampling has been incorporated into the protocol and glucuronide levels 
will be assessed in Part A of the study, as well as Part B. In addition, further 
administrative clarifications have been made.


2017N326600_01
CONFIDENTIAL
205184
4
Section # 
and Name
Description of Change
Brief Rationale
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
3.3.1. Risk 
Assessment
6.1. Inclusion 
Criteria
12.5. 
Appendix 5: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
An additional line for ‘Highly 
effective contraceptive method 
(WOCBP only)’ and ‘Contraception 
with male condoms (WOCBP using 
hormonal contraceptive method 
and male subjects with female 
partners of childbearing potential 
only)’ has been added to the SoA 
tables in Section 2.1. and Section 
2.2.
Updated wording for the subject 
selection for the risk of 
Reproductive Toxicity.
Updated wording for Inclusion 
Criteria 4 for Male and Female 
subjects.
Update of the contraception 
guidance wording for women of 
child bearing potential and male 
subjects with female partners of 
child bearing potential.
Female subjects of child-bearing potential 
who use hormonal contraception are 
required to have their sexual partners use a 
male condom from the first dose of study 
drug until the follow-up visit to avoid 
conception until at least 30 days after the 
last administration of drug.
This is being added as a precautionary 
measure for all WOCBP because an AE of 
“breakthrough bleeding” was reported in 
Cohort 1 TP2 of this study in a female 
subject who is on a combination oral 
contraceptive pill. In the FTiH Study 
200975, there was no increase detected in 
an in vivo marker for CYP3A4 enzyme 
activity following repeat dose administration 
up to 120 mg BID.  Measurement of 4β-
hydroxycholesterol is being evaluated in 
this study to determine CYP3A4 enzyme 
activity in repeat dose administration up to 
720 mg/day.  Until data are available the 
added contraception is being required.
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
9.6. Genetics
12.6. 
Appendix 6: 
Genetics
A line for Pharmacogenetic 
Sampling has been added to both 
Part A and Part B of the study.
A Genetics section has been added 
to the protocol (9.6) and appendix 
(6)
To take a pharmacogenetic sample from 
consenting subjects.
One subject in Cohort 1 (not the subject 
with break through bleeding), had 
consistently high exposure to GSK2982772 
compared to the other subjects (~2-fold 
higher Cmax) for the 120 mg and 240 mg 
TID dose levels. This may be due to a 
UGT1A9 genetic polymorphism, which is 
responsible for the conversion to the 
glucuronide metabolite of GSK2982772.
2.1. Time and 
Events Table 
– Part A 
Addition of a note in PK blood
sampling row to state “Remaining 
PK plasma samples from Part A 
may be analysed for metabolite 
To include the assessment of metabolite 
concentrations in Part A of the study
(currently Part B only).


2017N326600_01
CONFIDENTIAL
205184
5
Section # 
and Name
Description of Change
Brief Rationale
(Cohort 1)
Synopsis-
Objectives 
and 
Endpoints 
Section 4. 
Objectives 
and 
Endpoints
9.4.2. Sample 
Analysis
sampling.”
Metabolite sampling will be 
assessed after single-day of 
dosing, as well as repeat dosing.
Updated wording to in this section 
to state “any remaining plasma 
sample may be analysed for any 
compound-related material and the 
results may be reported as part of 
this study or under a separate PTS-
IVIVT, GlaxoSmithKline protocol.”
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
A pre-dose PK sampling time point 
has been added to the Note ‘f’ for
Cohort 2 and Cohort 3.
No pre-dose sample was written into the 
original protocol on Days 9 and 11 of 
Cohorts 2 and 3.
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
Addition of a PK sampling timepoint 
at 17hr post-first dose in the TID 
Dosing regimens in Cohort 1.
Addition of a PK sampling timepoint 
at 17 hr post-first dose in the TID 
Dosing regimen of Cohorts 2 and 3.
An additional PK sampling time point at 3hr 
post-last dose has been added to better 
characterize the PK profile and to ensure 
the Cmax is not missed.
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
6.2. Exclusion 
Criteria
12.2. 
‘Cotinine Screen’ has been 
changed to ‘Smoking Screen’ and 
‘Cotinine Breath Test’ has been 
changed to ‘Smoking Breath Test’ 
in Section 2.1. and Section 2.2.
Carbon monoxide levels have been 
included in Exclusion Criteria 24.
In the ‘Other Screening Tests’
section, ‘Cotinine Breath Test’ has 
The ‘Cotinine Breath Test’ either includes 
urine cotinine and/or smoking breath test. 
The study will determine evidence of 
current smoking using a non-invasive 
breath carbon monoxide (CO) test device,
which will provide CO levels to determine 
evidence of smoking.


2017N326600_01
CONFIDENTIAL
205184
6
Section # 
and Name
Description of Change
Brief Rationale
Appendix 2: 
Clinical 
Laboratory 
Tests
been changed to ‘Smoking Breath 
Test’.
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
12.2. 
Appendix 2: 
Clinical 
Laboratory 
Tests
In Part A of the study, 
Haem/Chem/Urinalysis 
assessments can be non-fasted for 
Day -1 and the Follow-Up Visit.
In Part B of the study 
Haem/Chem/Urinalysis 
assessments can be non-fasted for 
Day -1 only.
Additional wording included to Note 
2 in Table 3 - Non-fasted samples 
can be collected on Day -1 (All 
Parts) and at the Follow-Up visit 
(Part A Only).
The fasting lipid panel in Part B was 
separated out in the SoA since it was noted 
to be performed on Day -1 or Day 1.  This 
was moved to Day 1 only since subjects will 
not be fasted on Day -1. The 4β-
hydroxycholesterol will be checked on Day 
1, as a fasted sample.
It is recommended that all other lab time 
points being performed (inclusive of the 
follow-up visit) are to be performed under 
fasted conditions since this is essential to 
assess lipid profiles.
6.2. Exclusion 
Criteria
An additional Exclusion Criteria 
(16) has been added. “The subject 
has participated in a clinical trial 
and has received an investigational 
product within the following time 
period prior to the first dosing day 
in the current study: 30 days, 5 
half-lives or twice the duration of 
the biological effect of the 
investigational product (whichever 
is longer). All subsequent exclusion 
criteria numbers have increased by 
1.
To define the minimum length of time since 
a subject was last exposed to a new 
chemical entity.
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
7.2. Method 
of Treatment 
Updated wording in the ‘Notes’ 
section under the procedure 
“Randomization” in Section 2.1. 
and Section 2.2 to state:
“Randomization can occur on either 
Day -1 or Day 1 in both Parts A and 
B of the study.”
Updated wording to include that 
randomization can take place on 
Day -1 or Day 1 in Section 7.2.
There was a discrepancy in the SoA under 
the procedure “Randomization” in both Part 
A and B on Day -1 and Section 7.2. 
Randomization can take place on either 
Day -1 or Day 1.


2017N326600_01
CONFIDENTIAL
205184
7
Section # 
and Name
Description of Change
Brief Rationale
Assignment
9.3.3. Vital 
Signs
The semi-supine position has been 
removed from this section.
To remove any ambiguity with this 
assessment, the supine position will be the 
only position used to assess vital signs.
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
A comment has been added to the 
Meals row to state that “Meals will 
be served as per the site schedule
on Days -1, 16 and 17.”
Clarification of the wording for the meal 
schedule on non-dosing and non PK 
sampling days.
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
Superscript ‘g’ has been removed 
from the PK blood sampling on Day 
1.
Superscript ‘g’ refers to study assessments 
on Day 14 of the protocol and not Day 1. 
This is a correction of a typographical error.
6.2. Exclusion 
Criteria
Update of the wording in Exclusion 
Criteria 3 to change the definition of 
what constitutes a positive 
tuberculin skin test from <5 mm 
skin induration at 48 to 72 hours to 
>5 mm skin induration at 48 to 72 
hours.
Correction of a typographical error. An 
induration of >5 mm skin induration at 48 to 
72 hours is considered a positive TB test.
7.2. Method 
of Treatment 
Assignment
The Method of Treatment 
Assignment has been updated to 
note that subjects in Cohort 1 will 
be randomized to 1 of 4 treatment 
sequences rather than 1 of 3. The 
additional treatment sequence 
(ABC) has been added. 
Correction of a typographical error. There is 
no change to the randomization ratio, which 
is 3:1.
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
Removal of the 10hr time interval 
post-last dose in note ‘b’ for TID 
dosing. This now reads “TID 
dosing: GSK2982772 or placebo 
will be administered using a 7hr, 
7hr dosing interval.”
Correction of a typographical error. Since 
Part A is a single-day of dosing, this 10hr 
interval has been removed.
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
The Neurological Examination 
originally on Day 4 has been 
moved to Day 3.
Correction of a typographical error. 48hr 
post-first dose assessment would be on 
Day 3.
6.2. Exclusion 
Criteria
Exclusion Criteria 29 has been 
updated to state “Fasting total 
cholesterol” rather than “Total 
fasting cholesterol”.
Correction of typographical error.


2017N326600_01
CONFIDENTIAL
205184
8
Section # 
and Name
Description of Change
Brief Rationale
5.7. Dose 
Justification
The title in Figure 2 has been 
changed from “Monkey Cmax” to 
“Monkey AUC(0-24)”.
Correction of the PK parameter stated in 
the Figure 2 title.
12.4. 
Appendix 4: 
Adverse 
Events: 
Definitions 
and 
Procedures 
for Recording, 
Evaluating 
and Follow-
Up 
Assessments
In the ‘Reporting of SAE to GSK’ 
section, facsimile transmission of 
the SAE paper CRF has been 
changed to email transmission.
Notification of an SAE via email is the 
preferred method of transmission to the 
Medical Monitor and SAE Coordinator.


2017N326600_01
CONFIDENTIAL
205184
9
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SYNOPSIS FOR STUDY 205184......................................................12
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................16
2.1.
Time and Events Table – Part A (Cohort 1) ................................................17
2.2.
Time and Events Table – Part B (Cohorts 2-4) ...........................................20
3.
INTRODUCTION....................................................................................................27
3.1.
Study Rationale ..........................................................................................27
3.2.
Background ................................................................................................27
3.3.
Benefit/Risk Assessment ............................................................................27
3.3.1.
Risk Assessment .........................................................................28
3.3.2.
Benefit Assessment.....................................................................35
3.3.3.
Overall Benefit:Risk Conclusion...................................................35
4.
OBJECTIVES AND ENDPOINTS...........................................................................36
5.
STUDY DESIGN ....................................................................................................37
5.1.
Overall Design ............................................................................................37
5.2.
Number of Participants ...............................................................................38
5.3.
Sentinel Dosing...........................................................................................38
5.4.
Dose Escalation Decisions .........................................................................38
5.5.
Participant and Study Completion...............................................................38
5.6.
Scientific Rationale for Study Design ..........................................................39
5.7.
Dose Justification........................................................................................39
6.
STUDY POPULATION...........................................................................................42
6.1.
Inclusion Criteria.........................................................................................42
6.2.
Exclusion Criteria........................................................................................43
6.3.
Lifestyle Restrictions...................................................................................45
6.3.1.
Meals and Dietary Restrictions ....................................................45
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................46
6.3.3.
Activity .........................................................................................46
6.4.
Screen Failures...........................................................................................46
7.
TREATMENTS.......................................................................................................47
7.1.
Treatments Administered............................................................................47
7.2.
Method of Treatment Assignment ...............................................................47
7.3.
Blinding.......................................................................................................48
7.4.
Preparation/Handling/Storage/Accountability..............................................49
7.5.
Treatment Compliance................................................................................49
7.6.
Concomitant Therapy..................................................................................49
7.7.
Treatment after the End of the Study ..........................................................50
8.
DISCONTINUATION CRITERIA.............................................................................51
8.1.
Discontinuation of Study Treatment ............................................................51


2017N326600_01
CONFIDENTIAL
205184
10
8.1.1.
Dose Modification/Stopping Criteria.............................................51
8.1.2.
Pharmacokinetic Dose Modification or Stopping Criteria..............51
8.1.3.
Liver Chemistry Stopping Criteria ................................................52
8.1.4.
QTc Stopping Criteria ..................................................................52
8.1.5.
Individual Safety Stopping Criteria ...............................................53
8.1.6.
Group Safety Stopping Criteria ....................................................53
8.1.7.
Nervous System Stopping Criteria ...............................................53
8.1.8.
Rechallenge.................................................................................54
8.1.8.1.
Study Treatment Restart or Rechallenge....................54
8.2.
Withdrawal from the Study..........................................................................54
8.3.
Lost to Follow Up........................................................................................54
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................56
9.1.
Adverse Events...........................................................................................56
9.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................56
9.1.2.
Method of Detecting AEs and SAEs.............................................57
9.1.3.
Follow-up of AEs and SAEs.........................................................57
9.1.4.
Regulatory Reporting Requirements for SAEs .............................57
9.1.5.
Pregnancy ...................................................................................58
9.2.
Treatment of Overdose...............................................................................58
9.3.
Safety Assessments ...................................................................................58
9.3.1.
Physical Examinations.................................................................58
9.3.2.
Neurological Exams.....................................................................59
9.3.3.
Vital Signs....................................................................................59
9.3.4.
Electrocardiograms......................................................................59
9.3.5.
Clinical Safety Laboratory Assessments ......................................60
9.3.6.
Suicidal Risk Monitoring...............................................................60
9.4.
Pharmacokinetics .......................................................................................61
9.4.1.
Blood Sample Collection..............................................................61
9.4.2.
Sample Analysis ..........................................................................61
9.4.3.
Plasma Sample for CYP3A4 Enzyme Activity ..............................62
9.5.
Pharmacodynamics ....................................................................................62
9.6.
Genetics .....................................................................................................62
9.7.
Pharmacological Biomarkers ......................................................................62
10. STATISTICAL CONSIDERATIONS........................................................................63
10.1.
Sample Size Determination ........................................................................63
10.2.
Sample Size Sensitivity...............................................................................64
10.3.
Populations for Analyses ............................................................................66
10.4.
Statistical Analyses.....................................................................................66
10.4.1.
Safety Analyses...........................................................................66
10.4.2.
PK Analyses ................................................................................66
10.4.3.
Other Analyses ............................................................................67
10.4.4.
Interim Analyses ..........................................................................67
10.5.
Dose Escalation Committee........................................................................67
11. REFERENCES.......................................................................................................69
12. APPENDICES........................................................................................................70
12.1.
Appendix 1: Abbreviations and Trademarks................................................70
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................73


2017N326600_01
CONFIDENTIAL
205184
11
12.3.
Appendix 3: Study Governance Considerations..........................................75
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................79
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................84
12.6.
Appendix 6: Genetics..................................................................................88
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................89
12.8.
Appendix 8:  Nervous System Adverse Events (CTCAE Criteria) ...............91
12.9.
Appendix 9: Protocol Amendment History.................................................101


2017N326600_01
CONFIDENTIAL
205184
12
1.
PROTOCOL SYNOPSIS FOR STUDY 205184
Protocol Title: A single-centre, randomized, double-blind (sponsor-unblinded), placebo-
controlled study to evaluate the safety, tolerability and pharmacokinetics of GSK2982772 
in repeat oral doses in healthy subjects.
Short Title: GSK2982772 high dose safety and PK study in healthy volunteers.
Rationale: The purpose of this study is to evaluate the safety, tolerability and 
pharmacokinetics (PK) of repeat oral doses of GSK2982772 (TID and BID, if required) 
in healthy subjects. TID dosing will be administered as a 7hr, 7hr, 10hr dosing interval 
and BID as a 12hr dosing interval. 
Objectives and Endpoints:
Objective
Endpoint
Primary

To investigate the safety and tolerability of 
repeat doses of GSK2982772 in healthy 
subjects.

Adverse events.

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature).

Physical examinations.

12-Lead ECG monitoring.
Secondary

To characterise the PK profile of repeat 
doses of GSK2982772 in healthy subjects.

A 24 hr profile to be collected on Day 1 of 
Part A and Day 14 of Part B. On Day 1 of 
Part B, the PK profile will be evaluated 
following the first dose only. Derived PK 
parameters for GSK2982772, including area 
under the plasma drug concentration versus 
time curve over 24 hr (AUC(0-24)) and AUC 
over each dose interval (i.e. AUC(0-7), AUC(7-
14) and AUC(14-24) for TID and AUC(0-12) and 
AUC(12-24) for BID). Maximum observed 
plasma drug concentration (Cmax) following
each dose, time to maximum observed 
plasma drug concentration (Tmax) following 
each dose, observed trough plasma drug 
concentrations (C0, C7, C14 and C24 for TID
dosing and C0, C12 and C24 for BID dosing).

To assess the impact of food on the PK of 
repeat doses of GSK2982772 in healthy 
subjects at steady state

Derived PK parameters for GSK2982772, 
including AUC(0-7), AUC(7-14), Cmax, after 1st
dose of day and Tmax after 1st dose of day.


2017N326600_01
CONFIDENTIAL
205184
13
Objective
Endpoint

To assess potential effect of repeat doses 
of GSK2982772 on CYP3A4 enzyme 
activity.

Plasma 4β-hydroxycholesterol to 
cholesterol ratio pre-treatment and following 
14 days of repeat dosing of GSK2982772.
Exploratory

To investigate the levels of circulating 
glucuronide metabolite (M8; GSK3562183)
and desmethyl metabolite (M9; 
GSK2997852) in healthy subjects after 
single-day and repeat dosing of 
GSK2982772.

Quantify M8 (GSK3562183) and M9 
(GSK2997852) in select plasma PK 
samples after single-day dosing and at pre-
dose and 2 hr following Day 14 of repeat 
dosing of GSK2982772.
Overall Design:
This is a single-centre, randomized, double-blind (sponsor-unblinded), placebo-controlled 
study to evaluate the safety, tolerability and pharmacokinetics of GSK2982772, in repeat 
oral doses in healthy subjects. The study design schematic is depicted in the Figure
below:
Study Design
*With Food Effect Treatment
Part A - Single-Day Ascending Doses
1 Day
3:1 Randomized 
GSK2982772:Placebo
Part B – Repeat Doses 
14 Days
3:1 Randomized 
GSK2982772:Placebo
Cohort 1
N=12
120 mg TID (1 Day) followed by,
240 mg TID (1 Day) followed by,
360 mg BID (1 Day)
Cohort 2
N=12
120 mg TID
14 Days *
Cohort 3
N=12
240 mg TID
14 Days *
Cohort 4
N=12
360 mg BID
14 Days


2017N326600_01
CONFIDENTIAL
205184
14
Type and Number of Participants:
Healthy volunteer subjects will be enrolled, such that up to approximately 12 subjects (9 
active, 3 placebo) in each Cohort (up to approximately 48 in total) complete dosing and 
critical assessments. A subject is defined to have completed the study when he/she has 
attended all study visits.
Sentinel dosing will be employed within each Cohort for both Part A and Part B of the 
study. The doses in the single-ascending dose portion of the study (Part A) will be 
staggered such that for each of the three treatment periods, on Day 1, two of the 12 
subjects will be randomized to treatment (one subject will receive GSK2982772 and one 
subject will receive matched-placebo). Assuming 2 subjects are dosed on Day 1 and 
assuming adequate safety in the judgment of the Principal Investigator (e.g., vital signs, 
ECGs, and adverse events) through approximately 24 hours after their last dose on Day 1, 
the remaining subjects may be randomized to dosing in that period. The doses in the 
repeat dose portion of the study (Part B) will be staggered such that for each treatment 
period on Day 1, two of the 12 subjects will be randomized to treatment (one subject will 
receive GSK2982772 and one subject will receive matched-placebo) and dosed for at 
least 7 days before the rest of the cohort is randomized. Assuming 2 subjects are dosed on 
Day 1 to 7 and assuming adequate safety in the judgment of the Principal Investigator 
(e.g., vital signs, ECGs, and adverse events) through approximately Day 7, the remaining 
subjects may be randomized to dosing.
If subjects prematurely discontinue the study, additional replacement subjects may be 
randomized in order to guarantee that sufficient subjects are treated with GSK2982772 at 
any given dose before escalating to the following dose. Replacement subjects will be 
assigned to the same treatment sequence (Cohort 1) or treatment (Cohorts 2-4) and start 
from the period to be replaced at the discretion of the Sponsor and in consultation with 
the Principal Investigator.
Treatment Groups and Duration:
The study duration, including screening and follow-up, is not expected to exceed 
13 weeks for Part A and 8 weeks for Part B of the study.
Study Duration – Cohort 1
Screening
Approximately 28 days.
Number of Subjects
One Cohort of 12 subjects (N=12).
Treatment Period
Cohort 1 will comprise of three treatment periods, investigating three dosing regimens. 
Each dose regimen consists of 1 day treatment duration, with subjects in house for 4
nights (through at least 48 hours post-last dose). Subjects will be admitted to the unit 
the day before dosing, will remain in the unit overnight, and will be released following 
completion of the assessments on Day 4 of each treatment period, provided there are 
no safety concerns.
Washout Period 
Will be at least 7 days between dose regimens for an individual subject.
Follow-up
At least 7 days and no greater than 14 days after last study drug administration. If 
warranted, additional follow-up visits may be scheduled.


2017N326600_01
CONFIDENTIAL
205184
15
Study Duration – Cohorts 2-4
Screening
Approximately 28 days.
Number of Subjects
Three Cohorts of 12 subjects each (N=36).
Treatment Period
The treatment duration will be 14 days. Subjects will be admitted to the unit the day 
before dosing, will remain in the unit overnight and will be released following 
completion of the assessments on Day 17, provided there are no safety concerns.
Follow-up
At least 7 days and no greater than 14 days after last study drug administration. If 
warranted, additional follow-up visits may be scheduled.


2017N326600_01
CONFIDENTIAL
205184
16
2.
SCHEDULE OF ACTIVITIES (SOA)
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Activities (SoA) tables (Section 2.1 and Section 2.2), are 
essential and required for study conduct.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the Study Reference Manual (SRM). The SRM will provide the site 
personnel with administrative and detailed technical information that does not impact 
subject safety.
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the SoA tables (Section 2.1 and Section 2.2).
The following points must be noted:

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-Lead ECG
2. Vital Signs
3. Blood Draws
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, or other 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.

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File, which is approved by the relevant GSK 
study team member and then archived in the study sponsor and site study files, 
but this will not constitute a protocol amendment.

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.

The Institutional Review Board/Independent Ethics Committee (IRB/IEC) will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form.
A table defining the allowed variance in timings of assessments without being considered 
a protocol deviation will be included in the SRM.


2017N326600_01
CONFIDENTIAL
205184
17
2.1.
Time and Events Table – Part A (Cohort 1)
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up  
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
Outpatient Visit
X
X
Admission to Clinical Unit
X
Inpatient Stay at Clinical Unit
==X==
Discharge from Clinical Unit
X
Following completion of all assessments.
Informed Consent
X
Inclusion and Exclusion Criteria
X
Demography
X
Full Physical Examination
X
Additional exams/screens may be performed, or brief exams made full exams, by the 
Investigator, as deemed necessary (e.g. where safety or laboratory findings indicate). Tests 
will be conducted within site specified standards.
Brief Physical Examination
X
X
X
Height
X
Weight
X
Drug/Alcohol/Smoking Screen
X
X
Tests include alcohol breath test, smoking breath test and urine drug screen.
Medical/Medication/Drug/Alcohol 
History
X
HIV, Hepatitis B and C Screening
X
Tuberculosis Test
X
Conducted at the standard practice of the site.
Serum Pregnancy Test (WOCBP 
only)
X
X
Urine Pregnancy Test (WOCBP 
only)
X
X
Highly effective contraceptive 
method (WOCBP only)
X
X
X
X
X
X
X
Must use method for a minimum of 28 days prior to first dose of study medication until the 
follow-up visit
Contraception with male condoms  
(WOCBP using hormonal 
contraceptive method and male 
subjects with female partners of 
childbearing potential only)
X
X
X
X
X
X


2017N326600_01
CONFIDENTIAL
205184
18
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up  
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
Meals
X
Xa
X
X
X
a On Day 1, subjects will fast 8hr overnight prior to dose 1. A breakfast will be served 
approximately 2hr after dose 1. 
TID dosing: On Day 1, lunch and dinner will be served between 2 to 3hr prior to doses 2 and 
3, respectively. 
BID dosing: On Day 1, lunch will be served approximately 4 to 5hr after dose 1. Dinner will 
be served between 2 to 3hr prior to dose 2. A snack may be consumed approximately 2 to 
3hr after dose 2.
Water is permitted with dosing and at all times. Subjects will receive standardized meals 
scheduled at the same time in each period.
Haem/Chem/Urinalysis Test 
(Include Liver Chemistries)
X
X
X
X
X
X
Non-fasted samples can be collected on Day -1 and Follow-Up Visit.
PK Blood Sampling
X
X
TID Dosing: PK samples to be taken pre-dose on Day 1 and then at the following time points 
post first-dose: 20min, 40min, 1hr, 1hr 30min, 2hr, 3hr, 5hr, 7hr, 7hr 20min, 7hr 40 min, 8hr, 
8hr 30min, 9hr, 10hr, 12hr, 14hr, 14hr 20min, 14hr 40 min, 15hr, 15hr 30min, 16hr, 17hr, 
19hr, 22hr, 24hr.
BID Dosing: PK samples to be taken pre-dose on Day 1 and then at the following time 
points post first-dose: 20min, 40min, 1hr, 1hr 30min, 2hr, 3hr, 4hr, 6hr, 8hr, 10hr, 12hr, 12hr 
20min, 12hr 40min, 13hr, 13hr 30min, 14hr, 15hr, 16hr, 19hr, 22hr, 24hr.
Remaining PK plasma samples from Part A may be analysed for metabolite sampling.
Neuro. Examination
X
X
X
TID Dosing: Neurological examinations to be conducted either on Day -1 or pre-dose Day 1 
and then at the subsequent time points post first-dose on Day 1: 2hr, 9hr, 16hr, 24hr and 
48hr. Then 24 and 48hr after the last dose administered on Day 1.
BID Dosing: Neurological examinations to be conducted either on Day -1 or pre-dose Day 1 
and then at the subsequent time points post first-dose: 2hr, 14hr, 24hr and 48hr. Then 24 
and 48 hr after the last dose administered on Day 1.
Telemetry
X
Continuous at least 24hr post-evening dose. Initiate at least 15 min. prior to dosing.
12-Lead ECG
X
X
T
X
X
Vital signs to include HR, BP, temperature and respiration rate. 
TID Dosing: 12-Lead ECG and Vital Signs to be conducted on Day -1 and pre-dose on Day 


2017N326600_01
CONFIDENTIAL
205184
19
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up  
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
Vital Signs
X
X
T
X
X
X
1 and then at the subsequent time points post first-dose: 40min, 2hr, 4hr, 7hr (pre-2nd dose), 
9hr, 14hr (pre-3rd dose), 16hr, 24hr and 48hr. Then 24 and 48hr after the last dose 
administered on Day 1.
BID Dosing: 12-Lead ECG and Vital Signs to be conducted on Day -1 and pre-dose on Day 
1 and then at the subsequent time points post first-dose: 40 min, 2hr, 4hr, pre-2nd dose, 12hr
20 min, 14hr, 24hr and 48 hr. Then 24 and 48hr after the last dose administered on Day 1.
T = Triplicate.
Randomization
X
Randomization can occur on either Day -1 or Day 1.
Study Treatment
Xb
b TID dosing: GSK2982772 or placebo will be administered using a 7hr, 7hr dosing interval.
BID dosing: GSK2982772 or placebo will be administered using a 12hr dosing interval.
Pharmacogenetic Sample (PGx)
X
A PGx blood sample is collected at the Day 1 visit, after the subject has been randomized 
and provided informed consent for genetic research. If the sample is not collected at the Day 
1 visit, it can be collected at any time during the study after randomization.
AE Review
=======X======
X
SAE Review
=======X======
X
Concomitant Medication Review
X
=======X======
X


2017N326600_01
CONFIDENTIAL
205184
20
2.2.
Time and Events Table – Part B (Cohorts 2-4)
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Outpatient Visit
X
X
Admission to Clinical 
Unit
X
Inpatient Stay at 
Clinical Unit
================================X===============================
Discharge from 
Clinical Unit
X
Following completion of all 
assessments.
Informed Consent
X
Inclusion and 
Exclusion Criteria
X
Demography
X
Full Physical 
Examination
X
X
Additional exams/screens may be 
performed, or brief exams made full 
exams, by the Investigator, as deemed 
necessary (e.g. where safety or 
laboratory findings indicate). Tests will 
be conducted within site specified 
standards.
Brief Physical 
Examination
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
Drug/Alcohol/Smoking 
Screen
X
X
Tests include alcohol breath test,
smoking breath test and urine drug 
screen.
Medical/Medication/
Drug/Alcohol History
X
HIV, Hepatitis B and 
X


2017N326600_01
CONFIDENTIAL
205184
21
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
C Screening
Tuberculosis Test
X
Anti-Nuclear Antibody
X
X
X
Serum Pregnancy 
Test (WOCBP only)
X
X
Urine Pregnancy Test 
(WOCBP only)
X
X
Highly effective 
contraceptive method 
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Must use method for a minimum of 28 
days prior to first dose of study 
medication until the follow-up visit.
Contraception with 
male condoms  
(WOCBP using 
hormonal 
contraceptive method 
and male subjects 
with female partners 
of childbearing 
potential only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
Xc
May be completed on either Day -1 or 
Day 1, but no later than 1hr prior to 
dosing. To be completed pre-dose on 
Day 7.
c C-SSRS to be conducted on follow-up 
only in the instance that a subject 
withdraws from the study.
Meals
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TID Dosing: On Day 1 through 14 
subjects will fast 8hr overnight. 
Breakfast will be served approximately 


2017N326600_01
CONFIDENTIAL
205184
22
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
2hr after dosing on Days 1-8, 10, 12 
and 13 and 2hr after dosing on Day 14. 
A “standard” and a “high fat” breakfast 
will be served approximately 30 
minutes prior to dosing on Day 9 and 
Day 11, respectively. On all study days, 
lunch and dinner will be served 
between 2 to 3hr prior to dose 2 and 
dose 3, respectively.     
BID Dosing: On Day 1 through 14, 
subjects will fast 8hr overnight prior to 
dose 1. A breakfast will be served 
approximately 2hr after dose 1. Lunch 
will be served approximately 4-5hr after 
dose 1. Dinner will be served between 
2-3hr prior to dose 2. A snack may be 
consumed approximately 2-3hr after 
dose 2.
Water is permitted with dosing and at 
all times. Subjects will receive 
standardized meals scheduled at the 
same time in each period.
Meals will be served as per the site 
schedule on Days -1, 16 and 17.
Haem/Chem/
Urinalysis Test 
(Include Liver 
Chemistries)
X
X
X
X
X
X
X
X
X
Collection on Day 1 no later than 1hr 
prior to dosing. To be drawn pre-dose 
on Days 2, 4, 7 and 10.
Fasting lipid panel
X
X
X
X
X
X
X
X
Collection on Day 1 no later than 1hr 


2017N326600_01
CONFIDENTIAL
205184
23
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
prior to dosing. To be drawn pre-dose 
on Days 2, 4, 7 and 10.
Telemetry
X
X
X
Continuous at least 24 hr post-evening 
dose. Initiate at least 15 min. prior to 
dosing.
PK blood sampling
Xd
Xe
Xe
Xe
Xe
Xe
Xf
Xf
Xg
dOn Day 1, PK samples will be 
collected pre-dose and at the following 
time points post first-dose: 20min, 
40min, 1hr, 1hr 30min, 2hr, 3hr, 5hr
and 7hr.
eOnDays 2,3 4, 5 and 7 pre-dose 
samples only.
f Days 9, and 11: Cohort 2 and Cohort 
3 PK sampling will be collected pre-
dose and at the following time points 
post first-dose: 20min, 40min, 1hr, 1hr 
30min, 2hr, 3hr, 5hr, 7hr (prior to 2nd
dose) 7hr 20min, 7hr 40 min, 8hr, 8hr 
30min, 9hr, 10hr, 12hr. Cohort 4 is 
currently not planned to have PK 
assessment but may be included 
depending on outcome of food effect in 
Cohorts 2 and 3.
g Day 14 sampling for Cohorts 2, 3 and 
4 will be over 24hr according to the 
following schedules:
For TID Dosing: PK samples to be 
taken pre-dose and then at the 
following time points post first-dose: 


2017N326600_01
CONFIDENTIAL
205184
24
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
20min, 40min, 1hr, 1hr 30min, 2hr, 3hr, 
5hr, 7hr (pre-2nd dose) 7hr 20min, 7hr 
40 min, 8hr, 8hr 30min, 9hr, 10hr, 12hr, 
14hr (pre 3rd dose), 14hr 20min, 14hr 
40 min, 15hr, 15hr 30min, 16hr, 17hr, 
19hr, 22hr, 24hr.
For BID Dosing: PK samples to be 
taken pre-dose on Day 1 and then at 
the subsequent time points post first-
dose: 20min, 40min, 1hr, 1hr 30min, 
2hr, 3hr, 4hr, 6hr, 8hr, 10hr, 12hr (pre 
2nd dose), 12hr 20min, 12hr 40min, 
13hr, 13hr 30min, 14hr, 15hr, 16hr, 
19hr, 22hr, 24hr.
Metabolite sampling
Xh
hMetabolite sampling will be conducted 
pre-dose and 2hr post first dose on 
Day 14 only.
4β-hydroxycholesterol 
sampling
Xi
Xj
i Sample to be taken pre-dose on Day 1 
in a fasted state.
j Sample to be taken at 24hr post first 
dose on Day 14. Sample should be in a 
fasted state.
Neuro. examination
X
X
X
X
X
TID Dosing: Neurological 
examinations to be conducted either on 
Day-1 or pre-dose Day 1 and then at 
the subsequent time points post first 
dose: 2hr, 9hr, 16hr, 24hr and 48hr. To 
be completed pre-dose on Day 7 and 
then 48 hr post-last dose on Day 14.


2017N326600_01
CONFIDENTIAL
205184
25
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
BID Dosing: Neurological 
examinations to be conducted pre-dose 
either on Day-1 or Day 1 and then at 
the subsequent time points post first 
dose: 2hr, 14hr, 24hr and 48hr. To be 
completed pre-dose on Day 7 and then 
48hr post-last dose on Day 14.
12-Lead ECG
X
X
T
X
X
X
X
X
Vital signs to include HR, BP, 
temperature and respiration rate. 
On Day 1:
TID Dosing: 12-Lead ECG and Vital 
Signs to be conducted on Day-1 and 
pre-dose Day 1 and then at the 
subsequent time points post first-dose: 
40min, 2hr, 4hr, 7hr (pre-2nd dose), 9hr, 
14hr (pre-3rd dose), 16hr, 24hr, 48hr.
Then 24 and 48hr after the first dose 
and last dose administered on Day 14.
BID Dosing: 12-Lead ECG and Vital 
Signs to be conducted pre-dose either 
on Day-1 or Day 1 and then at the 
subsequent time points post first-dose: 
40 min, 2hr, 4hr, 12hr (pre-2nd dose), 
14hr, 24hr, 48hr. Then 24 and 48hr
after the first and last dose 
administered on Day 14.
OnDays 3 to 14, pre-dose samples 
only.
T = Triplicate.
Vital signs
X
X
T
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


2017N326600_01
CONFIDENTIAL
205184
26
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Randomization
X
Randomization can occur on either Day 
-1 or Day 1.
Study Treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TID dosing: GSK2982772 or placebo 
will be administered using a 7hr, 7hr 
and 10hr dosing interval.
BID dosing: GSK2982772 or placebo 
will be administered using a 12hr 
dosing interval.
Pharmacogenetic 
Sample (PGx)
X
A PGx blood sample is collected at the 
Day 1 visit, after the subject has been 
randomized and provided informed 
consent for genetic research. If the 
sample is not collected on Day 1, it can 
be collected at any time during the 
study after randomization.
AE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

The timing and number of planned study assessments, including safety, pharmacokinetic or other 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 informed consent form (ICF).


2017N326600_01
CONFIDENTIAL
205184
27
3.
INTRODUCTION
3.1.
Study Rationale
The current study is being conducted to support administration of higher dose levels than 
initially studied in the First Time in Human (FTiH) study - 200975. The dose in the FTiH 
study was capped at 120 mg BID based on exposure margins with the no observable
adverse effect limit (NOAEL) in the 28-day monkey toxicology study (10 mg/kg/day). 
Subsequently, a 13-week toxicity study in monkeys has completed which increased the 
NOAEL to 30 mg/kg/day which will allow for an approximate 4-fold increase in the 
safety margins, in terms of systemic exposure to GSK2982772. The current study is 
being conducted to explore administration of higher dose levels than achieved in the 
FTiH study to support subsequent Phase 2a Proof of Concept (PoC) studies and Phase 2b 
dose range studies in subjects with psoriasis (PsO), rheumatoid arthritis (RA) and 
ulcerative colitis (UC).
3.2.
Background
GSK2982772 is a first-in-class, highly selective, small molecule inhibitor of receptor-
interacting serine/threonine protein-1 (RIP1) kinase. RIP1 is a member of the receptor-
interacting serine/threonine kinase family containing an amino-terminal kinase domain, 
an intermediate domain and a carboxy-terminal death domain. RIP1 regulates 
inflammatory signalling in response to stimuli such as tumour necrosis factor (TNF) and 
ligands of the Toll-like receptor family in both kinase-dependent and -independent 
manners [Ofengeim, 2013]. Upon binding to its receptor, tumour necrosis factor receptor-
1 (TNFR1), TNFα triggers one of three distinct cellular fates; NFκB activation, apoptosis, 
or the more recently identified programmed necrosis [Ofengeim, 2013]. In addition, 
recent studies have shown that the programmed necrosis signalling complex also 
regulates the induction of certain cytokines. Although RIP1 serves as a key decision 
checkpoint for all three of these pathways, its kinase activity is only requisite for the 
initiation of programmed necrosis and pro-inflammatory cytokine production [Berger, 
2014]. The discovery of this newly defined inflammatory, programmed necrotic pathway 
calls into question the major contributor to human disease downstream of the TNFR1. As 
such, a RIP1 kinase inhibitor represents a novel, selective mechanism for the treatment of 
inflammatory conditions such as Crohn’s Disease, Plaque Psoriasis, and Rheumatoid 
Arthritis through multiple mechanisms, including the blockade of cell death, danger 
associated molecular pattern (DAMP)-driven inflammation and pro-inflammatory 
cytokine production.
3.3.
Benefit/Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2982772 can be found in the Investigator’s Brochure (IB). The following section 
outlines the risk assessment and mitigation strategy for this protocol:


2017N326600_01
CONFIDENTIAL
205184
28
3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Investigational Product (IP) GSK2982772
Central Nervous System (CNS) Effects
Non-Clinical Data:
In the 4-week GLP toxicology study, CNS 
findings were observed in 2/12 monkeys which 
were administered 100 or 300 mg/kg/day. CNS 
findings included uncoordination, irregular gait, 
trembling, hunched appearance and decreased 
activity. The NOAEL for this study was 
determined at 10 mg/kg/day.
In the 13-week GLP toxicology study, there were 
no CNS findings observed in monkeys 
administered 10, 30 or 100 mg/kg/day. The 
NOAEL for this study was determined at 30 
mg/kg/day.
Clinical Data:
A FTiH study with single ascending and multiple 
ascending dose study has been performed in 67 
healthy male volunteers to date (see IB 
[GlaxoSmithKline Document Number 
2014N204126_02]). No drug-associated CNS 
adverse events (AEs) were identified and no 
Serious AEs (SAEs) were reported.
Subject Selection:
Subjects with known history of significant 
neurologic disorders including but not limited to 
progressive multiple sclerosis (MS), Amyotrophic
lateral sclerosis (ALS), Alzheimer’s and dementia 
will be excluded. 
Individuals with potentially increased 
susceptibility for neurologic effects will be 
excluded based on medical history at screening.
Subject Monitoring:
Subjects will be monitored for standard CNS-
related AEs.


2017N326600_01
CONFIDENTIAL
205184
29
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Immunosuppression
The possibility of immunosuppression, including 
an increase in the frequency and/or severity of 
infection, may result from the intended 
pharmacologic effect of GSK2982772. This may 
be enhanced in subjects taking other 
immunomodulating drugs or corticosteroids.
Clinical Data:
In the FTiH study, no SAEs were reported. One 
subject experienced an Adverse Event (AE) 
herpes zoster approximately 27 days after 
receiving his last dose with GSK2982772 or 
placebo. The blinded investigator determined this 
to be potentially drug-related.
Subject Selection:
Subjects with recurrent, chronic or active 
infections will be excluded from the study.
Subjects will be screened for TB, HIV, Hepatitis 
B and C, and excluded from the study if positive.
Investigators are expected to follow local and/or 
national guidelines with respect to vaccinations, 
including against influenza and pneumococcus.
Subject Monitoring:
Subjects will be monitored for signs of infection.
See Individual Safety Stopping Criteria for 
atypical or opportunistic infections (Section 
8.1.5).
Vaccinations
There is a theoretical risk that GSK2982772 
could decrease an individual’s immune response 
to vaccines or allow symptoms to develop 
following vaccination with a live vaccine when 
administered while on therapy.
Subject Selection:
Attenuated or live vaccines should not be 
administered to subjects from 30 days prior to 
the first dose of GSK2982772, during the study 
and for 5 half-lives plus 30 days (total 32 days) 
after GSK2982772 is discontinued.


2017N326600_01
CONFIDENTIAL
205184
30
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
If indicated, non-live vaccines (e.g. inactivated 
influenza vaccines) may be administered while 
receiving GSK2982772 based on a treating 
physician assessment of the benefit: risk (e.g., 
risk of theoretical decreased responsiveness).
Investigators will be expected to have followed 
local and/or national guidelines with respect to 
vaccinations, including against influenza and 
pneumococcus.
Respiratory
Non-clinical data:
In the single-dose Safety Cardiovascular and 
Respiratory Study in monkeys, a decrease in 
minute volume (MV) and respiratory rate was 
observed at all doses (10, 100, and 300 mg/kg).  
These findings were noted to be reversible and 
mild in severity.
In a 14-day repeat dose Safety Respiratory 
Study in monkeys, no respiratory effects on total 
pulmonary ventilation (MV) or respiratory rate 
were observed at doses of 1 or 10 mg/kg/day. 
See IB for GSK2982772 [GlaxoSmithKline 
Document Number 2014N204126_02].
Subject Monitoring:
Subjects should be monitored for standard 
respiratory-related AEs.
Vital signs will be monitored during study visits.


2017N326600_01
CONFIDENTIAL
205184
31
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Clinical data:
In the FTiH study, repeat doses of GSK2982772 
up to 120 mg BID were administered x 14 days 
in 48 healthy male volunteers. Extensive 
respiratory monitoring with end-tidal CO2 
(ETCO2), oxygen saturation (SpO2) and 
nocturnal respiratory rate monitoring was 
performed.   No SAEs occurred, and no drug-
associated respiratory-related AEs were 
identified.
Suicidality
GSK2982772 is considered to be a CNS-active 
drug based on pre-clinical studies.
Clinical Data:
In the FTiH study, there have been some reports 
of lethargy, abnormal dreams and depressed 
mood. No events of suicidal ideation or 
behaviour or changes in behaviour were 
reported.
Subject Selection:
Subjects with a current history of Suicidal 
Ideation Behaviour (SIB) as measured using the 
Columbia Suicide Severity Rating Scale (C-
SSRS) or a history of attempted suicide will be 
excluded from the study.
Subject Monitoring:
Subjects should be monitored appropriately and 
observed closely for suicidal ideation and 
behaviour or any other unusual changes in 
behaviour.
Baseline and treatment emergent assessment of 


2017N326600_01
CONFIDENTIAL
205184
32
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
suicidality will be conducted by trained site 
personnel using the C-SSRS in all subjects.
Reproductive Toxicity
Non-Clinical Data:
In the rat embryofetal development study, there 
were no maternal or developmental toxicity at 
doses ≤200 mg/kg/day.
In the rabbit embryofetal development study, 
GSK2982772 was administered at doses of 0, 
10, 100, 300 or 600 mg/kg/day on gestation day 
7 to 19. No developmental toxicity was evident at 
doses up to 300 mg/kg/day.
Subject Selection:
Female subjects of childbearing potential will be 
included in this study only if they agree to use 
one of the highly effective methods of 
contraception beginning at least 28 days prior to 
first dose of study drug until 30 days after the last 
administration of study drug. Women using a 
hormonal contraceptive method will also be 
required to have partners use a male condom 
from the first dose of study drug and until the 
follow-up visit to avoid conception until at least 
30 days after the last administration of study 
drug.  
Male subjects with female partners of 
childbearing potential must agree to use male 
condoms to avoid conception for defined periods 
of time before first administration of study drug 
until 90 days after the last administration of study 
drug. It is also recommended that a male subject 
with a female partner of childbearing potential 
employ a highly effective contraceptive method 
throughout this same period of time.
Females of childbearing potential will undergo 


2017N326600_01
CONFIDENTIAL
205184
33
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
serum pregnancy test at screening and then 
urine pregnancy testing at regular intervals 
during the study.
Pregnant and lactating females are not eligible 
for inclusion in the study.
Withdrawal Criteria:
If a female subject should become pregnant 
during the study, study medication should be 
discontinued. The subject will be followed to 
determine the outcome of the pregnancy. Any 
pregnancy complication or elective termination of 
a pregnancy will be reported as an AE or SAE.
Drug Interaction
Non-Clinical Data:
In vitro studies with GSK2982772 assessing 
potential drug-drug interactions with Cytochrome 
P450 3A4 (CYP3A4) substrates and P-
glycoprotein (Pgp) inhibitors were completed. To 
date, formal drug interaction studies in humans 
have not been performed with GSK2982772.
There is a low risk that GSK2982772 could be an 
Subject Selection:
Subjects who are taking concomitant 
medications known to inhibit Pgp or are CYP3A4 
narrow therapeutic index (NTI) substrates will be 
excluded from the study.
Subject Monitoring:
Subjects’ concomitant medication usage will be 


2017N326600_01
CONFIDENTIAL
205184
34
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
inducer of CYP3A4 and therefore may lower 
circulating levels of concomitant medications that 
are metabolised by CYP3A4 when co-
administered with GSK2982772.
GSK2982772 is a Pgp substrate and therefore 
co-administration with concomitant medications 
that are Pgp inhibitors could increase circulating 
levels of GSK2982772.  See Section 4.3.6 of 
GSK2982772 IB [GlaxoSmithKline Document 
Number 2014N204126_02].
reviewed prior to inclusion and monitored 
throughout the study.
Subjects should be monitored throughout the 
study for potential effects of interaction between 
GSK2982772 and other concomitant 
medications.


2017N326600_01
CONFIDENTIAL
205184
35
3.3.2.
Benefit Assessment
The proposed study with GSK2982772 will be conducted in healthy volunteers; no 
medical benefit will be derived by volunteers’ participation. Subjects will indirectly gain 
through their contribution to the process of developing new therapies in an area of unmet 
need.
3.3.3.
Overall Benefit:Risk Conclusion
The known risks associated with GSK2982772 can be appropriately mitigated by the 
careful selection of study participants and the proposed safety monitoring procedures. As 
such, the risk to potential subjects is considered low. Routine safety and tolerability will 
be evaluated from reported AEs, scheduled physical examinations, vital sign 
measurements, cardiac rhythm monitoring, 12-lead ECGs, and clinical laboratory test 
results as well as continued observation by clinical staff.
The study will be conducted in a hospital-based unit or unit with immediate access to 
hospital facilities for the treatment of medical emergencies. The in-house periods as 
detailed in the SoA (Section 2) will allow for continuous medical monitoring for all 
subjects following the first dose in each treatment group. Subjects will only be discharged 
from the unit 48 hours post-dose if the Investigator deems it safe to do so.
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with GSK2982772 are justified by the 
anticipated benefits that may be afforded by the future development of a new therapy in 
an area of unmet need.


2017N326600_01
CONFIDENTIAL
205184
36
4.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary

To investigate the safety and tolerability of 
repeat doses of GSK2982772 in healthy 
subjects.

Adverse events.

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature).

Physical examinations.

12-Lead ECG monitoring.
Secondary

To characterise the pharmacokinetic (PK)
profile of repeat doses of GSK2982772 in 
healthy subjects.

A 24 hr profile to be collected on Day 1 of 
Part A and Day 14 of Part B. On Day 1 of 
Part B, the PK profile will be evaluated 
following the first dose only. Derived PK 
parameters for GSK2982772, including area 
under the plasma drug concentration versus 
time curve over 24 hr (AUC(0-24)) and AUC 
over each dose interval (i.e. AUC(0-7), AUC(7-
14) and AUC(14-24) for TID and AUC(0-12) and 
AUC(12-24) for BID). Maximum observed 
plasma drug concentration (Cmax) following
each dose, time to maximum observed 
plasma drug concentration (Tmax) following 
each dose, observed trough plasma drug 
concentrations (C0, C7, C14 and C24 for TID
dosing and C0, C12 and C24 for BID dosing).

To assess the impact of food on the PK of 
repeat doses of GSK2982772 in healthy 
subjects at steady state 

Derived PK parameters for GSK2982772, 
including AUC(0-7), AUC(7-14), Cmax, after 1st
dose of day and Tmax after 1st dose of day.

To assess potential effect of repeat doses 
of GSK2982772 on CYP3A4 enzyme 
activity.

Plasma 4β-hydroxycholesterol to 
cholesterol ratio pre-treatment and following 
14 days of repeat dosing of GSK2982772.
Exploratory

To investigate the levels of circulating 
glucuronide metabolite (M8; GSK3562183) 
and desmethyl metabolite (M9; 
GSK2997852) in healthy subjects after 
single-day and repeat dosing of 
GSK2982772.

Quantify M8 (GSK3562183) and M9 
(GSK2997852) in select plasma PK 
samples after single-day dosing and at pre-
dose and 2 hr following Day 14 of repeat 
dosing of GSK2982772.


2017N326600_01
CONFIDENTIAL
205184
37
5.
STUDY DESIGN
5.1.
Overall Design
This is a single-centre, randomized, double-blind (sponsor-unblinded), placebo-controlled 
study to evaluate the safety, tolerability and pharmacokinetics of GSK2982772, in repeat 
oral doses in healthy subjects. The study design schematic is depicted in Figure 1.
Figure 1
Study Design
*With Food Effect Treatment
This study is planned to include approximately 48 subjects and consists of 2 parts:

Part A (Cohort 1) – single ascending dose, randomized, placebo-controlled, 3-way 
crossover.  

Part B (Cohorts 2, 3 and 4) – repeat dose, randomized, placebo-controlled, 
sequential-group.
For TID dosing, GSK2982772 or placebo will be administered using a 7hr, 7hr and 10hr
dosing interval. For BID dosing, GSK2982772 or placebo will be administered using a 
12hr dosing interval. 
The impact of food on the PK of GSK2982772 will be investigated during the 14 Day 
repeat dose phase of the study (Part B) in Cohorts 2 and 3. On Days 1 to 14, subjects will 
fast for 8hr overnight. Breakfast will be served 2hr after dosing on Days 1 through 8, 10, 
Part A - Single-Day Ascending Doses
1 Day
3:1 Randomized 
GSK2982772:Placebo
Part B – Repeat Doses 
14 Days
3:1 Randomized 
GSK2982772:Placebo
Cohort 1
N=12
120 mg TID (1 Day) followed by,
240 mg TID (1 Day) followed by,
360 mg BID (1 Day)
Cohort 2
N=12
120 mg TID
14 Days *
Cohort 3
N=12
240 mg TID
14 Days *
Cohort 4
N=12
360 mg BID
14 Days


2017N326600_01
CONFIDENTIAL
205184
38
12 and 14. A standard breakfast will be served 30 minutes prior to dosing on Day 9, and a 
high fat breakfast will be served 30 minutes prior to dosing on Day 11. 
All of the Cohorts in this study will be double-blind with respect to the subjects, 
investigator and site staff (with the exception of the site pharmacist). The Sponsor, the 
GSK study team, will be unblinded throughout.
5.2.
Number of Participants
Sufficient number of healthy subjects will be enrolled, such that approximately 12 
subjects in each Cohort complete dosing and critical assessments. If subjects prematurely 
discontinue the study, additional replacement subjects may be randomized in order to 
guarantee that sufficient subjects are treated with GSK2982772 at any given dose before 
escalating to the following dose. Subjects that participate in Part A of the study cannot 
participate in Part B.
5.3.
Sentinel Dosing
Sentinel dosing will be employed within each dosing period in Part A of the study. The 
doses in the single-ascending dose portion of the study (Part A) will be staggered such 
that for each of the three treatment periods, on Day 1, two of the 12 subjects will be 
randomized to treatment (one subject will receive GSK2982772 and one subject will 
receive matched-placebo). Assuming 2 subjects are dosed on Day 1 and assuming 
adequate safety in the judgment of the Principal Investigator (e.g., vital signs, ECGs, and 
AEs) through approximately 24 hours after their last dose on Day 1, the remaining 
subjects may be randomized to dosing in that period. The doses in the repeat dose portion 
of the study (Part B) will be staggered such that for each treatment period on Day 1, two 
of the 12 subjects will be randomized to treatment (one subject will receive GSK2982772 
and one subject will receive matched-placebo) and dosed for at least 7 days before the 
rest of the cohort is randomized. If participants prematurely discontinue the study, 
additional replacement participants may be recruited and assigned to the same treatment 
sequence, at the discretion of the Sponsor in consultation with the investigator.
5.4.
Dose Escalation Decisions
The decision to proceed to the next dose level of GSK2982772 within the study will be 
made by a Dose Escalation Committee (DEC) consisting of Principal Investigator, or 
delegate, and other relevant GSK clinical staff (See Section 10.5).
5.5.
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 scheduled procedure shown in the SoA (Section 2).
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA for the last participant in the trial 
globally.


2017N326600_01
CONFIDENTIAL
205184
39
5.6.
Scientific Rationale for Study Design
In Part A, each cohort will initially evaluate the safety, tolerability and PK of 
GSK2982772 administered for 1 day as a TID or BID dosing regimen (Cohort 1). 
In Part B, the 14-day TID or BID repeat dosing (Cohort 2, 3 and 4) was chosen since it 
will provide sufficient safety and tolerability data to bridge to longer duration studies 
with the recently achieved safety margins from the 13-week toxicology study in 
monkeys. In the previous FTiH study (200975), GSK2982772 was administered up to 
120 mg BID for 14 days and was well tolerated with no safety concerns identified. Please 
see GSK2982772 IB [GlaxoSmithKline Document Number 2014N204126_02].
Cohort 4, 360 mg BID dosing regimen, may only be evaluated if the results of a modified 
release (MR) formulation study (205017) being conducted in parallel with the current 
study indicate that a MR formulation is not feasible for GSK2982772. In which case a 
BID regimen using the current immediate release formulation may be taken forward in to
Phase 2a PoC studies. Additionally, Cohort 4 dose may be modified to include the 
repetition of a previous or lower TID or BID dose based on the results of the safety and 
tolerability review or if further characterization of the safety profile at a previously tested
dose is required.     
In the previous FTiH (Study 200975), the impact of a high-fat meal on the absorption of 
GSK2982772 was investigated following single dose administration of GSK2982772 at a 
dose of 40 mg. The rate and extent of absorption was similar in the fed state as compared 
to the fasted state, although there was evidence of a time lag in the absorption in the fed 
state, probably as a result of delayed gastric emptying. It is likely that higher doses to be 
used in this study will have a similar food effect to that observed at 40 mg. Therefore,
this study plans to evaluate the impact of food during the repeat dose phase in Cohorts 2 
and 3 rather than conducting a standalone single dose food effect PK study.
5.7.
Dose Justification
An adaptive dose-escalation approach, guided by the observed safety, tolerability and 
plasma PK exposure will be taken to allow an efficient evaluation of a range of doses 
above the 120 mg BID dose that was evaluated in the FTiH study.    
The initial starting dose planned is 120 mg TID and the maximum daily dose is 
anticipated to be approximately 720 mg administered as 240 mg TID and 360 mg BID.  
For doses of up to 120 mg BID, the pharmacokinetics of GSK2982772 are approximately 
linear. Please see GSK2982772 IB [GlaxoSmithKline Document Number 
2014N204126_02]. After attainment of  Cmax, at approximately 2 hours post-dose, 
GSK2982772 concentrations decline rapidly until about 12 hours post-dose, with a t1/2 of 
approximately 2 to 3 hours. The majority of the systemic exposure to GSK2982772 is 
observed within the first 12 hours after administration. Following repeat dosing of 
GSK2982772, there is no evidence of drug accumulation for either a QD or BID dosing 
regimen. The major circulating metabolite is an N-glucuronide which accounts for 
approximately 70% of drug related material in plasma. Since glucuronidation is a high 


2017N326600_01
CONFIDENTIAL
205184
40
capacity clearance mechanism it is unlikely that the kinetics of GSK2982772 will become 
saturable with more frequent dosing nor at the higher doses planned in the current study.   
Due to the short half-life of GSK2982772 (~2-3 hr), it is expected that steady-state will 
be achieved by Day 2 of dosing and that negligible accumulation will be observed. 
Therefore, the PK safety margins described for Day 1 and for Day 14 of dosing will be 
similar. 
The predicted mean AUC(0-24) for the highest planned doses of 240 mg TID and 360 mg 
BID (40.2 μg*h/mL) approximates parity with the mean AUC(0-24) observed at the 
NOAEL (30 mg/kg/day) in the 13-week monkey toxicology study (48.4 μg*h/ml). Mean 
Cmax values for the 240 mg TID (3.21 μg/mL) and 360 mg BID (4.31 μg/mL) doses are 
predicted to be 1/4th and 1/3rd respectively, of the Cmax observed at the NOAEL (12.3 
μg/mL). The doses for Cohorts 2 and 3 may be adjusted based on PK/safety data from 
previous treatment periods. It is planned that the 95th percentile for the predicted 
AUC(0-24) values will not exceed the maximum AUC(0-24) value observed at the NOAEL
and for Cmax the 95th percentile will not exceed the mean Cmax and the NOAEL. The 
current predicted 5th -95th percentiles for AUC(0-24) and Cmax values using repeat dose PK 
data from FTiH study and mean/individual AUC(0-24) and Cmax values from the 13-week 
Monkey Study at 30 mg/kg/day (NOAEL) and 100 mg/kg/day are shown in Figure 2 and 
Figure 3, respectively.
Figure 2
Mean and 95% Prediction Interval for Human AUC(0-24) Values 
versus Mean and Individual Monkey AUC(0-24) Values at Week 13


2017N326600_01
CONFIDENTIAL
205184
41
Figure 3
Mean and 95% Prediction Interval for Human Cmax values Versus 
Mean and Individual Monkey Cmax values at Week 13


2017N326600_01
CONFIDENTIAL
205184
42
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1.
Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2.
Healthy as determined by the Investigator or medically qualified designee based on a 
medical evaluation including medical history, physical examination, neurological 
examination, laboratory tests and cardiac monitoring.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the Investigator in 
consultation with the Medical Monitor (if required) agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures.
Note: Screened subjects with laboratory values outside of the normal range may be 
repeated once for inclusion into the study at the discretion of the Investigator.
WEIGHT
3.
Body weight 50 kg and body mass index (BMI) within the range 19 - 30 kg/m2
(inclusive).
SEX
4.
Male and/or Female Subjects
a. Male participants:
A male participant with a female partner of reproductive potential must agree to use 
contraception as detailed in Appendix 5 of this clinical study proposal during the 
treatment period and for at least 90 days after the last dose of study treatment and 
refrain from donating sperm during this period.
b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 


2017N326600_01
CONFIDENTIAL
205184
43
not breastfeeding, and at least one of the following conditions applies:
i.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
ii. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
for a minimum of 28 days days prior to the treatment period and for at least 30 
days after the last administration of study drug. A WOCBP using a hormonal 
method of highly effective contraception must also agree to partner use of a 
male condom during the treatment period and for at least 30 days after the last 
administration of study drug.
INFORMED CONSENT
5.
Capable of giving signed informed consent as described in Appendix 3 which
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
MEDICAL CONDITIONS
1.
History or presence of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; 
constituting a risk when taking the study treatment; or interfering with the 
interpretation of data.
2.
History of herpes zoster (shingles) reactivation.
3.
Evidence of active or latent tuberculosis (TB) as documented by medical history and 
examination, chest x-rays (posterior anterior and lateral), and TB testing: either a 
positive tuberculin skin test (TST; defined as a skin induration >5 mm at 48 to 72 
hours, regardless of Bacillus Calmette-Guerin (BCG) or other vaccination history) or 
a positive (not indeterminate) QuantiFERON-TB Gold test.
NOTE: The choice to perform a TST or a QuantiFERON-TB Gold test will be made 
by the investigator according to local licensing and standard of care. The 
QuantiFERON-TB Gold test can only be used in countries where it is licensed, and 
the use of this test is dependent on previous treatment(s). This test may not be 
suitable if previous treatment(s) produced significant immunosuppression.
4.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).
5.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 
6.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)


2017N326600_01
CONFIDENTIAL
205184
44
7.
QTc >450 msec
NOTES:

The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-
read or manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to initiation 
of the study. In other words, several different formulae cannot be used to 
calculate the QTc for an individual subject and then the lowest QTc value used 
to include or discontinue the subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).
8.
History of serious or recurrent infections or has had an active infection within 14 
days of receiving study medication.
9.
History of diagnosis of obstructive sleep apnoea or significant respiratory disorder.  
Childhood asthma that has fully resolved is permitted.
10. Part A: History of active SIB within the past 6 months or any history of attempted 
suicide in a participant’s lifetime.
11. History of current evidence of febrile seizures, epilepsy, convulsions, significant 
head injury, or other significant neurologic conditions.
PRIOR/CONCOMITANT THERAPY
12. Past or intended use of over-the-counter or prescription medication, including herbal 
medications, within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 
half-lives (whichever is the longest) prior to dosing. Specific medications listed in 
Section 7.6 may be allowed.
13. Subject received a vaccine (either live attenuated or now-live) within 30 days prior to 
randomisation, or plans to receive a live attenuated vaccine within 30 days + 5 half-
lives (32 days) of the last dose of study medication.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
14. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within a 56-day period.
15. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
16. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).


2017N326600_01
CONFIDENTIAL
205184
45
DIAGNOSTIC ASSESSMENTS 
17. Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C 
antibody test result at screening.
18. Positive pre-study drug/alcohol screen.
19. Positive human immunodeficiency virus (HIV1 and 2) antibody test.
20. Regular use of known drugs of abuse.
21. Subjects with impaired renal function defined as Chronic Kidney Disease 
Epidemiology Collaboration (CKS-EPI) Creatinine > 1.6mg/dL with an age 
appropriate GFR mL/min/1.73 m2) estimated by the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation [Snyder, 2009 and Levey, 2010].
22. An elevated C-reactive protein (CRP) outside of the normal reference range.
OTHER EXCLUSIONS
23. Regular alcohol consumption within 6 months prior to the study defined as: 

For UK - an average weekly intake of >14 units for males and females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 
mL) of wine or 1 (25 mL) measure of spirits. 
24. Cotinine or carbon monoxide levels indicative of smoking or history or regular use 
of tobacco- or nicotine-containing products within 6 months prior to screening.
25. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study
26. Unwilling or unable to swallow multiple size 00 capsules as part of study 
participation.
PART B SPECIFIC CRITERIA
27. History of SIB as measured using the C-SSRS or a history of attempted suicide.
28. A positive anti-nuclear antibody (ANA) outside of the normal reference range.
29. Fasting total cholesterol 300 mg/dL or triglycerides 250 mg/dL.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice, 
pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days prior to
each first dose of study treatment in Part A up until discharge from the unit. In Part B, 
subjects must refrain from consumption of red wine, Seville oranges, grapefruit or 
grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 
days prior to the first dose of study treatment until after the final dose.


2017N326600_01
CONFIDENTIAL
205184
46
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 
hours before the start of dosing until after collection of the final PK sample.

During each dosing period, participants will abstain from alcohol for 24 hours before 
the start of dosing until after collection of the final PK sample.

Use of tobacco products will not be allowed from 6 months prior to 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 studies (e.g., watching television, reading).

Participants will abstain from travelling to regions of high endemic infection, as 
determined by the investigator, for the duration of the study.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. 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 SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened only on approval of the GSK Medical Monitor. Rescreened 
participants should be assigned the same participation number as for the initial screening.


2017N326600_01
CONFIDENTIAL
205184
47
7.
TREATMENTS
The term study treatment is used throughout the protocol and 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.
7.1.
Treatments Administered
Study Treatment
Product name:
GSK2982772
Placebo
Formulation description
API filled capsule
Placebo blend filled capsule
Dosage form:
HPMC capsule
HPMC capsule
Unite dose strength(s)/Dosage level(s):
120 mg maximum fill per capsule 
NA
Route of administration:
For oral use only
For oral use only
Dosing instructions:
Dose with water
Dose with water
Physical description:
Size 00, white, opaque capsule 
containing white to almost white 
solid
Size 00, white, opaque capsule 
containing white to almost white 
solid
Source of procurement
Study medication is supplied by 
GlaxoSmithKline
Study medication is supplied by 
GlaxoSmithKline
Method for individualizing dosage:
Site to assemble
Site to assemble
7.2.
Method of Treatment Assignment
On Day -1 or Day 1 participants will be assigned a unique number (randomization 
number) in ascending numerical order. The randomization number encodes the 
participant’s assignment to either GSK2982772 or placebo, according to the 
randomization schedule generated prior to the study by the Statistics Department at GSK, 
using validated internal software. 
All participants will be centrally randomized using an Interactive Voice/Web Response 
System (IVRS/IWRS). Before the study is initiated, the telephone number and call-in 
directions for the IVRS and/or the log in information & directions for the IWRS will be 
provided to the site.
Study treatment will be dispensed at the study visits summarized in SoA. Each participant 
will be dispensed blinded study treatment, labelled with his/her unique randomization 
number, throughout the study. Returned study treatment should not be re-dispensed to the 
participants
In all four cohorts, subjects will be randomized in a 3:1 ratio to either GSK2982772 or 
placebo. In Cohort 1, the subjects will be randomized to one of four sequences (ABC, 
ABP, APC, PBC), where the treatments are:
A
120 mg TID
B
240 mg TID


2017N326600_01
CONFIDENTIAL
205184
48
C
360 mg BID
P
Placebo
The planned dose levels are defined in Section 5.1.
The randomisation will reflect the fact that at least 2 of the 12 subjects (one subject will 
receive GSK2928772 and one subject will receive matched-placebo) will be dosed first 
(on Day 1) in each part to enable dose staggering. 
Once a treatment allocation number has been assigned to a subject, it cannot be 
reassigned to any other subject.
7.3.
Blinding
This will be a double blind (sponsor-unblinded) study and the following will apply:

The Investigator or treating physician will remain blinded to each participant’s 
assigned study treatment throughout the course of the study. In order to maintain 
this blind, an otherwise uninvolved 3rd party will be responsible for the 
reconstitution and dispensation of all study treatment and will endeavour to 
ensure that there are no differences in time taken to dispense following 
randomization

This 3rd party will instruct the participant to avoid discussing the taste, dosing 
frequency, or packaging of the study treatment with the investigator

Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) 
will be allowed access to un-blinded study treatment records at the site(s) to 
verify that randomization/dispensing has been done accurately.

The IVRS/IWRS will be programmed with blind-breaking instructions.

In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a participant’s treatment assignment is 
warranted. Participant safety must always be the first consideration in making 
such a determination.

If the investigator decides that unblinding is warranted, the investigator should 
make every effort to contact GSK prior to unblinding a participant’s treatment 
assignment unless this could delay emergency treatment of the participant.

If a participant’s treatment assignment is unblinded, GSK must be notified 
within 24 hours after breaking the blind.

The date and reason that the blind was broken must be recorded in the source 
documentation and Case Report Form (CRF), as applicable.

A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the 
event or condition which led to the unblinding) will be recorded in the CRF.


2017N326600_01
CONFIDENTIAL
205184
49

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of 
the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.
7.4.
Preparation/Handling/Storage/Accountability

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.

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.

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).

Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.5.
Treatment Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

When 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.
7.6.
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:


2017N326600_01
CONFIDENTIAL
205184
50

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. 
Paracetamol at doses of 2 grams/day, is permitted for use any time during the study. 
Other concomitant medication may be considered on a case-by-case basis by the 
Investigator in consultation with the Medical Monitor if required.
7.7.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK, or with GSK2982772, after 
completion of the study because only healthy volunteers are eligible for study 
participation.


2017N326600_01
CONFIDENTIAL
205184
51
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Dose Modification/Stopping Criteria
This protocol allows some alteration from the currently outlined dosing schedule, but the 
maximum total daily dose will not intentionally exceed the 13-week NOAEL exposure in 
monkeys. Currently, the highest planned dose is 720 mg/day of GSK2982772.
The decision to proceed to the next dose level of GSK2982772 in each part of this study 
will be made by the DEC, including the Medical Monitor and the Investigator and 
relevant clinical site staff (see Section 10.5) based on safety, tolerability, and preliminary 
PK data obtained in at least 6 subjects (through at least 24 hours post-dose) with at least 6
subjects having received active treatment (GSK2982772) at the prior dose level.  The 
actual doses to be administered may be adjusted based on safety, tolerability and 
preliminary PK data at previous dose levels; these dose adjustments may involve either 
an increase or a decrease in the planned dose, but will not exceed the PK criteria defined 
in Section 8.1.2.  Planned doses may also be repeated.
The Principal Investigator and the GSK Medical Monitor will review the following and 
dosing will be halted and progression to the next higher dose level stopped if:

One (1) or more subjects experience a SAE which has a reasonable possibility of 
relation to study drug.

Two (2) or more subjects experience a severe or clinically significant non-serious 
AE (based upon investigator judgment) which has a reasonable possibility of relation 
to study drug.

Two (2) or more subjects in a Part A cohort or 3 or more subjects in a Part B cohort 
experience the same AE of moderate severity which has a reasonable possibility of 
relation to study drug.

Consistent Common Terminology Criteria for Adverse Events (CTCAE) Nervous 
System AEs of any grade occur across subjects that have a reasonable possibility of 
relation to study drug.
If dosing is halted and if deemed acceptable by GSK internal safety review to proceed 
with or modify dose escalation to further characterize the safety profile, a formal request 
with appropriate data and substantial amendment will be submitted to MHRA (Medicines 
and Healthcare Products Regulatory Agency) for approval.
8.1.2.
Pharmacokinetic Dose Modification or Stopping Criteria
The 240 mg TID dose and/or the 360 mg BID dose in Cohorts 1, 3 and 4 may be adjusted 
up or down based on PK data from previous treatment periods. It is planned that the 95th
percentile for the predicted AUC(0-24) values will not exceed the maximum AUC(0-24)
value observed at the NOAEL and for Cmax the 95th percentile will not exceed the mean 
Cmax at the NOAEL. 


2017N326600_01
CONFIDENTIAL
205184
52
8.1.3.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when:

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 I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
8.1.4.
QTc Stopping Criteria
A subject that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.  

QTcF > 500 msec,

Change from baseline: QTc > 60 msec

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study (i.e., QTcF in this study).  
This formula may not be changed or substituted once the participant has been 
enrolled.
For example, if a participant is eligible for the protocol based on QTcF, then QTcF
must be used for discontinuation of this individual participant as well.


2017N326600_01
CONFIDENTIAL
205184
53

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs are 
an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period. If an 
ECG demonstrates a prolonged QTc, obtain 2 more ECGs over a brief period (5-10 
minutes), and then use the averaged QTc values of the 3 ECGs to determine whether 
the subject should be discontinued from the study.
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
8.1.5.
Individual Safety Stopping Criteria

If a participant experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is possibly, probably or definitely related to investigational product.

The participant becomes pregnant.

The participant initiates treatment with any prohibited medications.

The participant develops a serious opportunistic or atypical infection.

If any of the liver chemistry stopping criteria (See Section 8.1.3) or QTc stopping 
criteria (see Section 8.1.4) are met.

The participant experiences any signs of suicidal ideation or behaviour (See 
Section 9.3.6).
8.1.6.
Group Safety Stopping Criteria
In addition to the criteria specified above, AEs, SAEs, laboratory abnormalities, ECG 
abnormalities and changes in vital signs occurring across all randomized subjects will be 
regulatory reviewed by the Sponsor Safety Review Team (SRT) in order to ensure 
appropriate subject safety. Any changes to the study due to safety reasons will be 
promptly communicated to the appropriate Regulatory Authorities.
8.1.7.
Nervous System Stopping Criteria
The CNS observations in the 4-week GLP toxicology study in monkeys were found to be 
random, diverse, and unpredictable in monkeys (see Section 3.3.1).  There were no 
similar findings observed in the 13-week GLP toxicology study in monkeys.  The 
CTCAE Nervous System is a monitoring tool which provides the Principal Investigator 
the appropriate guidance for grading of a neurological event.  The significance of any 
neurological event experienced by a subject will be determined based on clinical 
judgment, characteristics of the event and/or based upon changes from a baseline 
assessment.


2017N326600_01
CONFIDENTIAL
205184
54
The Principal Investigator and the GSK Medical Monitor will review all neurological 
events utilizing the CTCAE Nervous System criteria and dosing may be halted if and 
progression to the next higher dose level stopped as per Section 8.1.1.
A subject will be withdrawn from the study if:

A Grade 3 or greater CTCAE Nervous System finding is observed or a significant 
neurologic change from a subject’s baseline physical examination is observed.

Any adverse event included in the CTCAE for Nervous System, which is also 
considered to be clinically significant by the Principal Investigator, will be reviewed 
for potential subject withdrawal.
Note:  Appendix 8 (Section 12.8) provides Guidance for Grading Adverse Events that is 
taken from the CTCAE Version 4.03.
8.1.8.
Rechallenge
8.1.8.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
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. The reason for withdrawal 
should be documented in the CRF.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
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 study discontinuation and 
follow-up and for any further evaluations that need to be completed.
If a subject chooses to withdraw from the study after dosing, then the Investigator must 
make every effort to complete the follow-up assessments detailed in the SoA (Section 2).
8.3.
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:


2017N326600_01
CONFIDENTIAL
205184
55

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 and, if necessary, a certified letter to the participant’s last known 
mailing address 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.


2017N326600_01
CONFIDENTIAL
205184
56
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should 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.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
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 the study treatment (see Section 8). 
9.1.1.
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 subject 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).


2017N326600_01
CONFIDENTIAL
205184
57

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 CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4. 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 4.
9.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.1.3.
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, and non-serious AEs of special 
interest (as defined in Section 3.3.1), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4.
9.1.4.
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 
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, 
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 


2017N326600_01
CONFIDENTIAL
205184
58
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.1.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study treatment and until 30 days 
after the last dose.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.
Treatment of Overdose
GSK does not recommend specific treatment for an overdose. The investigator will use 
clinical judgement to treat an overdose as and when they are made aware of this.
In the event of an overdose, the investigator or treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK2982772 can no longer be detected systemically (at least 2 days for 
GSK2982772).
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.
9.3.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.3.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.
Height (screening only) and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.


2017N326600_01
CONFIDENTIAL
205184
59
9.3.2.
Neurological Exams
Neurological examination will include, at a minimum, assessment of: mental status, gait, 
balance, coordination, cranial nerves, motor power, reflexes, and sensory system (light 
touch and pain). Assessments will be standardized across all scheduled time points (see 
SoA).  Significant changes from the baseline or any clinically significant changes will be 
noted as part of further scheduled examinations or unscheduled examinations (if needed).  
Clinically significant abnormalities or changes in status from baseline will be:

entered as an adverse event,

may trigger increased monitoring of the subject(s),

may result in withdrawal of the subject (see Section 8.2),

may result in referral to a specialist.
9.3.3.
Vital Signs

Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed in a supine position
with a completely automated device. Manual techniques will be used only if an 
automated device is not available.

Blood pressure and pulse measurements should 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 will be measured in a supine position after 5 minutes’ rest and will 
include temperature, systolic and diastolic blood pressure, and pulse and 
respiratory rate.

In Part A and B on Day 1, vital signs (to be taken before blood collection for 
laboratory tests) will consist of 3 pulse and 3 blood pressure measurements pre-
dose on Day 1 (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute). The average of the 3 blood pressure readings will 
be recorded on the CRF.
9.3.4.
Electrocardiograms

Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 2) 
using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. Refer to Section 8.1.4 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession with at least 2 
minutes but no more than 10 minutes apart. 

Continuous cardiac telemetry will be performed at time points indicated in the 
SoA (Section 2).  Full disclosures will be reviewed in detail and the review 
maintained as part of the subject’s source documents.


2017N326600_01
CONFIDENTIAL
205184
60
9.3.5.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 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 relevant 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 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 etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SRM and the SoA.
9.3.6.
Suicidal Risk Monitoring
GSK2982772 is considered to be a CNS-active drug.  There is some concern that some 
CNS-active drugs may be associated with an increased risk of suicidal thinking or 
behaviour when given to some subjects. Although this drug has not been shown to be 
associated with an increased risk of suicidal thinking or behaviour when given to healthy 
volunteers, GSK considers it important to monitor for such events before or during 
clinical studies with compounds such as this.
Participants being treated with GSK2982772 should be monitored appropriately and 
observed closely for suicidal ideation and behaviour or any other unusual changes in 
behaviour. All subjects who experience signs of suicidal ideation or behaviour must 
immediately be discontinued from study medication.
Families and caregivers of participants being treated with GSK2982772 should be alerted 
about the need to monitor participants for the emergence of unusual changes in 
behaviour, as well as the emergence of suicidal ideation and behaviour and to report such 
symptoms immediately to the study investigator.
At screening and baseline (pre-dose Day 1) in Part B only, the Baseline/Screening 
assessment of suicidal ideation and behaviour and treatment emergent suicidal ideation 
and behaviour will be monitored during study 205184 using C-SSRS. At Days 7 and 17 
of the study, the ‘Since Last Visit C-SSRS’ will be completed. Refer to Section 2, SoA,
for more information.
Subjects who answer ‘Yes’ to any suicidal behaviour or ‘Yes’ to suicidal ideation 
Questions 4 or 5 will be referred to their General Practitioner (GP) or appropriate 


2017N326600_01
CONFIDENTIAL
205184
61
psychiatric care. The medical monitor will be notified. If appropriate, an AE or SAE 
should be reported (see Section 9.1). In addition, the investigator should complete a 
Possible Suicidality Related Adverse Event (PSRAE) form to collect detailed information 
on the circumstances of the reported AEs which, in the investigator’s opinion, are 
possibly suicidality-related. These may include, but are not limited to, an event involving 
suicidal ideation, a preparatory act toward imminent suicidal behaviour, a suicide 
attempt, or a completed suicide.
9.4.
Pharmacokinetics
9.4.1.
Blood Sample Collection
Blood will be collected into EDTA tubes and processed to plasma for PK analysis of 
GSK2982772 at the time points indicated in Section 2, SoA Tables. The actual date and 
time (24-hour clock time) of each blood sample collection will be recorded. The timing 
of PK samples may be altered and/or PK samples may be obtained at additional time 
points to ensure thorough PK monitoring.  
Blood will be collected into EDTA tubes and processed to plasma for PK analysis of M8 
(GSK3562183) and M9 (GSK2997852). This will be collected at the time points 
indicated in Section 2, SoA Tables. The actual date and time of each blood sample 
collection will be recorded. 
Blood will be collected into EDTA tubes and processed to plasma for
4β-hydroxycholesterol and cholesterol. This will be collected at the time points indicated 
in Section 2, SoA Tables. The actual date and time of each blood sample collection will 
be recorded. 
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the SRM. 
9.4.2.
Sample Analysis
Plasma analysis will be performed at a bioanalytical site (to be detailed in the SRM) 
under the control of Platform Technology and Science In Vitro/In Vivo Translation (PTS 
IVIVT) and Third Party Resource, GlaxoSmithKline. Concentrations of GSK2982772
will be determined in plasma samples, and concentrations of M8 (GSK3562183) and M9 
(GSK2997852) will be determined in select plasma samples, using the currently approved 
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in 
the SRM).
Once the plasma sample has been analysed for GSK2982772 (or M8 [GSK3562183] and 
M9 [GSK2997852] as indicated above), any remaining plasma sample may be analysed 
for any compound-related material and the results may be reported as part of this study or 
under a separate PTS-IVIVT, GlaxoSmithKline protocol.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.


2017N326600_01
CONFIDENTIAL
205184
62
9.4.3.
Plasma Sample for CYP3A4 Enzyme Activity
Plasma derived from select PK blood samples in Part B (as in the SoA Table), will be 
analyzed for 4β-hydroxycholesterol and cholesterol as a potential in vivo marker of 
CYP3A4 enzyme activity. Samples collected pre-treatment and at steady-state will be 
compared to evaluate this potential marker.
Details on CYP3A4 enzyme activity marker plasma sample collection, processing, 
storage and shipping procedures are provided in the SRM.
Baseline and Day 14, post-treatment plasma samples will be analyzed using a validated, 
specific, and sensitive liquid chromatography–mass spectrometry (LC-MS/MS) method 
to determine concentrations of 4β-hydroxycholesterol and total cholesterol.  A 
comparison will be made between the ratio of 4β-hydroxycholesterol : cholesterol at 
baseline and on Day 14 to assess potential changes in CYP3A4 enzyme activity 
following GSK2982772 treatment.
Analysis will be performed at a bioanalytical site (to be detailed in the SRM) under the 
control of PTS-IVIVT and Third Party Resource, GlaxoSmithKline.
9.5.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.6.
Genetics
A blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 6 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the Study 
Reference Manual.
9.7.
Pharmacological Biomarkers
Pharmacological biomarkers are not evaluated in this study.


2017N326600_01
CONFIDENTIAL
205184
63
10.
STATISTICAL CONSIDERATIONS
The objectives of this study are to assess the safety and tolerability of single and repeat 
ascending doses of GSK2982772. No formal hypotheses will be tested.  
An estimation approach will be used to describe PK of GSK2982772, where point 
estimates and corresponding 90% confidence intervals will be constructed.
10.1.
Sample Size Determination
No statistical techniques were used to calculate the sample size, and sample size is based 
on feasibility.
The primary objective of the study is safety, where the number of safety events are of 
interest.  A maximum of 9 subjects will receive each active dose and; therefore, if 0/9 of 
a particular safety event in the GSK2982772 group is observed, the upper limit of the 
exact 95% CI indicates that a true incidence rate of 33.6% could not be ruled out.  
Whereas if 1/9 of the same safety event in the GSK2982772 group is observed, the upper 
limit of the exact 95% CI indicates that a true incidence rate of 48.2% could not be ruled 
out.
Using a Bayesian approach to determine the confidence interval around an observed 
safety event, we would assume a flat Beta (1,1) prior, and if we were to observe one
safety event in 9 then the posterior distribution would be Beta (2, 9), as outlined below:
Bayesian Approach to Determine Confidence in a Safety Event.
Thus, we can be 95% certain that the true probability of the safety event lies between 
0.04 and 0.39.


2017N326600_01
CONFIDENTIAL
205184
64
Pharmacokinetic Parameters
To date the pharmacokinetics of GSK2982772 have been studied up to 120 mg BID. The 
maximum between-subject coefficient of variation (CVb) for AUC(0-τ) and Cmax observed 
in study 200975 was 27.1 and 36.1 respectively. 
Based on these estimates of variability, slightly more conservative for a cross-over study
and a sample size of 9 completers in Cohort 2, it is estimated that the lower and upper 
bounds of the 90% confidence interval for the means of AUC and Cmax will be within 
approximately 17.9% and 24.2% of the point estimate, respectively.
10.2.
Sample Size Sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint, to 
investigate different safety event rates. If the number of subjects who completed each 
active dose, then the true incidence rates of safety events that could not be ruled out (as 
outlined in Section 10.1 Sample Size Determination) would change.  These changes are 
outlined in Table 1:


2017N326600_01
CONFIDENTIAL
205184
65
Table 1
Safety Events - Sample Size Sensitivity
N Completing 
Cohort
Number of a particular safety event 
observed with GSK2982772
Upper limit of exact 95%CI indicating that a true 
incidence rate of x% could not be ruled out
9
2
60.0%
3
70.0%
4
78.8%
8
0
36.9%
1
52.7%
2
65.1%
3
75.5%
7
0
41.0%
1
57.8%
2
70.9%
3
81.6%
Pharmacokinetic Parameters
A sample size sensitivity analysis has also been conducted on the PK parameters to 
investigate the effect of fewer number of subjects, or 10% difference in the between-
subject coefficient of variation on the precision of the point estimate.  These changes are 
outlined in Table 2:
Table 2
Pharmacokinetic Parameters – Sample Size Sensitivity
Number of Subjects
CVb
Precision (%)
Cmax
6
26.1%
29.8
6
28.8%
33.4
6
31.5%
37.0
9
19.6%
21.7
9
21.7%
24.2
9
23.7%
26.7
AUC(0-tau)
6
19.7%
21.8
6
21.9%
24.5
6
24.0%
27.1
9
14.9%
16.1
9
16.5%
17.9
9
18.1%
19.8


2017N326600_01
CONFIDENTIAL
205184
66
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
PK
The ‘PK Population' is defined as subjects in the ‘Safety’ population 
for whom a PK sample was obtained and analyzed.
10.4.
Statistical Analyses
10.4.1.
Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarised 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Primary
All safety evaluations will be based on the Safety population.  Clinical 
interpretation will be based on the review and displays of adverse events, 
clinical laboratory values, vital sign measurements and 12-lead ECG 
monitoring.
10.4.2.
PK Analyses
Endpoint
Statistical Analysis Methods
Secondary
PK analyses will be described in the RAP. 
The PK of TID and BID dosing on Day 1 in Part A will be evaluated. In 
Part B the comparisons of interest will be:
The PK profile following the 1st dose of the day following administration 
in the fed state (standard meal on Day 9 and high fat meal on Day 11) or in 
the fasted state (Day 14).  
The pharmacokinetic profile following the 1st dose on Day 14 (fasted) and 
the 1st dose on Day 1 (fasted);  
Pharmacokinetic data will be listed and presented in graphical form and 
will be summarized descriptively. 
Statistical summaries of the PK parameter data will be the responsibility of 


2017N326600_01
CONFIDENTIAL
205184
67
Endpoint
Statistical Analysis Methods
Clinical Statistics, GlaxoSmithKline.
Descriptive statistics (n, arithmetic mean, standard deviation, 95% CI, 
minimum, median and maximum,) will be calculated for all 
pharmacokinetic parameters by treatment. In addition, for loge-transformed 
variables geometric mean, 95% confidence interval and %CVb (100 * √ 
(exp(SD2) -1)) will be provided, where the SD is the standard deviation of 
log-transformed data.
10.4.3.
Other Analyses
Descriptive statistics (n, arithmetic mean, standard deviation, 95% CI, minimum, median 
and maximum) of circulating glucuronide metabolite (M8; GSK3562183) and des-methyl 
metabolite will be investigated in healthy subjects after single-day and repeat dosing of 
GSK2982772. 
10.4.4.
Interim Analyses
An interim analysis may be performed during the study on completed cohorts in Part A 
and Part B of the study to aid internal decision making only. There will be no changes to 
the study design or planned number of subjects in future cohorts as a result of the interim 
analysis.
For Parts A and B of the study, interim PK analyses will be performed on plasma 
GSK2982772 concentration-time data generated during the conduct of this study.
The decision to proceed to higher dose strengths will be made by the DEC based on 
assessment of safety, tolerability and pharmacokinetic data at the preceding dose. The 
exception to this will be in Part A where only a safety assessment (not PK) for the 120 
mg TID dose will be performed. To date, the PK of GSK2982772 has been well-
characterised up to 120 mg BID in the FTiH study and the 120 mg TID for Part A 
represents a 50% increase in dose where PK simulations are predictable. This analysis 
can include review of individual subject data, summaries, graphical presentations and/or 
statistical analysis.
The RAP will describe the planned interim analyses in greater detail.
10.5.
Dose Escalation Committee
The decision to proceed to the next dose level of GSK2982772 in each Cohort will be 
made by a DEC consisting of the Principal Investigator (or appropriate designee), 
Medical Monitor, GSK Clinical Investigational lead and/or Study Team Leader, GSK 
Pharmacokineticist, a GSK GCSP representative and GSK Statistician. All GSK 
personnel including the GSK Statistician and the GSK Pharmacokineticist will remain 
unblinded throughout the course of the study. 


2017N326600_01
CONFIDENTIAL
205184
68
For Part A, dose escalation decisions will be based on data obtained from 6 or more 
subjects receiving GSK2982772 at the prior dose level. The review of the data set will 
consist at a minimum of: listings of all AEs, clinical laboratory results, flagged vital 
signs, flagged findings during continuous cardiac monitoring (telemetry), ECG and PK 
results derived from 24-hour plasma profiles.
The decision and selection of dose to proceed to Part B, will be made by the DEC based 
on safety, tolerability, and PK data from the same dose levels evaluated in Part A.  
For Part B, dose escalation decisions will be based on data obtained from 6 or more 
subjects receiving GSK2982772 at the prior dose level. The review of the data set will 
consist at a minimum of: listings of all AEs, clinical laboratory results, flagged vital 
signs, flagged findings during continuous cardiac monitoring (telemetry) and ECG 
findings through Day 16 of the previous cohorts(s) in Part B. Also included will be any 
PK results derived through at least Day 7 of the previous cohort(s).


2017N326600_01
CONFIDENTIAL
205184
69
11.
REFERENCES
Berger SB, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M, et al. Cutting edge: 
RIP1 kinase activity is dispensable for normal development but is a key regulator of 
inflammation in SHARPIN-deficient mice. J Immunol. 2014; 192(12):5476-80.
GlaxoSmithKline Document Number 2014N204126_02. GSK2982772 Investigator’s 
Brochure, Version 3. Effective Date: 27-January-2017.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos. 2009; 37:1779-1784.
Levey AS and Stevens LA. Estimating GFR Using the CKD Epidemiology Collaboration 
(CKD-EPI) Creatinine Equation: More Accurate GFR Estimates, Lower CKD Prevalence 
Estimates and Better Risk Predictions. Am J Kidney Dis. 2010; 55:622-627.
Ofengeim D and Yuan J. Regulation of RIP1 kinase signalling at the crossroads of 
inflammation and cell death. Nat Rev Mol Cell Biol. 2013; 14(11):727-736.
Snyder JJ, Foley RN, and Collins AJ. Prevalence of CKD in the United States: A 
Sensitivity Analysis Using the National Health and Nutrition Examination Survey 
(NHANES) 1999-2004. Am J Kidney Dis. 2009; 53(2):218-228.


2017N326600_01
CONFIDENTIAL
205184
70
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALS
Amyotrophic lateral sclerosis
ALT
Alanine aminotransferase
ANA
Anti-nuclear Antibody
API
Active Pharmaceutical Ingredient
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC(0-7)
Area under the concentration-time curve from time zero to 7 hours 
post first dose (TID dosing)
AUC(7-14)
Area under the concentration-time curve from 7 to 14 hours post 
first dose (TID dosing)
AUC(14-24)
Area under the concentration-time curve from 14 to 24 hours post 
first dose (TID dosing)
AUC(0-12)
Area under the concentration-time curve from 0 to 12 hours post 
first dose (BID dosing)
AUC(12-24)
Area under the concentration-time curve from 12 to 24 hours post 
first dose (BID dosing)
AUC(0-24)
Area under the concentration-time curve from time zero to 24 
hours post first dose
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) 
to last time of quantifiable concentration within a subject across all 
treatments
AUC(0-τ)
AUC from 0 hours to the time of next dosing.
BID
Twice a day
BMI
Body Mass Index
BP
Blood Pressure
CFR
Code of Federal Regulations
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum observed concentration
CNS
Central Nervous System
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CRF
Case Report Form
CRP
C-Reactive Protein
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CVb
Coefficient of Variation
CYP3A4
Cytochrome P450 3A4


2017N326600_01
CONFIDENTIAL
205184
71
DEC
Dose Escalation Committee
ECG
Electrocardiogram
eGFR
Estimated glomerular filtration rate
FSH
Follicle stimulating hormone
FTiH
First Time in Human
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance 
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HPLC
High performance liquid chromatography
HPMC
Hydroxypropylmethyl cellulose
HR
Heart Rate
HRT
Hormonal replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IgG
Immunoglobulin G
IP
Investigational Product
IRB/IEC
The Institutional Review Board/ Independent Ethics Committee
IUD
Intrauterine device
IUS 
Intrauterine hormone-releasing system
kg 
Kilogram
LDH
Lactate dehydrogenase
MCH
Mean corpuscular haemoglobin
MCV
Mean corpuscular volume
mg
Milligram
mL
Millilitre
MR
Modified Release
MS
Multiple Sclerosis
MSDS
Material Safety Data Sheet
NFκB
Nuclear factor kappa-light-chain-enhancer of activated B cells
NOAEL
No observable adverse effect limit
NTI
Narrow Therapeutic Index
Pgp
P-glycoprotein
PGx
Pharmacogenetics
PK
Pharmacokinetics
PoC
Proof of Concept
PsO
Psoriasis
PSRAE
Possible Suicidality Related Adverse Event
QTc
Electrocardiogram QT interval corrected for heart rate
QTcB
Electrocardiogram QT interval corrected for heart rate using 
Bazett’s formula


2017N326600_01
CONFIDENTIAL
205184
72
QTcF
Electrocardiogram QT interval corrected for heart rate using 
Fridericia’s formula
RA
Rheumatoid Arthritis
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RIP1
Receptor-interacting protein-1
SAE
Serious Adverse Event
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SIB
Suicidal Ideation Behaviour
SoA
Schedule of Activities
SOP
Standard Operating Procedure
SRM
Study Reference Manual
SRT
Safety Review Team
SUSAR
Suspected unexpected serious adverse events
TB
Tuberculosis
TID
Three times a day
Tmax
Time taken to maximum observed plasma drug concentration
TNF
Tumour Necrosis Factor
TNFR1
Tumour Necrosis Factor Receptor-1
UC
Ulcerative Colitis
UDP
Uridine diphosphate
μg
Microgram
UGT
Uridine 5’-diphospho-glucuronosyltransferase
UK
United Kingdom
ULN
Upper Limit of Normal
WOCBP
Woman of Child Bearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Quantiferon


2017N326600_01
CONFIDENTIAL
205184
73
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 3 will be performed by the Doctor’s 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 3
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Red Blood Cell (RBC)
Indices:
Mean Corpuscular 
Volume (MCV)
Mean corpuscular 
haemoglobin (MCH)
%Reticulocytes
White Blood Cell (WBC)
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose 
(Fasted)2
Calcium
Alkaline 
phosphatase
Albumin
Anti-nuclear 
antibody [(ANA), 
Part B only]
C-reactive protein 
(CRP)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Alcohol breath test and urine drug screen (to include at minimum: 


2017N326600_01
CONFIDENTIAL
205184
74
Laboratory 
Assessments
Parameters
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)]

Smoking Breath Test 

Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential). To be done at screening and Day 17 of 
Part B.

Urine hCG pregnancy test (as needed for women of child bearing potential)3

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody)

Tuberculosis test

Total Cholesterol, Low-density lipoprotein, triglycerides (Part B only)

Estimated glomerular filtration rate (eGFR) will be calculated using the CKD-
EPI formula.
The results of each test must be entered into the CRF.
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 6 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).
2.
Non-fasted samples can be collected on Day -1 (All Parts) and at the Follow-Up visit (Part A Only).
3.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
Laboratory that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded.


2017N326600_01
CONFIDENTIAL
205184
75
12.3.
Appendix 3: 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 (e.g., 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 Code of Federal Regulations (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 


2017N326600_01
CONFIDENTIAL
205184
76
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 centre. 

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. 

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with Standard Operating 
Procedure (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, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.


2017N326600_01
CONFIDENTIAL
205184
77
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.

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 subjects, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

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.
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 (e.g., 
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. 


2017N326600_01
CONFIDENTIAL
205184
78

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 
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.

A study specific source documentation list will be finalised by the sponsor 
before the start of the clinical phase of the study. The document will identify 
what data should be considered source data for this study.
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


2017N326600_01
CONFIDENTIAL
205184
79
12.4.
Appendix 4: 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 assessmentse.g.eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., 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.
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 


2017N326600_01
CONFIDENTIAL
205184
80
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 (e.g., 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.
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 (e.g., 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 


2017N326600_01
CONFIDENTIAL
205184
81
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.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., 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 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.


2017N326600_01
CONFIDENTIAL
205184
82
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 
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.


2017N326600_01
CONFIDENTIAL
205184
83
Reporting of SAE to GSK
SAE Reporting to GSK via Paper CRF

Email transmission of the SAE paper CRF is the preferred method to transmit this 
information to the medical monitor or the SAE coordinator.

In rare circumstances and in the absence of email equipment, 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 Study Reference Manual.


2017N326600_01
CONFIDENTIAL
205184
84
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrolment.
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 during the treatment phase and 
until at least 90 days after the last administration of study drug: 

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 

Agree to use a male condom and recommend subject or partner use of an 
additional method of contraception with a failure rate of <1% per year as 


2017N326600_01
CONFIDENTIAL
205184
85
described in Table 4 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 

In addition, male participants must refrain from donating sperm for duration of 
study and for 90 days after study completion or from last dose
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 4 for a minimum of 28 days prior to the first dose of study drug and until at least 30 
days after the last administration of study drug. For female particpants using a hormonal 
method of contraception, partner use of male condoms is also required during the 
treatment period and until at least 28 days after the last administration of study drug.
Table 4
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 ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

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 


2017N326600_01
CONFIDENTIAL
205184
86
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. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case the use of a male condom should be utilized during the treatment period 
and for at least 30 days after the last dose of study treatment.
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test 

Additional pregnancy testing at admission to each study period and at the follow-up 
visit.

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.

Pregnancy testing, with a sensitivity of 25 mIU/mL will be performed using the test 
kit approved by the sponsor and in accordance with instructions provided in its 
package insert.
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 
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. 


2017N326600_01
CONFIDENTIAL
205184
87
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

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 Appendix 4. 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 discontinue study 
treatment.


2017N326600_01
CONFIDENTIAL
205184
88
12.6.
Appendix 6: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis.

DNA samples will be used for research related to GSK2982772 or immuno-
inflammatory and related diseases. They may also be used to develop tests/assays 
including diagnostic tests) related to GSK2982772 (or study treatments of this drug 
class) and immuno-inflammatory diseases. Genetic research may consist of the 
analysis of one or more candidate genes or the analysis of genetic markers 
throughout the genome [or analysis of the entire genome] (as appropriate)

DNA samples will be analyzed for UDP-glucuronosyltransferase 1-9 family, 
polypeptide A cluster enzyme that is encoded by the UGT1A9 gene complex.  
Additonal analyses may be conducted if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK2982772 or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK2982772 (or study treatments of 
this class) continues but no longer than 15 years after the last subject last visit or 
other period as per local requirements.


2017N326600_01
CONFIDENTIAL
205184
89
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
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 event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hr

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 24 hours of 
last dose4 

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

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
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 


2017N326600_01
CONFIDENTIAL
205184
90
Liver Chemistry Stopping Criteria 
liver event follow up assessments within 24-
72 hr

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects 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 forms.
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 subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen 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 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
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 subject’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. 


2017N326600_01
CONFIDENTIAL
205184
91
12.8.
Appendix 8:  Nervous System Adverse Events (CTCAE Criteria)
Taken from the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
The purpose of this Appendix is to provide guidance and is to be used in conjunction with the Investigator’s judgment.
Table 5
Guidance For Grading Adverse Events
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Abducens nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the abducens nerve (sixth cranial nerve).
Accessory nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the accessory nerve (eleventh cranial 
nerve).
Acoustic nerve disorder 
NOS
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the acoustic nerve (eighth cranial nerve).
Akathisia
Mild restlessness or 
increased motor activity
Moderate restlessness 
or increased motor 
activity; limiting 
instrumental ADL
Severe restlessness or 
increased motor 
activity; limiting self 
care ADL
-
-
A disorder characterized by an 
uncomfortable feeling of inner restlessness 
and inability to stay still; this is a side effect 
of some psychotropic drugs.
Amnesia
Mild; transient memory 
loss
Moderate; short term 
memory loss; limiting 
instrumental ADL
Severe; long term 
memory loss; limiting 
self care ADL
-
-
A disorder characterized by systematic and 
extensive loss of memory.
Aphonia
-
-
Voicelessness; unable 
to speak
-
-
A disorder characterized by the inability to 
speak. It may result from injuries to the 
vocal cords or may be functional 
(psychogenic).


2017N326600_01
CONFIDENTIAL
205184
92
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Arachnoiditis
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
of the arachnoid membrane and adjacent 
subarachnoid space.
Ataxia
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL; 
mechanical assistance 
indicated
-
-
A disorder characterized by lack of 
coordination of muscle movements 
resulting in the impairment or inability to 
perform voluntary activities.
Brachial plexopathy
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by regional 
paresthesia of the brachial plexus, marked 
discomfort and muscle weakness, and 
limited movement in the arm or hand.
Central nervous system 
necrosis
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
corticosteroids 
indicated
Severe symptoms; 
medical intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by a necrotic 
process occurring in the brain and/or spinal 
cord.
Cerebrospinal fluid 
leakage
Post-craniotomy: 
asymptomatic; Post-
lumbar puncture: 
transient headache; 
postural care indicated
Post-craniotomy: 
moderate symptoms; 
medical intervention 
indicated; Post-lumbar 
puncture: persistent 
moderate symptoms; 
blood patch indicated
Severe symptoms; 
medical intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by loss of 
cerebrospinal fluid into the surrounding 
tissues.
Cognitive disturbance
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; 
specialized educational 
services/devices not 
indicated
Moderate cognitive 
disability; interfering 
with work/school/life 
performance but 
capable of 
independent living; 
specialized resources 
on part time basis 
indicated
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance
-
-
A disorder characterized by a conspicuous 
change in cognitive function.


2017N326600_01
CONFIDENTIAL
205184
93
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Concentration 
impairment
Mild inattention or 
decreased level of 
concentration
Moderate impairment 
in attention or 
decreased level of 
concentration; limiting 
instrumental ADL
Severe impairment in 
attention or decreased 
level of concentration; 
limiting self care ADL
-
-
A disorder characterized by a deterioration 
in the ability to concentrate.
Depressed level of 
consciousness
Decreased level of 
alertness
Sedation; slow 
response to stimuli; 
limiting instrumental 
ADL
Difficult to arouse
Life-threatening 
consequences
Death
A disorder characterized by a decrease in 
ability to perceive and respond.
Dizziness
Mild unsteadiness or 
sensation of movement
Moderate 
unsteadiness or 
sensation of 
movement; limiting
instrumental ADL
Severe unsteadiness 
or sensation of 
movement; limiting self 
care ADL
-
-
A disorder characterized by a disturbing 
sensation of lightheadedness, 
unsteadiness, giddiness, spinning or 
rocking.
Dysarthria
Mild slurred speech
Moderate impairment 
of articulation or 
slurred speech
Severe impairment of 
articulation or slurred 
speech
-
-
A disorder characterized by slow and 
slurred speech resulting from an inability to 
coordinate the muscles used in speech.
Dysesthesia
Mild sensory alteration
Moderate sensory 
alteration; limiting 
instrumental ADL
Severe sensory 
alteration; limiting self 
care ADL
-
-
A disorder characterized by distortion of 
sensory perception, resulting in an 
abnormal and unpleasant sensation.
Dysgeusia
Altered taste but no
change in diet
Altered taste with 
change in diet (e.g., 
oral supplements); 
noxious or unpleasant 
taste; loss of taste
-
-
-
A disorder characterized by abnormal 
sensual experience with the taste of 
foodstuffs; it can be related to a decrease 
in the sense of smell.
Dysphasia
Awareness of receptive 
or expressive 
characteristics; not 
impairing ability to 
communicate
Moderate receptive or 
expressive 
characteristics; 
impairing ability to 
communicate 
spontaneously
Severe receptive or 
expressive 
characteristics; 
impairing ability to 
read, write or 
communicate 
intelligibly
-
-
A disorder characterized by impairment of 
verbal communication skills, often resulting 
from brain damage.


2017N326600_01
CONFIDENTIAL
205184
94
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Edema cerebral
-
-
-
Life-threatening 
consequences; 
urgent 
intervention 
indicated
A disorder characterized by swelling due to 
an excessive accumulation of fluid in the 
brain.
Encephalopathy
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by a pathologic 
process involving the brain.
Extrapyramidal disorder
Mild involuntary 
movements
Moderate involuntary 
movements; limiting 
instrumental ADL
Severe involuntary 
movements or 
torticollis; limiting self 
care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by abnormal, 
repetitive, involuntary muscle movements, 
frenzied speech and extreme restlessness.
Facial muscle weakness
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by a reduction in 
the strength of the facial muscles.
Facial nerve disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the facial nerve (seventh cranial nerve).
Glossopharyngeal nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by involvement of 
the glossopharyngeal nerve (ninth cranial 
nerve).
Headache
Mild pain
Moderate pain; limiting 
instrumental ADL
Severe pain; limiting 
self care ADL
-
-
A disorder characterized by a sensation of 
marked discomfort in various parts of the 
head, not confined to the area of 
distribution of any nerve.


2017N326600_01
CONFIDENTIAL
205184
95
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Hydrocephalus
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
intervention not 
indicated
Severe symptoms or 
neurological deficit; 
intervention indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by an abnormal 
increase of cerebrospinal fluid in the 
ventricles of the brain.
Hypersomnia
Mild increased need for
sleep
Moderate increased 
need for sleep
Severe increased 
need for sleep
-
-
A disorder characterized by characterized 
by excessive sleepiness during the 
daytime.
Hypoglossal nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the hypoglossal nerve (twelfth cranial 
nerve).
Intracranial hemorrhage
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
medical intervention 
indicated
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or 
operative intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by bleeding from 
the cranium.
Ischemia 
cerebrovascular
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms
-
-
-
A disorder characterized by a decrease or 
absence of blood supply to the brain 
caused by obstruction (thrombosis or 
embolism) of an artery resulting in 
neurological damage.
IVth nerve disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the trochlear nerve (fourth cranial nerve).
Lethargy
Mild symptoms; reduced 
alertness and 
awareness
Moderate symptoms; 
limiting instrumental 
ADL
-
-
-
A disorder characterized by a decrease in 
consciousness characterized by mental 
and physical inertness.


2017N326600_01
CONFIDENTIAL
205184
96
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Leukoencephalopathy
Asymptomatic; small 
focal T2/FLAIR 
hyperintensities; 
involving periventricular 
white matter or <1/3 of 
susceptible areas of 
cerebrum mild 
increase in 
subarachnoid space 
(SAS) and/or mild 
ventriculomegaly
Moderate symptoms; 
focal T2/FLAIR 
hyperintensities, 
involving 
periventricular white 
matter extending into 
centrum semiovale or 
involving 1/3 to 2/3 of 
susceptible areas of 
cerebrum moderate 
increase in SAS and/or 
moderate 
ventriculomegaly
Severe symptoms; 
extensive T2/FLAIR 
hyperintensities, 
involving 
periventricular white 
matter involving 2/3 or 
more of susceptible 
areas of cerebrum 
moderate to severe 
increase in SAS and/or 
moderate to severe 
ventriculomegaly
Life-threatening 
consequences; 
extensive 
T2/FLAIR 
hyperintensities, 
involving 
periventricular 
white matter 
involving most of 
susceptible 
areas of 
cerebrum 
moderate to 
severe increase 
in SAS and/or 
moderate to 
severe 
ventriculomegaly
Death
A disorder characterized by diffuse 
reactive astrocytosis with multiple areas of 
necrotic foci without inflammation.
Memory impairment
Mild memory impairment
Moderate memory 
impairment; limiting 
instrumental ADL
Severe memory 
impairment; limiting 
self care ADL
-
-
A disorder characterized by a deterioration 
in memory function.
Meningismus
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by neck stiffness, 
headache, and photophobia resulting from 
irritation of the cerebral meninges.
Movements involuntary
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by uncontrolled 
and purposeless movements.
Myelitis
Asymptomatic; mild 
signs (e.g., Babinski's 
reflex or Lhermitte's 
sign)
Moderate weakness or 
sensory loss; limiting 
instrumental ADL
Severe weakness or 
sensory loss; limiting 
self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
involving the spinal cord. Symptoms 
include weakness, paresthesia, sensory 
loss, marked discomfort and incontinence.


2017N326600_01
CONFIDENTIAL
205184
97
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Neuralgia
Mild pain
Moderate pain; limiting 
instrumental ADL
Severe pain; limiting 
self care ADL
-
-
A disorder characterized by intense painful 
sensation along a nerve or group of 
nerves.
Nystagmus
-
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involuntary 
movements of the eyeballs.
Oculomotor nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the oculomotor nerve (third cranial nerve).
Olfactory nerve disorder
-
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the olfactory nerve (first cranial nerve).
Paresthesia
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by functional 
disturbances of sensory neurons resulting 
in abnormal cutaneous sensations of 
tingling, numbness, pressure, cold, and 
warmth that are experienced in the 
absence of a stimulus.
Peripheral motor 
neuropathy
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL; 
assistive device 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
or degeneration of the peripheral motor 
nerves.
Peripheral sensory 
neuropathy
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
or degeneration of the peripheral sensory 
nerves.
Phantom pain
Mild pain
Moderate pain; limiting 
instrumental ADL
Severe pain; limiting 
self care ADL
-
-
A disorder characterized by marked 
discomfort related to a limb or an organ 
that is removed from or is not physically 
part of the body.


2017N326600_01
CONFIDENTIAL
205184
98
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Presyncope
-
Present (e.g., near 
fainting)
-
-
-
A disorder characterized by an episode of 
lightheadedness and dizziness which may 
precede an episode of syncope.
Pyramidal tract 
syndrome
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by dysfunction of 
the corticospinal (pyramidal) tracts of the 
spinal cord. Symptoms include  an 
increase in the muscle tone in the lower 
extremities, hyperreflexia, positive Babinski 
and a decrease in fine motor coordination.
Radiculitis
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL; medical 
intervention indicated
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
involving a nerve root. Patients experience 
marked discomfort radiating along a nerve 
path because of spinal pressure on the 
connecting nerve root.
Recurrent laryngeal 
nerve palsy
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms
Severe symptoms; 
medical intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection)
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by paralysis of 
the recurrent laryngeal nerve.
Reversible posterior 
leukoencephalopathy 
syndrome
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
abnormal imaging 
studies; limiting 
instrumental ADL
Severe symptoms; 
very abnormal imaging 
studies; limiting self 
care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by headaches, 
mental status changes, visual 
disturbances, and seizures associated with 
imaging findings of posterior 
leukoencephalopathy. It has been 
observed in association with hypertensive 
encephalopathy, eclampsia, and 
immunosuppressive and cytotoxic drug 
treatment. It is an acute or subacute 
reversible condition.
Seizure
Brief partial seizure; no 
loss of consciousness
Brief generalized 
seizure
Multiple seizures 
despite medical 
intervention
Life-threatening; 
prolonged 
repetitive 
seizures
Death
A disorder characterized by a sudden, 
involuntary skeletal muscular contractions 
of cerebral or brain stem origin.
Sinus pain
Mild pain
Moderate pain; limiting 
instrumental ADL
Severe pain; limiting 
self care ADL
-
-
A disorder characterized by marked 
discomfort in the face, between the eyes, 
or upper teeth originating from the sinuses.


2017N326600_01
CONFIDENTIAL
205184
99
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Somnolence
Mild but more than usual 
drowsiness or 
sleepiness
Moderate sedation; 
limiting instrumental 
ADL
Obtundation or stupor
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by characterized 
by excessive sleepiness and drowsiness.
Spasticity
Mild or slight increase in 
muscle tone
Moderate increase in 
muscle tone and 
increase in resistance 
through range of 
motion
Severe increase in 
muscle tone and 
increase in resistance 
through range of 
motion
Life-threatening; 
unable to move 
active or passive 
range of motion
Death
A disorder characterized by increased 
involuntary muscle tone that affects the 
regions interfering with voluntary 
movement. It results in gait, movement, 
and speech disturbances.
Stroke
Asymptomatic or mild 
neurologic deficit; 
radiographic findings 
only
Moderate neurologic 
deficit
Severe neurologic 
deficit
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by a sudden loss 
of sensory function due to an intracranial 
vascular event.
Syncope
-
-
Fainting; orthostatic 
collapse
-
-
A disorder characterized by spontaneous 
loss of consciousness caused by 
insufficient blood supply to the brain.
Transient ischemic 
attacks
Mild neurologic deficit 
with or without imaging 
confirmation
Moderate neurologic 
deficit with or without 
imaging confirmation
-
-
-
A disorder characterized by a brief attack 
(less than 24 hours) of cerebral 
dysfunction of vascular origin, with no 
persistent neurological deficit.
Tremor
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms;
limiting self care ADL
-
-
A disorder characterized by the 
uncontrolled shaking movement of the 
whole body or individual parts.
Trigeminal nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the trigeminal nerve (fifth cranial nerve).
Vagus nerve disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by involvement of 
the vagus nerve (tenth cranial nerve).


2017N326600_01
CONFIDENTIAL
205184
100
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Vasovagal reaction
-
-
Present
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by a sudden drop 
of the blood pressure, bradycardia, and 
peripheral vasodilation that may lead to 
loss of consciousness. It results from an 
increase in the stimulation of the vagus 
nerve.
Nervous system 
disorders - Other, 
specify
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations 
only; intervention not 
indicated
Moderate; minimal, 
local or noninvasive 
intervention indicated; 
limiting age-
appropriate 
instrumental ADL
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
existing hospitalization 
indicated; disabling;  
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
-


2017N326600_01
CONFIDENTIAL
205184
101
12.9.
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).


2017N326600_03
CONFIDENTIAL
GlaxoSmithKline group of companies
205184
1
TITLE PAGE
Protocol Title: A single-centre, randomized, double-blind (sponsor-unblinded), placebo-
controlled study to evaluate the safety, tolerability and pharmacokinetics of GSK2982772 
in repeat oral doses in healthy subjects.
Protocol Number: 205184/ Amendment 02
Short Title: GSK2982772 high dose safety and PK study in healthy volunteers.
Compound Number:
GSK2982772
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
Regulatory Agency Identifying Number(s):  EudraCT 2017-002662-45
Approval Date: 26-Feb-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


2017N326600_03
CONFIDENTIAL
205184
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 02 Republishing
26-Feb-2018
Amendment 02
15-FEB-2018
Amendment 01
07-DEC-2017
Original Protocol
31-JUL-2017
Amendment 02 Republishing 26-Feb-2018
Overall Rationale for the Amendment:
Due to a number of asymptomatic, non-serious and self-limiting cardiac arrhythmias
observed in Cohorts 1 and 2 prompting a temporary dosing hold, the 120 mg TID for 14 
days will be repeated in Cohort 3. The randomization ratio has been changed to 9:5 
(Active:Placebo) in the remaining Cohorts of Part B (Cohorts 3, 4 and 5) to provide a 
more balanced comparison between subjects on active and placebo. Furthermore, 24 hour 
Holter monitoring will now be conducted at the screening visit to better understand the 
background telemetry patterns of each subject prior to the start of dosing.
Two additional PK timepoints will be collected on Day 1 in Cohorts 3 and 4 to enable the 
Cmax to be determined following the second dose of the day.
In addition, further administrative clarifications have been made.


2017N326600_03
CONFIDENTIAL
205184
4
Section # 
and Name
Description of Change
Brief Rationale
1. Protocol 
Synopsis for 
Study 205184
5.1. Overall 
Design
5.2. Number 
of Participants
5.3. Sentinel 
Dosing
5.6. Scientific 
Rationale for 
Study Design
7.2. Method 
of Treatment 
Assignment
10.2. Sample 
Size 
Sensitivity
The Study Design schematic has 
been updated to add Cohort 3 and 
adjust the randomization ratio from 
3:1 to 9:5 in Cohorts 3, 4 and 5.
The Type and Number of 
Participants has been raised to 14 
subjects in each Cohort 3, 4 and 5, 
which has been reflected in the 
Treatment Groups Table.
Figure 1 Study Design has been 
updated to add an additional 
Cohort and adjust the 
randomization ratio from 3:1 to 9:5 
in Cohorts 3, 4 and 5.
The text has been edited to state 
that there will be 12 subjects in 
each Cohort 1 and Cohort 2 and 14 
subjects in each of Cohorts 3, 4
and 5.
The wording has been updated 
such that sentinel dosing will take 
place in all Cohorts, except Cohort 
3.
The additional Cohort (3) has been 
included in the rationale for Part B 
of the study.
The randomization ratio has been 
changed from 3:1 to 9:5 in Cohorts 
3, 4 and 5. No sentinel dosing will 
take place in Cohort 3.
The title for Table 1 has been 
updated to Safety Events - Sample 
Size Sensitivity on Active Dose.
Except for the two sentinel subjects in 
Cohort 2, dosing was not completed in this 
Cohort because of the temporary halt, 
therefore this dose level will be repeated 
under the new Cohort designation of Cohort 
3.
Cohort 3 will not require sentinel dosing 
since this was completed in the original 
dose level (Cohort 2).
The randomization ratio for Cohorts 3, 4
and 5 has changed from 3:1 to 9:5, with the 
overall number of subjects participating in 
each of these Cohorts increasing from 12 to 
14. This will provide a more balanced 
review with the number of subjects on 
active and placebo.
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-5)
9.3.7. Holter 
An additional row has been added
to the SoA to include 24-hour 
Holter monitoring at screening. 
A section has been added to 
include 24-hour Holter monitoring 
24-hour Holter monitoring has been 
included in the screening visit for Cohorts 3, 
4 and 5 to better understand the 
background telemetry patterns of each 
subject prior to the start of study drug.


2017N326600_03
CONFIDENTIAL
205184
5
Section # 
and Name
Description of Change
Brief Rationale
Monitoring
at screening.
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-5)
2 additional PK timepoints have 
been added on Day 1 of the TID 
dose Cohorts, at 9hr and 11hr post-
first dose of the day.
To ensure the Cmaxhas been analysed after 
the second-dose of Day 1 in the TID 
Cohorts.
12.9. 
Appendix 9: 
Protocol 
Amendment 
History
The summary of changes from 
Protocol Amendment 01 have been 
moved from the Protocol 
Amendment Summary of Changes 
Table to Appendix 9.
Update for Protocol Amendment 02.


2017N326600_03
CONFIDENTIAL
205184
6
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SYNOPSIS FOR STUDY 205184........................................................9
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................13
2.1.
Time and Events Table – Part A (Cohort 1) ................................................14
2.2.
Time and Events Table – Part B (Cohorts 2-5) ...........................................17
3.
INTRODUCTION....................................................................................................25
3.1.
Study Rationale ..........................................................................................25
3.2.
Background ................................................................................................25
3.3.
Benefit/Risk Assessment ............................................................................25
3.3.1.
Risk Assessment .........................................................................26
3.3.2.
Benefit Assessment.....................................................................33
3.3.3.
Overall Benefit:Risk Conclusion...................................................33
4.
OBJECTIVES AND ENDPOINTS...........................................................................34
5.
STUDY DESIGN ....................................................................................................35
5.1.
Overall Design ............................................................................................35
5.2.
Number of Participants ...............................................................................36
5.3.
Sentinel Dosing...........................................................................................36
5.4.
Dose Escalation Decisions .........................................................................36
5.5.
Participant and Study Completion...............................................................36
5.6.
Scientific Rationale for Study Design ..........................................................37
5.7.
Dose Justification........................................................................................37
6.
STUDY POPULATION...........................................................................................40
6.1.
Inclusion Criteria.........................................................................................40
6.2.
Exclusion Criteria........................................................................................41
6.3.
Lifestyle Restrictions...................................................................................44
6.3.1.
Meals and Dietary Restrictions ....................................................44
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................45
6.3.3.
Activity .........................................................................................45
6.4.
Screen Failures...........................................................................................45
7.
TREATMENTS.......................................................................................................46
7.1.
Treatments Administered............................................................................46
7.2.
Method of Treatment Assignment ...............................................................46
7.3.
Blinding.......................................................................................................47
7.4.
Preparation/Handling/Storage/Accountability..............................................48
7.5.
Treatment Compliance................................................................................48
7.6.
Concomitant Therapy..................................................................................49
7.7.
Treatment after the End of the Study ..........................................................49
8.
DISCONTINUATION CRITERIA.............................................................................50
8.1.
Discontinuation of Study Treatment ............................................................50


2017N326600_03
CONFIDENTIAL
205184
7
8.1.1.
Dose Modification/Stopping Criteria.............................................50
8.1.2.
Pharmacokinetic Dose Modification or Stopping Criteria..............50
8.1.3.
Liver Chemistry Stopping Criteria ................................................51
8.1.4.
QTc Stopping Criteria ..................................................................51
8.1.5.
Individual Safety Stopping Criteria ...............................................52
8.1.6.
Group Safety Stopping Criteria ....................................................52
8.1.7.
Nervous System Stopping Criteria ...............................................52
8.1.8.
Rechallenge.................................................................................53
8.1.8.1.
Study Treatment Restart or Rechallenge....................53
8.2.
Withdrawal from the Study..........................................................................53
8.3.
Lost to Follow Up........................................................................................53
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................55
9.1.
Adverse Events...........................................................................................55
9.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................55
9.1.2.
Method of Detecting AEs and SAEs.............................................56
9.1.3.
Follow-up of AEs and SAEs.........................................................56
9.1.4.
Regulatory Reporting Requirements for SAEs .............................56
9.1.5.
Pregnancy ...................................................................................57
9.2.
Treatment of Overdose...............................................................................57
9.3.
Safety Assessments ...................................................................................57
9.3.1.
Physical Examinations.................................................................57
9.3.2.
Neurological Exams.....................................................................58
9.3.3.
Vital Signs....................................................................................58
9.3.4.
Electrocardiograms......................................................................58
9.3.5.
Clinical Safety Laboratory Assessments ......................................59
9.3.6.
Suicidal Risk Monitoring...............................................................59
9.3.7.
Holter Monitoring .........................................................................60
9.4.
Pharmacokinetics .......................................................................................60
9.4.1.
Blood Sample Collection..............................................................60
9.4.2.
Sample Analysis ..........................................................................60
9.4.3.
Plasma Sample for CYP3A4 Enzyme Activity ..............................61
9.5.
Pharmacodynamics ....................................................................................61
9.6.
Genetics .....................................................................................................61
9.7.
Pharmacological Biomarkers ......................................................................62
10. STATISTICAL CONSIDERATIONS........................................................................63
10.1.
Sample Size Determination ........................................................................63
10.2.
Sample Size Sensitivity...............................................................................64
10.3.
Populations for Analyses ............................................................................66
10.4.
Statistical Analyses.....................................................................................66
10.4.1.
Safety Analyses...........................................................................66
10.4.2.
PK Analyses ................................................................................66
10.4.3.
Other Analyses ............................................................................67
10.4.4.
Interim Analyses ..........................................................................67
10.5.
Dose Escalation Committee........................................................................67
11. REFERENCES.......................................................................................................69
12. APPENDICES........................................................................................................70
12.1.
Appendix 1: Abbreviations and Trademarks................................................70


2017N326600_03
CONFIDENTIAL
205184
8
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................73
12.3.
Appendix 3: Study Governance Considerations..........................................75
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................79
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................84
12.6.
Appendix 6: Genetics..................................................................................88
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................89
12.8.
Appendix 8: Nervous System Adverse Events (CTCAE Criteria) ................91
12.9.
Appendix 9: Protocol Amendment History.................................................101


2017N326600_03
CONFIDENTIAL
205184
9
1.
PROTOCOL SYNOPSIS FOR STUDY 205184
Protocol Title: A single-centre, randomized, double-blind (sponsor-unblinded), placebo-
controlled study to evaluate the safety, tolerability and pharmacokinetics of GSK2982772 
in repeat oral doses in healthy subjects.
Short Title: GSK2982772 high dose safety and PK study in healthy volunteers.
Rationale: The purpose of this study is to evaluate the safety, tolerability and 
pharmacokinetics (PK) of repeat oral doses of GSK2982772 (TID and BID, if required) 
in healthy subjects. TID dosing will be administered as a 7hr, 7hr, 10hr dosing interval 
and BID as a 12hr dosing interval. 
Objectives and Endpoints:
Objective
Endpoint
Primary

To investigate the safety and tolerability of 
repeat doses of GSK2982772 in healthy 
subjects.

Adverse events.

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature).

Physical examinations.

12-Lead ECG monitoring.
Secondary

To characterise the PK profile of repeat 
doses of GSK2982772 in healthy subjects.

A 24 hr profile to be collected on Day 1 of 
Part A and Day 14 of Part B. On Day 1 of 
Part B, the PK profile will be evaluated 
following the first dose only. Derived PK 
parameters for GSK2982772, including area 
under the plasma drug concentration versus 
time curve over 24 hr (AUC(0-24)) and AUC 
over each dose interval (i.e. AUC(0-7), AUC(7-
14) and AUC(14-24) for TID and AUC(0-12) and 
AUC(12-24) for BID). Maximum observed 
plasma drug concentration (Cmax) following
each dose, time to maximum observed 
plasma drug concentration (Tmax) following 
each dose, observed trough plasma drug 
concentrations (C0, C7, C14 and C24 for TID
dosing and C0, C12 and C24 for BID dosing).

To assess the impact of food on the PK of 
repeat doses of GSK2982772 in healthy 
subjects at steady state

Derived PK parameters for GSK2982772, 
including AUC(0-7), AUC(7-14), Cmax, after 1st
dose of day and Tmax after 1st dose of day.


2017N326600_03
CONFIDENTIAL
205184
10
Objective
Endpoint

To assess potential effect of repeat doses 
of GSK2982772 on CYP3A4 enzyme 
activity.

Plasma 4β-hydroxycholesterol to 
cholesterol ratio pre-treatment and following 
14 days of repeat dosing of GSK2982772.
Exploratory

To investigate the levels of circulating 
glucuronide metabolite (M8; GSK3562183)
and desmethyl metabolite (M9; 
GSK2997852) in healthy subjects after 
single-day and repeat dosing of 
GSK2982772.

Quantify M8 (GSK3562183) and M9 
(GSK2997852) in select plasma PK 
samples after single-day dosing and at pre-
dose and 2 hr following Day 14 of repeat 
dosing of GSK2982772.
Overall Design:
This is a single-centre, randomized, double-blind (sponsor-unblinded), placebo-controlled 
study to evaluate the safety, tolerability and pharmacokinetics of GSK2982772, in repeat 
oral doses in healthy subjects. The study design schematic is depicted in the Figure
below:
Study Design
*With Food Effect Treatment
Part A - Single-Day Ascending Doses
1 Day
3:1 Randomized 
GSK2982772:Placebo
Part B – Repeat Doses 
14 Days
3:1 Randomized 
GSK2982772:Placebo
Cohort 1
N=12
120 mg TID (1 Day) followed by,
240 mg TID (1 Day) followed by,
360 mg BID (1 Day)
Cohort 2
N=12
120 mg TID
14 Days *
Cohort 4
N=14
240 mg TID
14 Days *
Cohort 5
N=14
360 mg BID
14 Days
Cohort 3
N=14
120 mg TID
14 Days *
Part B – Repeat Doses 
14 Days
9:5 Randomized 
GSK2982772:Placebo


2017N326600_03
CONFIDENTIAL
205184
11
Type and Number of Participants:
Healthy volunteer subjects will be enrolled, such that up to approximately 12 subjects (9 
active, 3 placebo) in Cohorts 1 and 2 (up to approximately 24 in total) and 14 subjects (9 
active, 5 placebo) in Cohorts 3, 4 and 5 (up to approximately 42 in total) complete dosing 
and critical assessments. A subject is defined to have completed the study when he/she 
has attended all study visits.
Sentinel dosing will be employed within each Cohort for both Part A and Part B of the 
study, except Cohort 3 since this was completed in the original dose level (Cohort 2). The 
doses in the single-ascending dose portion of the study (Part A) will be staggered such 
that for each of the three treatment periods, on Day 1, two of the 12 subjects will be 
randomized to treatment (one subject will receive GSK2982772 and one subject will 
receive matched-placebo). Assuming 2 subjects are dosed on Day 1 and assuming 
adequate safety in the judgment of the Principal Investigator (e.g., vital signs, ECGs, and 
adverse events) through approximately 24 hours after their last dose on Day 1, the 
remaining subjects may be randomized to dosing in that period. The doses in the repeat 
dose portion of the study (Part B) will be staggered such that for each treatment period on 
Day 1, two of the 12 subjects in Cohort 2 and two of the 14 subjects in Cohorts 4 and 5
will be randomized to treatment (one subject will receive GSK2982772 and one subject 
will receive matched-placebo) and dosed for at least 7 days before the rest of the cohort is 
randomized. Assuming 2 subjects are dosed on Day 1 to 7 and assuming adequate safety 
in the judgment of the Principal Investigator (e.g., vital signs, ECGs, and adverse events) 
through approximately Day 7, the remaining subjects may be randomized to dosing.
If subjects prematurely discontinue the study, additional replacement subjects may be 
randomized in order to guarantee that sufficient subjects are treated with GSK2982772 at 
any given dose before escalating to the following dose. Replacement subjects will be 
assigned to the same treatment sequence (Cohort 1) or treatment (Cohorts 2-4) and start 
from the period to be replaced at the discretion of the Sponsor and in consultation with 
the Principal Investigator.
Treatment Groups and Duration:
The study duration, including screening and follow-up, is not expected to exceed 
13 weeks for Part A and 8 weeks for Part B of the study.


2017N326600_03
CONFIDENTIAL
205184
12
Study Duration – Cohort 1
Screening
Approximately 28 days.
Number of Subjects
One Cohort of 12 subjects (N=12).
Treatment Period
Cohort 1 will comprise of three treatment periods, investigating three dosing regimens. 
Each dose regimen consists of 1 day treatment duration, with subjects in house for 4
nights (through at least 48 hours post-last dose). Subjects will be admitted to the unit 
the day before dosing, will remain in the unit overnight, and will be released following 
completion of the assessments on Day 4 of each treatment period, provided there are 
no safety concerns.
Washout Period 
Will be at least 7 days between dose regimens for an individual subject.
Follow-up
At least 7 days and no greater than 14 days after last study drug administration. If 
warranted, additional follow-up visits may be scheduled.
Study Duration – Cohort 2
Screening
Approximately 28 days.
Number of Subjects
One Cohort of 12 subjects (N=12).
Treatment Period
The treatment duration will be 14 days. Subjects will be admitted to the unit the day 
before dosing, will remain in the unit overnight and will be released following 
completion of the assessments on Day 17, provided there are no safety concerns.
Follow-up
At least 7 days and no greater than 14 days after last study drug administration. If 
warranted, additional follow-up visits may be scheduled.
Study Duration – Cohorts 3, 4 and 5
Screening
Approximately 28 days.
Number of Subjects
Three Cohorts of 14 subjects each (N=42).
Treatment Period
The treatment duration will be 14 days. Subjects will be admitted to the unit the day 
before dosing, will remain in the unit overnight and will be released following 
completion of the assessments on Day 17, provided there are no safety concerns.
Follow-up
At least 7 days and no greater than 14 days after last study drug administration. If 
warranted, additional follow-up visits may be scheduled.


2017N326600_03
CONFIDENTIAL
205184
13
2.
SCHEDULE OF ACTIVITIES (SOA)
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Activities (SoA) tables (Section 2.1 and Section 2.2), are 
essential and required for study conduct.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the Study Reference Manual (SRM). The SRM will provide the site 
personnel with administrative and detailed technical information that does not impact 
subject safety.
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the SoA tables (Section 2.1 and Section 2.2).
The following points must be noted:

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-Lead ECG
2. Vital Signs
3. Blood Draws
Note: The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, or other 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.

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File, which is approved by the relevant GSK 
study team member and then archived in the study sponsor and site study files, 
but this will not constitute a protocol amendment.

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.

The Institutional Review Board/Independent Ethics Committee (IRB/IEC) will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the Informed Consent Form.
A table defining the allowed variance in timings of assessments without being considered 
a protocol deviation will be included in the SRM.


2017N326600_03
CONFIDENTIAL
205184
14
2.1.
Time and Events Table – Part A (Cohort 1)
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up  
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
Outpatient Visit
X
X
Admission to Clinical Unit
X
Inpatient Stay at Clinical Unit
==X==
Discharge from Clinical Unit
X
Following completion of all assessments.
Informed Consent
X
Inclusion and Exclusion Criteria
X
Demography
X
Full Physical Examination
X
Additional exams/screens may be performed, or brief exams made full exams, by the 
Investigator, as deemed necessary (e.g. where safety or laboratory findings indicate). Tests 
will be conducted within site specified standards.
Brief Physical Examination
X
X
X
Height
X
Weight
X
Drug/Alcohol/Smoking Screen
X
X
Tests include alcohol breath test, smoking breath test and urine drug screen.
Medical/Medication/Drug/Alcohol 
History
X
HIV, Hepatitis B and C Screening
X
Tuberculosis Test
X
Conducted at the standard practice of the site.
Serum Pregnancy Test (WOCBP 
only)
X
X
Urine Pregnancy Test (WOCBP 
only)
X
X
Highly effective contraceptive 
method (WOCBP only)
X
X
X
X
X
X
X
Must use method for a minimum of 28 days prior to first dose of study medication until the 
follow-up visit
Contraception with male condoms  
(WOCBP using hormonal 
contraceptive method and male 
subjects with female partners of 
childbearing potential only)
X
X
X
X
X
X


2017N326600_03
CONFIDENTIAL
205184
15
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up  
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
Meals
X
Xa
X
X
X
a On Day 1, subjects will fast 8hr overnight prior to dose 1. A breakfast will be served 
approximately 2hr after dose 1. 
TID dosing: On Day 1, lunch and dinner will be served between 2 to 3hr prior to doses 2 and 
3, respectively. 
BID dosing: On Day 1, lunch will be served approximately 4 to 5hr after dose 1. Dinner will 
be served between 2 to 3hr prior to dose 2. A snack may be consumed approximately 2 to 
3hr after dose 2.
Water is permitted with dosing and at all times. Subjects will receive standardized meals 
scheduled at the same time in each period.
Haem/Chem/Urinalysis Test 
(Include Liver Chemistries)
X
X
X
X
X
X
Non-fasted samples can be collected on Day -1 and Follow-Up Visit.
PK Blood Sampling
X
X
TID Dosing: PK samples to be taken pre-dose on Day 1 and then at the following time points 
post first-dose: 20min, 40min, 1hr, 1hr 30min, 2hr, 3hr, 5hr, 7hr, 7hr 20min, 7hr 40 min, 8hr, 
8hr 30min, 9hr, 10hr, 12hr, 14hr, 14hr 20min, 14hr 40 min, 15hr, 15hr 30min, 16hr, 17hr, 
19hr, 22hr, 24hr.
BID Dosing: PK samples to be taken pre-dose on Day 1 and then at the following time 
points post first-dose: 20min, 40min, 1hr, 1hr 30min, 2hr, 3hr, 4hr, 6hr, 8hr, 10hr, 12hr, 12hr 
20min, 12hr 40min, 13hr, 13hr 30min, 14hr, 15hr, 16hr, 19hr, 22hr, 24hr.
Remaining PK plasma samples from Part A may be analysed for metabolite sampling.
Neuro. Examination
X
X
X
TID Dosing: Neurological examinations to be conducted either on Day -1 or pre-dose Day 1 
and then at the subsequent time points post first-dose on Day 1: 2hr, 9hr, 16hr, 24hr and 
48hr. Then 24 and 48hr after the last dose administered on Day 1.
BID Dosing: Neurological examinations to be conducted either on Day -1 or pre-dose Day 1 
and then at the subsequent time points post first-dose: 2hr, 14hr, 24hr and 48hr. Then 24 
and 48 hr after the last dose administered on Day 1.
Telemetry
X
Continuous at least 24hr post-evening dose. Initiate at least 15 min. prior to dosing.
12-Lead ECG
X
X
T
X
X
Vital signs to include HR, BP, temperature and respiration rate. 
TID Dosing: 12-Lead ECG and Vital Signs to be conducted on Day -1 and pre-dose on Day 


2017N326600_03
CONFIDENTIAL
205184
16
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-Up  
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
Vital Signs
X
X
T
X
X
X
1 and then at the subsequent time points post first-dose: 40min, 2hr, 4hr, 7hr (pre-2nd dose), 
9hr, 14hr (pre-3rd dose), 16hr, 24hr and 48hr. Then 24 and 48hr after the last dose 
administered on Day 1.
BID Dosing: 12-Lead ECG and Vital Signs to be conducted on Day -1 and pre-dose on Day 
1 and then at the subsequent time points post first-dose: 40 min, 2hr, 4hr, pre-2nd dose, 12hr
20 min, 14hr, 24hr and 48 hr. Then 24 and 48hr after the last dose administered on Day 1.
T = Triplicate.
Randomization
X
Randomization can occur on either Day -1 or Day 1.
Study Treatment
Xb
b TID dosing: GSK2982772 or placebo will be administered using a 7hr, 7hr dosing interval.
BID dosing: GSK2982772 or placebo will be administered using a 12hr dosing interval.
Pharmacogenetic Sample (PGx)
X
A PGx blood sample is collected at the Day 1 visit, after the subject has been randomized
and provided informed consent for genetic research. If the sample is not collected at the Day 
1 visit, it can be collected at any time during the study after randomization.
AE Review
=======X======
X
SAE Review
=======X======
X
Concomitant Medication Review
X
=======X======
X


2017N326600_03
CONFIDENTIAL
205184
17
2.2.
Time and Events Table – Part B (Cohorts 2-5)
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Outpatient Visit
X
X
Admission to Clinical 
Unit
X
Inpatient Stay at 
Clinical Unit
================================X===============================
Discharge from 
Clinical Unit
X
Following completion of all 
assessments.
Informed Consent
X
Inclusion and 
Exclusion Criteria
X
Demography
X
Full Physical 
Examination
X
X
Additional exams/screens may be 
performed, or brief exams made full 
exams, by the Investigator, as deemed 
necessary (e.g. where safety or 
laboratory findings indicate). Tests will 
be conducted within site specified 
standards.
Brief Physical 
Examination
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
Drug/Alcohol/Smoking 
Screen
X
X
Tests include alcohol breath test,
smoking breath test and urine drug 
screen.
Medical/Medication/
Drug/Alcohol History
X
HIV, Hepatitis B and 
X


2017N326600_03
CONFIDENTIAL
205184
18
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
C Screening
Tuberculosis Test
X
Anti-Nuclear Antibody
X
X
X
Serum Pregnancy 
Test (WOCBP only)
X
X
Urine Pregnancy Test 
(WOCBP only)
X
X
Highly effective 
contraceptive method 
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Must use method for a minimum of 28 
days prior to first dose of study 
medication until the follow-up visit.
Contraception with 
male condoms  
(WOCBP using 
hormonal 
contraceptive method 
and male subjects 
with female partners 
of childbearing 
potential only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
Xc
May be completed on either Day -1 or 
Day 1, but no later than 1hr prior to 
dosing. To be completed pre-dose on 
Day 7.
c C-SSRS to be conducted on follow-up 
only in the instance that a subject 
withdraws from the study.
Meals
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TID Dosing: On Day 1 through 14 
subjects will fast 8hr overnight. 
Breakfast will be served approximately 


2017N326600_03
CONFIDENTIAL
205184
19
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
2hr after dosing on Days 1-8, 10, 12 
and 13 and 2hr after dosing on Day 14. 
A “standard” and a “high fat” breakfast 
will be served approximately 30 
minutes prior to dosing on Day 9 and 
Day 11, respectively. On all study days, 
lunch and dinner will be served 
between 2 to 3hr prior to dose 2 and 
dose 3, respectively.     
BID Dosing: On Day 1 through 14, 
subjects will fast 8hr overnight prior to 
dose 1. A breakfast will be served 
approximately 2hr after dose 1. Lunch 
will be served approximately 4-5hr after 
dose 1. Dinner will be served between 
2-3hr prior to dose 2. A snack may be 
consumed approximately 2-3hr after 
dose 2.
Water is permitted with dosing and at 
all times. Subjects will receive 
standardized meals scheduled at the 
same time in each period.
Meals will be served as per the site 
schedule on Days -1, 16 and 17.
Haem/Chem/
Urinalysis Test 
(Include Liver 
Chemistries)
X
X
X
X
X
X
X
X
X
Collection on Day 1 no later than 1hr 
prior to dosing. To be drawn pre-dose 
on Days 2, 4, 7 and 10.
Fasting lipid panel
X
X
X
X
X
X
X
X
Collection on Day 1 no later than 1hr 


2017N326600_03
CONFIDENTIAL
205184
20
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
prior to dosing. To be drawn pre-dose 
on Days 2, 4, 7 and 10.
Holter Monitoring (24-
hour)
X
Telemetry
X
X
X
Continuous at least 24 hr post-evening 
dose. Initiate at least 15 min. prior to 
dosing.
PK blood sampling
Xd
Xe
Xe
Xe
Xe
Xe
Xf
Xf
Xg
dOn Day 1, PK samples will be 
collected pre-dose and at the following 
time points post first-dose: 20min, 
40min, 1hr, 1hr 30min, 2hr, 3hr, 5hr,
7hr, 9hr and 11hr.
eOnDays 2,3 4, 5 and 7 pre-dose 
samples only.
f Days 9, and 11: Cohort 2, 3 and 
Cohort 4 PK sampling will be collected 
pre-dose and at the following time 
points post first-dose: 20min, 40min, 
1hr, 1hr 30min, 2hr, 3hr, 5hr, 7hr (prior 
to 2nd dose) 7hr 20min, 7hr 40 min, 8hr, 
8hr 30min, 9hr, 10hr, 12hr. Cohort 5 is 
currently not planned to have PK 
assessment but may be included 
depending on outcome of food effect in 
Cohorts 2, 3 and 4.
g Day 14 sampling for Cohorts 2, 3, 4
and 5 will be over 24hr according to the 
following schedules:
For TID Dosing: PK samples to be 


2017N326600_03
CONFIDENTIAL
205184
21
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
taken pre-dose and then at the 
following time points post first-dose: 
20min, 40min, 1hr, 1hr 30min, 2hr, 3hr, 
5hr, 7hr (pre-2nd dose) 7hr 20min, 7hr 
40 min, 8hr, 8hr 30min, 9hr, 10hr, 12hr, 
14hr (pre 3rd dose), 14hr 20min, 14hr 
40 min, 15hr, 15hr 30min, 16hr, 17hr, 
19hr, 22hr, 24hr.
For BID Dosing: PK samples to be 
taken pre-dose on Day 1 and then at 
the subsequent time points post first-
dose: 20min, 40min, 1hr, 1hr 30min, 
2hr, 3hr, 4hr, 6hr, 8hr, 10hr, 12hr (pre 
2nd dose), 12hr 20min, 12hr 40min, 
13hr, 13hr 30min, 14hr, 15hr, 16hr, 
19hr, 22hr, 24hr.
Metabolite sampling
Xh
hMetabolite sampling will be conducted 
pre-dose and 2hr post first dose on 
Day 14 only.
4β-hydroxycholesterol 
sampling
Xi
Xj
i Sample to be taken pre-dose on Day 1 
in a fasted state.
j Sample to be taken at 24hr post first 
dose on Day 14. Sample should be in a 
fasted state.
Neuro. examination
X
X
X
X
X
TID Dosing: Neurological 
examinations to be conducted either on 
Day-1 or pre-dose Day 1 and then at 
the subsequent time points post first 
dose: 2hr, 9hr, 16hr, 24hr and 48hr. To 


2017N326600_03
CONFIDENTIAL
205184
22
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
be completed pre-dose on Day 7 and 
then 48 hr post-last dose on Day 14.
BID Dosing: Neurological 
examinations to be conducted pre-
dose either on Day-1 or Day 1 and 
then at the subsequent time points post 
first dose: 2hr, 14hr, 24hr and 48hr. To 
be completed pre-dose on Day 7 and 
then 48hr post-last dose on Day 14.
12-Lead ECG
X
X
T
X
X
X
X
X
Vital signs to include HR, BP, 
temperature and respiration rate. 
On Day 1:
TID Dosing: 12-Lead ECG and Vital 
Signs to be conducted on Day-1 and 
pre-dose Day 1 and then at the 
subsequent time points post first-dose: 
40min, 2hr, 4hr, 7hr (pre-2nd dose), 9hr, 
14hr (pre-3rd dose), 16hr, 24hr, 48hr.
Then 24 and 48hr after the first dose 
and last dose administered on Day 14.
BID Dosing: 12-Lead ECG and Vital 
Signs to be conducted pre-dose either 
on Day-1 or Day 1 and then at the 
subsequent time points post first-dose: 
40 min, 2hr, 4hr, 12hr (pre-2nd dose), 
14hr, 24hr, 48hr. Then 24 and 48hr
after the first and last dose 
administered on Day 14.
OnDays 3 to 14, pre-dose samples 
Vital signs
X
X
T
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


2017N326600_03
CONFIDENTIAL
205184
23
Procedure
Screening
(Up to 28 
days before 
Day 1)
Study Period (Days)
Follow-up
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
only.
T = Triplicate.
Randomization
X
Randomization can occur on either Day 
-1 or Day 1.
Study Treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TID dosing: GSK2982772 or placebo 
will be administered using a 7hr, 7hr 
and 10hr dosing interval.
BID dosing: GSK2982772 or placebo 
will be administered using a 12hr 
dosing interval.
Pharmacogenetic 
Sample (PGx)
X
A PGx blood sample is collected at the 
Day 1 visit, after the subject has been 
randomized and provided informed 
consent for genetic research. If the 
sample is not collected on Day 1, it can 
be collected at any time during the 
study after randomization.
AE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

The timing and number of planned study assessments, including safety, pharmacokinetic or other 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. 


2017N326600_03
CONFIDENTIAL
205184
24

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 informed consent form (ICF).


2017N326600_03
CONFIDENTIAL
205184
25
3.
INTRODUCTION
3.1.
Study Rationale
The current study is being conducted to support administration of higher dose levels than 
initially studied in the First Time in Human (FTiH) study - 200975. The dose in the FTiH 
study was capped at 120 mg BID based on exposure margins with the no observable 
adverse effect limit (NOAEL) in the 28-day monkey toxicology study (10 mg/kg/day). 
Subsequently, a 13-week toxicity study in monkeys has completed which increased the 
NOAEL to 30 mg/kg/day which will allow for an approximate 4-fold increase in the 
safety margins, in terms of systemic exposure to GSK2982772. The current study is 
being conducted to explore administration of higher dose levels than achieved in the 
FTiH study to support subsequent Phase 2a Proof of Concept (PoC) studies and Phase 2b 
dose range studies in subjects with psoriasis (PsO), rheumatoid arthritis (RA) and 
ulcerative colitis (UC).
3.2.
Background
GSK2982772 is a first-in-class, highly selective, small molecule inhibitor of receptor-
interacting serine/threonine protein-1 (RIP1) kinase. RIP1 is a member of the receptor-
interacting serine/threonine kinase family containing an amino-terminal kinase domain, 
an intermediate domain and a carboxy-terminal death domain. RIP1 regulates 
inflammatory signalling in response to stimuli such as tumour necrosis factor (TNF) and 
ligands of the Toll-like receptor family in both kinase-dependent and -independent 
manners [Ofengeim, 2013]. Upon binding to its receptor, tumour necrosis factor receptor-
1 (TNFR1), TNFα triggers one of three distinct cellular fates; NFκB activation, apoptosis, 
or the more recently identified programmed necrosis [Ofengeim, 2013]. In addition, 
recent studies have shown that the programmed necrosis signalling complex also 
regulates the induction of certain cytokines. Although RIP1 serves as a key decision 
checkpoint for all three of these pathways, its kinase activity is only requisite for the 
initiation of programmed necrosis and pro-inflammatory cytokine production [Berger, 
2014]. The discovery of this newly defined inflammatory, programmed necrotic pathway 
calls into question the major contributor to human disease downstream of the TNFR1. As 
such, a RIP1 kinase inhibitor represents a novel, selective mechanism for the treatment of 
inflammatory conditions such as Crohn’s Disease, Plaque Psoriasis, and Rheumatoid 
Arthritis through multiple mechanisms, including the blockade of cell death, danger 
associated molecular pattern (DAMP)-driven inflammation and pro-inflammatory 
cytokine production.
3.3.
Benefit/Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2982772 can be found in the Investigator’s Brochure (IB). The following section 
outlines the risk assessment and mitigation strategy for this protocol:


2017N326600_03
CONFIDENTIAL
205184
26
3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Investigational Product (IP) GSK2982772
Central Nervous System (CNS) Effects
Non-Clinical Data:
In the 4-week GLP toxicology study, CNS 
findings were observed in 2/12 monkeys which 
were administered 100 or 300 mg/kg/day. CNS 
findings included uncoordination, irregular gait, 
trembling, hunched appearance and decreased 
activity. The NOAEL for this study was 
determined at 10 mg/kg/day.
In the 13-week GLP toxicology study, there were 
no CNS findings observed in monkeys 
administered 10, 30 or 100 mg/kg/day. The 
NOAEL for this study was determined at 30 
mg/kg/day.
Clinical Data:
A FTiH study with single ascending and multiple 
ascending dose study has been performed in 67 
healthy male volunteers to date (see IB 
[GlaxoSmithKline Document Number 
2014N204126_02]). No drug-associated CNS 
adverse events (AEs) were identified and no 
Serious AEs (SAEs) were reported.
Subject Selection:
Subjects with known history of significant 
neurologic disorders including but not limited to 
progressive multiple sclerosis (MS), Amyotrophic
lateral sclerosis (ALS), Alzheimer’s and dementia 
will be excluded. 
Individuals with potentially increased 
susceptibility for neurologic effects will be 
excluded based on medical history at screening.
Subject Monitoring:
Subjects will be monitored for standard CNS-
related AEs.


2017N326600_03
CONFIDENTIAL
205184
27
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Immunosuppression
The possibility of immunosuppression, including 
an increase in the frequency and/or severity of 
infection, may result from the intended 
pharmacologic effect of GSK2982772. This may 
be enhanced in subjects taking other 
immunomodulating drugs or corticosteroids.
Clinical Data:
In the FTiH study, no SAEs were reported. One 
subject experienced an Adverse Event (AE) 
herpes zoster approximately 27 days after 
receiving his last dose with GSK2982772 or 
placebo. The blinded investigator determined this 
to be potentially drug-related.
Subject Selection:
Subjects with recurrent, chronic or active 
infections will be excluded from the study.
Subjects will be screened for TB, HIV, Hepatitis 
B and C, and excluded from the study if positive.
Investigators are expected to follow local and/or 
national guidelines with respect to vaccinations, 
including against influenza and pneumococcus.
Subject Monitoring:
Subjects will be monitored for signs of infection.
See Individual Safety Stopping Criteria for 
atypical or opportunistic infections (Section 
8.1.5).
Vaccinations
There is a theoretical risk that GSK2982772 
could decrease an individual’s immune response 
to vaccines or allow symptoms to develop 
following vaccination with a live vaccine when 
administered while on therapy.
Subject Selection:
Attenuated or live vaccines should not be 
administered to subjects from 30 days prior to 
the first dose of GSK2982772, during the study 
and for 5 half-lives plus 30 days (total 32 days) 
after GSK2982772 is discontinued.


2017N326600_03
CONFIDENTIAL
205184
28
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
If indicated, non-live vaccines (e.g. inactivated 
influenza vaccines) may be administered while 
receiving GSK2982772 based on a treating 
physician assessment of the benefit: risk (e.g., 
risk of theoretical decreased responsiveness).
Investigators will be expected to have followed 
local and/or national guidelines with respect to 
vaccinations, including against influenza and 
pneumococcus.
Respiratory
Non-clinical data:
In the single-dose Safety Cardiovascular and 
Respiratory Study in monkeys, a decrease in 
minute volume (MV) and respiratory rate was 
observed at all doses (10, 100, and 300 mg/kg).  
These findings were noted to be reversible and 
mild in severity.
In a 14-day repeat dose Safety Respiratory 
Study in monkeys, no respiratory effects on total 
pulmonary ventilation (MV) or respiratory rate 
were observed at doses of 1 or 10 mg/kg/day. 
See IB for GSK2982772 [GlaxoSmithKline 
Document Number 2014N204126_02].
Subject Monitoring:
Subjects should be monitored for standard 
respiratory-related AEs.
Vital signs will be monitored during study visits.


2017N326600_03
CONFIDENTIAL
205184
29
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
Clinical data:
In the FTiH study, repeat doses of GSK2982772 
up to 120 mg BID were administered x 14 days 
in 48 healthy male volunteers. Extensive 
respiratory monitoring with end-tidal CO2 
(ETCO2), oxygen saturation (SpO2) and 
nocturnal respiratory rate monitoring was 
performed.   No SAEs occurred, and no drug-
associated respiratory-related AEs were 
identified.
Suicidality
GSK2982772 is considered to be a CNS-active 
drug based on pre-clinical studies.
Clinical Data:
In the FTiH study, there have been some reports 
of lethargy, abnormal dreams and depressed 
mood. No events of suicidal ideation or 
behaviour or changes in behaviour were 
reported.
Subject Selection:
Subjects with a current history of Suicidal 
Ideation Behaviour (SIB) as measured using the 
Columbia Suicide Severity Rating Scale (C-
SSRS) or a history of attempted suicide will be 
excluded from the study.
Subject Monitoring:
Subjects should be monitored appropriately and 
observed closely for suicidal ideation and 
behaviour or any other unusual changes in 
behaviour.
Baseline and treatment emergent assessment of 


2017N326600_03
CONFIDENTIAL
205184
30
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
suicidality will be conducted by trained site 
personnel using the C-SSRS in all subjects.
Reproductive Toxicity
Non-Clinical Data:
In the rat embryofetal development study, there 
were no maternal or developmental toxicity at 
doses ≤200 mg/kg/day.
In the rabbit embryofetal development study, 
GSK2982772 was administered at doses of 0, 
10, 100, 300 or 600 mg/kg/day on gestation day 
7 to 19. No developmental toxicity was evident at 
doses up to 300 mg/kg/day.
Subject Selection:
Female subjects of childbearing potential will be 
included in this study only if they agree to use 
one of the highly effective methods of 
contraception beginning at least 28 days prior to 
first dose of study drug until 30 days after the last 
administration of study drug. Women using a 
hormonal contraceptive method will also be 
required to have partners use a male condom 
from the first dose of study drug and until the 
follow-up visit to avoid conception until at least 
30 days after the last administration of study 
drug.  
Male subjects with female partners of 
childbearing potential must agree to use male 
condoms to avoid conception for defined periods 
of time before first administration of study drug 
until 90 days after the last administration of study 
drug. It is also recommended that a male subject 
with a female partner of childbearing potential 
employ a highly effective contraceptive method 
throughout this same period of time.
Females of childbearing potential will undergo 


2017N326600_03
CONFIDENTIAL
205184
31
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
serum pregnancy test at screening and then 
urine pregnancy testing at regular intervals 
during the study.
Pregnant and lactating females are not eligible 
for inclusion in the study.
Withdrawal Criteria:
If a female subject should become pregnant 
during the study, study medication should be 
discontinued. The subject will be followed to 
determine the outcome of the pregnancy. Any 
pregnancy complication or elective termination of 
a pregnancy will be reported as an AE or SAE.
Drug Interaction
Non-Clinical Data:
In vitro studies with GSK2982772 assessing 
potential drug-drug interactions with Cytochrome 
P450 3A4 (CYP3A4) substrates and P-
glycoprotein (Pgp) inhibitors were completed. To 
date, formal drug interaction studies in humans 
have not been performed with GSK2982772.
There is a low risk that GSK2982772 could be an 
Subject Selection:
Subjects who are taking concomitant 
medications known to inhibit Pgp or are CYP3A4 
narrow therapeutic index (NTI) substrates will be 
excluded from the study.
Subject Monitoring:
Subjects’ concomitant medication usage will be 


2017N326600_03
CONFIDENTIAL
205184
32
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk 
Mitigation Strategy
inducer of CYP3A4 and therefore may lower 
circulating levels of concomitant medications that 
are metabolised by CYP3A4 when co-
administered with GSK2982772.
GSK2982772 is a Pgp substrate and therefore 
co-administration with concomitant medications 
that are Pgp inhibitors could increase circulating 
levels of GSK2982772.  See Section 4.3.6 of 
GSK2982772 IB [GlaxoSmithKline Document 
Number 2014N204126_02].
reviewed prior to inclusion and monitored 
throughout the study.
Subjects should be monitored throughout the 
study for potential effects of interaction between 
GSK2982772 and other concomitant 
medications.


2017N326600_03
CONFIDENTIAL
205184
33
3.3.2.
Benefit Assessment
The proposed study with GSK2982772 will be conducted in healthy volunteers; no 
medical benefit will be derived by volunteers’ participation. Subjects will indirectly gain 
through their contribution to the process of developing new therapies in an area of unmet 
need.
3.3.3.
Overall Benefit:Risk Conclusion
The known risks associated with GSK2982772 can be appropriately mitigated by the 
careful selection of study participants and the proposed safety monitoring procedures. As 
such, the risk to potential subjects is considered low. Routine safety and tolerability will 
be evaluated from reported AEs, scheduled physical examinations, vital sign 
measurements, cardiac rhythm monitoring, 12-lead ECGs, and clinical laboratory test 
results as well as continued observation by clinical staff.
The study will be conducted in a hospital-based unit or unit with immediate access to 
hospital facilities for the treatment of medical emergencies. The in-house periods as 
detailed in the SoA (Section 2) will allow for continuous medical monitoring for all 
subjects following the first dose in each treatment group. Subjects will only be discharged 
from the unit 48 hours post-dose if the Investigator deems it safe to do so.
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with GSK2982772 are justified by the 
anticipated benefits that may be afforded by the future development of a new therapy in 
an area of unmet need.


2017N326600_03
CONFIDENTIAL
205184
34
4.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary

To investigate the safety and tolerability of 
repeat doses of GSK2982772 in healthy 
subjects.

Adverse events.

Clinical laboratory values (clinical chemistry, 
haematology and urinalysis).

Vital sign measurements (blood pressure, 
heart rate, respiratory rate and body 
temperature).

Physical examinations.

12-Lead ECG monitoring.
Secondary

To characterise the pharmacokinetic (PK)
profile of repeat doses of GSK2982772 in 
healthy subjects.

A 24 hr profile to be collected on Day 1 of 
Part A and Day 14 of Part B. On Day 1 of 
Part B, the PK profile will be evaluated 
following the first dose only. Derived PK 
parameters for GSK2982772, including area 
under the plasma drug concentration versus 
time curve over 24 hr (AUC(0-24)) and AUC 
over each dose interval (i.e. AUC(0-7), AUC(7-
14) and AUC(14-24) for TID and AUC(0-12) and 
AUC(12-24) for BID). Maximum observed 
plasma drug concentration (Cmax) following
each dose, time to maximum observed 
plasma drug concentration (Tmax) following 
each dose, observed trough plasma drug 
concentrations (C0, C7, C14 and C24 for TID
dosing and C0, C12 and C24 for BID dosing).

To assess the impact of food on the PK of 
repeat doses of GSK2982772 in healthy 
subjects at steady state 

Derived PK parameters for GSK2982772, 
including AUC(0-7), AUC(7-14), Cmax, after 1st
dose of day and Tmax after 1st dose of day.

To assess potential effect of repeat doses 
of GSK2982772 on CYP3A4 enzyme 
activity.

Plasma 4β-hydroxycholesterol to 
cholesterol ratio pre-treatment and following 
14 days of repeat dosing of GSK2982772.
Exploratory

To investigate the levels of circulating 
glucuronide metabolite (M8; GSK3562183) 
and desmethyl metabolite (M9; 
GSK2997852) in healthy subjects after 
single-day and repeat dosing of 
GSK2982772.

Quantify M8 (GSK3562183) and M9 
(GSK2997852) in select plasma PK 
samples after single-day dosing and at pre-
dose and 2 hr following Day 14 of repeat 
dosing of GSK2982772.


2017N326600_03
CONFIDENTIAL
205184
35
5.
STUDY DESIGN
5.1.
Overall Design
This is a single-centre, randomized, double-blind (sponsor-unblinded), placebo-controlled 
study to evaluate the safety, tolerability and pharmacokinetics of GSK2982772, in repeat 
oral doses in healthy subjects. The study design schematic is depicted in Figure 1.
Figure 1
Study Design
*With Food Effect Treatment
This study is planned to include approximately 66 subjects and consists of 2 parts:

Part A (Cohort 1) – single ascending dose, randomized, placebo-controlled, 3-way 
crossover.  

Part B (Cohorts 2, 3, 4 and 5) – repeat dose, randomized, placebo-controlled, 
sequential-group.
For TID dosing, GSK2982772 or placebo will be administered using a 7hr, 7hr and 10hr
dosing interval. For BID dosing, GSK2982772 or placebo will be administered using a 
12hr dosing interval. 
The impact of food on the PK of GSK2982772 will be investigated during the 14 Day 
repeat dose phase of the study (Part B) in Cohorts 2, 3 and 4. On Days 1 to 14, subjects 
Part B – Repeat Doses 
14 Days
9:5 Randomized 
GSK2982772:Placebo
Part A - Single-Day Ascending Doses
1 Day
3:1 Randomized 
GSK2982772:Placebo
Part B – Repeat Doses 
14 Days
3:1 Randomized 
GSK2982772:Placebo
Cohort 1
N=12
120 mg TID (1 Day) followed by,
240 mg TID (1 Day) followed by,
360 mg BID (1 Day)
Cohort 2
N=12
120 mg TID
14 Days *
Cohort 4
N=14
240 mg TID
14 Days *
Cohort 5
N=14
360 mg BID
14 Days
Cohort 3
N=14
120 mg TID
14 Days *
Part B – Repeat Doses 
14 Days
9:5 Randomized 
GSK2982772:Placebo


2017N326600_03
CONFIDENTIAL
205184
36
will fast for 8hr overnight. Breakfast will be served 2hr after dosing on Days 1 through 8, 
10, 12 and 14. A standard breakfast will be served 30 minutes prior to dosing on Day 9, 
and a high fat breakfast will be served 30 minutes prior to dosing on Day 11. 
All of the Cohorts in this study will be double-blind with respect to the subjects, 
investigator and site staff (with the exception of the site pharmacist). The Sponsor, the 
GSK study team, will be unblinded throughout.
5.2.
Number of Participants
Sufficient number of healthy subjects will be enrolled, such that approximately 12 
subjects in Cohorts 1 and 2 and 14 subjects in Cohorts 3, 4 and 5 complete dosing and 
critical assessments. If subjects prematurely discontinue the study, additional replacement 
subjects may be randomized in order to guarantee that sufficient subjects are treated with 
GSK2982772 at any given dose before escalating to the following dose. Subjects that 
participate in Part A of the study cannot participate in Part B.
5.3.
Sentinel Dosing
Sentinel dosing will be employed within each dosing period in Part A of the study. The 
doses in the single-ascending dose portion of the study (Part A) will be staggered such 
that for each of the three treatment periods, on Day 1, two of the 12 subjects will be 
randomized to treatment (one subject will receive GSK2982772 and one subject will 
receive matched-placebo). Assuming 2 subjects are dosed on Day 1 and assuming 
adequate safety in the judgment of the Principal Investigator (e.g., vital signs, ECGs, and 
AEs) through approximately 24 hours after their last dose on Day 1, the remaining 
subjects may be randomized to dosing in that period. The doses in the repeat dose portion 
of the study (Part B) will be staggered such that for each treatment period on Day 1, two 
subjects in each Cohort, except Cohort 3 since this was completed in the original dose 
level (Cohort 2), will be randomized to treatment (one subject will receive GSK2982772 
and one subject will receive matched-placebo) and dosed for at least 7 days before the 
rest of the cohort is randomized. If participants prematurely discontinue the study, 
additional replacement participants may be recruited and assigned to the same treatment 
sequence, at the discretion of the Sponsor in consultation with the investigator.
5.4.
Dose Escalation Decisions
The decision to proceed to the next dose level of GSK2982772 within the study will be 
made by a Dose Escalation Committee (DEC) consisting of Principal Investigator, or 
delegate, and other relevant GSK clinical staff (See Section 10.5).
5.5.
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 scheduled procedure shown in the SoA (Section 2).
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA for the last participant in the trial 
globally.


2017N326600_03
CONFIDENTIAL
205184
37
5.6.
Scientific Rationale for Study Design
In Part A, each cohort will initially evaluate the safety, tolerability and PK of 
GSK2982772 administered for 1 day as a TID or BID dosing regimen (Cohort 1). 
In Part B, the 14-day TID or BID repeat dosing (Cohort 2, 3, 4 and 5) was chosen since it 
will provide sufficient safety and tolerability data to bridge to longer duration studies 
with the recently achieved safety margins from the 13-week toxicology study in 
monkeys. In the previous FTiH study (200975), GSK2982772 was administered up to 
120 mg BID for 14 days and was well tolerated with no safety concerns identified. Please 
see GSK2982772 IB [GlaxoSmithKline Document Number 2014N204126_02].
Cohort 5, 360 mg BID dosing regimen, may only be evaluated if the results of a modified 
release (MR) formulation study (205017) being conducted in parallel with the current 
study indicate that a MR formulation is not feasible for GSK2982772. In which case a 
BID regimen using the current immediate release formulation may be taken forward in to
Phase 2a PoC studies. Additionally, Cohort 5 dose may be modified to include the 
repetition of a previous or lower TID or BID dose based on the results of the safety and 
tolerability review or if further characterization of the safety profile at a previously tested
dose is required.     
In the previous FTiH (Study 200975), the impact of a high-fat meal on the absorption of 
GSK2982772 was investigated following single dose administration of GSK2982772 at a 
dose of 40 mg. The rate and extent of absorption was similar in the fed state as compared 
to the fasted state, although there was evidence of a time lag in the absorption in the fed 
state, probably as a result of delayed gastric emptying. It is likely that higher doses to be 
used in this study will have a similar food effect to that observed at 40 mg. Therefore,
this study plans to evaluate the impact of food during the repeat dose phase in Cohorts 2, 
3 and 4 rather than conducting a standalone single dose food effect PK study.
5.7.
Dose Justification
An adaptive dose-escalation approach, guided by the observed safety, tolerability and 
plasma PK exposure will be taken to allow an efficient evaluation of a range of doses 
above the 120 mg BID dose that was evaluated in the FTiH study.    
The initial starting dose planned is 120 mg TID and the maximum daily dose is 
anticipated to be approximately 720 mg administered as 240 mg TID and 360 mg BID.  
For doses of up to 120 mg BID, the pharmacokinetics of GSK2982772 are approximately 
linear. Please see GSK2982772 IB [GlaxoSmithKline Document Number 
2014N204126_02]. After attainment of Cmax, at approximately 2 hours post-dose, 
GSK2982772 concentrations decline rapidly until about 12 hours post-dose, with a t1/2 of 
approximately 2 to 3 hours. The majority of the systemic exposure to GSK2982772 is 
observed within the first 12 hours after administration. Following repeat dosing of 
GSK2982772, there is no evidence of drug accumulation for either a QD or BID dosing 
regimen. The major circulating metabolite is an N-glucuronide which accounts for 
approximately 70% of drug related material in plasma. Since glucuronidation is a high 


2017N326600_03
CONFIDENTIAL
205184
38
capacity clearance mechanism it is unlikely that the kinetics of GSK2982772 will become 
saturable with more frequent dosing nor at the higher doses planned in the current study.   
Due to the short half-life of GSK2982772 (~2-3 hr), it is expected that steady-state will 
be achieved by Day 2 of dosing and that negligible accumulation will be observed. 
Therefore, the PK safety margins described for Day 1 and for Day 14 of dosing will be 
similar. 
The predicted mean AUC(0-24) for the highest planned doses of 240 mg TID and 360 mg 
BID (40.2 μg*h/mL) approximates parity with the mean AUC(0-24) observed at the 
NOAEL (30 mg/kg/day) in the 13-week monkey toxicology study (48.4 μg*h/ml). Mean 
Cmax values for the 240 mg TID (3.21 μg/mL) and 360 mg BID (4.31 μg/mL) doses are 
predicted to be 1/4th and 1/3rd respectively, of the Cmax observed at the NOAEL (12.3 
μg/mL). The doses for Cohorts 2, 3, 4 and 5 may be adjusted based on PK/safety data 
from previous treatment periods. It is planned that the 95th percentile for the predicted 
AUC(0-24) values will not exceed the maximum AUC(0-24) value observed at the NOAEL
and for Cmax the 95th percentile will not exceed the mean Cmax and the NOAEL. The 
current predicted 5th -95th percentiles for AUC(0-24) and Cmax values using repeat dose PK 
data from FTiH study and mean/individual AUC(0-24) and Cmax values from the 13-week 
Monkey Study at 30 mg/kg/day (NOAEL) and 100 mg/kg/day are shown in Figure 2 and 
Figure 3, respectively.
Figure 2
Mean and 95% Prediction Interval for Human AUC(0-24) Values 
versus Mean and Individual Monkey AUC(0-24) Values at Week 13


2017N326600_03
CONFIDENTIAL
205184
39
Figure 3
Mean and 95% Prediction Interval for Human Cmax values Versus 
Mean and Individual Monkey Cmax values at Week 13


2017N326600_03
CONFIDENTIAL
205184
40
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1.
Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent.
TYPE OF PARTICIPANT AND DISEASE CHARACTERISTICS
2.
Healthy as determined by the Investigator or medically qualified designee based on a 
medical evaluation including medical history, physical examination, neurological 
examination, laboratory tests and cardiac monitoring.
A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range 
for the population being studied may be included only if the Investigator in 
consultation with the Medical Monitor (if required) agree and document that the 
finding is unlikely to introduce additional risk factors and will not interfere with the 
study procedures.
Note: Screened subjects with laboratory values outside of the normal range may be 
repeated once for inclusion into the study at the discretion of the Investigator.
WEIGHT
3.
Body weight 50 kg and body mass index (BMI) within the range 19 - 30 kg/m2
(inclusive).
SEX
4.
Male and/or Female Subjects
a. Male participants:
A male participant with a female partner of reproductive potential must agree to use 
contraception as detailed in Appendix 5 of this clinical study protocol during the 
treatment period and for at least 90 days after the last dose of study treatment and 
refrain from donating sperm during this period.
b. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 


2017N326600_03
CONFIDENTIAL
205184
41
SEX
not breastfeeding, and at least one of the following conditions applies:
i.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
ii. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5
for a minimum of 28 days days prior to the treatment period and for at least 30 
days after the last administration of study drug. A WOCBP using a hormonal 
method of highly effective contraception must also agree to partner use of a 
male condom during the treatment period and for at least 30 days after the last 
administration of study drug.
INFORMED CONSENT
5.
Capable of giving signed informed consent as described in Appendix 3 which
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
MEDICAL CONDITIONS
1.
History or presence of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable of 
significantly altering the absorption, metabolism, or elimination of drugs; 
constituting a risk when taking the study treatment; or interfering with the 
interpretation of data.
2.
History of herpes zoster (shingles) reactivation.
3.
Evidence of active or latent tuberculosis (TB) as documented by medical history and 
examination, chest x-rays (posterior anterior and lateral), and TB testing: either a 
positive tuberculin skin test (TST; defined as a skin induration >5 mm at 48 to 72 
hours, regardless of Bacillus Calmette-Guerin (BCG) or other vaccination history) or 
a positive (not indeterminate) QuantiFERON-TB Gold test.
NOTE: The choice to perform a TST or a QuantiFERON-TB Gold test will be made 
by the investigator according to local licensing and standard of care. The 
QuantiFERON-TB Gold test can only be used in countries where it is licensed, and 
the use of this test is dependent on previous treatment(s). This test may not be 
suitable if previous treatment(s) produced significant immunosuppression.
4.
Alanine transaminase (ALT) >1.5x upper limit of normal (ULN).
5.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 


2017N326600_03
CONFIDENTIAL
205184
42
MEDICAL CONDITIONS
6.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
7.
QTc >450 msec
NOTES:

The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-
read or manually over-read.

The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to initiation 
of the study. In other words, several different formulae cannot be used to 
calculate the QTc for an individual subject and then the lowest QTc value used 
to include or discontinue the subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).
8.
History of serious or recurrent infections or has had an active infection within 14 
days of receiving study medication.
9.
History of diagnosis of obstructive sleep apnoea or significant respiratory disorder.  
Childhood asthma that has fully resolved is permitted.
10. Part A: History of active SIB within the past 6 months or any history of attempted 
suicide in a participant’s lifetime.
11. History of current evidence of febrile seizures, epilepsy, convulsions, significant 
head injury, or other significant neurologic conditions.
PRIOR/CONCOMITANT THERAPY
12. Past or intended use of over-the-counter or prescription medication, including herbal 
medications, within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 
half-lives (whichever is the longest) prior to dosing. Specific medications listed in 
Section 7.6 may be allowed.
13. Subject received a vaccine (either live attenuated or now-live) within 30 days prior to 
randomization, or plans to receive a live attenuated vaccine within 30 days + 5 half-
lives (32 days) of the last dose of study medication.
PRIOR/CONCURRENT CLINICAL STUDY EXPERIENCE
14. Participation in the study would result in loss of blood or blood products in excess of 
500 mL within a 56-day period.
15. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day.
16. The subject has participated in a clinical trial and has received an investigational 


2017N326600_03
CONFIDENTIAL
205184
43
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).


2017N326600_03
CONFIDENTIAL
205184
44
DIAGNOSTIC ASSESSMENTS 
17. Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C 
antibody test result at screening.
18. Positive pre-study drug/alcohol screen.
19. Positive human immunodeficiency virus (HIV1 and 2) antibody test.
20. Regular use of known drugs of abuse.
21. Subjects with impaired renal function defined as Chronic Kidney Disease 
Epidemiology Collaboration (CKS-EPI) Creatinine > 1.6mg/dL with an age 
appropriate GFR mL/min/1.73 m2) estimated by the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation [Snyder, 2009 and Levey, 2010].
22. An elevated C-reactive protein (CRP) outside of the normal reference range.
OTHER EXCLUSIONS
23. Regular alcohol consumption within 6 months prior to the study defined as: 

For UK - an average weekly intake of >14 units for males and females.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 
mL) of wine or 1 (25 mL) measure of spirits. 
24. Cotinine or carbon monoxide levels indicative of smoking or history or regular use 
of tobacco- or nicotine-containing products within 6 months prior to screening.
25. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or medical monitor, contraindicates 
participation in the study
26. Unwilling or unable to swallow multiple size 00 capsules as part of study 
participation.
PART B SPECIFIC CRITERIA
27. History of SIB as measured using the C-SSRS or a history of attempted suicide.
28. A positive anti-nuclear antibody (ANA) outside of the normal reference range.
29. Fasting total cholesterol 300 mg/dL or triglycerides 250 mg/dL.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice, 
pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days prior to
each first dose of study treatment in Part A up until discharge from the unit. In Part B, 
subjects must refrain from consumption of red wine, Seville oranges, grapefruit or 
grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 
days prior to the first dose of study treatment until after the final dose.


2017N326600_03
CONFIDENTIAL
205184
45
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing period, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 
hours before the start of dosing until after collection of the final PK sample.

During each dosing period, participants will abstain from alcohol for 24 hours before 
the start of dosing until after collection of the final PK sample.

Use of tobacco products will not be allowed from 6 months prior to 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 studies (e.g., watching television, reading).

Participants will abstain from travelling to regions of high endemic infection, as 
determined by the investigator, for the duration of the study.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. 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 SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened only on approval of the GSK Medical Monitor. Rescreened 
participants should be assigned the same participation number as for the initial screening.


2017N326600_03
CONFIDENTIAL
205184
46
7.
TREATMENTS
The term study treatment is used throughout the protocol and 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.
7.1.
Treatments Administered
Study Treatment
Product name:
GSK2982772
Placebo
Formulation description
API filled capsule
Placebo blend filled capsule
Dosage form:
HPMC capsule
HPMC capsule
Unite dose strength(s)/Dosage level(s):
120 mg maximum fill per capsule 
NA
Route of administration:
For oral use only
For oral use only
Dosing instructions:
Dose with water
Dose with water
Physical description:
Size 00, white, opaque capsule 
containing white to almost white 
solid
Size 00, white, opaque capsule 
containing white to almost white 
solid
Source of procurement
Study medication is supplied by 
GlaxoSmithKline
Study medication is supplied by 
GlaxoSmithKline
Method for individualizing dosage:
Site to assemble
Site to assemble
7.2.
Method of Treatment Assignment
On Day -1 or Day 1 participants will be assigned a unique number (randomization 
number) in ascending numerical order. The randomization number encodes the 
participant’s assignment to either GSK2982772 or placebo, according to the 
randomization schedule generated prior to the study by the Statistics Department at GSK, 
using validated internal software. 
All participants will be centrally randomized using an Interactive Voice/Web Response 
System (IVRS/IWRS). Before the study is initiated, the telephone number and call-in 
directions for the IVRS and/or the log in information & directions for the IWRS will be 
provided to the site.
Study treatment will be dispensed at the study visits summarized in SoA. Each participant 
will be dispensed blinded study treatment, labelled with his/her unique randomization 
number, throughout the study. Returned study treatment should not be re-dispensed to the 
participants
In Cohorts 1 and 2, subjects will be randomized in a 3:1 ratio to either GSK2982772 or 
placebo. In Cohorts 3, 4 and 5, subjects will be randomized in a 9:5 ratio to either
GSK2982772 or placebo. In Cohort 1, the subjects will be randomized to one of four
sequences (ABC, ABP, APC, PBC), where the treatments are:


2017N326600_03
CONFIDENTIAL
205184
47
A
120 mg TID
B
240 mg TID
C
360 mg BID
P
Placebo
The planned dose levels are defined in Section 5.1.
The randomization will reflect the fact that at least 2 of the 12 subjects in Cohorts 1 and 2 
and at least 2 of the 14 subjects in Cohort 4 and 5 (one subject will receive GSK2928772 
and one subject will receive matched-placebo) will be dosed first (on Day 1) in each part 
to enable dose staggering.
Once a treatment allocation number has been assigned to a subject, it cannot be 
reassigned to any other subject.
7.3.
Blinding
This will be a double blind (sponsor-unblinded) study and the following will apply:

The Investigator or treating physician will remain blinded to each participant’s 
assigned study treatment throughout the course of the study. In order to maintain 
this blind, an otherwise uninvolved 3rd party will be responsible for the 
reconstitution and dispensation of all study treatment and will endeavour to 
ensure that there are no differences in time taken to dispense following 
randomization

This 3rd party will instruct the participant to avoid discussing the taste, dosing 
frequency, or packaging of the study treatment with the investigator

Unblinded monitors and in the event of a Quality Assurance audit, the auditor(s) 
will be allowed access to un-blinded study treatment records at the site(s) to 
verify that randomization/dispensing has been done accurately.

The IVRS/IWRS will be programmed with blind-breaking instructions.

In case of an emergency, the investigator has the sole responsibility for 
determining if unblinding of a participant’s treatment assignment is 
warranted. Participant safety must always be the first consideration in making 
such a determination.

If the investigator decides that unblinding is warranted, the investigator should 
make every effort to contact GSK prior to unblinding a participant’s treatment 
assignment unless this could delay emergency treatment of the participant.

If a participant’s treatment assignment is unblinded, GSK must be notified 
within 24 hours after breaking the blind.

The date and reason that the blind was broken must be recorded in the source 
documentation and Case Report Form (CRF), as applicable.


2017N326600_03
CONFIDENTIAL
205184
48

A subject will be withdrawn if the subject’s treatment code is unblinded by the 
investigator or treating physician. The primary reason for discontinuation (the 
event or condition which led to the unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind 
the treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of 
the report, identifying the subject’s treatment assignment, may be sent to 
investigators in accordance with local regulations and/or GSK policy.
7.4.
Preparation/Handling/Storage/Accountability

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.

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.

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).

Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.5.
Treatment Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site staff. 

When 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.


2017N326600_03
CONFIDENTIAL
205184
49
7.6.
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. 
Paracetamol at doses of 2 grams/day, is permitted for use any time during the study. 
Other concomitant medication may be considered on a case-by-case basis by the 
Investigator in consultation with the Medical Monitor if required.
7.7.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK, or with GSK2982772, after 
completion of the study because only healthy volunteers are eligible for study 
participation.


2017N326600_03
CONFIDENTIAL
205184
50
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Dose Modification/Stopping Criteria
This protocol allows some alteration from the currently outlined dosing schedule, but the 
maximum total daily dose will not intentionally exceed the 13-week NOAEL exposure in 
monkeys. Currently, the highest planned dose is 720 mg/day of GSK2982772.
The decision to proceed to the next dose level of GSK2982772 in each part of this study 
will be made by the DEC, including the Medical Monitor and the Investigator and 
relevant clinical site staff (see Section 10.5) based on safety, tolerability, and preliminary 
PK data obtained in at least 6 subjects (through at least 24 hours post-dose) with at least 6
subjects having received active treatment (GSK2982772) at the prior dose level.  The 
actual doses to be administered may be adjusted based on safety, tolerability and 
preliminary PK data at previous dose levels; these dose adjustments may involve either 
an increase or a decrease in the planned dose, but will not exceed the PK criteria defined 
in Section 8.1.2. Planned doses may also be repeated.
The Principal Investigator and the GSK Medical Monitor will review the following and 
dosing will be halted and progression to the next higher dose level stopped if:

One (1) or more subjects experience a SAE which has a reasonable possibility of 
relation to study drug.

Two (2) or more subjects experience a severe or clinically significant non-serious 
AE (based upon investigator judgment) which has a reasonable possibility of relation 
to study drug.

Two (2) or more subjects in a Part A cohort or 3 or more subjects in a Part B cohort 
experience the same AE of moderate severity which has a reasonable possibility of 
relation to study drug.

Consistent Common Terminology Criteria for Adverse Events (CTCAE) Nervous 
System AEs of any grade occur across subjects that have a reasonable possibility of 
relation to study drug.
If dosing is halted and if deemed acceptable by GSK internal safety review to proceed 
with or modify dose escalation to further characterize the safety profile, a formal request 
with appropriate data and substantial amendment will be submitted to MHRA (Medicines 
and Healthcare Products Regulatory Agency) for approval.
8.1.2.
Pharmacokinetic Dose Modification or Stopping Criteria
The 240 mg TID dose and/or the 360 mg BID dose in Cohorts 1, 4 and 5 may be adjusted 
up or down based on PK data from previous treatment periods. It is planned that the 95th
percentile for the predicted AUC(0-24) values will not exceed the maximum AUC(0-24)
value observed at the NOAEL and for Cmax the 95th percentile will not exceed the mean 
Cmax at the NOAEL.


2017N326600_03
CONFIDENTIAL
205184
51
8.1.3.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when:

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 I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 7.
8.1.4.
QTc Stopping Criteria
A subject that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment.  

QTcF > 500 msec,

Change from baseline: QTc > 60 msec

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study (i.e., QTcF in this study).  
This formula may not be changed or substituted once the participant has been 
enrolled.
For example, if a participant is eligible for the protocol based on QTcF, then QTcF
must be used for discontinuation of this individual participant as well.


2017N326600_03
CONFIDENTIAL
205184
52

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs are 
an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period. If an 
ECG demonstrates a prolonged QTc, obtain 2 more ECGs over a brief period (5-10 
minutes), and then use the averaged QTc values of the 3 ECGs to determine whether 
the subject should be discontinued from the study.
See the SoA for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
8.1.5.
Individual Safety Stopping Criteria

If a participant experiences a serious or severe clinically significant AE that in the 
clinical judgement of the Investigator, after consultation with the medical monitor, 
is possibly, probably or definitely related to investigational product.

The participant becomes pregnant.

The participant initiates treatment with any prohibited medications.

The participant develops a serious opportunistic or atypical infection.

If any of the liver chemistry stopping criteria (See Section 8.1.3) or QTc stopping 
criteria (see Section 8.1.4) are met.

The participant experiences any signs of suicidal ideation or behaviour (See 
Section 9.3.6).
8.1.6.
Group Safety Stopping Criteria
In addition to the criteria specified above, AEs, SAEs, laboratory abnormalities, ECG 
abnormalities and changes in vital signs occurring across all randomized subjects will be 
regulatory reviewed by the Sponsor Safety Review Team (SRT) in order to ensure 
appropriate subject safety. Any changes to the study due to safety reasons will be 
promptly communicated to the appropriate Regulatory Authorities.
8.1.7.
Nervous System Stopping Criteria
The CNS observations in the 4-week GLP toxicology study in monkeys were found to be 
random, diverse, and unpredictable in monkeys (see Section 3.3.1).  There were no 
similar findings observed in the 13-week GLP toxicology study in monkeys.  The 
CTCAE Nervous System is a monitoring tool which provides the Principal Investigator 
the appropriate guidance for grading of a neurological event.  The significance of any 
neurological event experienced by a subject will be determined based on clinical 
judgment, characteristics of the event and/or based upon changes from a baseline 
assessment.


2017N326600_03
CONFIDENTIAL
205184
53
The Principal Investigator and the GSK Medical Monitor will review all neurological 
events utilizing the CTCAE Nervous System criteria and dosing may be halted if and 
progression to the next higher dose level stopped as per Section 8.1.1.
A subject will be withdrawn from the study if:

A Grade 3 or greater CTCAE Nervous System finding is observed or a significant 
neurologic change from a subject’s baseline physical examination is observed.

Any adverse event included in the CTCAE for Nervous System, which is also 
considered to be clinically significant by the Principal Investigator, will be reviewed 
for potential subject withdrawal.
Note:  Appendix 8 (Section 12.8) provides Guidance for Grading Adverse Events that is 
taken from the CTCAE Version 4.03.
8.1.8.
Rechallenge
8.1.8.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
8.2.
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. The reason for withdrawal 
should be documented in the CRF.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
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 study discontinuation and 
follow-up and for any further evaluations that need to be completed.
If a subject chooses to withdraw from the study after dosing, then the Investigator must 
make every effort to complete the follow-up assessments detailed in the SoA (Section 2).
8.3.
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:


2017N326600_03
CONFIDENTIAL
205184
54

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 and, if necessary, a certified letter to the participant’s last known 
mailing address 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.


2017N326600_03
CONFIDENTIAL
205184
55
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should 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.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
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 the study treatment (see Section 8). 
9.1.1.
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 subject 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).


2017N326600_03
CONFIDENTIAL
205184
56

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 CRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4. 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 4.
9.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.1.3.
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, and non-serious AEs of special 
interest (as defined in Section 3.3.1), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4.
9.1.4.
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 
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, 
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 


2017N326600_03
CONFIDENTIAL
205184
57
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.1.5.
Pregnancy

Details of all pregnancies in female participants and, if indicated, female partners of 
male participants will be collected after the start of study treatment and until 30 days 
after the last dose.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.
Treatment of Overdose
GSK does not recommend specific treatment for an overdose. The investigator will use 
clinical judgement to treat an overdose as and when they are made aware of this.
In the event of an overdose, the investigator or treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK2982772 can no longer be detected systemically (at least 2 days for 
GSK2982772).
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.
9.3.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.3.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.
Height (screening only) and weight will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.


2017N326600_03
CONFIDENTIAL
205184
58
9.3.2.
Neurological Exams
Neurological examination will include, at a minimum, assessment of: mental status, gait, 
balance, coordination, cranial nerves, motor power, reflexes, and sensory system (light 
touch and pain). Assessments will be standardized across all scheduled time points (see 
SoA).  Significant changes from the baseline or any clinically significant changes will be 
noted as part of further scheduled examinations or unscheduled examinations (if needed).  
Clinically significant abnormalities or changes in status from baseline will be:

entered as an adverse event,

may trigger increased monitoring of the subject(s),

may result in withdrawal of the subject (see Section 8.2),

may result in referral to a specialist.
9.3.3.
Vital Signs

Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed in a supine position
with a completely automated device. Manual techniques will be used only if an 
automated device is not available.

Blood pressure and pulse measurements should 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 will be measured in a supine position after 5 minutes’ rest and will 
include temperature, systolic and diastolic blood pressure, and pulse and 
respiratory rate.

In Part A and B on Day 1, vital signs (to be taken before blood collection for 
laboratory tests) will consist of 3 pulse and 3 blood pressure measurements pre-
dose on Day 1 (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute). The average of the 3 blood pressure readings will 
be recorded on the CRF.
9.3.4.
Electrocardiograms

Triplicate 12-lead ECG will be obtained as outlined in the SoA (see Section 2) 
using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals. Refer to Section 8.1.4 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession with at least 2 
minutes but no more than 10 minutes apart. 

Continuous cardiac telemetry will be performed at time points indicated in the 
SoA (Section 2).  Full disclosures will be reviewed in detail and the review 
maintained as part of the subject’s source documents.


2017N326600_03
CONFIDENTIAL
205184
59
9.3.5.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 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 relevant 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 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 etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SRM and the SoA.
9.3.6.
Suicidal Risk Monitoring
GSK2982772 is considered to be a CNS-active drug.  There is some concern that some 
CNS-active drugs may be associated with an increased risk of suicidal thinking or 
behaviour when given to some subjects. Although this drug has not been shown to be 
associated with an increased risk of suicidal thinking or behaviour when given to healthy 
volunteers, GSK considers it important to monitor for such events before or during 
clinical studies with compounds such as this.
Participants being treated with GSK2982772 should be monitored appropriately and 
observed closely for suicidal ideation and behaviour or any other unusual changes in 
behaviour. All subjects who experience signs of suicidal ideation or behaviour must 
immediately be discontinued from study medication.
Families and caregivers of participants being treated with GSK2982772 should be alerted 
about the need to monitor participants for the emergence of unusual changes in 
behaviour, as well as the emergence of suicidal ideation and behaviour and to report such 
symptoms immediately to the study investigator.
At screening and baseline (pre-dose Day 1) in Part B only, the Baseline/Screening 
assessment of suicidal ideation and behaviour and treatment emergent suicidal ideation 
and behaviour will be monitored during study 205184 using C-SSRS. At Days 7 and 17 
of the study, the ‘Since Last Visit C-SSRS’ will be completed. Refer to Section 2, SoA,
for more information.
Subjects who answer ‘Yes’ to any suicidal behaviour or ‘Yes’ to suicidal ideation 
Questions 4 or 5 will be referred to their General Practitioner (GP) or appropriate 


2017N326600_03
CONFIDENTIAL
205184
60
psychiatric care. The medical monitor will be notified. If appropriate, an AE or SAE 
should be reported (see Section 9.1). In addition, the investigator should complete a 
Possible Suicidality Related Adverse Event (PSRAE) form to collect detailed information 
on the circumstances of the reported AEs which, in the investigator’s opinion, are 
possibly suicidality-related. These may include, but are not limited to, an event involving 
suicidal ideation, a preparatory act toward imminent suicidal behaviour, a suicide 
attempt, or a completed suicide.
9.3.7.
Holter Monitoring
Holter monitoring will be performed at screening only. This 24-hour Holter ECG will be 
performed to eliminate subjects with clinically significant cardiac arrhythmias and to 
inform whether possible cardiac rhythm abnormalities potentially observed during 
continuous cardiac telemetry monitoring or 12-lead ECG are different from baseline. If 
necessary, additional or extended monitoring (e.g., telemetry or Holter) may be 
performed at the investigator or sponsor’s discretion to further characterize any emerging 
safety signals.
9.4.
Pharmacokinetics
9.4.1.
Blood Sample Collection
Blood will be collected into EDTA tubes and processed to plasma for PK analysis of 
GSK2982772 at the time points indicated in Section 2, SoA Tables. The actual date and 
time (24-hour clock time) of each blood sample collection will be recorded. The timing 
of PK samples may be altered and/or PK samples may be obtained at additional time 
points to ensure thorough PK monitoring.  
Blood will be collected into EDTA tubes and processed to plasma for PK analysis of M8 
(GSK3562183) and M9 (GSK2997852). This will be collected at the time points 
indicated in Section 2, SoA Tables. The actual date and time of each blood sample 
collection will be recorded. 
Blood will be collected into EDTA tubes and processed to plasma for
4β-hydroxycholesterol and cholesterol. This will be collected at the time points indicated 
in Section 2, SoA Tables. The actual date and time of each blood sample collection will 
be recorded. 
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the SRM. 
9.4.2.
Sample Analysis
Plasma analysis will be performed at a bioanalytical site (to be detailed in the SRM) 
under the control of Platform Technology and Science In Vitro/In Vivo Translation (PTS 
IVIVT) and Third Party Resource, GlaxoSmithKline. Concentrations of GSK2982772
will be determined in plasma samples, and concentrations of M8 (GSK3562183) and M9 
(GSK2997852) will be determined in select plasma samples, using the currently approved 


2017N326600_03
CONFIDENTIAL
205184
61
bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in 
the SRM).
Once the plasma sample has been analysed for GSK2982772 (or M8 [GSK3562183] and 
M9 [GSK2997852] as indicated above), any remaining plasma sample may be analysed 
for any compound-related material and the results may be reported as part of this study or 
under a separate PTS-IVIVT, GlaxoSmithKline protocol.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
9.4.3.
Plasma Sample for CYP3A4 Enzyme Activity
Plasma derived from select PK blood samples in Part B (as in the SoA Table), will be 
analyzed for 4β-hydroxycholesterol and cholesterol as a potential in vivo marker of 
CYP3A4 enzyme activity. Samples collected pre-treatment and at steady-state will be 
compared to evaluate this potential marker.
Details on CYP3A4 enzyme activity marker plasma sample collection, processing, 
storage and shipping procedures are provided in the SRM.
Baseline and Day 14, post-treatment plasma samples will be analyzed using a validated, 
specific, and sensitive liquid chromatography–mass spectrometry (LC-MS/MS) method
to determine concentrations of 4β-hydroxycholesterol and total cholesterol.  A 
comparison will be made between the ratio of 4β-hydroxycholesterol : cholesterol at 
baseline and on Day 14 to assess potential changes in CYP3A4 enzyme activity 
following GSK2982772 treatment.
Analysis will be performed at a bioanalytical site (to be detailed in the SRM) under the 
control of PTS-IVIVT and Third Party Resource, GlaxoSmithKline.
9.5.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
9.6.
Genetics
A blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 6 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the Study 
Reference Manual.


2017N326600_03
CONFIDENTIAL
205184
62
9.7.
Pharmacological Biomarkers
Pharmacological biomarkers are not evaluated in this study.


2017N326600_03
CONFIDENTIAL
205184
63
10.
STATISTICAL CONSIDERATIONS
The objectives of this study are to assess the safety and tolerability of single and repeat 
ascending doses of GSK2982772. No formal hypotheses will be tested.  
An estimation approach will be used to describe PK of GSK2982772, where point 
estimates and corresponding 90% confidence intervals will be constructed.
10.1.
Sample Size Determination
No statistical techniques were used to calculate the sample size, and sample size is based 
on feasibility.
The primary objective of the study is safety, where the number of safety events are of 
interest.  A maximum of 9 subjects will receive each active dose and; therefore, if 0/9 of 
a particular safety event in the GSK2982772 group is observed, the upper limit of the 
exact 95% CI indicates that a true incidence rate of 33.6% could not be ruled out.  
Whereas if 1/9 of the same safety event in the GSK2982772 group is observed, the upper 
limit of the exact 95% CI indicates that a true incidence rate of 48.2% could not be ruled 
out.
Using a Bayesian approach to determine the confidence interval around an observed 
safety event, we would assume a flat Beta (1,1) prior, and if we were to observe one
safety event in 9 then the posterior distribution would be Beta (2, 9), as outlined below:
Bayesian Approach to Determine Confidence in a Safety Event.
Thus, we can be 95% certain that the true probability of the safety event lies between 
0.04 and 0.39.


2017N326600_03
CONFIDENTIAL
205184
64
Pharmacokinetic Parameters
To date the pharmacokinetics of GSK2982772 have been studied up to 120 mg BID. The 
maximum between-subject coefficient of variation (CVb) for AUC(0-τ) and Cmax observed 
in study 200975 was 27.1 and 36.1 respectively. 
Based on these estimates of variability, slightly more conservative for a cross-over study
and a sample size of 9 completers in Cohort 2, it is estimated that the lower and upper 
bounds of the 90% confidence interval for the means of AUC and Cmax will be within 
approximately 17.9% and 24.2% of the point estimate, respectively.
10.2.
Sample Size Sensitivity
A sample size sensitivity analysis has been conducted on the primary endpoint, to 
investigate different safety event rates. If the number of subjects who completed each 
active dose changes, then the true incidence rates of safety events that could not be ruled 
out (as outlined in Section 10.1 Sample Size Determination) would change.  These 
changes are outlined in Table 1:


2017N326600_03
CONFIDENTIAL
205184
65
Table 1
Safety Events - Sample Size Sensitivity on Active Dose
N Completing 
Cohort
Number of a particular safety event 
observed with GSK2982772
Upper limit of exact 95%CI indicating that a true 
incidence rate of x% could not be ruled out
9
2
60.0%
3
70.0%
4
78.8%
8
0
36.9%
1
52.7%
2
65.1%
3
75.5%
7
0
41.0%
1
57.8%
2
70.9%
3
81.6%
Pharmacokinetic Parameters
A sample size sensitivity analysis has also been conducted on the PK parameters to 
investigate the effect of fewer number of subjects, or 10% difference in the between-
subject coefficient of variation on the precision of the point estimate.  These changes are 
outlined in Table 2:
Table 2
Pharmacokinetic Parameters – Sample Size Sensitivity
Number of Subjects
CVb
Precision (%)
Cmax
6
26.1%
29.8
6
28.8%
33.4
6
31.5%
37.0
9
19.6%
21.7
9
21.7%
24.2
9
23.7%
26.7
AUC(0-tau)
6
19.7%
21.8
6
21.9%
24.5
6
24.0%
27.1
9
14.9%
16.1
9
16.5%
17.9
9
18.1%
19.8


2017N326600_03
CONFIDENTIAL
205184
66
10.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
PK
The ‘PK Population' is defined as subjects in the ‘Safety’ population 
for whom a PK sample was obtained and analyzed.
10.4.
Statistical Analyses
10.4.1.
Safety Analyses
Safety data will be presented in tabular and/or graphical format and summarised 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Primary
All safety evaluations will be based on the Safety population.  Clinical 
interpretation will be based on the review and displays of adverse events, 
clinical laboratory values, vital sign measurements and 12-lead ECG 
monitoring.
10.4.2.
PK Analyses
Endpoint
Statistical Analysis Methods
Secondary
PK analyses will be described in the RAP. 
The PK of TID and BID dosing on Day 1 in Part A will be evaluated. In 
Part B the comparisons of interest will be:
The PK profile following the 1st dose of the day following administration 
in the fed state (standard meal on Day 9 and high fat meal on Day 11) or in 
the fasted state (Day 14).  
The pharmacokinetic profile following the 1st dose on Day 14 (fasted) and 
the 1st dose on Day 1 (fasted);  
Pharmacokinetic data will be listed and presented in graphical form and 
will be summarized descriptively. 
Statistical summaries of the PK parameter data will be the responsibility of 


2017N326600_03
CONFIDENTIAL
205184
67
Endpoint
Statistical Analysis Methods
Clinical Statistics, GlaxoSmithKline.
Descriptive statistics (n, arithmetic mean, standard deviation, 95% CI, 
minimum, median and maximum,) will be calculated for all 
pharmacokinetic parameters by treatment. In addition, for loge-transformed 
variables geometric mean, 95% confidence interval and %CVb (100 * √ 
(exp(SD2) -1)) will be provided, where the SD is the standard deviation of 
log-transformed data.
10.4.3.
Other Analyses
Descriptive statistics (n, arithmetic mean, standard deviation, 95% CI, minimum, median 
and maximum) of circulating glucuronide metabolite (M8; GSK3562183) and des-methyl 
metabolite will be investigated in healthy subjects after single-day and repeat dosing of 
GSK2982772. 
10.4.4.
Interim Analyses
An interim analysis may be performed during the study on completed cohorts in Part A 
and Part B of the study to aid internal decision making only. There will be no changes to 
the study design or planned number of subjects in future cohorts as a result of the interim 
analysis.
For Parts A and B of the study, interim PK analyses will be performed on plasma 
GSK2982772 concentration-time data generated during the conduct of this study.
The decision to proceed to higher dose strengths will be made by the DEC based on 
assessment of safety, tolerability and pharmacokinetic data at the preceding dose. The 
exception to this will be in Part A where only a safety assessment (not PK) for the 120 
mg TID dose will be performed. To date, the PK of GSK2982772 has been well-
characterised up to 120 mg BID in the FTiH study and the 120 mg TID for Part A 
represents a 50% increase in dose where PK simulations are predictable. This analysis 
can include review of individual subject data, summaries, graphical presentations and/or 
statistical analysis.
The RAP will describe the planned interim analyses in greater detail.
10.5.
Dose Escalation Committee
The decision to proceed to the next dose level of GSK2982772 in each Cohort will be 
made by a DEC consisting of the Principal Investigator (or appropriate designee), 
Medical Monitor, GSK Clinical Investigational lead and/or Study Team Leader, GSK 
Pharmacokineticist, a GSK GCSP representative and GSK Statistician. All GSK 
personnel including the GSK Statistician and the GSK Pharmacokineticist will remain 
unblinded throughout the course of the study. 


2017N326600_03
CONFIDENTIAL
205184
68
For Part A, dose escalation decisions will be based on data obtained from 6 or more 
subjects receiving GSK2982772 at the prior dose level. The review of the data set will 
consist at a minimum of: listings of all AEs, clinical laboratory results, flagged vital 
signs, flagged findings during continuous cardiac monitoring (telemetry), ECG and PK 
results derived from 24-hour plasma profiles.
The decision and selection of dose to proceed to Part B, will be made by the DEC based 
on safety, tolerability, and PK data from the same dose levels evaluated in Part A.  
For Part B, dose escalation decisions will be based on data obtained from 6 or more 
subjects receiving GSK2982772 at the prior dose level. The review of the data set will 
consist at a minimum of: listings of all AEs, clinical laboratory results, flagged vital 
signs, flagged findings during continuous cardiac monitoring (telemetry) and ECG 
findings through Day 16 of the previous cohorts(s) in Part B. Also included will be any 
PK results derived through at least Day 7 of the previous cohort(s).


2017N326600_03
CONFIDENTIAL
205184
69
11.
REFERENCES
Berger SB, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M, et al. Cutting edge: 
RIP1 kinase activity is dispensable for normal development but is a key regulator of 
inflammation in SHARPIN-deficient mice. J Immunol. 2014; 192(12):5476-80.
GlaxoSmithKline Document Number 2014N204126_02. GSK2982772 Investigator’s 
Brochure, Version 3. Effective Date: 27-January-2017.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos. 2009; 37:1779-1784.
Levey AS and Stevens LA. Estimating GFR Using the CKD Epidemiology Collaboration 
(CKD-EPI) Creatinine Equation: More Accurate GFR Estimates, Lower CKD Prevalence 
Estimates and Better Risk Predictions. Am J Kidney Dis. 2010; 55:622-627.
Ofengeim D and Yuan J. Regulation of RIP1 kinase signalling at the crossroads of 
inflammation and cell death. Nat Rev Mol Cell Biol. 2013; 14(11):727-736.
Snyder JJ, Foley RN, and Collins AJ. Prevalence of CKD in the United States: A 
Sensitivity Analysis Using the National Health and Nutrition Examination Survey 
(NHANES) 1999-2004. Am J Kidney Dis. 2009; 53(2):218-228.


2017N326600_03
CONFIDENTIAL
205184
70
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALS
Amyotrophic lateral sclerosis
ALT
Alanine aminotransferase
ANA
Anti-nuclear Antibody
API
Active Pharmaceutical Ingredient
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC(0-7)
Area under the concentration-time curve from time zero to 7 hours 
post first dose (TID dosing)
AUC(7-14)
Area under the concentration-time curve from 7 to 14 hours post 
first dose (TID dosing)
AUC(14-24)
Area under the concentration-time curve from 14 to 24 hours post 
first dose (TID dosing)
AUC(0-12)
Area under the concentration-time curve from 0 to 12 hours post 
first dose (BID dosing)
AUC(12-24)
Area under the concentration-time curve from 12 to 24 hours post 
first dose (BID dosing)
AUC(0-24)
Area under the concentration-time curve from time zero to 24 
hours post first dose
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) 
to last time of quantifiable concentration within a subject across all 
treatments
AUC(0-τ)
AUC from 0 hours to the time of next dosing.
BID
Twice a day
BMI
Body Mass Index
BP
Blood Pressure
CFR
Code of Federal Regulations
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum observed concentration
CNS
Central Nervous System
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CRF
Case Report Form
CRP
C-Reactive Protein
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CVb
Coefficient of Variation
CYP3A4
Cytochrome P450 3A4


2017N326600_03
CONFIDENTIAL
205184
71
DEC
Dose Escalation Committee
ECG
Electrocardiogram
eGFR
Estimated glomerular filtration rate
FSH
Follicle stimulating hormone
FTiH
First Time in Human
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance 
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HPLC
High performance liquid chromatography
HPMC
Hydroxypropylmethyl cellulose
HR
Heart Rate
HRT
Hormonal replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IgG
Immunoglobulin G
IP
Investigational Product
IRB/IEC
The Institutional Review Board/ Independent Ethics Committee
IUD
Intrauterine device
IUS 
Intrauterine hormone-releasing system
kg 
Kilogram
LDH
Lactate dehydrogenase
MCH
Mean corpuscular haemoglobin
MCV
Mean corpuscular volume
mg
Milligram
mL
Millilitre
MR
Modified Release
MS
Multiple Sclerosis
MSDS
Material Safety Data Sheet
NFκB
Nuclear factor kappa-light-chain-enhancer of activated B cells
NOAEL
No observable adverse effect limit
NTI
Narrow Therapeutic Index
Pgp
P-glycoprotein
PGx
Pharmacogenetics
PK
Pharmacokinetics
PoC
Proof of Concept
PsO
Psoriasis
PSRAE
Possible Suicidality Related Adverse Event
QTc
Electrocardiogram QT interval corrected for heart rate
QTcB
Electrocardiogram QT interval corrected for heart rate using 
Bazett’s formula


2017N326600_03
CONFIDENTIAL
205184
72
QTcF
Electrocardiogram QT interval corrected for heart rate using 
Fridericia’s formula
RA
Rheumatoid Arthritis
RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RIP1
Receptor-interacting protein-1
SAE
Serious Adverse Event
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SIB
Suicidal Ideation Behaviour
SoA
Schedule of Activities
SOP
Standard Operating Procedure
SRM
Study Reference Manual
SRT
Safety Review Team
SUSAR
Suspected unexpected serious adverse events
TB
Tuberculosis
TID
Three times a day
Tmax
Time taken to maximum observed plasma drug concentration
TNF
Tumour Necrosis Factor
TNFR1
Tumour Necrosis Factor Receptor-1
UC
Ulcerative Colitis
UDP
Uridine diphosphate
μg
Microgram
UGT
Uridine 5’-diphospho-glucuronosyltransferase
UK
United Kingdom
ULN
Upper Limit of Normal
WOCBP
Woman of Child Bearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Quantiferon


2017N326600_03
CONFIDENTIAL
205184
73
12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 3 will be performed by the Doctor’s 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 3
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Red Blood Cell (RBC)
Indices:
Mean Corpuscular 
Volume (MCV)
Mean corpuscular 
haemoglobin (MCH)
%Reticulocytes
White Blood Cell (WBC)
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose 
(Fasted)2
Calcium
Alkaline 
phosphatase
Albumin
Anti-nuclear 
antibody [(ANA), 
Part B only]
C-reactive protein 
(CRP)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Alcohol breath test and urine drug screen (to include at minimum: 


2017N326600_03
CONFIDENTIAL
205184
74
Laboratory 
Assessments
Parameters
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)]

Smoking Breath Test 

Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential). To be done at screening and Day 17 of 
Part B.

Urine hCG pregnancy test (as needed for women of child bearing potential)3

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis 
C virus antibody)

Tuberculosis test

Total Cholesterol, Low-density lipoprotein, triglycerides (Part B only)2

Estimated glomerular filtration rate (eGFR) will be calculated using the CKD-
EPI formula.
The results of each test must be entered into the CRF.
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 8.1.3 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).
2.
Non-fasted samples can be collected on Day -1 (All Parts) and at the Follow-Up visit (Part A Only).
3.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.
Laboratory that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded.


2017N326600_03
CONFIDENTIAL
205184
75
12.3.
Appendix 3: 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 (e.g., 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 Code of Federal Regulations (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 


2017N326600_03
CONFIDENTIAL
205184
76
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 centre. 

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. 

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with Standard Operating 
Procedure (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, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.


2017N326600_03
CONFIDENTIAL
205184
77
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.

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 subjects, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

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.
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 (e.g., 
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. 


2017N326600_03
CONFIDENTIAL
205184
78

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 
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.

A study specific source documentation list will be finalised by the sponsor 
before the start of the clinical phase of the study. The document will identify 
what data should be considered source data for this study.
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


2017N326600_03
CONFIDENTIAL
205184
79
12.4.
Appendix 4: 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 assessmentse.g.eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., 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.
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 


2017N326600_03
CONFIDENTIAL
205184
80
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 (e.g., 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.
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 (e.g., 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 


2017N326600_03
CONFIDENTIAL
205184
81
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.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., 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 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.


2017N326600_03
CONFIDENTIAL
205184
82
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 
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.


2017N326600_03
CONFIDENTIAL
205184
83
Reporting of SAE to GSK
SAE Reporting to GSK via Paper CRF

Email transmission of the SAE paper CRF is the preferred method to transmit this 
information to the medical monitor or the SAE coordinator.

In rare circumstances and in the absence of email equipment, 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 Study Reference Manual.


2017N326600_03
CONFIDENTIAL
205184
84
12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrolment.
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 during the treatment phase and 
until at least 90 days after the last administration of study drug: 

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 

Agree to use a male condom and recommend subject or partner use of an 
additional method of contraception with a failure rate of <1% per year as 


2017N326600_03
CONFIDENTIAL
205184
85
described in Table 4 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 

In addition, male participants must refrain from donating sperm for duration of 
study and for 90 days after study completion or from last dose
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 4 for a minimum of 28 days prior to the first dose of study drug and until at least 30 
days after the last administration of study drug. For female particpants using a hormonal 
method of contraception, partner use of male condoms is also required during the 
treatment period and until at least 28 days after the last administration of study drug.
Table 4
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 ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

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 


2017N326600_03
CONFIDENTIAL
205184
86
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. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case the use of a male condom should be utilized during the treatment period 
and for at least 30 days after the last dose of study treatment.
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test 

Additional pregnancy testing at admission to each study period and at the follow-up 
visit.

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.

Pregnancy testing, with a sensitivity of 25 mIU/mL will be performed using the test 
kit approved by the sponsor and in accordance with instructions provided in its 
package insert.
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 
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. 


2017N326600_03
CONFIDENTIAL
205184
87
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

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 Appendix 4. 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 discontinue study 
treatment.


2017N326600_03
CONFIDENTIAL
205184
88
12.6.
Appendix 6: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis.

DNA samples will be used for research related to GSK2982772 or immuno-
inflammatory and related diseases. They may also be used to develop tests/assays 
including diagnostic tests) related to GSK2982772 (or study treatments of this drug 
class) and immuno-inflammatory diseases. Genetic research may consist of the 
analysis of one or more candidate genes or the analysis of genetic markers 
throughout the genome [or analysis of the entire genome] (as appropriate)

DNA samples will be analyzed for UDP-glucuronosyltransferase 1-9 family, 
polypeptide A cluster enzyme that is encoded by the UGT1A9 gene complex.  
Additonal analyses may be conducted if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK2982772 or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK2982772 (or study treatments of 
this class) continues but no longer than 15 years after the last subject last visit or 
other period as per local requirements.


2017N326600_03
CONFIDENTIAL
205184
89
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
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 event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hr

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for pharmacokinetic 
(PK) analysis, obtained within 24 hours of 
last dose4 

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

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
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 


2017N326600_03
CONFIDENTIAL
205184
90
Liver Chemistry Stopping Criteria 
liver event follow up assessments within 24-
72 hr

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects 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 forms.
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 subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen 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 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
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 subject’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. 


2017N326600_03
CONFIDENTIAL
205184
91
12.8.
Appendix 8: Nervous System Adverse Events (CTCAE Criteria)
Taken from the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
The purpose of this Appendix is to provide guidance and is to be used in conjunction with the Investigator’s judgment.
Table 5
Guidance For Grading Adverse Events
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Abducens nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the abducens nerve (sixth cranial nerve).
Accessory nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the accessory nerve (eleventh cranial 
nerve).
Acoustic nerve disorder 
NOS
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of
the acoustic nerve (eighth cranial nerve).
Akathisia
Mild restlessness or 
increased motor activity
Moderate restlessness 
or increased motor 
activity; limiting 
instrumental ADL
Severe restlessness or 
increased motor 
activity; limiting self 
care ADL
-
-
A disorder characterized by an 
uncomfortable feeling of inner restlessness 
and inability to stay still; this is a side effect 
of some psychotropic drugs.
Amnesia
Mild; transient memory 
loss
Moderate; short term 
memory loss; limiting 
instrumental ADL
Severe; long term 
memory loss; limiting 
self care ADL
-
-
A disorder characterized by systematic and 
extensive loss of memory.
Aphonia
-
-
Voicelessness; unable 
to speak
-
-
A disorder characterized by the inability to 
speak. It may result from injuries to the 
vocal cords or may be functional 
(psychogenic).


2017N326600_03
CONFIDENTIAL
205184
92
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Arachnoiditis
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
of the arachnoid membrane and adjacent 
subarachnoid space.
Ataxia
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL;
mechanical assistance 
indicated
-
-
A disorder characterized by lack of 
coordination of muscle movements 
resulting in the impairment or inability to 
perform voluntary activities.
Brachial plexopathy
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by regional 
paresthesia of the brachial plexus, marked 
discomfort and muscle weakness, and 
limited movement in the arm or hand.
Central nervous system 
necrosis
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
corticosteroids 
indicated
Severe symptoms; 
medical intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by a necrotic 
process occurring in the brain and/or spinal 
cord.
Cerebrospinal fluid 
leakage
Post-craniotomy: 
asymptomatic; Post-
lumbar puncture: 
transient headache; 
postural care indicated
Post-craniotomy: 
moderate symptoms; 
medical intervention 
indicated; Post-lumbar 
puncture: persistent 
moderate symptoms; 
blood patch indicated
Severe symptoms; 
medical intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by loss of 
cerebrospinal fluid into the surrounding 
tissues.
Cognitive disturbance
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; 
specialized educational 
services/devices not 
indicated
Moderate cognitive 
disability; interfering 
with work/school/life 
performance but 
capable of 
independent living; 
specialized resources 
on part time basis 
indicated
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance
-
-
A disorder characterized by a conspicuous 
change in cognitive function.


2017N326600_03
CONFIDENTIAL
205184
93
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Concentration 
impairment
Mild inattention or 
decreased level of 
concentration
Moderate impairment 
in attention or 
decreased level of 
concentration; limiting 
instrumental ADL
Severe impairment in 
attention or decreased 
level of concentration; 
limiting self care ADL
-
-
A disorder characterized by a deterioration 
in the ability to concentrate.
Depressed level of 
consciousness
Decreased level of 
alertness
Sedation; slow 
response to stimuli; 
limiting instrumental 
ADL
Difficult to arouse
Life-threatening 
consequences
Death
A disorder characterized by a decrease in 
ability to perceive and respond.
Dizziness
Mild unsteadiness or 
sensation of movement
Moderate 
unsteadiness or 
sensation of 
movement; limiting 
instrumental ADL
Severe unsteadiness 
or sensation of 
movement; limiting self 
care ADL
-
-
A disorder characterized by a disturbing 
sensation of lightheadedness, 
unsteadiness, giddiness, spinning or 
rocking.
Dysarthria
Mild slurred speech
Moderate impairment 
of articulation or 
slurred speech
Severe impairment of 
articulation or slurred 
speech
-
-
A disorder characterized by slow and 
slurred speech resulting from an inability to 
coordinate the muscles used in speech.
Dysesthesia
Mild sensory alteration
Moderate sensory 
alteration; limiting 
instrumental ADL
Severe sensory 
alteration; limiting self 
care ADL
-
-
A disorder characterized by distortion of 
sensory perception, resulting in an 
abnormal and unpleasant sensation.
Dysgeusia
Altered taste but no 
change in diet
Altered taste with 
change in diet (e.g., 
oral supplements); 
noxious or unpleasant 
taste; loss of taste
-
-
-
A disorder characterized by abnormal 
sensual experience with the taste of 
foodstuffs; it can be related to a decrease 
in the sense of smell.
Dysphasia
Awareness of receptive 
or expressive 
characteristics; not 
impairing ability to 
communicate
Moderate receptive or 
expressive 
characteristics; 
impairing ability to 
communicate 
spontaneously
Severe receptive or 
expressive 
characteristics; 
impairing ability to 
read, write or 
communicate 
intelligibly
-
-
A disorder characterized by impairment of 
verbal communication skills, often resulting 
from brain damage.


2017N326600_03
CONFIDENTIAL
205184
94
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Edema cerebral
-
-
-
Life-threatening 
consequences; 
urgent 
intervention 
indicated
A disorder characterized by swelling due to 
an excessive accumulation of fluid in the 
brain.
Encephalopathy
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by a pathologic 
process involving the brain.
Extrapyramidal disorder
Mild involuntary 
movements
Moderate involuntary 
movements; limiting 
instrumental ADL
Severe involuntary 
movements or 
torticollis; limiting self 
care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by abnormal, 
repetitive, involuntary muscle movements, 
frenzied speech and extreme restlessness.
Facial muscle weakness
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by a reduction in 
the strength of the facial muscles.
Facial nerve disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the facial nerve (seventh cranial nerve).
Glossopharyngeal nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by involvement of 
the glossopharyngeal nerve (ninth cranial 
nerve).
Headache
Mild pain
Moderate pain; limiting 
instrumental ADL
Severe pain; limiting 
self care ADL
-
-
A disorder characterized by a sensation of 
marked discomfort in various parts of the 
head, not confined to the area of 
distribution of any nerve.


2017N326600_03
CONFIDENTIAL
205184
95
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Hydrocephalus
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
intervention not 
indicated
Severe symptoms or 
neurological deficit; 
intervention indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by an abnormal 
increase of cerebrospinal fluid in the 
ventricles of the brain.
Hypersomnia
Mild increased need for 
sleep
Moderate increased 
need for sleep
Severe increased 
need for sleep
-
-
A disorder characterized by characterized 
by excessive sleepiness during the 
daytime.
Hypoglossal nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the hypoglossal nerve (twelfth cranial 
nerve).
Intracranial hemorrhage
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
medical intervention 
indicated
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or 
operative intervention 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by bleeding from 
the cranium.
Ischemia 
cerebrovascular
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms
-
-
-
A disorder characterized by a decrease or 
absence of blood supply to the brain 
caused by obstruction (thrombosis or 
embolism) of an artery resulting in 
neurological damage.
IVth nerve disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the trochlear nerve (fourth cranial nerve).
Lethargy
Mild symptoms; reduced 
alertness and 
awareness
Moderate symptoms; 
limiting instrumental 
ADL
-
-
-
A disorder characterized by a decrease in 
consciousness characterized by mental 
and physical inertness.


2017N326600_03
CONFIDENTIAL
205184
96
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Leukoencephalopathy
Asymptomatic; small 
focal T2/FLAIR 
hyperintensities; 
involving periventricular 
white matter or <1/3 of 
susceptible areas of 
cerebrum mild 
increase in 
subarachnoid space 
(SAS) and/or mild 
ventriculomegaly
Moderate symptoms; 
focal T2/FLAIR 
hyperintensities, 
involving 
periventricular white 
matter extending into 
centrum semiovale or 
involving 1/3 to 2/3 of 
susceptible areas of 
cerebrum moderate 
increase in SAS and/or 
moderate 
ventriculomegaly
Severe symptoms; 
extensive T2/FLAIR 
hyperintensities, 
involving 
periventricular white 
matter involving 2/3 or 
more of susceptible 
areas of cerebrum 
moderate to severe 
increase in SAS and/or 
moderate to severe 
ventriculomegaly
Life-threatening 
consequences; 
extensive 
T2/FLAIR 
hyperintensities, 
involving 
periventricular 
white matter 
involving most of 
susceptible 
areas of 
cerebrum 
moderate to 
severe increase 
in SAS and/or 
moderate to 
severe 
ventriculomegaly
Death
A disorder characterized by diffuse 
reactive astrocytosis with multiple areas of 
necrotic foci without inflammation.
Memory impairment
Mild memory impairment
Moderate memory 
impairment; limiting 
instrumental ADL
Severe memory 
impairment; limiting 
self care ADL
-
-
A disorder characterized by a deterioration 
in memory function.
Meningismus
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by neck stiffness, 
headache, and photophobia resulting from 
irritation of the cerebral meninges.
Movements involuntary
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by uncontrolled 
and purposeless movements.
Myelitis
Asymptomatic; mild 
signs (e.g., Babinski's 
reflex or Lhermitte's 
sign)
Moderate weakness or 
sensory loss; limiting 
instrumental ADL
Severe weakness or 
sensory loss; limiting 
self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
involving the spinal cord. Symptoms 
include weakness, paresthesia, sensory 
loss, marked discomfort and incontinence.


2017N326600_03
CONFIDENTIAL
205184
97
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Neuralgia
Mild pain
Moderate pain; limiting 
instrumental ADL
Severe pain; limiting 
self care ADL
-
-
A disorder characterized by intense painful 
sensation along a nerve or group of 
nerves.
Nystagmus
-
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involuntary 
movements of the eyeballs.
Oculomotor nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the oculomotor nerve (third cranial nerve).
Olfactory nerve disorder
-
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the olfactory nerve (first cranial nerve).
Paresthesia
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by functional 
disturbances of sensory neurons resulting 
in abnormal cutaneous sensations of 
tingling, numbness, pressure, cold, and 
warmth that are experienced in the 
absence of a stimulus.
Peripheral motor 
neuropathy
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL; 
assistive device 
indicated
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
or degeneration of the peripheral motor 
nerves.
Peripheral sensory 
neuropathy
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
or degeneration of the peripheral sensory 
nerves.
Phantom pain
Mild pain
Moderate pain; limiting 
instrumental ADL
Severe pain; limiting 
self care ADL
-
-
A disorder characterized by marked 
discomfort related to a limb or an organ 
that is removed from or is not physically 
part of the body.


2017N326600_03
CONFIDENTIAL
205184
98
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Presyncope
-
Present (e.g., near 
fainting)
-
-
-
A disorder characterized by an episode of 
lightheadedness and dizziness which may 
precede an episode of syncope.
Pyramidal tract 
syndrome
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by dysfunction of 
the corticospinal (pyramidal) tracts of the 
spinal cord. Symptoms include  an 
increase in the muscle tone in the lower 
extremities, hyperreflexia, positive Babinski 
and a decrease in fine motor coordination.
Radiculitis
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL; medical 
intervention indicated
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by inflammation 
involving a nerve root. Patients experience 
marked discomfort radiating along a nerve 
path because of spinal pressure on the 
connecting nerve root.
Recurrent laryngeal 
nerve palsy
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms
Severe symptoms; 
medical intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection)
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by paralysis of 
the recurrent laryngeal nerve.
Reversible posterior 
leukoencephalopathy 
syndrome
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
abnormal imaging 
studies; limiting 
instrumental ADL
Severe symptoms; 
very abnormal imaging 
studies; limiting self 
care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by headaches, 
mental status changes, visual 
disturbances, and seizures associated with 
imaging findings of posterior 
leukoencephalopathy. It has been 
observed in association with hypertensive 
encephalopathy, eclampsia, and 
immunosuppressive and cytotoxic drug 
treatment. It is an acute or subacute 
reversible condition.
Seizure
Brief partial seizure; no 
loss of consciousness
Brief generalized 
seizure
Multiple seizures 
despite medical 
intervention
Life-threatening; 
prolonged 
repetitive 
seizures
Death
A disorder characterized by a sudden, 
involuntary skeletal muscular contractions 
of cerebral or brain stem origin.
Sinus pain
Mild pain
Moderate pain; limiting 
instrumental ADL
Severe pain; limiting 
self care ADL
-
-
A disorder characterized by marked 
discomfort in the face, between the eyes, 
or upper teeth originating from the sinuses.


2017N326600_03
CONFIDENTIAL
205184
99
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Somnolence
Mild but more than usual 
drowsiness or 
sleepiness
Moderate sedation; 
limiting instrumental 
ADL
Obtundation or stupor
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by characterized 
by excessive sleepiness and drowsiness.
Spasticity
Mild or slight increase in 
muscle tone
Moderate increase in 
muscle tone and 
increase in resistance 
through range of 
motion
Severe increase in 
muscle tone and 
increase in resistance 
through range of 
motion
Life-threatening; 
unable to move 
active or passive 
range of motion
Death
A disorder characterized by increased 
involuntary muscle tone that affects the 
regions interfering with voluntary 
movement. It results in gait, movement, 
and speech disturbances.
Stroke
Asymptomatic or mild 
neurologic deficit; 
radiographic findings 
only
Moderate neurologic 
deficit
Severe neurologic 
deficit
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by a sudden loss 
of sensory function due to an intracranial 
vascular event.
Syncope
-
-
Fainting; orthostatic 
collapse
-
-
A disorder characterized by spontaneous 
loss of consciousness caused by 
insufficient blood supply to the brain.
Transient ischemic 
attacks
Mild neurologic deficit 
with or without imaging 
confirmation
Moderate neurologic 
deficit with or without 
imaging confirmation
-
-
-
A disorder characterized by a brief attack 
(less than 24 hours) of cerebral 
dysfunction of vascular origin, with no 
persistent neurological deficit.
Tremor
Mild symptoms
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by the 
uncontrolled shaking movement of the 
whole body or individual parts.
Trigeminal nerve 
disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
-
-
A disorder characterized by involvement of 
the trigeminal nerve (fifth cranial nerve).
Vagus nerve disorder
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated
Moderate symptoms; 
limiting instrumental 
ADL
Severe symptoms; 
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by involvement of 
the vagus nerve (tenth cranial nerve).


2017N326600_03
CONFIDENTIAL
205184
100
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term Definition
Vasovagal reaction
-
-
Present
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
A disorder characterized by a sudden drop 
of the blood pressure, bradycardia, and 
peripheral vasodilation that may lead to 
loss of consciousness. It results from an 
increase in the stimulation of the vagus 
nerve.
Nervous system 
disorders - Other, 
specify
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations 
only; intervention not 
indicated
Moderate; minimal, 
local or noninvasive 
intervention indicated; 
limiting age-
appropriate 
instrumental ADL
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
existing hospitalization 
indicated; disabling;  
limiting self care ADL
Life-threatening 
consequences; 
urgent 
intervention 
indicated
Death
-


2017N326600_03
CONFIDENTIAL
205184
101
12.9.
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 01 (07-Dec-2017)
Overall Rationale for the Amendment: Clarification of the allowed contraception 
methods for female participants of child bearing potential and male participants with 
female partners of child bearing potential. Pharmacogenetic sampling has been 
incorporated into the protocol and glucuronide levels will be assessed in Part A of the 
study, as well as Part B. In addition, further administrative clarifications have been made.


2017N326600_03
CONFIDENTIAL
205184
102
Section # 
and Name
Description of Change
Brief Rationale
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
3.3.1. Risk 
Assessment
6.1. Inclusion 
Criteria
12.5. 
Appendix 5: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
An additional line for ‘Highly 
effective contraceptive method 
(WOCBP only)’ and ‘Contraception 
with male condoms (WOCBP using 
hormonal contraceptive method 
and male subjects with female 
partners of childbearing potential 
only)’ has been added to the SoA 
tables in Section 2.1. and Section 
2.2.
Updated wording for the subject 
selection for the risk of 
Reproductive Toxicity.
Updated wording for Inclusion 
Criteria 4 for Male and Female 
subjects.
Update of the contraception 
guidance wording for women of 
child bearing potential and male 
subjects with female partners of 
child bearing potential.
Female subjects of child-bearing potential 
who use hormonal contraception are 
required to have their sexual partners use a 
male condom from the first dose of study 
drug until the follow-up visit to avoid 
conception until at least 30 days after the 
last administration of drug.
This is being added as a precautionary 
measure for all WOCBP because an AE of 
“breakthrough bleeding” was reported in 
Cohort 1 TP2 of this study in a female 
subject who is on a combination oral 
contraceptive pill. In the FTiH Study 
200975, there was no increase detected in 
an in vivo marker for CYP3A4 enzyme 
activity following repeat dose administration 
up to 120 mg BID.  Measurement of 4β-
hydroxycholesterol is being evaluated in 
this study to determine CYP3A4 enzyme 
activity in repeat dose administration up to 
720 mg/day.  Until data are available the 
added contraception is being required.
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
9.6. Genetics
12.6. 
Appendix 6: 
Genetics
A line for Pharmacogenetic 
Sampling has been added to both 
Part A and Part B of the study.
A Genetics section has been added 
to the protocol (9.6) and appendix 
(6)
To take a pharmacogenetic sample from 
consenting subjects.
One subject in Cohort 1 (not the subject 
with break through bleeding), had 
consistently high exposure to GSK2982772 
compared to the other subjects (~2-fold 
higher Cmax) for the 120 mg and 240 mg 
TID dose levels. This may be due to a 
UGT1A9 genetic polymorphism, which is 
responsible for the conversion to the 
glucuronide metabolite of GSK2982772.
2.1. Time and 
Events Table 
– Part A 
Addition of a note in PK blood 
sampling row to state “Remaining 
PK plasma samples from Part A 
may be analysed for metabolite 
To include the assessment of metabolite 
concentrations in Part A of the study 
(currently Part B only).


2017N326600_03
CONFIDENTIAL
205184
103
Section # 
and Name
Description of Change
Brief Rationale
(Cohort 1)
Synopsis-
Objectives 
and 
Endpoints 
Section 4. 
Objectives 
and 
Endpoints
9.4.2. Sample 
Analysis
sampling.”
Metabolite sampling will be 
assessed after single-day of 
dosing, as well as repeat dosing.
Updated wording to in this section 
to state “any remaining plasma 
sample may be analysed for any 
compound-related material and the 
results may be reported as part of 
this study or under a separate PTS-
IVIVT, GlaxoSmithKline protocol.”
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
A pre-dose PK sampling time point 
has been added to the Note ‘f’ for 
Cohort 2 and Cohort 3.
No pre-dose sample was written into the 
original protocol on Days 9 and 11 of 
Cohorts 2 and 3.
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
Addition of a PK sampling timepoint 
at 17hr post-first dose in the TID 
Dosing regimens in Cohort 1.
Addition of a PK sampling timepoint 
at 17 hr post-first dose in the TID 
Dosing regimen of Cohorts 2 and 3.
An additional PK sampling time point at 3hr 
post-last dose has been added to better 
characterize the PK profile and to ensure 
the Cmax is not missed.
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
6.2. Exclusion 
Criteria
12.2. 
‘Cotinine Screen’ has been 
changed to ‘Smoking Screen’ and 
‘Cotinine Breath Test’ has been 
changed to ‘Smoking Breath Test’ 
in Section 2.1. and Section 2.2.
Carbon monoxide levels have been 
included in Exclusion Criteria 24.
In the ‘Other Screening Tests’ 
section, ‘Cotinine Breath Test’ has 
The ‘Cotinine Breath Test’ either includes 
urine cotinine and/or smoking breath test. 
The study will determine evidence of 
current smoking using a non-invasive 
breath carbon monoxide (CO) test device, 
which will provide CO levels to determine 
evidence of smoking.


2017N326600_03
CONFIDENTIAL
205184
104
Section # 
and Name
Description of Change
Brief Rationale
Appendix 2: 
Clinical 
Laboratory 
Tests
been changed to ‘Smoking Breath 
Test’.
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
12.2. 
Appendix 2: 
Clinical 
Laboratory 
Tests
In Part A of the study, 
Haem/Chem/Urinalysis 
assessments can be non-fasted for 
Day -1 and the Follow-Up Visit.
In Part B of the study 
Haem/Chem/Urinalysis 
assessments can be non-fasted for 
Day -1 only.
Additional wording included to Note 
2 in Table 3 - Non-fasted samples 
can be collected on Day -1 (All 
Parts) and at the Follow-Up visit 
(Part A Only).
The fasting lipid panel in Part B was 
separated out in the SoA since it was noted 
to be performed on Day -1 or Day 1.  This 
was moved to Day 1 only since subjects will 
not be fasted on Day -1. The 4β-
hydroxycholesterol will be checked on Day 
1, as a fasted sample.
It is recommended that all other lab time 
points being performed (inclusive of the 
follow-up visit) are to be performed under 
fasted conditions since this is essential to 
assess lipid profiles.
6.2. Exclusion 
Criteria
An additional Exclusion Criteria 
(16) has been added. “The subject 
has participated in a clinical trial 
and has received an investigational 
product within the following time 
period prior to the first dosing day 
in the current study: 30 days, 5 
half-lives or twice the duration of 
the biological effect of the 
investigational product (whichever 
is longer). All subsequent exclusion 
criteria numbers have increased by 
1.
To define the minimum length of time since 
a subject was last exposed to a new 
chemical entity.
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
7.2. Method 
of Treatment 
Updated wording in the ‘Notes’ 
section under the procedure 
“Randomization” in Section 2.1. 
and Section 2.2 to state:
“Randomization can occur on either 
Day -1 or Day 1 in both Parts A and 
B of the study.”
Updated wording to include that 
randomization can take place on 
Day -1 or Day 1 in Section 7.2.
There was a discrepancy in the SoA under 
the procedure “Randomization” in both Part 
A and B on Day -1 and Section 7.2. 
Randomization can take place on either 
Day -1 or Day 1.


2017N326600_03
CONFIDENTIAL
205184
105
Section # 
and Name
Description of Change
Brief Rationale
Assignment
9.3.3. Vital 
Signs
The semi-supine position has been 
removed from this section.
To remove any ambiguity with this 
assessment, the supine position will be the 
only position used to assess vital signs.
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
A comment has been added to the 
Meals row to state that “Meals will 
be served as per the site schedule 
on Days -1, 16 and 17.”
Clarification of the wording for the meal 
schedule on non-dosing and non PK 
sampling days.
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
Superscript ‘g’ has been removed 
from the PK blood sampling on Day 
1.
Superscript ‘g’ refers to study assessments 
on Day 14 of the protocol and not Day 1. 
This is a correction of a typographical error.
6.2. Exclusion 
Criteria
Update of the wording in Exclusion 
Criteria 3 to change the definition of 
what constitutes a positive 
tuberculin skin test from <5 mm 
skin induration at 48 to 72 hours to 
>5 mm skin induration at 48 to 72 
hours.
Correction of a typographical error. An 
induration of >5 mm skin induration at 48 to 
72 hours is considered a positive TB test.
7.2. Method 
of Treatment 
Assignment
The Method of Treatment 
Assignment has been updated to 
note that subjects in Cohort 1 will 
be randomized to 1 of 4 treatment 
sequences rather than 1 of 3. The 
additional treatment sequence 
(ABC) has been added. 
Correction of a typographical error. There is 
no change to the randomization ratio, which 
is 3:1.
2.1. Time and 
Events Table 
– Part A 
(Cohort 1)
Removal of the 10hr time interval 
post-last dose in note ‘b’ for TID 
dosing. This now reads “TID 
dosing: GSK2982772 or placebo 
will be administered using a 7hr, 
7hr dosing interval.”
Correction of a typographical error. Since 
Part A is a single-day of dosing, this 10hr 
interval has been removed.
2.2. Time and 
Events Table 
– Part B 
(Cohorts 2-4)
The Neurological Examination 
originally on Day 4 has been 
moved to Day 3.
Correction of a typographical error. 48hr 
post-first dose assessment would be on 
Day 3.
6.2. Exclusion 
Criteria
Exclusion Criteria 29 has been 
updated to state “Fasting total 
cholesterol” rather than “Total 
fasting cholesterol”.
Correction of typographical error.


2017N326600_03
CONFIDENTIAL
205184
106
Section # 
and Name
Description of Change
Brief Rationale
5.7. Dose 
Justification
The title in Figure 2 has been 
changed from “Monkey Cmax” to 
“Monkey AUC(0-24)”.
Correction of the PK parameter stated in 
the Figure 2 title.
12.4. 
Appendix 4: 
Adverse 
Events: 
Definitions 
and 
Procedures 
for Recording, 
Evaluating 
and Follow-
Up 
Assessments
In the ‘Reporting of SAE to GSK’ 
section, facsimile transmission of 
the SAE paper CRF has been 
changed to email transmission.
Notification of an SAE via email is the 
preferred method of transmission to the 
Medical Monitor and SAE Coordinator.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205184
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 205184: A single-centre, 
randomized, double-blind (sponsor-unblinded), placebo-
controlled study to evaluate the safety, tolerability and 
pharmacokinetics of GSK2982772 in repeat oral doses in 
healthy subjects
Compound Number 
:
GSK2982772
Effective Date 
:
30-NOV-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205184.

This RAP is intended to describe the safety, tolerability and PK analyses required 
for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC deliverable).
RAP Author(s):
Approver
Date
Approval 
Method
19-NOV-2018
Email
Statistics Leader (II Clinical Statistics)
Principal Statistician I (Quanticate)
15-NOV-2018
Email
Principal Statistician (II Clinical Statistics)
13-NOV-2018
Email
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
205184
2
RAP Team Approvals:
Approver
Date
Approval 
Method
16-NOV-2018
Email
Clinical Development Scientist, GCSD II
15-NOV-2018
Email
Clinical Investigational Lead, iiTA
 
16-NOV-2018
Email
Director, CPMS
Project Physician Lead, iiTA
21-NOV-2018
Email
Senior Medical Director, GCSP SERM
19-NOV-2018
Email
 
19-NOV-2018
Email
Data Quality Lead, Global Clinical & Data 
Operations
15-NOV-2018
Email
Principal Programmer, II Clinical Programming
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval 
Method
28-NOV-2018
CARS 
e-Signature 
Senior Statistics Director, II Clinical Statistics
Programming Manager, II Clinical Programming
30-NOV-2018
CARS 
e-Signature
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
205184
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................5
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................5
2.2.
Study Objective(s) and Endpoint(s)...............................................................5
2.3.
Study Design ................................................................................................7
2.4.
Statistical Hypotheses / Statistical Analyses .................................................8
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS .....................................................................................9
4.1.
Protocol Deviations.......................................................................................9
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................11
5.1.
Study Treatment & Sub-group Display Descriptors.....................................11
5.2.
Baseline Definitions ....................................................................................11
5.3.
Multicentre Studies .....................................................................................12
5.4.
Examination of Covariates, Other Strata and Subgroups............................12
5.5.
Multiple Comparisons and Multiplicity .........................................................12
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................13
6.
SAFETY ANALYSES .............................................................................................14
6.1.
Adverse Events Analyses ...........................................................................14
6.2.
Clinical Laboratory Analyses.......................................................................14
6.3.
Other Safety Analyses ................................................................................14
7.
STUDY POPULATION ANALYSES .......................................................................15
7.1.
Overview of Planned Study Population Analyses........................................15
8.
PHARMACOKINETIC ANALYSES.........................................................................16
8.1.
Primary Pharmacokinetic Analyses.............................................................16
8.1.1.
Endpoint / Variables.....................................................................16
8.1.1.1.
Drug Concentration Measures....................................16
8.1.1.2.
Derived Pharmacokinetic Parameters.........................16
8.1.2.
Summary Measure ......................................................................16
8.1.3.
Population of Interest...................................................................17
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................17
8.2.
Secondary Pharmacokinetic Analyses........................................................17
8.2.1.
Endpoint / Variables.....................................................................17
8.2.1.1.
Drug Concentration Measures....................................17
9.
REFERENCES.......................................................................................................18
10. APPENDICES........................................................................................................19


CONFIDENTIAL
205184
4
10.1.
Appendix 1: Protocol Deviation Management .............................................19
10.2.
Appendix 2: Schedule of Activities ..............................................................20
10.2.1.
Protocol Defined Schedule of Events...........................................20
10.2.1.1.
Part A (Cohort 1) ........................................................20
10.2.1.2.
Part B (Cohorts 2-5) ...................................................23
10.3.
Appendix 3: Assessment Windows .............................................................41
10.3.1.
Definitions of Assessment Windows for Analyses........................41
10.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................42
10.4.1.
Study Phases ..............................................................................42
10.4.1.1.
Study Phases for Concomitant Medications ...............42
10.4.2.
Treatment Emergent Flag for Adverse Events .............................42
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................43
10.5.1.
Reporting Process .......................................................................43
10.5.2.
Reporting Standards....................................................................43
10.5.3.
Reporting Standards for Pharmacokinetic....................................44
10.6.
Appendix 6: Derived and Transformed Data ...............................................45
10.6.1.
General........................................................................................45
10.6.2.
Study Population..........................................................................45
10.6.3.
Safety ..........................................................................................46
10.7.
Appendix 7: Reporting Standards for Missing Data.....................................47
10.7.1.
Premature Withdrawals................................................................47
10.7.2.
Handling of Missing Data.............................................................47
10.7.2.1.
Handling of Missing and Partial Dates ........................48
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................49
10.8.1.
Laboratory Values........................................................................49
10.8.2.
ECG.............................................................................................50
10.8.3.
Vital Signs....................................................................................50
10.9.
Appendix 9: Abbreviations & Trade Marks ..................................................51
10.9.1.
Abbreviations...............................................................................51
10.9.2.
Trademarks .................................................................................52
10.10. Appendix 10: List of Data Displays..............................................................53
10.10.1. Data Display Numbering..............................................................53
10.10.2. Mock Example Shell Referencing ................................................53
10.10.3. Deliverables.................................................................................53
10.10.4. Study Population Tables..............................................................54
10.10.5. Safety Tables...............................................................................59
10.10.6. Safety Figures .............................................................................64
10.10.7. Pharmacokinetic Tables...............................................................65
10.10.8. Pharmacokinetic Figures .............................................................67
10.10.9. ICH Listings .................................................................................68
10.10.10.Non-ICH Listings..........................................................................78
10.11. Appendix 11: Example Mock Shells for Data Displays ................................80


CONFIDENTIAL
205184
5
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 205184:
Revision Chronology:
2017N326600_00
31-JUL-2017
Original
2017N326600_01
07-DEC-2017
Amendment 01
2017N326600_02
15-FEB-2018
Amendment 02
2017N326600_03
26-FEB-2018
Republished Amendment 02
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
An interim analysis may be 
performed during the study on 
completed cohorts in Part A and 
Part B of the study to aid internal 
decision making only. The RAP 
will describe the planned interim 
analyses in greater detail.
No formal IA will be conducted 
during the study. 
The DEC make decisions on 
proceeding to higher dose 
strengths based on assessment 
of safety, tolerability and 
pharmacokinetic data at the 
preceding dose only. 
Protocol Section 10.3 references 
an ‘Enrolled population’.
RAP uses the ‘Randomised 
Population’.
The population was renamed to 
match the current IDSL 
guidance. 
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To investigate the safety and 
tolerability of repeat doses of 
GSK2982772 in healthy subjects.

Adverse events.

Clinical laboratory values (clinical chemistry, haematology 
and urinalysis).

Vital sign measurements (blood pressure, heart rate, 
respiratory rate and body temperature).

Physical examinations.

12-Lead ECG monitoring.


CONFIDENTIAL
205184
6
Objectives
Endpoints
Secondary Objectives
Secondary Endpoints

To characterise the pharmacokinetic 
(PK) profile of repeat doses of 
GSK2982772 in healthy subjects.

A 24 hr profile to be collected on Day 1 of Part A and Day 
14 of Part B. On Day 1 of Part B, the PK profile will be 
evaluated following the first dose only. Derived PK 
parameters for GSK2982772, including area under the 
plasma drug concentration versus time curve over 24 hr 
(AUC(0-24)) and AUC over each dose interval (i.e. AUC(0-7), 
AUC(7-14) and AUC(14-24) for TID and AUC(0-12) and AUC(12-
24) for BID). Maximum observed plasma drug 
concentration (Cmax) following each dose, time to 
maximum observed plasma drug concentration (Tmax) 
following each dose, observed trough plasma drug 
concentrations (C0, C7, C14 and C24 for TIDdosing and C0, 
C12 and C24 for BID dosing).

To assess the impact of food on the 
PK of repeat doses of GSK2982772 in 
healthy subjects at steady state

Derived PK parameters for GSK2982772, including 
AUC(0-7), AUC(7-14), Cmax, after 1st dose of day and Tmax
after 1st dose of day.

To assess potential effect of repeat 
doses of GSK2982772 on CYP3A4 
enzyme activity

Plasma 4β-hydroxycholesterol to cholesterol ratio pre-
treatment and following 14 days of repeat dosing of 
GSK2982772.
Exploratory Objectives
Exploratory Endpoints

To investigate the levels of circulating 
glucuronide metabolite (M8; 
GSK3562183) and desmethyl 
metabolite (M9; GSK2997852) in 
healthy subjects after single-day and 
repeat dosing of GSK2982772.

Quantify M8 (GSK3562183) and M9 (GSK2997852) in 
select plasma PK samples at pre-dose and 2 hr following 
Day 14 of repeat dosing of GSK2982772.


CONFIDENTIAL
205184
7
2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

This is a single-centre, randomized, double-blind (sponsor-unblinded), placebo-
controlled study to evaluate the safety, tolerability and pharmacokinetics of 
GSK2982772 in repeat oral doses in healthy participants.

This study consists of 2 parts:

Part A (Cohort 1) – single ascending dose, randomized, placebo-controlled, 3-
way crossover.  

Part B (Cohorts 2, 3, 4 and 5) – repeat dose, randomized, placebo-controlled, 
sequential-group.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

The study is planned to enrol approximately 66 participants with approximately 12 
participants (9 active, 3 placebo) in Cohorts 1 and 2 (up to approximately 24 in total) 
and 14 participants (9 active, 5 placebo) in Cohorts 3, 4 and 5 (up to approximately 
42 in total).

If participants prematurely discontinue the study, additional replacement participants 
may be randomized in order to guarantee that sufficient participants are treated with 
GSK2982772 at any given dose before escalating to the following dose. 
Replacement participants will be assigned to the same treatment sequence (Cohort 
1) or treatment (Cohorts 2-5).

All participants will be centrally randomized using an Interactive Voice/Web 
Response System (IVRS/IWRS). Study treatment is dispensed at the study visits 
summarized in the Schedule of Activities (SoA). Each participant is dispensed
blinded study treatment, labelled with his/her unique randomization number, 
throughout the study. Returned study treatment should not be re-dispensed to the 
participants.


CONFIDENTIAL
205184
8
Overview of Study Design and Key Features

In Cohorts 1 and 2, participants will be randomized in a 3:1 ratio to either 
GSK2982772 or placebo. In Cohorts 3, 4 and 5, participants will be randomized in a 
9:5 ratio to either GSK2982772 or placebo. 

The randomization will reflect the fact that at least 2 of the 12 participants in Cohorts 
1 and 2 and at least 2 of the 14 participants in Cohort 4 and 5 (one participant will 
receive GSK2982772 and one participant will receive matched-placebo) will be dosed 
first (on Day 1) in each part to enable dose staggering.

In Cohort 1, the participants will be randomized to one of four sequences (ABC, ABP, 
APC, PBC), where the treatments are: 
      A
120 mg TID
      B
240 mg TID
      C
360 mg BID
      P
Placebo

Once a treatment allocation number has been assigned to a participant, it cannot be 
reassigned to any other participant.
Dosing

For TID dosing, GSK2982772 or placebo will be administered using a 7hr and 7hr 
dosing interval in Part A and a 7hr, 7hr and 10hr dosing interval in Part B. 

For BID dosing, GSK2982772 or placebo will be administered using a 12hr dosing 
interval.
Interim 
Analysis

No interim analyses will be performed.

The decision to proceed to higher dose strengths will be made by the Dose 
Escalation Committee (DEC) based on assessment of safety, tolerability and 
pharmacokinetic data at the preceding dose.
2.4.
Statistical Hypotheses / Statistical Analyses

The objectives of this study are to assess the safety and tolerability of single and 
repeat ascending doses of GSK2982772.  No formal hypotheses will be tested.  

An estimation approach will be used to describe pharmacokinetics of GSK2982772, 
where point estimates and corresponding 90% confidence intervals will be 
constructed, unless otherwise stated.


CONFIDENTIAL
205184
9
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analyses will be performed. The decision to proceed to higher dose strengths 
will be made by the Dose Escalation Committee (DEC) based on assessment of safety, 
tolerability and pharmacokinetic data at the preceding dose.
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
All Subjects

Comprises of all participant who were screened and 
allocated a subject number.

Screen Failure

Population 
Analysed.
Randomised

All participants who were randomly assigned to 
treatment in the study.

This population will be based on the treatment the 
participant was randomized to.

Age ranges
Safety

Comprises of all randomised participants who
received at least one dose of study treatment.

This population will be based on the treatment the 
subject was randomised to.

All other Study 
Population

Safety
Pharmacokinetic

Participants in the ‘Safety’ population for whom a 
pharmacokinetic sample was obtained and 
analysed.

PK
Refer to Appendix 10: List of Data Displays which details the population used for each display.
Note: All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects CDISC and 
GSK Data Display Standards terminology.
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.


CONFIDENTIAL
205184
10
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan (Version 4.0, 01 Feb 18)
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations 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 eCRF.


CONFIDENTIAL
205184
11
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
Order in 
TLF
P
Placebo TID Single Dose
Placebo 
1
Q
Placebo BID Single Dose
Placebo 
1
A
GSK2982772 120 mg TID Single Dose
GSK 120 mg TID
2
B
GSK2982772 240 mg TID Single Dose
GSK 240 mg TID
3
C
GSK2982772 360 mg BID Single Dose
GSK 360 mg BID
4
R
Placebo TID Repeat Dose
Placebo 
1
S
Placebo BID Repeat Dose
Placebo 
1
D
GSK2982772 120 mg TID Repeat Dose
GSK 120 mg TID 
2
E
GSK2982772 240 mg TID Repeat Dose
GSK 240 mg TID 
3
F
GSK2982772 360 mg BID Repeat Dose
GSK 360 mg BID 
4
G
GSK2982772 Cohort 3 Repeat Dose
GSK 120 mg TID
2
H
GSK2982772 Cohort 4 Repeat Dose
GSK 240 mg TID
3
J
GSK2982772 Cohort 5 Repeat Dose
GSK XX mg TID/BID [1]
3 or 4
T
Placebo Cohort 3 Repeat Dose
Placebo 
1
U
Placebo Cohort 4 Repeat Dose
Placebo 
1
V
Placebo Cohort 5 Repeat Dose
Placebo 
1
NOTES:
[1]  Dose level not required as the study met the PK stopping criteria at the end of Cohort 4. 
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline.
For Part A, baseline definitions defined in the table are applicable to each treatment 
period.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. The mean of triplicate measurements at any given time 
point will be used as the value for that time point unless otherwise stated.


CONFIDENTIAL
205184
12
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety
Clinical Chemistry/ 
Haematology/
Urinalysis
X
X
X
Day 1
12-lead ECG [1]
X
X
X
Day 1
Vital Signs
X
X
X
Day 1
C-SSRS (Part B only)
X
X
Day -1/Day 1
Pharmacokinetic
PK Concentrations/
Parameters
X
Day 1
NOTES:
[1]  ECG recordings will be performed in triplicate at screening. Use the mean of the triplicate measurements.
5.3.
Multicentre Studies
This is a single centre study. 
5.4.
Examination of Covariates, Other Strata and Subgroups
There are no covariates, strata or subgroups to be investigated in this study. 
5.5.
Multiple Comparisons and Multiplicity
No adjustments for multiplicity will be required. 


CONFIDENTIAL
205184
13
5.6.
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
10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol Population
10.2
Appendix 2: Schedule of Activities
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Reporting Standards for Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance
10.9
Appendix 9: Abbreviations & Trademarks
10.10
Appendix 10: List of Data Displays
10.11
Appendix 11: Example Mock Shells for Data Displays


CONFIDENTIAL
205184
14
6.
SAFETY ANALYSES
All safety analyses will be based on the” Safety” population, unless otherwise specified.
6.1.
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. The details of the 
planned displays are provided in Appendix 10: List of Data Displays.
6.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 10: List of Data Displays.
Additionally, plasma 4β-hydroxycholesterol to cholesterol ratio pre-treatment and 
following 14 days of repeat dosing of GSK2982772 will be summarised and listed.
In addition to GSK Core Data Standards, lipids (Total Cholesterol, Triglycerides, HDL 
cholesterol, LDL cholesterol and Total Cholesterol/HDL ratio) outside the normal range 
and percent change in lipids will be summarised. The fasting lipid status will be included 
in listings. 
6.3.
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. Suicide risk monitoring 
including analyses of Colombia Suicide Severity Rating Scale (C-SSRS) will be based on 
GSK Core Data Standards, unless otherwise specified. The details of the planned displays 
are presented in Appendix 10: List of Data Displays.


CONFIDENTIAL
205184
15
7.
STUDY POPULATION ANALYSES
7.1.
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, concomitant medication, and 
exposure and treatment compliance will be based on GSK Core Data Standards.  Details 
of the planned displays are presented in Appendix 10: List of Data Displays.


CONFIDENTIAL
205184
16
8.
PHARMACOKINETIC ANALYSES
8.1.
Primary Pharmacokinetic Analyses
8.1.1.
Endpoint / Variables
8.1.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3
Reporting Standards for Pharmacokinetic).
8.1.1.2.
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. All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from the plasma
concentration-time data, as data permits.
Parameter
Parameter Description
AUC(0-24)
Area under the curve from time zero hours to 24 hours
AUC(0-7)
Area under the curve from time zero hours to 7 hours (TID only)
AUC(7-14)
Area under the curve from time 7 hours to 14 hours (TID only)
AUC(14-24)
Area under the curve from time 14 hours to 24 hours (TID only)
AUC(0-12)
Area under the curve from time zero hours to 12 hours (BID only)
AUC(12-24)
Area under the curve from time 12 hours to 24 hours (BID only)
Cmax
Maximum observed concentration after 1st, 2nd and 3rd dose in Part A and on Day 14 in Part B
Tmax
Time to maximum observed concentration after 1st, 2nd and 3rd dose in Part A and on Day 14 in Part B
C0
Concentration at zero hours (pre-dose)
C7
Concentration at 7 hours post-dose (TID only)
C12
Concentration at 12 hours post-dose (BID only)
C14
Concentration at 14 hours post-dose (TID only)
C24
Concentration at 24 hours post-dose
NOTES:

Additional parameters may be included as required.
8.1.2.
Summary Measure

The PK of TID and BID dosing on Day 1 in Part A will be evaluated. In Part B the 
comparisons of interest will be:
o The PK profile following the 1st dose of the day following administration in the 
fed state (standard meal on Day 9 and high fat meal on Day 11) or in the fasted 
state (Day 14).  
o The pharmacokinetic profile following the 1st dose on Day 14 (fasted) and the 1st
dose on Day 1 (fasted);  


CONFIDENTIAL
205184
17

Descriptive statistics (n, arithmetic mean, standard deviation [SD] standard error 
[SE], 95% CI, minimum, median and maximum) will be calculated by treatment for 
all PK concentrations over time and for the derived PK parameters. In addition, for 
loge-transformed PK parameter variables geometric mean, 95% CI and %CVb (100 * 
√ (exp(SD2) -1)) will be provided, where the SD is the standard deviation of log-
transformed data.
8.1.3.
Population of Interest 
The primary pharmacokinetic analyses will be based on the “Pharmacokinetic” 
population, unless otherwise specified.
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events

Study completion (i.e. as specified in the protocol) was defined as completing all 
phases of the study including the follow-up visit.

Withdrawn participants may be replaced in the study. Replacement participants,
enrolled will be dosed with the next planned treatment of the withdrawn participant, 
and they will not receive any treatment that the withdrawn participant has already 
received with the exception of the need to increase participants numbers to obtain the 
minimum number of evaluable participants required for interim decisions, and to 
obtain data in any  other treatment that is required for a valid comparison. 
Replacement participants will receive the required treatments in the same order as 
planned for the original participant.

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. 
8.2.
Secondary Pharmacokinetic Analyses
8.2.1.
Endpoint / Variables
8.2.1.1.
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3
Reporting Standards for Pharmacokinetic).

Descriptive statistics (n, arithmetic mean, standard deviation, standard error, 95% CI, 
minimum, median and maximum) of circulating glucuronide metabolite (M8; 
GSK3562183) and des-methyl metabolite (M9; GSK2997852) will be investigated in 
healthy participants after single-day and repeat dosing of GSK2982772


CONFIDENTIAL
205184
18
9.
REFERENCES

PKOne and relevant information on Standards for the Transfer and Reporting of PK 
Data using HARP available within IDSL standards.


CONFIDENTIAL
205184
19
10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset.
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.


CONFIDENTIAL
205184
20
10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events
10.2.1.1.
Part A (Cohort 1)
Procedure
Screening
(Up to 28 
days 
before Day 
1)
Study Period (Days)
Follow-Up  
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
Outpatient Visit
X
X
Admission to Clinical Unit
X
Inpatient Stay at Clinical Unit
==X==
Discharge from Clinical Unit
X
Following completion of all assessments.
Informed Consent
X
Inclusion and Exclusion Criteria
X
Demography
X
Full Physical Examination
X
Additional exams/screens may be performed, or brief exams made full exams, by the 
Investigator, as deemed necessary (e.g. where safety or laboratory findings indicate). 
Tests will be conducted within site specified standards.
Brief Physical Examination
X
X
X
Height
X
Weight
X
Drug/Alcohol/Smoking Screen
X
X
Tests include alcohol breath test, smoking breath test and urine drug screen.
Medical/Medication/Drug/Alcohol 
History
X
HIV, Hepatitis B and C Screening
X
Tuberculosis Test
X
Conducted at the standard practice of the site.
Serum Pregnancy Test (WOCBP 
only)
X
X
Urine Pregnancy Test (WOCBP 
only)
X
X
Highly effective contraceptive 
method (WOCBP only)
X
X
X
X
X
X
X
Must use method for a minimum of 28 days prior to first dose of study medication until 
the follow-up visit


CONFIDENTIAL
205184
21
Procedure
Screening
(Up to 28 
days 
before Day 
1)
Study Period (Days)
Follow-Up  
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
Contraception with male condoms  
(WOCBP using hormonal 
contraceptive method and male 
subjects with female partners of 
childbearing potential only)
X
X
X
X
X
X
Meals
X
Xa
X
X
X
a On Day 1, subjects will fast 8hr overnight prior to dose 1. A breakfast will be served 
approximately 2hr after dose 1. 
TID dosing: On Day 1, lunch and dinner will be served between 2 to 3hr prior to doses 2 
and 3, respectively. 
BID dosing: On Day 1, lunch will be served approximately 4 to 5hr after dose 1. Dinner 
will be served between 2 to 3hr prior to dose 2. A snack may be consumed 
approximately 2 to 3hr after dose 2.
Water is permitted with dosing and at all times. Subjects will receive standardized meals 
scheduled at the same time in each period.
Haem/Chem/Urinalysis Test 
(Include Liver Chemistries)
X
X
X
X
X
X
Non-fasted samples can be collected on Day -1 and Follow-Up Visit.
PK Blood Sampling
X
X
TID Dosing: PK samples to be taken pre-dose on Day 1 and then at the following time 
points post first-dose: 20min, 40min, 1hr, 1hr 30min, 2hr, 3hr, 5hr, 7hr, 7hr 20min, 7hr 40 
min, 8hr, 8hr 30min, 9hr, 10hr, 12hr, 14hr, 14hr 20min, 14hr 40 min, 15hr, 15hr 30min, 
16hr, 17hr, 19hr, 22hr, 24hr.
BID Dosing: PK samples to be taken pre-dose on Day 1 and then at the following time 
points post first-dose: 20min, 40min, 1hr, 1hr 30min, 2hr, 3hr, 4hr, 6hr, 8hr, 10hr, 12hr, 
12hr 20min, 12hr 40min, 13hr, 13hr 30min, 14hr, 15hr, 16hr, 19hr, 22hr, 24hr.
Remaining PK plasma samples from Part A may be analysed for metabolite sampling.
Neuro. Examination
X
X
X
TID Dosing: Neurological examinations to be conducted either on Day -1 or pre-dose 
Day 1 and then at the subsequent time points post first-dose on Day 1: 2hr, 9hr, 16hr, 
24hr and 48hr. Then 24 and 48hr after the last dose administered on Day 1.
BID Dosing: Neurological examinations to be conducted either on Day -1 or pre-dose 
Day 1 and then at the subsequent time points post first-dose: 2hr, 14hr, 24hr and 48hr. 
Then 24 and 48 hr after the last dose administered on Day 1.
Telemetry
X
Continuous at least 24hr post-evening dose. Initiate at least 15 min. prior to dosing.


CONFIDENTIAL
205184
22
Procedure
Screening
(Up to 28 
days 
before Day 
1)
Study Period (Days)
Follow-Up  
(No more 
than 14 
days post 
last dose)
Notes
-1
1
2
3
4
12-Lead ECG
X
X
T
X
X
Vital signs to include HR, BP, temperature and respiration rate. 
TID Dosing: 12-Lead ECG and Vital Signs to be conducted on Day -1 and  pre-dose on 
Day 1 and then at the subsequent time points post first-dose: 40min, 2hr, 4hr, 7hr (pre-
2nd dose), 9hr, 14hr (pre-3rd dose), 16hr, 24hr and 48hr. Then 24 and 48hr after the last 
dose administered on Day 1.
BID Dosing: 12-Lead ECG and Vital Signs to be conducted on Day -1 and pre-dose on 
Day 1 and then at the subsequent time points post first-dose: 40 min, 2hr, 4hr, pre-2nd
dose, 12hr 20 min, 14hr, 24hr and 48 hr. Then 24 and 48hr after the last dose 
administered on Day 1.
T = Triplicate.
Vital Signs
X
X
T
X
X
X
Randomization
X
Randomization can occur on either Day -1 or Day 1.
Study Treatment
Xb
b TID dosing: GSK2982772 or placebo will be administered using a 7hr, 7hr dosing 
interval.
BID dosing: GSK2982772 or placebo will be administered using a 12hr dosing interval.
Pharmacogenetic Sample (PGx)
X
A PGx blood sample is collected at the Day 1 visit, after the subject has been 
randomized and provided informed consent for genetic research. If the sample is not 
collected at the Day 1 visit, it can be collected at any time during the study after 
randomization.
AE Review
=======X======
X
SAE Review
=======X======
X
Concomitant Medication Review
X
=======X======
X


CONFIDENTIAL
205184
23
10.2.1.2.
Part B (Cohorts 2-5)
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Outpatient Visit
X
X
Admission to Clinical 
Unit
X
Inpatient Stay at 
Clinical Unit
================================X===============================
Discharge from 
Clinical Unit
X
Following 
completion of 
all 
assessments.
Informed Consent
X
Inclusion and 
Exclusion Criteria
X
Demography
X
Full Physical 
Examination
X
X
Additional 
exams/screens 
may be 
performed, or 
brief exams 
made full 
exams, by the 
Brief Physical 
Examination
X
X
X
X
X
X
X


CONFIDENTIAL
205184
24
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Investigator, 
as deemed 
necessary 
(e.g. where 
safety or 
laboratory 
findings 
indicate). 
Tests will be 
conducted 
within site 
specified 
standards.
Height
X
Weight
X
X
X
Drug/Alcohol/Smoking 
Screen
X
X
Tests include 
alcohol breath 
test, smoking 
breath test and 
urine drug 
screen.
Medical/Medication/
Drug/Alcohol History
X
HIV, Hepatitis B and 
C Screening
X


CONFIDENTIAL
205184
25
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Tuberculosis Test
X
Anti-Nuclear Antibody
X
X
X
Serum Pregnancy 
Test (WOCBP only)
X
X
Urine Pregnancy Test 
(WOCBP only)
X
X
Highly effective 
contraceptive method 
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Must use 
method for a 
minimum of 28
days prior to 
first dose of 
study 
medication 
until the follow-
up visit.
Contraception with 
male condoms  
(WOCBP using 
hormonal 
contraceptive method 
and male subjects 
with female partners 
of childbearing 
potential only)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
Xc
May be 


CONFIDENTIAL
205184
26
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
completed on 
either Day -1 
or Day 1, but 
no later than 
1hr prior to 
dosing. To be 
completed pre-
dose on Day 7.
c C-SSRS to 
be conducted 
on follow-up 
only in the 
instance that a 
subject 
withdraws from 
the study.
Meals
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TID Dosing:
On Day 1 
through 14 
subjects will 
fast 8hr 
overnight. 
Breakfast will 
be served 
approximately 


CONFIDENTIAL
205184
27
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
2hr after 
dosing on 
Days 1-8, 10, 
12 and 13 and 
2hr after 
dosing on Day 
14. A 
“standard” and 
a “high fat” 
breakfast will 
be served 
approximately 
30 minutes 
prior to dosing 
on Day 9 and 
Day 11, 
respectively. 
On all study 
days, lunch 
and dinner will 
be served 
between 2 to 
3hr prior to 
dose 2 and 
dose 3, 


CONFIDENTIAL
205184
28
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
respectively.     
BID Dosing:
On Day 1 
through 14, 
subjects will 
fast 8hr 
overnight prior 
to dose 1. A 
breakfast will 
be served 
approximately 
2hr after dose 
1. Lunch will 
be served 
approximately 
4-5hr after 
dose 1. Dinner 
will be served 
between 2-3hr 
prior to dose 2. 
A snack may 
be consumed 
approximately 
2-3hr after 
dose 2.


CONFIDENTIAL
205184
29
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Water is 
permitted with 
dosing and at 
all times. 
Subjects will 
receive 
standardized 
meals 
scheduled at 
the same time 
in each period.
Meals will be 
served as per 
the site 
schedule on 
Days -1, 16 
and 17.
Haem/Chem/
Urinalysis Test 
(Include Liver 
Chemistries)
X
X
X
X
X
X
X
X
X
Collection on 
Day 1 no later 
than 1hr prior 
to dosing. To 
be drawn pre-
dose on Days 
2, 4, 7 and 10.
Fasting lipid panel
X
X
X
X
X
X
X
X
Collection on 


CONFIDENTIAL
205184
30
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Day 1 no later 
than 1hr prior 
to dosing. To 
be drawn pre-
dose on Days 
2, 4, 7 and 10.
Holter Monitoring (24-
hour)
X
Telemetry
X
X
X
Continuous at 
least 24 hr 
post-evening 
dose. Initiate 
at least 15 
min. prior to 
dosing.
PK blood sampling
Xd
Xe
Xe
Xe
Xe
Xe
Xf
Xf
Xg
d On Day 1, PK 
samples will 
be collected 
pre-dose and 
at the following 
time points 
post first-dose: 
20min, 40min, 
1hr, 1hr 30min, 
2hr, 3hr, 5hr, 


CONFIDENTIAL
205184
31
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
7hr, 9hr and 
11hr.
e OnDays 2,3 
4, 5 and 7 pre-
dose samples 
only.
f Days 9, and 
11: Cohort 2, 3 
and Cohort 4 
PK sampling 
will be 
collected pre-
dose and at 
the following 
time points 
post first-dose: 
20min, 40min, 
1hr, 1hr 30min, 
2hr, 3hr, 5hr, 
7hr (prior to 2nd
dose) 7hr 
20min, 7hr 40 
min, 8hr, 8hr 
30min, 9hr, 
10hr, 12hr. 


CONFIDENTIAL
205184
32
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Cohort 5 is 
currently not 
planned to 
have PK 
assessment 
but may be 
included 
depending on 
outcome of 
food effect in 
Cohorts 2, 3 
and 4.
g Day 14 
sampling for 
Cohorts 2, 3, 4 
and 5 will be 
over 24hr 
according to 
the following 
schedules:
For TID 
Dosing: PK 
samples to be 
taken pre-dose 
and then at the 


CONFIDENTIAL
205184
33
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
following time 
points post 
first-dose: 
20min, 40min, 
1hr, 1hr 30min, 
2hr, 3hr, 5hr, 
7hr (pre-2nd
dose) 7hr 
20min, 7hr 40 
min, 8hr, 8hr 
30min, 9hr, 
10hr, 12hr, 
14hr (pre 3rd
dose), 14hr 
20min, 14hr 40 
min, 15hr, 15hr 
30min, 16hr, 
17hr, 19hr, 
22hr, 24hr.
For BID 
Dosing: PK 
samples to be 
taken pre-dose 
on Day 1 and 
then at the 


CONFIDENTIAL
205184
34
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
subsequent 
time points 
post first-dose: 
20min, 40min, 
1hr, 1hr 30min, 
2hr, 3hr, 4hr, 
6hr, 8hr, 10hr, 
12hr (pre 2nd
dose), 12hr 
20min, 12hr 
40min, 13hr, 
13hr 30min, 
14hr, 15hr, 
16hr, 19hr, 
22hr, 24hr.
Metabolite sampling
Xh
h Metabolite 
sampling will 
be conducted 
pre-dose and 
2hr post first 
dose on Day 
14 only.
4β-hydroxycholesterol 
sampling
Xi
Xj
i Sample to be 
taken pre-dose 
on Day 1 in a 


CONFIDENTIAL
205184
35
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
fasted state.
j Sample to be 
taken at 24hr 
post first dose 
on Day 14. 
Sample should 
be in a fasted 
state.
Neuro. examination
X
X
X
X
X
TID Dosing: 
Neurological 
examinations 
to be 
conducted 
either on Day-
1 or pre-dose 
Day 1 and 
then at the 
subsequent 
time points 
post first dose: 
2hr, 9hr, 16hr, 
24hr and 48hr. 
To be 
completed pre-
dose on Day 7 


CONFIDENTIAL
205184
36
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
and then 48 hr 
post-last dose 
on Day 14.
BID Dosing: 
Neurological 
examinations 
to be 
conducted pre-
dose either on 
Day-1 or Day 1 
and then at the 
subsequent 
time points 
post first dose: 
2hr, 14hr, 24hr 
and 48hr. To 
be completed 
pre-dose on 
Day 7 and 
then 48hr post-
last dose on 
Day 14.
12-Lead ECG
X
X
T
X
X
X
X
X
Vital signs to 
include HR, 
BP, 
Vital signs
X
X
T
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


CONFIDENTIAL
205184
37
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
temperature 
and respiration 
rate. 
On Day 1:
TID Dosing:
12-Lead ECG 
and Vital Signs 
to be 
conducted on 
Day-1 and pre-
dose Day 1 
and then at the 
subsequent 
time points 
post first-dose: 
40min, 2hr, 
4hr, 7hr (pre-
2nd dose), 9hr, 
14hr (pre-3rd
dose), 16hr, 
24hr, 48hr. 
Then 24 and 
48hr after the 
first dose and 
last dose 


CONFIDENTIAL
205184
38
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
administered 
on Day 14.
BID Dosing:
12-Lead ECG 
and Vital Signs 
to be 
conducted pre-
dose either on 
Day-1 or Day 1 
and then at the 
subsequent 
time points 
post first-dose: 
40 min, 2hr, 
4hr, 12hr (pre-
2nd dose), 
14hr, 24hr, 
48hr. Then 24 
and 48hr after 
the first and 
last dose 
administered 
on Day 14.
OnDays 3 to 
14, pre-dose 


CONFIDENTIAL
205184
39
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
samples only.
T = Triplicate.
Randomization
X
Randomization 
can occur on 
either Day -1 
or Day 1.
Study Treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TID dosing:
GSK2982772 
or placebo will 
be 
administered 
using a 7hr, 
7hr and 10hr 
dosing interval.
BID dosing:
GSK2982772 
or placebo will 
be 
administered 
using a 12hr 
dosing interval.
Pharmacogenetic 
Sample (PGx)
X
A PGx blood 
sample is 
collected at the 
Day 1 visit, 


CONFIDENTIAL
205184
40
Procedure
Screening
(Up to 28
days 
before 
Day 1)
Study Period (Days)
Follow-
up
(No 
more 
than 14 
days 
post 
last 
dose)
Notes
-
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
after the 
subject has 
been 
randomized 
and provided 
informed 
consent for 
genetic 
research. If the 
sample is not 
collected on 
Day 1, it can 
be collected at 
any time 
during the 
study after 
randomization.
AE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


CONFIDENTIAL
205184
41
10.3.
Appendix 3: Assessment Windows
10.3.1.
Definitions of Assessment Windows for Analyses
No Assessment Windows will be defined for Analysis, and summaries and analyses will 
be based on nominal visits.


CONFIDENTIAL
205184
42
10.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
10.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
the start and/or stop date/time of the study treatment within the period for Part A and the 
start and/or stop date/time of the study treatment for Part B.
Study Phase
Definition
Pre-Treatment 
Date/Time ≤ Study Treatment Start Date/Time
On-Treatment
Study Treatment Start Date/Time < Date/Time ≤ Study Treatment Stop Date/Time
Post-Treatment
Date/Time > Study Treatment Stop Date/Time
10.4.1.1.
Study Phases for Concomitant Medications 
Treatment State
Definition
Prior
If medication end date is not missing and is before 28 days prior to screening visit
Concomitant
Any medication that is not a prior
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
10.4.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop 
date +1.

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 1 
days.

For studies with greater than one treatment period (e.g., crossover study), if AE 
onset is during one period and worsens during a later period it would be counted 
in both periods. For the initial period the logic would be as above. For the later 
period the logic would use the treatment dates associated with the later period:
      
Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop Date 
+ 1 days.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be Treatment Emergent.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.


CONFIDENTIAL
205184
43
10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Compound
One reporting effort will be set up for this study which combines Part A and Part B:
\ arenv \ arprod \ gsk2982772 \ mid205184 \final_01
Analysis Datasets 

Analysis datasets will be created according to Integrated Data Standards Library (IDSL) GSK A&R 
dataset standards 
Generation of RTF Files

RTF files will be generated for all tables within the final_01 reporting effort.
10.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless otherwise 
stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

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 

Do not include participant level listings in the main body of the GSK Clinical Study Report. All participant
level listings should be located in the modular appendices as ICH or non-ICH listings.

All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects CDISC and GSK 
Data Display Standards terminology.
Formats

All data will be reported according to the actual treatment the participant received, unless otherwise 
stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) 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 DP’s.
Planned and Actual Time

Reporting for tables and figures:

Planned time relative to dosing will be used in figures and summaries 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).


CONFIDENTIAL
205184
44

Unscheduled or unplanned readings will be presented within the participant’s listings.
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

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.
10.5.3.
Reporting Standards for Pharmacokinetic
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 
PKOne. 
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_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
The following PK parameters will be derived by the Programmer: C0, C7, C12, C14, 
C24.
Pharmacokinetic Parameter Data
Is 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.
Refer to PKOne.


CONFIDENTIAL
205184
45
10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
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 except for blood pressure measurements as only the average of the 3 
blood pressure readings will be recorded on the CRF.

If there are two values within a time window the value closest to the target day for that window will be 
used. If values are the same distance from the target, then the mean will be taken.

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    
10.6.2.
Study Population
Date of Birth 

Only the year of birth will be captured, and therefore the date of birth is then derived as follows:
Year of birth = YYYY → Date of birth = 30th June YYYY
Age


Calculated as the integer part of (date of screening – date of birth)
Age = integer part (date of screening – 30th June YYYY) / 365.25.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m) 2]
Treatment Compliance

Treatment compliance will be calculated based on the formula:  
Treatment Compliance = Number of Actual Doses / (Planned Treatment Duration in Days * 
Frequency)

Frequency is 2 for BID and 3 for TID. Treatment compliance could be greater than 100% if there are 
events of overdose. Cumulative compliance (since Day 1) at each visit will be calculated.

Planned Treatment Duration is defined as 1 day in Part A in each period and 14 days in Part B.
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. 

The cumulative dose will be based on the formula:
           Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.


CONFIDENTIAL
205184
46
10.6.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as:
o
If QTcF is machine read, then: 
                                     

If ECGs are manually read, the RR value preceding the measurement QT interval should be a 
collected value THEN do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals by Fridericia’s (QTcF) formulas 
will be calculated, in msec, depending on the availability of other measurements.

IF RR interval (msec) is provided then missing QTcF will be derived as: 
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 x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    


CONFIDENTIAL
205184
47
10.7.
Appendix 7: Reporting Standards for Missing Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e. as specified in the protocol) was defined as one who 
has completed all phases of the study including the last scheduled procedure shown in 
the SoA (see Appendix 2).

Withdrawn participants may be replaced in the study. Additional replacement 
participants may be randomized to guarantee that sufficient participants are treated 
with GSK2982772 at any given dose before escalating to the following dose. 
Replacement participants will be assigned to the same treatment sequence (Cohort 1) 
or treatment (Cohorts 2-5) but have different subject numbers and randomisation
numbers assigned.

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.
Liver 
Chemistry 
Stopping 
Criteria

Discontinuation of study treatment for abnormal liver tests is required when:
o
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.
o
ALT ≥ 3 x ULN.

Note: Refer to Appendix 7 of the protocol for details of the required assessments if a 
participant meets the above criteria.
QTc 
Stopping 
Criteria

A participant that meets either bulleted criterion based on the average of triplicate ECG
readings will be withdrawn from study treatment:
o
QTcF > 500 msec
o
Change from baseline: QTcF > 60 msec
Nervous 
System 
Stopping 
Criteria

A participant will be withdrawn from the study if:
o
A Grade 3 or greater CTCAE Nervous System finding is observed or a 
significant neurologic change from a participant’s baseline physical 
examination is observed.
o
Any adverse event included in the CTCAE for Nervous System, which is also 
considered to be clinically significant by the Principal Investigator, will be 
reviewed for potential participant withdrawal.
10.7.2.
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 is excluded from 
the table. 
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.


CONFIDENTIAL
205184
48
10.7.2.1.
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 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.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF 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.

The recorded partial date will be displayed in listings.


CONFIDENTIAL
205184
49
10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
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
∆from BL
↓0.075
Haemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
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
30
Calcium
mmol/L
2
2.75
Creatinine
umol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT


CONFIDENTIAL
205184
50
10.8.2.
ECG
ECG Parameter
Units
Category
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
H1
> 450 
< 480 
H2
≥ 480 
< 500 
H3
≥ 500 
Absolute PR Interval
msec
L, H
< 110
> 220
Absolute QRS Interval
msec
L, H
< 75
> 110
Change from Baseline
Increase from Baseline 
QTc
msec
H1
> 30  
≤ 59 
H2
≥ 60
10.8.3.
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
                   ≤ 8
                 ≥20
Temperature
ºC
   ≤ 35.5
≥37.8
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥ 20
≥ 40
≥ 20
≥ 40
Diastolic Blood Pressure
mmHg
≥ 10
≥ 20
≥ 10
≥ 20
Heart Rate
bpm
≥ 15
≥ 30
≥ 15
≥ 30


CONFIDENTIAL
205184
51
10.9.
Appendix 9: Abbreviations & Trade Marks
10.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
ALT
Alanine aminotransferase
A&R
Analysis and Reporting 
AUC
AUC Area under the concentration-time curve
AUC(0-7)
Area under the concentration-time curve from time zero to 7 hours post first 
dose (TID dosing)
AUC(7-14)
Area under the concentration-time curve from 7 to 14 hours post first dose 
(TID dosing)
AUC(14-24)
Area under the concentration-time curve from 14 to 24 hours post first dose 
(TID dosing)
AUC(0-12) 
Area under the concentration-time curve from 0 to 12 hours post first dose 
(BID dosing)
AUC(12-24)
Area under the concentration-time curve from 12 to 24 hours post first dose 
(BID dosing)
AUC(0-24) 
Area under the concentration-time curve from time zero to 24 hours post 
first dose
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to last 
time of quantifiable concentration within a participant across all treatments
AUC(0-τ)
AUC from 0 hours to the time of next dosing
BID
Twice a day
BMI
Body Mass Index
BP
Blood Pressure
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
Cmax
Maximum observed concentration
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CRF
Case Report Form
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
ECG
Electrocardiogram
EMA
European Medicines Agency
FDA
Food and Drug Administration


CONFIDENTIAL
205184
52
Abbreviation
Description
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Friderica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SoA
Schedule of Activities
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TID
Three times a day
Tmax
Time taken to maximum observed plasma drug concentration
10.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
HARP
NONMEM
SAS
WinNonlin


CONFIDENTIAL
205184
53
10.10.
Appendix 10: List of Data Displays
10.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.23
N/A
Safety
2.1 to 2.41
2.1 to 2.6
Pharmacokinetic
3.1 to 3.10
3.1 to 3.8
Section
Listings
ICH Listings
1 to 33 and 40 to 73
Other Listings
34 to 39 and 74 to 79
10.10.2.
Mock Example Shell Referencing
Non 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
N/A
N/A
N/A
Safety
N/A
SAFE_T1
SAFE_L1
Pharmacokinetic
N/A
N/A
N/A
NOTES: 

Non-Standard displays are indicated in the ‘IDSL Shell’ or ‘Programming Notes’ column as ‘[Non-Standard] + 
Reference.’
10.10.3.
Deliverables
Delivery
Description
SAC
Final Statistical Analysis Complete


CONFIDENTIAL
205184
54
10.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Part A (Cohort 1 – single ascending dose, 3-way crossover): Subject Disposition
1.1.
Safety
(Part A)
ES1A
Summary of Subject Disposition for the Subject Conclusion
Record (Part A)
ICH E3, FDAAA, EudraCT
Add footnote: Note: “Subjects” is used 
to refer to “Participants” in all data 
displays to reflect GSK display 
standards and CDISC SDTM/ADaM 
standards.
SAC
1.2.
Safety
(Part A)
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment (Part A)
ICH E3
SAC
1.3.
Safety
(Part A)
ES4
Summary of Disposition at Each Study Epoch (Part A)
ICH E3
SAC
1.4.
All Subject 
(Part A)
ES6
Summary of Screening Status and Reasons for Screen Failure
(Part A)
Journal Requirements
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Protocol Deviation
1.5.
Safety
(Part A)
DV1
Summary of Important Protocol Deviations (Part A)
ICH E3
SAC


CONFIDENTIAL
205184
55
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Part A (Cohort 1 – single ascending dose, 3-way crossover): Population Analysed
1.6.
All Subjects
(Part A)
SP1
Summary of Study Populations (Part A)
IDSL
Add the following footnotes:
[1] Subjects are included in the 
Randomised population if they were 
randomly assigned to treatment in the 
study.
[2] Subjects are included in the Safety 
population if they have been 
randomized and received at least one 
dose of study treatment.
[3] Subjects are included in the 
Pharmacokinetic population if they are 
in the Safety Population and a 
pharmacokinetic sample was obtained 
and analysed.
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Demographic and Baseline Characteristics
1.7.
Safety
(Part A)
DM3
Summary of Demographic Characteristics (Part A)
ICH E3, FDAAA, EudraCT
Do not include Weight (to be included in 
Vital Signs summary)
Add Footnote: 
[1] For calculating age, birth date is 
imputed as June 30 in the year of birth.
SAC


CONFIDENTIAL
205184
56
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.8.
Randomised
(Part A)
DM11
Summary of Age Ranges (Part A)
EudraCT
Only include age ranges applicable to 
the study (‘Adult (18-64 years)’ and 
‘>=65-84 years’))
Please add footnote to say that 
randomised population=enrolled 
population.
SAC
1.9.
Safety
(Part A)
DM5
Summary of Race and Racial Combinations (Part A)
ICH E3, FDA, FDAAA, EudraCT
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Medical Conditions and Prior and Concomitant Medications
1.10.
Safety
(Part A)
MH1 / 
MH4
Summary of Current/Past Medical Conditions (Part A)
ICH E3 
Separate summaries for Current & Past 
conditions, if collected.
SAC 
1.11.
Safety 
(Part A)
CM1
Summary of Concomitant Medications (Part A)
ICH E3
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Exposure and Treatment Compliance
1.12.
Safety 
(Part A)
EX5
Summary of Exposure to Study Treatment (Part A)
ICH E3
Total daily dose (mg) and number of 
days
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Subject Disposition
1.13.
Safety
(Part B)
ES1
Summary of Subject Disposition for the Subject Conclusion 
Record (Part B)
ICH E3, FDAAA, EudraCT
SAC
1.14.
Safety 
(Part B)
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment (Part B)
ICH E3
SAC


CONFIDENTIAL
205184
57
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.15.
All Subjects 
(Part B)
ES6
Summary of Screening Status and Reasons for Screen Failure 
(Part B)
Journal Requirements
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Protocol Deviation
1.16.
Safety
(Part B)
DV1
Summary of Important Protocol Deviations (Part B)
ICH E3
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Population Analysed
1.17.
Safety 
(Part B)
SP1
Summary of Study Populations (Part B)
IDSL
Add the following footnotes: 
[1] Subjects are included in the 
Randomised population if they were 
randomly assigned to treatment in the 
study.
[2] Subjects are included in the Safety 
population if they have been 
randomized and received at least one 
dose of study treatment.
[3] Subjects are included in the 
Pharmacokinetic population if they are 
in the Safety Population and a 
pharmacokinetic sample was obtained 
and analysed.
SAC


CONFIDENTIAL
205184
58
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Demographic and Baseline Characteristics
1.18.
Safety 
(Part B)
DM1
Summary of Demographic Characteristics (Part B)
ICH E3, FDAAA, EudraCT
Do not include Weight (to be included in 
Vital Signs summary)
[1] For calculating age, birth date is 
imputed as June 30 in the year of birth.
SAC
1.19.
Randomised
(Part B)
DM11
Summary of Age Ranges (Part B)
EudraCT
Only include age ranges applicable to 
the study (‘Adult (18-64 years)’ and 
‘>=65-84 years’))
SAC
1.20.
Safety 
(Part B)
DM5
Summary of Race and Racial Combinations (Part B)
ICH E3, FDA, FDAAA, EudraCT
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Medical Conditions and Prior and Concomitant Medications
1.21.
Safety
(Part B)
MH1 / 
MH4
Summary of Current/Past Medical Conditions (Part B)
ICH E3 
Separate summaries for Current & Past 
conditions, if collected.
SAC 
1.22.
Safety 
(Part B)
CM1
Summary of Concomitant Medications (Part B)
ICH E3
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Exposure and Treatment Compliance
1.23.
Safety 
(Part B)
EX1
Summary of Exposure to Study Treatment (Part B)
ICH E3
Total daily dose, cumulative actual 
dose and number of days.
SAC


CONFIDENTIAL
205184
59
10.10.5.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Part A (Cohort 1 – single ascending dose, 3-way crossover): Adverse Events (AEs)
2.1.
Safety
(Part A)
AE1
Summary of All Adverse Events by System Organ Class and
Preferred Term (Part A)
SAC
2.2.
Safety 
(Part A)
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term (Part A)
ICH E3
SAC
2.3.
Safety
(Part A)
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity (Part A)
ICH E3
SAC
2.4.
Safety 
(Part A)
AE15
Summary of Common (>=10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects
and Occurrences) (Part A)
FDAAA, EudraCT
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Serious and Other Significant Adverse Events
2.5.
Safety 
(Part A)
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) 
(Part A)
FDAAA, EudraCT
Only if 3 or more SAEs reported
SAC
2.6.
Safety 
(Part A)
AE3
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
Overall Frequency (Part A)
IDSL
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Laboratory: Chemistry 
2.7.
Safety
(Part A)
LB1
Summary of Chemistry Changes from Baseline (Part A)
ICH E3
SAC
2.8.
Safety 
(Part A)
LB17
Summary of Worst Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline (Part A)
ICH E3
SAC


CONFIDENTIAL
205184
60
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.9.
Safety 
(Part A)
LB17
Summary of Worst Case Lipids Outside Laboratory Normal 
Range Post-Baseline Relative to Baseline (Part A)
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Laboratory: Hematology
2.10.
Safety
(Part A)
LB1
Summary of Hematology Changes from Baseline (Part A)
ICH E3
SAC
2.11.
Safety 
(Part A)
LB17
Summary of Worst Case Hematology Results by PCI Criteria 
Post-Baseline Relative to Baseline (Part A)
ICH E3
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Laboratory: Urinalysis
2.12.
Safety
(Part A)
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline (Part A)
ICH E3
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Laboratory: Hepatobiliary (Liver)
2.13.
Safety 
(Part A)
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting (Part A)
IDSL
SAC
2.14.
Safety 
(Part A)
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities (Part A)
IDSL
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): ECG
2.15.
Safety 
(Part A)
EG1
Summary of ECG Findings (Part A)
IDSL
SAC
2.16.
Safety 
(Part A)
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category (Part A)
IDSL
SAC
2.17.
Safety 
(Part A)
EG2
Summary of Change from Baseline in ECG Values by Visit (Part 
A)
IDSL
SAC


CONFIDENTIAL
205184
61
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.18.
Safety
(Part A)
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category (Part A)
IDSL
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Vital Signs
2.19.
Safety 
(Part A)
VS1
Summary of Change from Baseline in Vital Signs (Part A)
ICH E3
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Suicide Risk Monitoring
2.20.
Safety
(Part A)
CSSRS1
Summary of Subjects with C-SSRS Suicidal Ideation or
Behaviour during Treatment (Part A)
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Adverse Events (AEs))
2.21.
Safety
(Part B)
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term (Part B)
ICH E3
SAC
2.22.
Safety
(Part B)
AE3
Summary of Common (>=10%) Adverse Events by Overall 
Frequency (Part B)
ICH E3
SAC
2.23.
Safety 
(Part B)
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity (Part B)
ICH E3
SAC
2.24.
Safety 
(Part B)
AE15
Summary of Common (>=10%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subject
and Occurrences) (Part B)
FDAAA, EudraCT
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Serious and Other Significant Adverse Events
2.25.
Safety 
(Part B)
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences) 
(Part B)
FDAAA, EudraCT
Only if 3 or more SAEs reported
SAC


CONFIDENTIAL
205184
62
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.26.
Safety
(Part B)
AE3
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
Overall Frequency (Part B)
IDSL
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Laboratory: Chemistry 
2.27.
Safety
(Part B)
LB1
Summary of Chemistry Changes from Baseline (Part B)
ICH E3
SAC
2.28.
Safety
(Part B)
LB17
Summary of Worst Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline (Part B)
ICH E3
SAC
2.29.
Safety 
(Part A)
LB17
Summary of Worst Case Lipids Outside Laboratory Normal 
Range Post-Baseline Relative to Baseline (Part B)
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Laboratory: Hematology
2.30.
Safety 
(Part B)
LB1
Summary of Hematology Changes from Baseline (Part B)
ICH E3
SAC
2.31.
Safety 
(Part B)
LB17
Summary of Worst Case Hematology Results by PCI Criteria 
Post-Baseline Relative to Baseline (Part B)
ICH E3
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Laboratory: Urinalysis
2.32.
Safety 
(Part B)
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline (Part B)
ICH E3
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Laboratory: Hepatobiliary (Liver)
2.33.
Safety
(Part B)
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting (Part B)
IDSL
SAC
2.34.
Safety 
(Part B)
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities (Part B)
IDSL
SAC


CONFIDENTIAL
205184
63
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Laboratory: Other
2.35.
Pharmacoki
netic
(Part B)
Non-Standard
SAFE_T1
Summary of Plasma 4β-hydroxycholesterol to Cholesterol Ratio
(Part B)
Include SE and 95% CI.
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): ECG
2.36.
Safety 
(Part B)
EG1
Summary of ECG Findings (Part B) 
IDSL
SAC
2.37.
Safety
(Part B)
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category (Part B)
IDSL
SAC
2.38.
Safety 
(Part B)
EG2
Summary of Change from Baseline in ECG Values by Visit (Part 
B)
IDSL
SAC
2.39.
Safety 
(Part B)
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category (Part B)
IDSL
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Vital Signs
2.40.
Safety 
(Part B)
VS1
Summary of Change from Baseline in Vital Signs (Part B)
ICH E3
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Suicide Risk Monitoring
2.41.
Safety 
(Part B)
CSSRS1
Summary of Subjects with C-SSRS Suicidal Ideation or
Behaviour during Treatment (Part B)
SAC


CONFIDENTIAL
205184
64
10.10.6.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Part A (Cohort 1 – single ascending dose, 3-way crossover): Adverse Events
2.1.
Safety
(Part A)
AE10
Plot of Common (>=10%) Adverse Events and Relative Risk
(Part A)
IDSL
Common defined as >10%
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Hepatobiliary (Liver)
2.2.
Safety
(Part A)
LIVER14
Scatter Plot of Maximum vs. Baseline for ALT (Part A)
SAC
2.3.
Safety 
(Part A)
LIVER9
Scatter Plot for Maximum ALT vs. Maximum Total Bilirubin (Part 
A)
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Adverse Events
2.4.
Safety 
(Part B)
AE10
Plot of Common (>=10%) Adverse Events and Relative Risk
(Part B)
IDSL
Common defined as >10%
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Hepatobiliary (Liver)
2.5.
Safety
(Part B)
LIVER14
Scatter Plot of Maximum vs. Baseline for ALT (Part B)
SAC
2.6.
Safety 
(Part B)
LIVER9
Scatter Plot for Maximum ALT vs. Maximum Total Bilirubin (Part 
B)
SAC


CONFIDENTIAL
205184
65
10.10.7.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Part A (Cohort 1 – single ascending dose, 3-way crossover): Pharmacokinetic Concentrations
3.1.
Pharmacokinetic 
(Part A)
PK01
Summary of Plasma GSK2982772 Pharmacokinetic 
Concentration-Time Data (Part A)
Include column for 95% CI.
SAC
3.2.
Pharmacokinetic 
(Part A)
PK01
Summary of Plasma M8 (GSK3562183) Pharmacokinetic 
Concentration-Time Data (Part A)
Include column for 95% CI.
SAC
3.3.
Pharmacokinetic 
(Part A)
PK01
Summary of Plasma M9 (GSK2997852) Pharmacokinetic 
Concentration-Time Data (Part A)
Include column for 95% CI.
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Pharmacokinetic Parameters
3.4.
Pharmacokinetic 
(Part A)
PK03
Summary of Derived Plasma GSK2982772 Pharmacokinetic 
Parameters (Part A)
Include columns for parameter, 
period, treatment, N, n, mean, 90% 
CI, standard deviation [SD],
standard error [SE], median, 
minimum and maximum.
SAC
3.5.
Pharmacokinetic 
(Part A)
PK05
Summary of Log-Transformed Derived Plasma GSK2982772 
Pharmacokinetic Parameters (Part A)
Include columns for parameter, 
period, treatment, N, n, geometric 
mean, 90% CI of geometric mean, 
standard deviation [SD] of logged 
data and %CVb.
Do not summarise Tmax.
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Pharmacokinetic Concentrations
3.6.
Pharmacokinetic 
(Part B)
PK01
Summary of Plasma GSK2982772 Pharmacokinetic 
Concentration-Time Data (Part B)
Include column for 95% CI and the 
SE.
SAC


CONFIDENTIAL
205184
66
Pharmacokinetic: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.7.
Pharmacokinetic 
(Part B)
PK01
Summary of Plasma M8 (GSK3562183) Pharmacokinetic 
Concentration-Time Data (Part B)
Include column for 95% CI and the 
SE.
SAC
3.8.
Pharmacokinetic 
(Part B)
PK01
Summary of Plasma M9 (GSK2997852) Pharmacokinetic 
Concentration-Time Data (Part B)
Include column for 95% CI and the 
SE.
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Pharmacokinetic Parameters
3.9.
Pharmacokinetic 
(Part B)
PK03
Summary of Derived Plasma GSK2982772 Pharmacokinetic 
Parameters (Part B)
Include columns for parameter, 
treatment, N, day, fed/fasted state, 
n, mean, 90% CI, standard 
deviation [SD], SE, median, 
minimum and maximum.
SAC
3.10.
Pharmacokinetic 
(Part B)
PK05
Summary of Log-Transformed Derived Plasma GSK2982772 
Pharmacokinetic Parameters (Part B)
Include columns for parameter, 
treatment, N, day, fed/fasted state, 
n, geometric mean, 90% CI of 
geometric mean, standard 
deviation [SD] of logged data and 
%CVb.
Do not summarise Tmax.
SAC


CONFIDENTIAL
205184
67
10.10.8.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Part A (Cohort 1 – single ascending dose, 3-way crossover): Pharmacokinetic Concentrations
3.1.
Pharmacokinetic 
(Part A)
PK16b
Individual Plasma GSK2982772 Concentration-Time Plots 
(Linear and Semi-log) (Part A)
SAC
3.2.
Pharmacokinetic 
(Part A)
PK24
Individual Plasma GSK2982772 Concentration-Time Plots 
(Linear and Semi-log) by Treatment (Part A)
SAC
3.3.
Pharmacokinetic 
(Part A)
PK19
Mean (+ SE) Plasma GSK2982772 Concentration-Time Plots 
(Linear and Semi-log) (Part A)
SAC
3.4.
Pharmacokinetic 
(Part A)
PK20
Median (Range) Plasma GSK2982772 Concentration-Time 
Plots (Linear and Semi-log) (Part A)
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Pharmacokinetic Concentrations
3.5.
Pharmacokinetic 
(Part B)
PK16a
Individual Plasma GSK2982772 Concentration-Time Plots 
(Linear and Semi-log) (Part B)
SAC
3.6.
Pharmacokinetic 
(Part B)
PK24
Individual Plasma GSK2982772 Concentration-Time Plots 
(Linear and Semi-log) by Treatment (Part B)
SAC
3.7.
Pharmacokinetic 
(Part B)
PK19
Mean (+ SE) Plasma GSK2982772 Concentration-Time Plots 
(Linear and Semi-log) (Part B)
SAC
3.8.
Pharmacokinetic 
(Part B)
PK20
Median (Range) Plasma GSK2982772 Concentration-Time 
Plots (Linear and Semi-log) (Part B)
SAC


CONFIDENTIAL
205184
68
10.10.9.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Part A (Cohort 1 – single ascending dose, 3-way crossover): Subject Disposition
1.
All Subjects 
(Part A)
ES7
Listing of Reasons for Screen Failure (Part A)
Journal Guidelines
SAC
2.
Safety
(Part A)
ES3
Listing of Reasons for Study Withdrawal (Part A)
ICH E3
SAC
3.
Safety 
(Part A)
SD3
Listing of Reasons for Study Treatment Discontinuation (Part 
A)
ICH E3
SAC
4.
Safety
(Part A)
BL2
Listing of Subjects for Whom the Treatment Blind was Broken
(Part A)
ICH E3
SAC
5.
Safety
(Part A)
TA1
Listing of Planned and Actual Treatments (Part A)
IDSL
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Protocol Deviations
6.
Safety
(Part A)
DV2A
Listing of Important Protocol Deviations (Part A)
ICH E3
SAC
7.
Safety
(Part A)
IE4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
(Part A)
ICH E3
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Populations Analysed
8.
All Subjects 
(Part A)
SP3a
Listing of Subjects Excluded from Any Population (Part A)
ICH E3
SAC


CONFIDENTIAL
205184
69
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Part A (Cohort 1 – single ascending dose, 3-way crossover): Demographic and Baseline Characteristics
9.
Safety
(Part A)
DM4
Listing of Demographic Characteristics (Part A)
ICH E3 
Do not include Weight.
SAC
10.
Safety
(Part A)
DM10
Listing of Race (Part A)
ICH E3
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Prior and Concomitant Medications
11.
Safety
(Part A)
CP_CM4
Listing of Concomitant Medications (Part A)
IDSL
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Exposure and Treatment Compliance
12.
Safety
(Part A)
EX4
Listing of Exposure Data (Part A)
ICH E3
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Adverse Events
13.
Safety 
(Part A)
AE9CP
Listing of All Adverse Events (Part A)
ICH E3
SAC
14.
Safety
(Part A)
AE7
Listing of Subject Numbers for Individual Adverse Events (Part 
A)
ICH E3
SAC
15.
Safety
(Part A)
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text (Part A)
IDSL
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Serious and Other Significant Adverse Events
16.
Safety
(Part A)
AE9CPa
Listing of Serious Adverse Events (Part A)
ICH E3
Include fatal and non-fatal status
SAC


CONFIDENTIAL
205184
70
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
17.
Safety 
(Part A)
AE14
Listing of Reasons for Considering as a Serious Adverse Event 
(Part A)
ICH E3
SAC
18.
Safety 
(Part A)
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment (Part A)
ICH E3
Include fatal and non-fatal status
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Hepatobiliary (Liver)
19.
Safety
(Part A)
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events (Part A)
IDSL
SAC
20.
Safety 
(Part A)
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events (Part A)
IDSL
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): All Laboratory
21.
Safety
(Part A)
LB6
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance (Part A)
ICH E3
SAC
22.
Safety 
(Part A)
LB6
Listing of Laboratory Values of Potential Clinical Importance 
(Part A)
SAC
23.
Safety
(Part A)
LB6
Listing of All Lipid Data for Subjects with Any Value outside of 
Laboratory Normal Range (Part A)
Please include additional column 
after Lab Param for fasting status 
(if present)
SAC
24.
Safety
(Part A)
LB14
Listing of Laboratory Data with Character Results (Part A)
ICH E3
SAC
25.
Safety
(Part A)
UR2B
Listing of All Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance (Part A)
ICH E3
SAC


CONFIDENTIAL
205184
71
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Part A (Cohort 1 – single ascending dose, 3-way crossover): ECG
26.
Safety
(Part A)
EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance (Part A)
IDSL
Include absolute PCI subjects.
Footnote:
Note: H= High absolute value, L= Low 
absolute value.
For QTc Interval H1= >450msec and 
<480msec, H2= >=480msec and 
<500msec, H3= >=500msec.
SAC
27.
Safety
(Part A)
EG4
Listing of All ECG Changes for Subjects with Any Change of 
Potential Clinical Importance (Part A)
Include change from baseline PCI 
subjects.
Footnote:
Note: H=High change from baseline 
value, L=Low change from baseline 
value.
For QTc Interval H1= >30msec and 
<=59msec, H2= >=60msec
SAC
28.
Safety
(Part A)
EG4
Listing of ECG Values of Potential Clinical Importance (Part A)
IDSL
Include absolute PCIs.
Footnote:
Note: H=High absolute value, L=Low 
absolute value.
For QTc Interval H1= >450msec and 
<480msec, H2= >=480msec and 
<500msec, H3= >=500msec.
SAC


CONFIDENTIAL
205184
72
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
29.
Safety
(Part A)
EG4
Listing of ECG Changes of Potential Clinical Importance (Part 
A)
Include change from baseline PCIs.
Footnote:
Note: H=High change from baseline 
value, L=Low change from baseline 
value.
For QTc Interval H1= >30msec and 
<=59msec, H2= >=60msec
SAC
30.
Safety 
(Part A)
EG6
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding (Part A)
IDSL
SAC
31.
Safety
(Part A)
EG6
Listing of Abnormal ECG Findings (Part A)
IDSL
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Vital Signs
32.
Safety 
(Part A)
VS5
Listing of All Vital Signs Values for Subjects with Any Value of 
Potential Clinical Importance (Part A)
IDSL
Footnote:
Note: For absolute results: H=High, 
L=Low. For change from baseline: 
H1=Lower Increase, H2=Upper 
Increase, L1=Lower Decrease, 
L2=Upper Decrease.
SAC
33.
Safety 
(Part A)
VS5
Listing of Vital Signs Values of Potential Clinical Importance 
(Part A)
IDSL
Footnote:
Note: For absolute results: H=High, 
L=Low. For change from baseline: 
H1=Lower Increase, H2=Upper 
Increase, L1=Lower Decrease, 
L2=Upper Decrease.
SAC


CONFIDENTIAL
205184
73
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group):  Disposition
40
All Subjects 
(Part B)
ES7
Listing of Reasons for Screen Failure (Part B)
Journal Guidelines
SAC
41
Safety 
(Part B)
ES2
Listing of Reasons for Study Withdrawal (Part B)
ICH E3
SAC
42
Safety 
(Part B)
SD2
Listing of Reasons for Study Treatment Discontinuation (Part 
B)
ICH E3
SAC
43
Safety 
(Part B)
BL1
Listing of Subjects for Whom the Treatment Blind was Broken 
(Part B)
ICH E3
SAC
44
Safety 
(Part B)
TA1 
Listing of Planned and Actual Treatments (Part B)
IDSL
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Protocol Deviations
45
Safety 
(Part B)
DV2
Listing of Important Protocol Deviations (Part B)
ICH E3
SAC
46
Safety (Part B)
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
(Part B)
ICH E3
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Populations Analysed
47
All Subjects 
(Part B)
SP3
Listing of Subjects Excluded from Any Population (Part B)
ICH E3
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Demographic and Baseline Characteristics
48
Safety
(Part B)
DM2
Listing of Demographic Characteristics (Part B)
ICH E3
Do not include Weight.
SAC


CONFIDENTIAL
205184
74
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
49
Safety
(Part B)
DM9
Listing of Race (Part B)
ICH E3
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Prior and Concomitant Medications
50
Safety
(Part B)
CP_CM3
Listing of Concomitant Medications (Part B)
IDSL
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Exposure and Treatment Compliance
51
Safety
(Part B)
EX3
Listing of Exposure Data (Part B)
ICH E3
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Adverse Events
52
Safety 
(Part B)
AE8CP
Listing of All Adverse Events (Part B)
ICH E3
SAC
53
Safety
(Part B)
AE7
Listing of Subject Numbers for Individual Adverse Events (Part 
B)
ICH E3
SAC
54
Safety 
(Part B)
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text (Part B)
IDSL
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Serious and Other Significant Adverse Events
55
Safety 
(Part B)
AE8CPa
Listing of Serious Adverse Events (Part B)
ICH E3
Include fatal and non-fatal status.
SAC
56
Safety
(Part B)
AE14
Listing of Reasons for Considering as a Serious Adverse Event 
(Part B)
ICH E3
SAC
57
Safety
(Part B)
AE8CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment (Part B)
ICH E3
Include fatal and non-fatal status.
SAC


CONFIDENTIAL
205184
75
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Hepatobiliary (Liver)
58
Safety
(Part B)
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events (Part B)
IDSL
SAC
59
Safety
(Part B)
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events (Part B)
IDSL
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): All Laboratory
60
Safety
(Part B)
LB5
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance (Part B)
ICH E3
SAC
61
Safety
(Part B)
LB5
Listing of Laboratory Values of Potential Clinical Importance 
(Part B)
SAC
62
Safety
(Part A)
LB6
Listing of All Lipid Data for Subjects with Any Value outside of 
Laboratory Normal Range
Please include additional column after 
Lab Param for fasting status (if 
present)
SAC
63
Safety 
(Part B)
LB14
Listing of Laboratory Data with Character Results (Part B)
ICH E3
SAC
64
Safety
(Part B)
UR2A
Listing of All Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance (Part B)
ICH E3
SAC
65
Pharmacokinetic 
(Part B)
Non-Standard
SAFE_L1
Listing of Plasma Cholesterol and 4β-hydroxycholesterol 
Concentration-Time (ug/mL) Data (Part B)
SAC


CONFIDENTIAL
205184
76
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): ECG
66
Safety
(Part B)
EG3
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance (Part B)
IDSL
Include absolute PCI subjects.
Footnote:
Note: H= High absolute value, L= Low 
absolute value.
For QTc Interval H1= >450msec and 
<480msec, H2= >=480msec and 
<500msec, H3= >=500msec.
SAC
67
Safety
(Part B)
EG3
Listing of All ECG Changes for Subjects with Any Change of 
Potential Clinical Importance (Part B)
Include change from baseline PCI 
subjects.
Footnote:
Note: H=High change from baseline 
value, L=Low change from baseline 
value.
For QTc Interval H1= >30msec and 
<=59msec, H2= >=60msec
SAC
68
Safety
(Part B)
EG3
Listing of ECG Values of Potential Clinical Importance (Part B)
IDSL
Include absolute PCIs.
Footnote:
Note: H=High absolute value, L=Low 
absolute value.
For QTc Interval H1= >450msec and 
<480msec, H2= >=480msec and 
<500msec, H3= >=500msec.
SAC


CONFIDENTIAL
205184
77
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
69
Safety
(Part B)
EG3
Listing of ECG Changes of Potential Clinical Importance (Part 
B)
Include change from baseline PCIs.
Footnote:
Note: H=High change from baseline 
value, L=Low change from baseline 
value.
For QTc Interval H1= >30msec and 
<=59msec, H2= >=60msec
SAC
70
Safety
(Part B)
EG5
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Finding (Part B)
IDSL
SAC
71
Safety
(Part B)
EG5
Listing of Abnormal ECG Findings (Part B)
IDSL
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Vital Signs
72
Safety
(Part B)
VS4
Listing of All Vital Signs Values for Subjects with Any Value of 
Potential Clinical Importance (Part B)
IDSL
Footnote:
Note: For absolute results: H=High, 
L=Low. For change from baseline: 
H1=Lower Increase, H2=Upper 
Increase, L1=Lower Decrease, 
L2=Upper Decrease.
SAC


CONFIDENTIAL
205184
78
ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
73
Safety
(Part B)
VS4
Listing of Vital Signs Values of Potential Clinical Importance 
(Part B)
IDSL
Footnote:
Note: For absolute results: H=High, 
L=Low. For change from baseline: 
H1=Lower Increase, H2=Upper 
Increase, L1=Lower Decrease, 
L2=Upper Decrease.
SAC
10.10.10. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Part A (Cohort 1 – single ascending dose, 3-way crossover): Columbia Suicide Severity Rating Scale (C-SSRS)
34
Safety
(Part A)
ECSSRS4
Listing of C-SSRS suicidal Ideation and Behaviour Data (Part 
A)
SAC
35
Safety
(Part A)
ECSSRS5
Listing of C-SSRS Suicidal Behaviour Details (Part A)
SAC
Part A (Cohort 1 – single ascending dose, 3-way crossover): Pharmacokinetic Data
36
Pharmacokinetic 
(Part A)
PK08
Listing of Plasma GSK2982772 Pharmacokinetic 
Concentration-Time Data (Part A)
SAC
37
Pharmacokinetic 
(Part A)
PK07
Listing of Plasma M8 (GSK3562183) Pharmacokinetic
Concentration-Time Data (Part A)
SAC


CONFIDENTIAL
205184
79
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
38
Pharmacokinetic 
(Part A)
PK07
Listing of Plasma M9 (GSK2997852) Pharmacokinetic
Concentration-Time Data (Part A)
SAC
39
Pharmacokinetic 
(Part A)
PK14
Listing of Derived Plasma GSK2982772 Pharmacokinetic 
Parameters (Part A)
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Columbia Suicide Severity Rating Scale (C-SSRS)
74
Safety
(Part B)
ECSSRS4
Listing of C-SSRS suicidal Ideation and Behaviour Data (Part 
B)
SAC
75
Safety
(Part B)
ECSSRS5
Listing of C-SSRS Suicidal Behaviour Details (Part B)
SAC
Part B (Cohorts 2, 3, 4 and 5 – repeat dose, sequential-group): Pharmacokinetic Data
76
Pharmacokinetic 
(Part B)
PK07
Listing of Plasma GSK2982772 Pharmacokinetic 
Concentration-Time Data (Part B)
SAC
77
Pharmacokinetic 
(Part B)
PK07
Listing of Plasma M8 (GSK3562183) Pharmacokinetic 
Concentration-Time Data (Part B)
SAC
78
Pharmacokinetic 
(Part B)
PK07
Listing of Plasma M9 (GSK2997852) Pharmacokinetic 
Concentration-Time Data (Part B)
SAC
79
Pharmacokinetic 
(Part B)
PK13
Listing of Derived Plasma GSK2982772 Pharmacokinetic 
Parameters (Part B)
SAC


CONFIDENTIAL
205184
80
10.11.
Appendix 11: Example Mock Shells for Data Displays
Example:    SAFE_T1
                 Page 1 of n
Protocol:     205184
Population: Pharmacokinetic
Table x.x
Summary of Plasma 4β-hydroxycholesterol to Cholesterol Ratio (Part B)
Parameter: xxxx
Treatment
N
Study Day
Planned 
Relative
Time
n
Mean
95% CI
(Lower, Upper)
SD
SE
Median
Min.
Max.
120mg TID
24
Day -1/1
Pre-dose
24
xxxx.x
(xxxx.xx,xxxx.xx)
xx.xx
xxxx.x
xxxx.x
xxxx
xxxx
Day 14
24 hr
23
xxxx.x
(xxxx.xx,xxxx.xx)
xx.xx
xxxx.x
xxxx.x
xxxx
xxxx
240mg TID
24
Day -1/1
Pre-dose
24
xxxx.x
(xxxx.xx,xxxx.xx)
xx.xx
xxxx.x
xxxx.x
xxxx
xxxx
Day 14
24 hr
21
xxxx.x
(xxxx.xx,xxxx.xx)
xx.xx
xxxx.x
xxxx.x
xxxx
xxxx
360mg BID
24
Day -1/1
Pre-dose
24
xxxx.x
(xxxx.xx,xxxx.xx)
xx.xx
xxxx.x
xxxx.x
xxxx
xxxx
Day 14
24 hr
24
xxxx.x
(xxxx.xx,xxxx.xx)
xx.xx
xxxx.x
xxxx.x
xxxx
xxxx


CONFIDENTIAL
205184
81
Example:    SAFE_L1
                 Page 1 of n
Protocol:     205184
Population: Pharmacokinetic
Table x.x
Listing of Plasma Cholesterol and 4B-hydroxycholesterol Concentration-Time (ug/mL) Data (Part B)
Treatment: XXXXX
Inv./
Subj.
Visit/
Date/
Study Day
Planned 
Relative
Time
Actual Time
Time 
Deviation 
(Hours)
Actual 
Relative 
Time
Analyte  
Concentration 
(ug/mL)         
Ratio  [1]
Excluded from 
Analysis? [2]
XXXXX/
XXXXXX
Part B Day 1
DDMMMYYYY/
1
Pre-dose
h:mm
-X.XX  
-Xh XXm  4BOH CHOLESTEROL
xxxx.x
xxx.xx
CHOLESTEROL     
xxxx.x
Part B Day 14
DDMMMYYYY/
1
Pre-dose
h:mm
-X.XX  
-Xh XXm  4BOH CHOLESTEROL
xxxx.x
CHOLESTEROL     
xxxx.x
[1] Plasma 4B-hydroxycholesterol to Cholesterol ratio.     
[2] Samples excluded from analyses due to >1% haemolysis.