Clinical trial NCT03590613
Conditions: Autoimmune Diseases
Keywords: Sentinel-dosing GSK2982772 Japnese Dose-ascending Crossover Healthy
Sponsor: GlaxoSmithKline
Start date: 2018-07-19; Completion date: 2018-09-26
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The study plans to enroll approximately 12 subjects. The main objective of the study is to assess the safety, tolerability and pharmacokinetics (PK) of the three times a day (TID), dosing of GSK2982772, in Japanese healthy male subjects. The study will comprise of four study periods each at least 7 days in duration with subjects in-house for 4 nights (through 72 hrs after the first dose). During each treatment period (TP), subjects will be admitted to the unit the day before dosing and will be discharged after completion of the 72 hours post-dose assessments. There will be a washout of atleast 7-days between the TP doses for each individual, post which there will be 7-days follow-up. The dose range proposed in this study is based on a low starting dose, which will be escalated to the highest dose that is intended for the Phase 2b dose range study. The decision to proceed to the next dose-level, of GSK2982772 within the study will be made by principal investigator and GSK Medical Monitor per each dosing periods. The study duration is approximately 22 weeks.

Detailed description:

Arms: arm 1: The eligible subjects in this arm will receive placebo TID in TP1, GSK2982772 60 mg TID in TP2, GSK2982772 120mg TID in TP3 and GSK2982772 240 mg TID in TP4. GSK2982772 or placebo will be administered at 0 hour (the first dosing), 7 hours (the second dosing) and 14 hours (the third dosing) on Day 1 in each TP. Subjects will fast overnight for 8 hours before first dose. Each TP will be followed by a washout period of at least 7 days, for each subject. arm 2: The eligible subjects in this arm will receive GSK2982772 60 mg TID in TP1, placebo TID in TP2, GSK2982772 120mg TID in TP3 and GSK2982772 240 mg TID in TP4. GSK2982772 or placebo will be administered at 0 hour (the first dosing), 7 hours (the second dosing) and 14 hours (the third dosing) on Day 1 in each TP. Subjects will fast overnight for 8 hours before first dose. Each TP will be followed by a washout period of at least 7 days, for each subject. arm 3: The eligible subjects in this arm will receive GSK2982772 60 mg TID in TP1, GSK2982772 120mg TID in TP2, placebo TID in TP3 and GSK2982772 240 mg TID in TP4. GSK2982772 or placebo will be administered at 0 hour (the first dosing), 7 hours (the second dosing) and 14 hours (the third dosing) on Day 1 in each TP. Subjects will fast overnight for 8 hours before first dose. Each TP will be followed by a washout period of at least 7 days, for each subject. arm 4: The eligible subjects in this arm will receive GSK2982772 60 mg TID in TP1, GSK2982772 120mg TID in TP2, GSK2982772 240 mg TID in TP3 and placebo TID in TP4. GSK2982772 or placebo will be administered at 0 hour (the first dosing), 7 hours (the second dosing) and 14 hours (the third dosing) on Day 1 in each TP. Subjects will fast overnight for 8 hours before first dose. Each TP will be followed by a washout period of at least 7 days, for each subject.
Interventions: intervention 1: GSK2982772 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK2982772 will be available as white to almost white, round, film coated tablets to be administered via oral route intervention 2: Placebo matching GSK2982772 will be available as white to almost white, round, film coated tablets to be administered via oral route.

Protocol documents:
Prot_001.pdf: 
2017N311130_00  
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
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TITLE PAGE 
Protocol Title: A single-centre, randomized, double-blind, dose-ascending, placebo-
controlled study to evaluate the safety, tolerability, and pharmacokinetics of oral TID 
doses (one day) of GSK2982772 in Japanese healthy male subjects 
Protocol Number: 205037 
Short Title: Phase I study of GSK2982772 in Japanese healthy male subjects 
Compound Number: GSK2982772 
 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline K.K. (GSK) 
Akasaka Intercity AIR, 8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052 Japan 
Medical Monitor Name and Contact Information: 
 
GlaxoSmithKline K.K. (GSK) 
Akasaka Intercity AIR, 8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052 Japan 
Regulatory Agency Identifying Number(s): Not applicable 
Approval Date: 7-JUN-2018 
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 
PPD


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SPONSOR SIGNATORY: 
 
 
Kosuke Kozaiwa 
VP & Head of Medicines Development 
Development & Medical Affairs 
GlaxoSmithKline K.K. 
 
Date 
 


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TABLE OF CONTENTS 
PAGE 
1. 
SYNOPSIS ............................................................................................................... 5 
2. 
SCHEDULE OF ACTIVITIES (SOA) ......................................................................... 8 
3. 
INTRODUCTION .................................................................................................... 12 
3.1. 
Study Rationale .......................................................................................... 12 
3.2. 
Background ................................................................................................ 12 
3.3. 
Benefit/Risk Assessment ............................................................................ 13 
3.3.1. 
Risk Assessment ......................................................................... 14 
3.3.2. 
Benefit Assessment ..................................................................... 18 
3.3.3. 
Overall Benefit: Risk Conclusion .................................................. 18 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 18 
5. 
STUDY DESIGN .................................................................................................... 18 
5.1. 
Overall Design ............................................................................................ 18 
5.2. 
Number of Subjects .................................................................................... 19 
5.3. 
Sentinel Dosing........................................................................................... 19 
5.4. 
Dose Escalation Decisions ......................................................................... 20 
5.5. 
Participant and Study Completion ............................................................... 20 
5.6. 
Scientific Rationale for Study Design .......................................................... 20 
5.7. 
Dose Justification ........................................................................................ 21 
6. 
STUDY POPULATION ........................................................................................... 22 
6.1. 
Inclusion Criteria ......................................................................................... 22 
6.2. 
Exclusion Criteria ........................................................................................ 23 
6.3. 
Lifestyle Restrictions ................................................................................... 25 
6.3.1. 
Meals and Dietary Restrictions .................................................... 25 
6.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 25 
6.3.3. 
Activity ......................................................................................... 25 
6.4. 
Screen Failures........................................................................................... 25 
7. 
TREATMENTS ....................................................................................................... 26 
7.1. 
Treatments Administered ............................................................................ 26 
7.2. 
Method of Treatment Assignment ............................................................... 26 
7.3. 
Blinding ....................................................................................................... 27 
7.4. 
Preparation/Handling/Storage/Accountability .............................................. 27 
7.5. 
Treatment Compliance ................................................................................ 28 
7.6. 
Concomitant Therapy.................................................................................. 28 
7.7. 
Treatment after the End of the Study .......................................................... 28 
8. 
DISCONTINUATION CRITERIA ............................................................................. 28 
8.1. 
Discontinuation of Study Treatment ............................................................ 28 
8.1.1. 
Dose Stopping Criteria ................................................................. 28 
8.1.2. 
Liver Chemistry Stopping Criteria ................................................ 29 
8.1.3. 
QTc Stopping Criteria .................................................................. 30 
8.1.4. 
Individual Safety Stopping Criteria ............................................... 30 
8.1.5. 
Nervous System Stopping Criteria ............................................... 30 
8.2. 
Withdrawal from the Study .......................................................................... 31 


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8.3. 
Lost to Follow Up ........................................................................................ 31 
9. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 32 
9.1. 
Adverse Events........................................................................................... 32 
9.1.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 32 
9.1.2. 
Method of Detecting AEs and SAEs ............................................. 33 
9.1.3. 
Follow-up of AEs and SAEs ......................................................... 33 
9.1.4. 
Regulatory Reporting Requirements for SAEs ............................. 33 
9.1.5. 
Pregnancy ................................................................................... 33 
9.2. 
Treatment of Overdose ............................................................................... 34 
9.3. 
Safety Assessments ................................................................................... 34 
9.3.1. 
Physical Examinations ................................................................. 34 
9.3.2. 
Neurological Examinations .......................................................... 34 
9.3.3. 
Vital Signs .................................................................................... 35 
9.3.4. 
Electrocardiograms ...................................................................... 35 
9.3.5. 
Clinical Safety Laboratory Assessments ...................................... 35 
9.3.6. 
Suicidal Risk Monitoring ............................................................... 36 
9.4. 
Pharmacokinetics ....................................................................................... 36 
9.5. 
Genetics ..................................................................................................... 36 
10. STATISTICAL CONSIDERATIONS ........................................................................ 37 
10.1. Sample Size Determination ........................................................................ 37 
10.2. Sample Size Sensitivity ............................................................................... 38 
10.3. Populations for Analyses ............................................................................ 39 
10.4. Statistical Analyses ..................................................................................... 40 
10.4.1. 
Safety Analyses ........................................................................... 40 
10.4.2. 
Pharmacokinetic Analyses ........................................................... 41 
10.4.3. 
Interim Analyses .......................................................................... 41 
11. REFERENCES ....................................................................................................... 42 
12. APPENDICES ........................................................................................................ 43 
12.1. Appendix 1: Abbreviations and Trademarks ................................................ 43 
12.2. Appendix 2: Clinical Laboratory Tests ......................................................... 46 
12.3. Appendix 3: Study Governance Considerations .......................................... 47 
12.4. Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 52 
12.5. Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 57 
12.6. Appendix 6: Genetics .................................................................................. 59 
12.7. Appendix 7: Liver Safety Required Actions and Follow up 
Assessments .............................................................................................. 61 
12.8. Appendix 8: Country-specific requirements ................................................. 63 
12.8.1. 
Regulatory and Ethical Considerations ........................................ 63 
12.8.2. 
Informed Consent ........................................................................ 63 
12.8.3. 
Study Period ................................................................................ 63 
12.8.4. 
Study Administrative Structure ..................................................... 63 
12.9. Appendix 9: Nervous System Adverse Events (CTCAE Criteria) ................ 66 
12.10. Appendix 10: Protocol Amendment History ................................................. 76 
 


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1. 
SYNOPSIS 
Protocol Title: A single-centre, randomized, double-blind, dose-ascending, placebo-
controlled study to evaluate the safety, tolerability, and pharmacokinetics of oral TID 
doses (one day) of GSK2982772 in Japanese healthy male subjects 
Short Title: Phase I study of GSK2982772 in Japanese healthy male subjects 
Rationale:  
This study is the first administration of GSK2982772 to Japanese. The purpose of this 
study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral doses of 
TID doses for one day with GSK2982772 in Japanese healthy male subjects. 
GSK2982772 or placebo will be administered at 0 hr (the first dosing), 7 hr (the second 
dosing) and 14 hr (the third dosing) on Day 1 in each period. The intention of this study 
is to provide sufficient confidence in the safety of the molecule to inform progression to 
further repeat dose studies in patients. The dose range proposed in this study is based on a 
low starting dose escalating to the highest dose that is intended for the Phase 2b dose 
range study. 
Objectives and Endpoints: 
Objectives 
Endpoints 
To assess the safety and tolerability of TID 
doses for one day of GSK2982772 in Japanese 
healthy male subjects 
Adverse events (AEs) 
Change in laboratory values (clinical chemistry, 
haematology and urinalysis), 12-lead ECG and 
cardiac telemetry, vital signs (blood pressure, 
pulse rate, and body temperature) 
Physical examinations, including neurological 
examinations 
To characterise the PK profile of TID doses for 
one day of GSK2982772 in Japanese healthy 
male subjects 
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)), 
maximum observed plasma drug concentration 
(Cmax) following each dose, time to maximum 
observed plasma drug concentration (Tmax) 
following each dose, terminal half-life (t1/2) 
following the third dose, observed trough 
plasma drug concentrations (C0, C7, C14 and 
C24), where data allow 
Overall Design:  
This study will be a double-blind with respect to subjects, investigators and site staff 
(with the exception of the unblinded site pharmacist), TID oral doses for one day, 


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ascending dose, randomized, placebo-controlled, 4-way crossover study, shown as the 
table below; 
 
Group 
N 
Period 1 
Period 2 
Period 3 
Period 4 
A 
3 
Placebo, TID 
60 mg, TID 
120 mg, TID 
240 mg, TID 
B 
3 
60 mg, TID 
Placebo, TID 
120 mg, TID 
240 mg, TID 
C 
3 
60 mg, TID 
120 mg, TID 
Placebo, TID 
240 mg, TID 
D 
3 
60 mg, TID 
120 mg, TID 
240 mg, TID 
Placebo, TID 
Number of Participants:  
Sufficient Japanese healthy male subjects will be enrolled such that up to approximately 
12 subjects 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. Replacement subjects will be 
assigned to the same treatment sequence and start from the period to be replaced at the 
discretion of the GSK and in consultation with the principal investigator. 
Sentinel Dosing: 
The doses will be staggered such that for each dose, on Day 1 of Period 1, 2 and 3, 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 (AEs, clinical labs, vital signs, 12-Lead ECGs and Cardiac 
telemetry) in the judgment of the principal investigator and GSK Medical Monitor 
through at least 24 hrs after their third dose on Day 1, the remaining subjects may be 
randomized to dosing in that period.  
Treatment Groups and Duration: 
Screening 
Within 30 days prior to the first dose on Day1. 
Treatment Period 
The study will be comprised of four study periods each at least 7 days in 
duration with subjects in-house for 4 nights (through 72 hrs after the first 
dose). During each treatment period, subjects will be admitted to the unit 
the day before dosing and will be discharged after completion of the 72 hrs 
post-dose assessments.  
Each subject will receive oral TID doses of GSK2982772 in each treatment 
period. For TID dosing, GSK2982772 or placebo will be administered at 0 
hr (the first dosing), 7 hr (the second dosing) and 14 hr (the third dosing) on 
Day 1 in each period. On Day 1, subjects will fast 8hr overnight prior to first 
dose. A breakfast will be served approximately 2hr after first dose.  
Lunch and dinner will be served between 2 to 3hr prior to second and third 
doses, respectively. 
Washout Period 
Will be at least 7 days between treatment period doses for an individual 


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subject. 
Follow-up 
At least 7 days, and no greater than 14 days after last study treatment 
administration. If warranted, additional follow-up visits may be scheduled. 


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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, are essential and required for study 
conduct. 
The Study Reference Manual (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.  
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. 
A table defining the allowed variance in timings of assessments without being considered 
a protocol deviation will be included in the SRM. 
 


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Time and Events Table for Screening and Follow-up Assessments 
Procedure 
Screening1 
Follow-up Visit2 
Notes 
Outpatient Visit 
X 
X 
 
Informed Consent 
X 
 
 
Medical/medication/drug 
/alcohol history 
X 
 
 
Demographics 
X 
 
 
Physical Examination 
X 
X 
Additional examinations may be performed, by the Investigators, as deemed necessary. 
Drug screen 
X 
 
Additional tests may be performed by the Investigators, as deemed necessary. Tests will be conducted within site specified standards. 
Syphilis, Human immunodeficiency virus 
(HIV), Human T-cell leulemia virus type 1 
(HTLV-1), Hepatitis B (Hep B) and Hepatitis 
C (Hep C) screen 
X 
 
 
Tuberculosis (TB) Test 
X 
 
Conducted at the standard practice of the site. 
X-ray Test 
X 
 
Anterior & lateral chest X-ray will be taken. 
Hema/Chem/Urinalysis tests 
X 
X 
 
Height and weight 
X 
 
 
12-lead ECG and vital signs 
X 
X 
Vital signs to include pulse rate (PR), blood pressure (BPs) and temperature. 
AE Review 
X 
X 
All Serious Adverse Effects (SAEs) will be collected from the signing of the informed consent form (ICF) until the follow-up visit at the 
time points specified. All AEs will be collected from the start of treatment until the follow-up visit at the time points specified. 
Concomitant Medication Review 
X 
X 
 
1: Within 30 days prior to the first dosing 
2: Follow-up Visit to occur at least 7 days, and no greater than 14 days after last study treatment administration. If a participant withdrew from the study after received GSK2982772 or placebo dose, the safety 
assessments listed at follow-up visit will be required.   
 


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Detailed Time and Events Table for Days 1-4 (common Period1-4) 
Procedure 1 
Day 
 -1 
Day 1 
Pre- 
dose 
0 
20 
min 
40 
min 
1 
hr 
1.5 
hr 
2 
hr 
3 
hr 
4 
hr 
5 
hr 
7 
hr 
7 
hr 
20 
min 
7 
hr 
40 
min 
8 
hr 
8.5 
hr 
9 
hr 
10 
hr 
11 
hr 
12 
hr 
14 
hr 
14 
hr 
20 
min 
14 
hr 
40 
min 
15 
hr 
15.5 
hr 
Admission 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
X 
 
 
 
 
 
X 
 
 
 
X6 
 
 
 
 
 
 
 
 
X6 
 
 
 
 
Hema/Chem/ 
Urinalysis tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 2 
 
X 
 
 
 
 
 
X 
 
 
 
X6 
 
 
 
 
 
 
 
 
X6 
 
 
 
 
12-lead ECG 
 
X 
 
 
 
 
 
X 
 
 
 
X6 
 
 
 
 
 
 
 
 
X6 
 
 
 
 
Cardiac telemetry 3  
 
 
<============================================================================================================================================= 
PK blood sampling 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X7 
X 
X 
X 
X 
X 
X 
 
X 
X7 
X 
X 
X 
X 
Neurological 
Examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X8 
 
 
 
 
Study Treatment 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenetic 
Sampling (PGx) 4 
 
 
<============================================================================================================================================= 
Meals Served 
X 
 
 
 
 
 
 
X9 
 
X9 
 
 
 
 
 
 
 
X9 
 
 
 
 
 
AE Review 5 
 
<==================================================================================================================================================== 
Concomitant 
Medication Review 
 
<==================================================================================================================================================== 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedure 1 
Day 2 
Day 3 
Day 4 
16 hr 
17 hr 
19 hr 
22 hr 
24 hr 
28 hr 
32 hr 
36 hr 
48 hr 
60 hr 
72 hr 
Admission 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
 
 
 
 
X 
 
 
X 
X 
 
X 
Hema/Chem/ 
Urinalysis tests 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs 2 
 
 
 
 
X 
 
 
 
X 
 
X 
12-lead ECG 
 
 
 
 
X 
 
 
 
X 
 
X 
Cardiac telemetry 3 
===================================================================> 
 
 
 
 
 
 
PK blood sampling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological 
Examination 
 
 
 
 
X 
 
 
 
X 
 
X 
Study Treatment 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic 
Sampling (PGx) 4 
=======================================================================================================================================================> 
Meals Served 
 
 
 
 
 
X10 
 
X10 
X10 
X10 
 
AE Review 5 
=======================================================================================================================================================> 
Concomitant 
Medication Review 
=======================================================================================================================================================> 
Discharge 
 
 
 
 
 
 
 
 
 
 
X 
1: In this study, baseline is Day -1 and Day 1 pre-dose tests. 
2: Vital signs include PR, BPs and temperature. 
3: Only 24 hrs following the first dose administration 
4: A PGx blood sample will be collected at any time during the study after randomization and provided informed consent for genetic reserch. The participation is optional for each subject. 
5: All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points specified. All AEs will be collected from the start of treatment until the follow-up visit at the time points specified.  
6: Physical Examination, Vital signs and 12-lead ECG of 7hr and 14hr time point are to be performed prior to second or third dose. 
7: PK blood sampling of 7hr and 14hr time point are to be performed right prior to second or third dose. 
8: Neurological Examination of 14hr time point are to be performed prior to third dose.  
9: On Day 1, breakfast will be served approximately 2hr after the first dose, lunch will be served between 2 to 3 hr prior to second dose and dinner will be served between 2 to 3 hr prior to third dose.  
10: On Day 2-3, meal will be served per unit schedule. Mealtime will be described in SRM. 


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3. 
INTRODUCTION 
GSK2982772 is a first-in-class highly selective, RIP1 kinase inhibitor being developed 
for the treatment of inflammatory bowel disease (IBD), plaque psoriasis (PsO), 
rheumatoid arthritis (RA) and other disease conditions. 
3.1. 
Study Rationale 
The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics 
(PK) of oral doses of TID doses for one day with GSK2982772 in Japanese healthy male 
subjects. This study is the first administration of GSK2982772 to Japanese.  
3.2. 
Background 
GSK2982772 is a first-in-class, highly selective, small molecule inhibitor of RIP1 kinase. 
RIP1 is a member of the receptor-interacting Ser/Thr kinase family containing an amino-
terminal kinase domain, an intermediate domain and a carboxy-terminal death domain. 
RIP1 is a key signalling node which plays an essential role in inflammation and cell death 
in response to signals including TNF family cytokines, ligands for TLR3/TLR4, sensors 
of viral infection, and interferons [Ofengeim, 2013]. Through tight regulation by 
ubiquitylation, deubiquitylation and interaction with its receptors, RIP1 has dual roles as 
a kinase and a scaffolding protein, and serves as an upstream checkpoint for both cell 
death and survival [Ofengeim, 2013]. Detailed understanding of RIP1 kinase function has 
not been fully elucidated, but it is known that RIP1 exerts it signalling functions through 
both its catalytic kinase activity and by acting as a scaffolding protein for signalling 
complexes. Recent work has demonstrated that RIP1 catalytic kinase activity can regulate 
TNF-mediated necroptosis [Ofengeim, 2013] and noncanonical apoptosis [Wang, 2008, 
Dondelinger, 2013]. In addition, the production of certain inflammatory cytokines can be 
regulated by RIP1 kinase activity. In contrast, RIP1’s scaffolding function acts to 
facilitate other immune processes including TNF mediated classical apoptosis and 
Nuclear factor-kappaB (NF-kB)-signalling [Ofengeim, 2013, Humphries, 2015]. With 
this, an inhibitor of RIP1 kinase activity with GSK2982772 may fill a unique niche in the 
treatment of inflammatory conditions (eg. PsO, RA and IBD) through multiple 
mechanisms, including inhibition of inflammation-induced cell death (necroptosis and 
apoptosis) and inhibition of the production of certain pro-inflammatory cytokines.  
A range of nonclinical studies have been conducted to support the administration of 
GSK2982772 to humans [GlaxoSmithKline Document Number 2014N204126_04]. 
The First Time in Human (FTiH) study which was single (fed and fasted) and repeat dose 
escalation study (Study 200975) of GSK2982772 in healthy male subjects of 
predominantly White/Caucasian/European heritage in United Kingdom, 67 subjects were 
exposed to active treatment. GSK2982772 was well-tolerated up to 120 mg BID for 14 
days, with no deaths or other non-fatal SAEs being reported.  
The PK of GSK2982772 appeared approximately dose proportional over the single dose 
range 0.1 to 120 mg. Following14 days of repeat dose administration, the Cmax and 
AUC(0-t) increased approximately proportionally 20 and 60 mg QD, 60 and 120 mg BID. 


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There was no evidence of accumulation in any of the dosing regimens and trough plasma 
concentrations appeared to reach steady state from Day 2. Following oral administration 
of GSK2982772, the median time to Cmax was between 1.5 and 2.5 hr after attainment of 
Cmax. GSK2982772 concentrations decline rapidly until about 12 hrs post-dose, with a 
t1/2 of approximately 2 to 6 hrs. The majority of the systemic exposure to GSK2982772 
is observed within the first 12 hrs after administration. 
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 days repeat dose toxicology 
study in monkeys (10 mg/kg/day). Subsequently, a 13 week repeat dose 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.  
Thus, currently the study in non-Japanese (Study 205184) 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 planned Phase 2b dose range 
studies in subjects with PsO, RA and UC. Study 205184 includes dosing sessions of 120 
mg TID (1 day and 14 days), 240 mg TID (1 day and 14 days) and 360 mg BID (1 day 
and 14 days), in which all 1-day dosing regimens have been completes and GSK2982772 
was tolerated in all 1-days dosing sessions. 
Detailed information on the safety and PK of GSK2982772 in human can be found in the 
Investigators Brochure (IB) for GSK2982772 [GlaxoSmithKline Document Number 
2014N204126_04]. 
3.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2982772 may be found in the IB. The 
following section outlines the risk assessment and mitigation strategy for this protocol. 
 


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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 repeat dose Good 
Laboratory Practice (GLP) toxicology 
study, CNS findings were observed 
in 4/12 monkeys which were 
administered 100 or 300 mg/kg/day. 
CNS findings included uncoordinated 
movement, irregular gait, trembling, 
hunched appearance, and 
decreased activity. The clinical 
relevance of these findings in 
humans is not known. In the 13 and 
39 week repeat dose GLP toxicology 
studies, no CNS findings observed in 
monkeys at highest dose levels of 
100 and 60 mg/kg/day, respectively. 
The NOAEL for 39 week study was 
determined at 60 mg/kg/day, which 
corresponds to a gender-averaged 
Cmax 23.2 µg/mL and AUC 
182 µg･hr/mL in plasma. 
  
Clinical data: 
A FTiH study with single ascending 
and multiple ascending doses has 
been performed in 67 healthy male 
subjects to date (Study 200975). See 
IB for GSK2982772 
[GlaxoSmithKline Document Number 
2014N204126_04]. No drug-
associated CNS adverse events 
were identified and no SAEs were 
reported. See IB for GSK2982772 
[GlaxoSmithKline Document Number 
2014N204126_04]. 
In the phase IIa psoriasis study 
(Study 203167), there was one SAE 
of death via accidental overdose of 
Ecstasy/MDMA in a 19 year old male 
subject who was treated with 
GSK2982772 60 mg BID or placebo. 
There was no evidence reported 
to suggest that this event was a 
suicide. 
 
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 
signs of CNS-related effects. 
• Targeted physical examinations 
with comprehensive neurological 
assessments will be conducted at 
appropriate intervals throughout 
the study. 


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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 (Study 200975), no 
SAEs were reported. One subject 
experienced an AE herpes zoster 
27 days after receiving with placebo 
and 42 days after receiving dose with 
GSK2982772 80 mg. The blinded 
principal investigator determined this 
to be drug-related. 
In the IIa psoriasis study (Study 
203167) one subject experienced an 
AE of herpes zoster on Study Day 9 
(either 60 mg BID GSK2982772 or 
placebo). The blinded investigator 
considered the AE to be of moderate 
severity and not related to study 
drug. 
Subject Selection: 
• Subjects with recurrent, chronic or 
active infections will be excluded 
from the study. 
• Subjects will be screened for T 
Spot. 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 
8.1.4) 
 
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 
for 30 days prior to the first dose 
of GSK2982772, during study 
participation and for five half-lives 
plus 30 days (total 32 days) after 
GSK2982772 is discontinued. 
• 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 decreased 
responsiveness). 
• Investigators will be expected to 
have followed local and/or 
national guidelines with respect 
tovaccinations, including against 
influenza and pneumococcus. 
 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Respiratory effects 
Non-Clinical data: 
In the single dose Safety 
Cardiovascular and Respiratory 
Study in monkeys, a decrease in 
minute volume (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 days 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_04]. 
 
Clinical data: 
In the FTiH study, repeat doses of 
GSK2982772 up to 120 mg BID were 
administered 14 days in 36 healthy 
male subjects. 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. 
Subject Monitoring: 
• Subjects should be monitored for 
standard respiratory-related AEs. 
• Vital signs will be monitored 
during study visits. 
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 abnormal 
behaviour were reported. 
In the phase IIa psoriasis study 
(203167), one subject reported 
suicidal ideation at Day 43 via the 
Columbia Suicide Severity Rating 
Scale. This subject informed the 
investigator that he had similar 
thoughts prior to joining the study but 
had no  intention of acting on this.  
The investigator determined the 
subject was of low risk and allowed 
the subject to remain in the study. 
Subject Selection: 
• Subjects with a current history of 
Suicidal Ideation and Behaviour 
(SIB) or a history of attempted 
suicide will be excluded from the 
study. 
 
Subject Monitoring: 
• Although this drug has not been 
shown to be associated with an 
increased risk of suicidal thinking 
or behaviour when given to 
healthy volunteers, Participants 
being treated with GSK2982772 
should be monitored appropriately 
and observed closely for SIB or 
any other unusual changes in 
behaviour. 
• Families and caregivers of 
participants being treated with 
GSK2982772 should be alerted 
about the need to monitor 
participants for the emergence of 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
unusual changes in behaviour, as 
well as the emergence of SIB and 
to report such symptoms 
immediately to the study 
investigator. 
 
Reproductive Toxicity 
Non-Clinical Data: 
In the rat embryofetal development 
study, there were no maternal or 
developmental toxicity at doses ≤200 
mg/kg/day. There were maternal and 
developmental toxicity at dose of 
450 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. There 
was maternal toxicity at dose of 
≥300 mg/kg/day and no tolerability at 
dose of 600 mg/kg/day. 
 
Subject Selection: 
• Males will be included in this 
study only if they agree to use 
highly effective methods of 
contraception and avoid 
conception until last visit. 
 
Withdrawal Criteria: 
• If a female partner should become 
pregnant during the study, study 
medication should be 
discontinued. She will be followed 
to determine the outcome of the 
pregnancy.  
Drug Interaction 
Non-Clinical Data: 
In vitro studies with GSK2982772 
assessing potential drug-drug 
interactions with Cytochrome P450 
3A4 (CYP3A4) substrates and  
P-glycoprotein (P-gp) 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 P-gp substrate 
and therefore co-administration with 
concomitant medications that are P-
gp inhibitors could increase 
circulating levels of GSK2982772. 
There is a low risk that GSK2982772 
could be a perpetrator of organic 
anion transporter 3 (OAT3) 
substrates. Methotrexate(MTX) is an 
OAT3 substrate in which 
GSK2982772 could potentially impair 
the clearance of MTX. 
See Section 4.3.6 of GSK2982772 IB 
[GlaxoSmithKline Document Number 
2014N204126_04]. 
Subject Selection: 
• Subjects who are taking 
concomitant medications known 
to inhibit P-gp or CYP3A4 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. 


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3.3.2. 
Benefit Assessment 
This study is being conducted in healthy participant with no significant medical history. 
Subjects will not receive benefit from this study. However, knowledge from this study 
may contribute to the development of GSK2982772 and may benefit patients in the future. 
3.3.3. 
Overall Benefit: Risk Conclusion 
It is considered acceptable to conduct this study in healthy subjects, because whilst they 
will receive no direct medical benefit, the risks from the study treatment and procedures 
are minimal. The study will be conducted in a fully equipped clinical pharmacology unit 
with access to hospital emergency facilities.  
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. 
4. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
To assess the safety and tolerability of TID 
doses for one day of GSK2982772 in Japanese 
healthy male subjects 
Adverse events (AEs) 
Change in laboratory values (clinical chemistry, 
haematology and urinalysis), 12-lead ECG and 
cardiac telemetry, vital signs (blood pressure, 
pulse rate, and body temperature) 
Physical examinations, including neurological 
examinations 
To characterise the PK profile of TID doses for 
one day of GSK2982772 in Japanese healthy 
male subjects 
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)), 
maximum observed plasma drug concentration 
(Cmax) following each dose, time to maximum 
observed plasma drug concentration (Tmax) 
following each dose, terminal half-life (t1/2) 
following the third dose, observed trough 
plasma drug concentrations (C0, C7, C14 and 
C24), where data allow 
5. 
STUDY DESIGN 
5.1. 
Overall Design 
This study will be a double-blind with respect to subjects, investigators and site staff 
(with the exception of the unblinded site pharmacist), TID oral doses for one day, 


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ascending dose, randomized, placebo-controlled, 4-way crossover study, shown as the 
table below; 
Group 
N 
Period 1 
Period 2 
Period 3 
Period 4 
A 
3 
Placebo, TID 
60 mg, TID 
120 mg, TID 
240 mg, TID 
B 
3 
60 mg, TID 
Placebo, TID 
120 mg, TID 
240 mg, TID 
C 
3 
60 mg, TID 
120 mg, TID 
Placebo, TID 
240 mg, TID 
D 
3 
60 mg, TID 
120 mg, TID 
240 mg, TID 
Placebo, TID 
Treatment Groups and Duration: 
Screening 
Within 30 days prior to the first dose on Day1. 
Treatment Period 
The study will be comprised of four study periods each at least 7 days in 
duration with subjects in-house for 4 nights (through 72 hrs after the first 
dose). During each treatment period, subjects will be admitted to the unit the 
day before dosing and will be discharged after completion of the 72 hrs 
post-dose assessments.  
Each subject will receive oral TID doses of GSK2982772 in each treatment 
period. For TID dosing, GSK2982772 or placebo will be administered at 0 hr 
(the first dosing), 7 hr (the second dosing) and 14 hr (the third dosing) on 
Day 1 in each period. On Day 1, subjects will fast 8hr overnight prior to first 
dose. A breakfast will be served approximately 2hr after first dose. Lunch 
and dinner will be served between 2 to 3hr prior to second and third doses, 
respectively. 
Washout Period 
Will be at least 7 days between treatment period doses for an individual 
subject. 
Follow-up 
At least 7 days, and no greater than 14 days after last study treatment 
administration. If warranted, additional follow-up visits may be scheduled. 
5.2. 
Number of Subjects 
Sufficient Japanese healthy male subjects will be enrolled such that up to 12 subjects 
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. Replacement subjects will be 
assigned to the same treatment sequence and start from the period to be replaced at the 
discretion of the GSK and in consultation with the principal investigator. 
5.3. 
Sentinel Dosing 
The doses will be staggered such that for each dose, on Day 1 of Period 1, 2 and 3, 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 (AEs, clinical labs, vital signs, 12-Lead ECGs and findings 
during continuous cardiac telemetry) in the blind judgment of the principal investigator 


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and GSK Medical Monitor through at least 24 hrs after their third dose on Day 1, the 
remaining subjects may be randomized to dosing in that period.  
5.4. 
Dose Escalation Decisions 
The decision to proceed to the next dose level of GSK2982772 within the study will be 
made by principal investigator and GSK Medical Monitor per each dosing periods. 
Dose escalation decisions will be based on blind 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: all AEs, clinical laboratory values, vital signs, 12-Lead ECG up to Day 4 (at 
discharge) and findings during continuous cardiac telemetry in the previous dose (Section 
8.1.1.). 
5.5. 
Participant and Study Completion 
A participant is considered to have completed the study if he has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the SoA. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5.6. 
Scientific Rationale for Study Design 
This study will include a placebo control study, to allow for evaluation of AEs 
attributable to treatment versus those independent of treatment. 
In Study 200975, 67 subjects were exposed to active treatment. GSK2982772 was well-
tolerated, with no deaths or other non-fatal SAEs being reported. Sentinel dosing 
approach was taken in Study 200975, where two subjects receive placebo or 
GSK2982772 on Day 1 and the remaining subjects are dosed after safety evaluation at 24 
hrs of preceding two subjects. Since this study is the first study in Japanese subjects, this 
study adopts a cautious approach including sentinel dosing and will include rigorous 
safety monitoring to confirm the safety profile prior to dose-escalation of single dose of 
the next dose strength, which was the same way taken in the past non-Japanese study. 
In the 4 week repeat dose nonclinical toxicology studies, neurological related events 
(uncoordinated movement, irregular gait, trembling, hunched appearance and decreased 
activity) were observed in some rats and monkeys. On the other hand, in the 13 week 
repeat dose nonclinical toxicology studies in rats or monkeys, or in the 39 week repeat 
dose nonclinical toxicology study in monkeys, no neurological-related events were 
observed in rats or monkeys. There have been some reports of lethargy, abnormal dreams, 
and depressed mood in Study 200975 (See IB for GSK2982772 [GlaxoSmithKline 
Document Number 2014N204126_04]). This study includes neurological exams by 
considering these findings from Study 200975. 
In the currently ongoing non-Japanese healthy volunteer study (Study 205184) being 
conducted in the United Kingdom (UK), several asymptomatic arthyhmias were detected 
in 6 out of 25 subjects treated with GSK2982772 or placebo.  The study was temporarily 


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put on hold by GSK to assess the totality of these events.  A formal review by the GSK 
Internal Cardiac Safety Panel, inclusive of both internal and external cardiologists, 
determined that the arrhythmic events were not likely related to GSK2982772 
administration based on the timing and random occurrences of the events, the 
heterogeneity of the arrhythmias, the length of cardiac monitoring being performed 
during the study, and no findings in preclinical studies.  Subsequently, the protocol was 
amended to increase the number of placebo subjects to balance randomization between 
active and placebo to understand the background cardiac patterns of subjects who are 
enrolled compared to when on treatment. Approval to proceed with the study was 
received from Medicines and Healthcare products Regulatory Agency (MHRA) on 22 
March 2018. Study 200975 and Study 205184 did include telemetry, while the cardiac 
events related to the study drug were not observed in non-Japanese subkects including 
Study 205184, Since this study is the first study in Japanese subjects, telemetry will be 
planed in this study. 
GSK2982772 concentrations decline rapidly until about 12 hrs post-dose, with a t1/2 of 
approximately 2 to 3 hrs. It, therefore, is considered sufficient to allow at least 7 days 
washout between dosing periods. Also, 7 days follow up after the last dose is considered 
to be sufficient for safety evaluation. 
In the ongoing Study 205184, there are two TID dose regimens of 120 mg TID and 240 
mg TID.  This study plans also TID dose regimen, which allows to compare the PK 
between Japanese subjects and non-Japanese subjects in order to support dosing of 
GSK2982772 in Japanese patient population in the Phase 2b dose ranging studies. 
5.7. 
Dose Justification 
The initial starting dose planned is 60 mg TID and the maximum dose is 720 mg/day 
administered as 240 mg TID, which cover the dose range for the proposed Phase 2b study. 
In Study 200975, all of the administered regimens (single dose; 0.1-120 mg, repeat dose; 
20 and 60 mg QD, 60 and 120 mg BID for 14 days) appeared to be well tolerated, and no 
dose limiting AEs or safety findings were observed. There were no clinically significant 
patterns of abnormal vital sign measurements, physical and neurological examinations, 
12-lead ECG and holter ECG changes or clinical laboratory (e.g., hematology, chemistry 
or urinalysis) findings observed in healthy subjects. There were no deaths or SAEs 
reported in the study.  
Since the target dose per day currently planed in Phase IIb study is 720 mg, the dose 
regimens in Study 205184 in non-Japanese are 120 mg TID, 240 mg TID and 360 mg 
BID. For the 360 mg BID dose (single day dosing), one subject exceeded Cmax limit 
with several other subjects approaching the Cmax limit. In addtion, and the AUC(0-24) at 
360 mg was also higher than that predicted but within the limits of stopping criteria. 
Based on the data in Study 205184, 240 mg TID is considered as the maximum dose in 
this study. 
The predicted mean AUC(0-24) for the highest planned doses in the current study of 240 
mg TID (40.2 μg･h/mL) approximates parity with the mean AUC(0-24) observed at the 


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NOAEL (30 mg/kg/day) in the 13 week repeat dose toxicity study in monkey (48.4 μg･
h/mL) and is approximately 1/5th to 1/4th of the mean AUC(0-24) observed at the 
NOAEL (60 mg/kg/day) in the 39 week repeat dose toxicity study in monkey (182 ug･
h/mL). Mean Cmax values for 240 mg TID (3.21 μg/mL) doses are predicted to be 1/4th 
of the mean Cmax observed at the NOAEL in the 13 week monkey study (12.3 µg/mL) 
and 1/7th of the mean Cmax  at the NOAEL in the 39 week monkey study (23.2 µg/mL). 
Please see GSK2982772 IB [GlaxoSmithKline Document Number 2014N204126_04]. 
The major circulating metabolite is an N-glucuronide which accounts for approximately 
70% of drug related material in plasma. Since glucuronidation is a high capacity 
clearance mechanism it is unlikely that the kinetics of GSK2982772 will become 
saturable at the higher doses planned in this study. 
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 20 to 64 years of age inclusive, at the time of signing the 
informed consent. 
Type of Participant and Disease Characteristics 
2. Healthy as determined by the Investigators based on a medical evaluation including 
medical history, physical examination, neurological examination, laboratory tests, 
and ECG. 
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 Investigators in 
consultation with the GSK Medical Monitor 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 Investigators 
Weight 
3. Body weight ≥ 50 kg and body mass index (BMI) within the range 18.5-24.9 kg/m2 
(inclusive). 


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Sex 
4. Japanese Male 
A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and until follow up visit. 
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 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. Abnormal blood pressure as determined by the investigators 
3. Symptomatic herpes zoster within 3 months prior to screening 
4. Evidence of active or latent TB as documented by medical history and examination, 
chest X-rays (anterior and lateral), and TB testing (T Spot. TB) 
5. Alanine Aminotransferase (ALT) >1.5x upper limit of normal (ULN) 
6. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) 
7. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
8. History of active infections within 14 days of first receiving study medication. 
9. QTcF > 450 msec 
NOTES: 
• The QTc is the QT interval corrected for heart rate according to 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. 


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• For purposes of data analysis, 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). 
10. History or diagnosis of obstructive sleep apnoea, or a significant respiratory disorder. 
Childhood asthma that was fully resolved is permitted. 
11. History of active Suicidal Ideation Behaviour within the past 6 months or any history 
of attempted suicide in a participant’s lifetime. 
12. History or current evidence of febrile seizures, epilepsy, convulsions, significant 
head injury, or other significant neurologic conditions. 
Prior/Concomitant Therapy 
13. Past or intended use of over-the-counter or prescription medication including herbal 
medications within 14 days prior to dosing. 
14. Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines 
during the study 
Prior/Concurrent Clinical Study Experience  
15. History of donation of blood or blood products ≥ 400 mL within 3 months or ≥ 
200 mL within 1 month prior to screening 
16. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day  
17. The subject has participated in a other clinical study or other medical research within 
4 months prior to the first dosing day in the current study. 
Diagnostic assessments 
18. The subject is positive Serological test for syphilis (RPR and TP), Tuberculosis, HIV 
Antigen/Antibody, Hep B surface antigen (HbsAg), Hep C virus (HCV) antibody, or 
HTLV-1 antibody at screening. 
19. Positive pre-study drug screen  
20. Regular use of known drugs of abuse  
Other Exclusions 
21. Regular alcohol consumption within 6 months prior to the study defined as: 
• For an average weekly intake of > 14 units for males. One unit is equivalent to 
350 mL of beer, 150 mL of wine or 45 mL of 80 proof distilled spirits 
22. Smoking or history or regular use of tobacco- or nicotine-containing products within 
6 months prior to screening 
23. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigators or GSK Medical Monitor, 
contraindicates participation in the study 


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6.3. 
Lifestyle Restrictions 
6.3.1. 
Meals and Dietary Restrictions 
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice, 
pomelos, citrus fruits, grapefruit hybrids, or fruit juices from 7 days prior to the start of 
study treatment until follow-up visit. 
Once in the clinical unit subjects will not be allowed to eat anything other than the food 
provided by the study centre. 
• 
Subjects must then fast from all food and drink (except water) for 8 hrs prior to first 
dose. 
• 
Subjects must then fast from all food and drink (except water) for 8 hrs prior to any 
clinical laboratory evaluations. 
• 
Water is permitted with dosing and at all times except 1 hr pre-dose through 2 hrs 
post-dose. 
• 
On Day 1, breakfast will be served approximately 2 hr after first dose. Lunch will be 
served between 2 to 3 hr prior to second dose. Dinner will be served between 2 to 3 
hr prior to third dose. On Day 2-3, meal will be served per unit schedule. Mealtime 
will be described in SRM. 
6.3.2. 
Caffeine, Alcohol, and Tobacco 
• 
During each dosing period, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hrs 
before the start of dosing until after collection of the final PK sample. 
• 
During each dosing period, subjects will abstain from alcohol for 24 hrs before the 
start of dosing until after collection of the final PK sample. 
• 
Use of tobacco, nicotine, or nicotine-containing products (including nicotine patch) 
will not be allowed from 6-months before screening until after collection of the final 
PK sample. 
6.3.3. 
Activity 
Subjects will abstain from strenuous exercise for 48 hrs prior to each blood collection for 
clinical laboratory tests. Subjects may participate in light recreational activities during 
studies (e.g., watching television, read). 
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 


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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 
judged ineligible) may not be rescreened. 
7. 
TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
7.1. 
Treatments Administered 
Study 
Treatment 
Name 
GSK2982772  
30 mg  
GSK2982772 
120 mg  
Placebo to match 
GSK2982772 30mg 
Placebo to match 
GSK2982772 120mg 
Dosage 
formulation 
Tablet 
Tablet 
Tablet 
Tablet 
Unit dose 
strength(s)/Do
sage level(s) 
30 mg 
120 mg 
NA 
NA 
Route of 
Administration 
Oral 
Oral 
Oral 
Oral 
Dosing 
instructions 
As directed 
As directed 
As directed 
As directed 
Physical 
description 
White to almost 
white, round, film-
coated tablet 
White to almost 
white, oval, film-
coated tablet 
White to almost 
white, round, film-
coated tablet 
White to almost 
white, oval, film-
coated tablet 
Packaging and 
Labelling 
Study Treatment will 
be labelled as 
required per country 
requirement. 
Study Treatment will 
be labelled as 
required per country 
requirement. 
Study Treatment will 
be labelled as 
required per country 
requirement. 
Study Treatment will 
be labelled as 
required per country 
requirement. 
Manufacturer 
Aptuit (Italy) 
GSK (UK) 
Aptuit (Italy) 
GSK (UK) 
 
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 one of the 4 groups, according to the randomization schedule generated 
prior to the study by the Biomedical Data Sciences Department at GSK. Each participant 
will be dispensed blinded study treatment, labelled with his unique randomization 
number, throughout the study. 
Subjects will be randomized to one of four sequences (A, B, C and D), where the 
treatments in the sequences are:  


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• 
A: Placebo TID / 60 mg TID / 120 mg TID / 240 mg TID 
• 
B: 60 mg TID / Placebo TID / 120 mg TID / 240 mg TID 
• 
C: 60 mg TID / 120 mg TID / Placebo TID / 240 mg TID 
• 
D: 60 mg TID / 120 mg TID / 240 mg TID / Placebo TID 
7.3. 
Blinding 
This study will be a double-blind with respect to subjects, investigators and site staff 
(with the exception of the unblinded site pharmacist). 
Investigators will remain blinded to each participant’s assigned study treatment 
throughout the course of the study.  
A participant will be withdrawn if the participant’s treatment code is unblinded. The 
primary reason for discontinuation (the event or condition which led to the unblinding) 
will be recorded in the case report form (CRF). 
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant 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 participant’s treatment assignment, may be sent to principal 
investigator in accordance with local regulations and/or GSK policy. 
7.4. 
Preparation/Handling/Storage/Accountability 
1. The investigators or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
2. Only participants randomized 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 investigators and authorized site staff. 
3. The investigators, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study treatment 
are provided in the 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 investigators, where this is required by local laws, or is available 
upon request from GSK. 


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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 investigators 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 
enrollment 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 GSK Medical Monitor should be contacted if there are any questions regarding 
concomitant therapy. 
Participants must abstain from taking prescription or nonprescription 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 
investigators and GSK, the medication will not interfere with the study.  
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 subjects are eligible for study participation. 
8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
8.1.1. 
Dose Stopping Criteria 
The decision to proceed to the next dose level of GSK2982772 in each part of this study 
will be made by the principal investigator and GSK Medical Monitor based on safety 
results (AEs, clinical labs, vital signs, 12-Lead ECGs and findings during continuous 
cardiac telemetry) obtained in at least 6 subjects having received active treatment 
(GSK2982772) at the prior dose level.  


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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 treatment. 
• 
Two (2) or more subjects experience a severe or clinically significant non-serious AE 
(based upon principal investigator judgment) which has a reasonable possibility of 
relation to study treatment. 
• 
Two (2) or more subjects experience the same AE of moderate severity which has a 
reasonable possibility of relation to study treatment. 
• 
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 treatment. 
• 
Female partner become pregnant during the treatment period. 
8.1.2. 
Liver Chemistry Stopping Criteria 
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met: 


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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. 
8.1.3. 
QTc Stopping Criteria 
A subject that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment. 
See Section 9.3.4. about 12-lead ECG. 
• 
QTcF > 500 msec 
• 
QTcF increase > 60 msec from baseline 
8.1.4. 
Individual Safety Stopping Criteria 
• 
If a participant experiences a serious or severe clinically significant AE that in the 
clinical judgement of the principal investigator, after consultation with the GSK 
Medical Monitor, is possibly, probably or definitely related to investigational product. 
• 
The participant develops a serious opportunistic or atypical infection. 
• 
If any of the liver chemistry stopping criteria (See Section 8.1.2) or QTc stopping 
criteria (see Section 8.1.3) are met. 
8.1.5. 
Nervous System Stopping Criteria 
The CTCAE Nervous System disorder is a monitoring tool which provides the 
investigators 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. 


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The principal investigator and the GSK Medical Monitor will review all neurological 
events utilizing the CTCAE Nervous System disorder 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 disorder 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 disorder, which is 
also considered to be clinically significant by the principal investigator, will be 
reviewed for potential subject withdrawal. 
Note: Appendix 9 (Section 8.1.1) provides Guidance for Grading AEs that is taken from 
the CTCAE Version 4.03. 
8.2. 
Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his own request, or may be 
withdrawn at any time at the discretion of the investigators for safety, behavioral, 
compliance or administrative reasons. 
• 
If the participant withdraws consent for disclosure of future information, the GSK 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• 
If a participant withdraws from the study, he 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. 
8.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he 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: 
• 
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 investigators 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. 


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• 
Should the participant continue to be unreachable, he will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA.  
• 
Protocol waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the GSK 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 principal 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.  
• 
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 400 
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 investigators 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 (see Section 8).  
9.1.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the SoA (Section 2).  
• 
All AEs will be collected from the start of treatment until the follow-up visit at the 
time points specified in the SoA (Section 2). 
• 
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the CRF not the AE section. 
• 
All SAEs will be recorded and reported to the GSK or designee immediately and 
under no circumstance should this exceed 24 hrs, as indicated in Appendix 4. The 


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investigators will submit any updated SAE data to the GSK within 24 hrs of it being 
available. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigators 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 
investigators must promptly notify the GSK. 
• 
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 investigators 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 investigators to the GSK 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.  
• 
GSK has a legal responsibility to notify both the local regulatory authority about the 
safety of a study treatment under clinical investigation. The GSK will comply with 
country-specific regulatory requirements relating to safety reporting to the regulatory 
authority, Institutional Review Boards (IRB), and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and GSK 
policy and forwarded to principal investigator as necessary. 
• 
An principal investigator who receives an investigator safety report describing a SAE 
or other specific safety information (e.g., summary or listing of SAE) from the GSK 
will review and then file it along with the IB and will notify the IRB, if appropriate 
according to local requirements. 
9.1.5. 
Pregnancy 
• 
Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until the follow-up visit. 


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• 
If a pregnancy is reported, the investigators should inform GSK within 24 hrs 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 
For this study, any dose of GSK2982772 greater than 720 mg within a 24-hr time period 
will be considered an overdose. 
GSK does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigators should: 
1. Contact the GSK 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 GSK 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 investigators 
in consultation with the GSK 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 
and weight will only be measured and recorded on screening. 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
9.3.2. 
Neurological Examinations 
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). 


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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 
• 
Axillary temperature, pulse rate, and blood pressure will be assessed. 
• 
Blood pressure and pulse measurements will be assessed 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 rate.  
9.3.4. 
Electrocardiograms 
• 
Single 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 QTcF intervals. Refer to Section 8.1.3 for QTc withdrawal criteria and additional 
QTcF readings that may be necessary. 
• 
Single ECGs will be obtained at each time point. 
• 
If QTcF is appeared the value applied the discontinuation criteria, ECG must be 
conducted two additional readings and be confirmed whether apply the 
discontinuation criteria. 
• 
Continuous cardiac telemetry will be performed at time points indicated in the SoA 
(see Section 2). Full disclosures will be reviewed in detail and the review maintained 
as part of the subject’s source documents. 
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 investigators 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 investigators to be more severe 
than expected for the participant's condition. 


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• 
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 investigators or 
GSK Medical Monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigators, the etiology should be identified and the GSK 
notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual of study site 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 SIB 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 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 SIB and to report such symptoms immediately to the study investigators. 
9.4. 
Pharmacokinetics 
• 
Blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of GSK2982772 as specified in the SoA. Instructions for the 
collection and handling of biological samples will be described in the SRM. The 
actual date and time (24-hr clock time) of each sample will be recorded. 
• 
Samples will be used to evaluate the PK of GSK2982772. Samples collected for 
analyses of GSK2982772 plasma concentration may also be used to evaluate safety 
aspects related to concerns arising during or after the study. 
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
9.5. 
Genetics 
In this study, genetics may be evaluated after review by the ethical review committee 
established by GSK in accordance with Japanese ethical guidelines for human 
genome/gene analysis research. 


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A 6 mL 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 SRM. 
10. 
STATISTICAL CONSIDERATIONS 
The objectives of this study are to evaluate safety, tolerability and PK of GSK2982772 in 
healthy Japanese subjects. No formal statistical hypotheses will be tested. Descriptive 
statistics will be used to assess safety and tolerability. An estimation approach will be 
used to address the pharmacokinetic study objectives, where point estimates and 
corresponding confidence intervals (CI) will be constructed. 
10.1. 
Sample Size Determination 
In a 4-way crossover design, total 12 subjects will be randomized in four groups with a 
randomization ratio of 1:1:1:1; 3 subjects in each group. The sample size for this study is 
based on the feasibility rather than statistical considerations. The number of subjects who 
will take a placebo, 60 mg, 120 mg, or 240 mg dose will be 12 with totalizing four groups. 
No calculations for formal power and sample size are performed.  
One of the objectives of this study is safety, where a number of safety events are of 
interest. A maximum of 12 subjects will receive each active dose and; therefore, if 0/12 
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 26.5% could not be ruled out. 
Whereas if 1/12 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 38.5% could not be 
ruled out. 
Using a Bayesian approach to determine the CI around an observed safety event, we 
would assume a flat Beta (1, 1) prior, and if we were to observe one safety event in 12 
then the posterior distribution would be Beta (2, 12), as outlined in Figure 1. Thus, we 
can 95% certain that the true probability of the safety event lies between 0.02 and 0.36. 


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0.0
0.2
0.4
0.6
0.8
1.0
0
1
2
3
4
5
1 Event in 12 Subjects
 Beta(2,12)
True Response Rate
Prior Probability Density
Posterior 95% credible in
 ( 0.02 ,  0.36 )
 
Figure 1 
Bayesian Approach to Determine Confidence in Safety Event 
 
Between-subject variability of Cmax and AUC(0-t) of GSK2982772 is estimated to be 
32.9% (CV%) and 23.5% (CV%), respectively (based on PK results of 60 mg BID on 
Day 1 and 120 mg BID on Day1 from Study 200975 Part B). Based on these variability 
estimates and the sample size of 12, the upper limit value of 95% CI of geometric mean 
of Cmax and AUC(0-t) is estimated to be approximately 22.6% and 15.9%, respectively. 
10.2. 
Sample Size Sensitivity 
Different safety event rates were investigated for sample size sensitivity analysis. If the 
number of subjects who completed each active dose was different, then the true incidence 
rates of safety events that could not be ruled out would change. These changes are 
outlined as below. 


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Completed N 
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 
12 
2 
48.4% 
3 
57.2% 
4 
65.1% 
11 
0 
28.5% 
1 
41.3% 
2 
51.8% 
3 
61.0% 
10 
0 
30.8% 
1 
44.5% 
2 
55.6% 
3 
65.2% 
Following table shows how the results could have variabilities with changing between-
subject estimates of variability (CV%) and number of subjects. Estimates of the upper 
limit values of 95% CI of geometric mean are described using proportions (%) of 
variability to geometric mean of PK parameters. 
N 
Estimate of between-subject variability (CV%) 
20 
30 
40 
50 
11 
14.2% 
21.8% 
29.5% 
37.3% 
12 
13.4% 
20.5% 
27.7% 
35.0% 
13 
12.7% 
19.4% 
26.2% 
33.0% 
14 
12.1% 
18.4% 
24.9% 
31.4% 
 
10.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Screened 
All subjects who have a screening visit will be included. 
Enrolled 
All subjects who passed screening and entered the study will be 
included. 
Note screening failures (who never passed screening even if 
rescreened) and subjects screened but never enrolled into the study 
(Reserve, Not Used) are excluded from the Enrolled population as 
they did not enter the study. 


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Population 
Description 
Safety analyses 
All subjects who have received at least one dose of study treatment 
will be included. This population will be used for the safety analyses. 
PK analyses 
All subjects in the Safety population for whom a PK sample has been 
obtained and analyzed will be included. This population will be used 
for the PK analyses. 
 
10.4. 
Statistical Analyses 
10.4.1. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. Safety data will be 
presented in tabular and/or graphical format and summarized descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards. 
The tables, figures, and listings will use the Safety Population unless otherwise specified. 
AEs, changes in clinical laboratory values, 12-Lead ECGs, findings during continuous 
cardiac telemetry and vital signs will be summarized by dose group (i.e. placebo, 60 mg, 
120 mg, and 240 mg) to assess the safety and tolerability of GSK2982772. The safety and 
tolerability results will not to be formally compared between each group and comparison 
with placebo will be based on review of descriptive summaries. 


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10.4.2. 
Pharmacokinetic Analyses 
All PK analyses will be performed on the PK Population.  
Statistical Analysis Methods 
Plasma GSK2982772 concentration-time data will be analysed by non-compartmental methods with 
WinNonlin. Calculations will be based on the actual sampling times recorded during the study. 
From the plasma concentration-time data, the following PK parameters will be determined, as data 
permit: AUC(0-24), AUC(0-7), AUC(7-14) and AUC(14-24), Cmax following each dose, time to 
maximum observed plasma drug concentration (Tmax) following each dose,t1/2 following the third 
dose, observed trough plasma concentrations (C0, C7, C14 and C24). 
PK data will be presented in graphical and/or tabular form and will be summarised descriptively. 
Listings will be generated and summary statistics (n, arithmetic mean with associated 95% CI, 
standard deviation (SD), minimum, median, maximum, geometric mean with associated 95% CI, SD 
on log-scale and %CVb) will be calculated for each derived plasma PK parameter for each dose. 
The PK-dose relationship will be examined graphically by plotting derived plasma PK parameters for 
each dose group. Dose proportionality for AUC(0-24), AUC(0-7) and Cmax following the first dose 
will be assessed by using a power model as described below: 
loge (PK parameter) = μ + Si + β*loge (Dj) + εij 
where μ is the intercept, β is the slope, Si is the random effect for subject i, Dj is the dose (j = 
60 mg, 120 mg, or 240 mg), εij is the random error. Point estimates for the slope of PK parameters 
and their associated 90% CI will be presented. 
 
10.4.3. 
Interim Analyses 
A review of safety data will be conducted at the end of each period.  
The decision to proceed to higher dose strengths will be made by principal investigator 
and GSK’s Medical Monitor based on assessment of safety and tolerability at the 
preceding dose. This review can include individual subject data. 
 


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11. 
REFERENCES 
GSK2982772 Investigator’s Brochure, GlaxoSmithKline Document Number 
2014N204126_04. 
Berger S, 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. Journal of Immunology, 2014; 192:5476-80. 
Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E et al. 
RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions 
of cIAP1/2 depletion or TAK1 kinase inhibition. Cell Death and Differentiation, 
2013;20:1381-92.  
Humphries F, Yang S, Wang B, Moynagh P N. RIP kinases: key decision makers in cell 
death and innate immunity. Cell Death and Differentiation, 2015;22:225-236. 
Ofengeim D and Yuan J. Regulation of RIP1 kinase signaling at the crossroads of 
inflammation and cell death. Nature Reviews Molecular Cell Biology, 2013; 14:727-36. 
Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. 
Cell, 2008; 133(4):693-703. 
 


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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
Abbreviations 
ADL 
Activities of daily life 
AE 
Adverse event 
ALS 
Amyotrophic lateral sclerosis 
AUC 
Area under concentration-time curve 
AUC(0-7) 
Area under the concentration-time curve from time 0 to 7 hr 
AUC(7-14) 
Area under the concentration-time curve from time 7 to 14 hr 
AUC(14-24) 
Area under the concentration-time curve from time 14 to 24 hr 
AUC(0-t) 
Area under the concentration-time curve from time 0 to the time of 
the last measurable drug concentration 
AUC(0-∞) 
Area under the concentration-time curve from time 0 to infinity 
BID 
Bis in die 
BMI 
Body mass index 
BP 
Blood pressure 
CFR 
Code of Federal Regulation 
CI 
Confidence interval 
Cmax 
Maximum observed plasma drug concentration 
C0 
Plasma drug concetration at pre-dose 
C7 
Plasma drug concetration at 7 hr after dosing 
C14 
Plasma drug concetration at 14 hr after dosing 
C24 
Plasma drug concetration at 24 hr after dosing 
CNS 
Central nervous system 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTN 
Clinical Trial Notification 
CV 
Coefficient of variance 
CYP 
Cytochrome P450 
DAMP 
Damage associated molecular pattern 
e.g. 
Exempli gratia 
ECG 
Electrocardiogram 
FLAIR 
FLuid-Attenuated Inversion Recovery 
FTiH 
First Time in Human 
g 
Gram 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GLP 
Good Laboratory Practice 
GSK 
GlaxoSmithKline 
h/hr(s) 
Hour(s) 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
Hep B 
Hepatitis B 


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Hep C 
Hepatitis C 
HIV 
Human immunodeficiency virus 
HTLV-1 
Human T-cell leulemia virus type 1 
i.e. 
id est 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
INR 
International Normalized Ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
kg 
Kilogram 
loge 
Natural logarithm 
µg 
Micrograms 
mg 
Milligrams 
min 
Minute 
mL 
Milliliter 
msec 
Milliseconds 
MV 
Minute volume 
MTX 
Methotrexate 
m2 
Square metre 
NA 
Not applicable 
ng 
Nanograms 
nL 
Nanoliter 
NOS 
Not otherwise specified 
NOAEL 
No Observable Adverse Effect Level 
OAT3 
Organic anion transporter 3 
P-gp 
P-glycoprotein 
pH 
Pondus Hydrogenii 
PK 
Pharmacokinetics 
PsO 
Psoriasis 
PR 
Pulse rate 
QD 
Quaque die 
RA 
Rheumatoid arthritis 
RIP1 
Receptor-interacting serine/threonine protein-1 
RNA 
Ribonucleic acid 
RPR 
Rapid Plasma Reagin 
SAE 
Serious adverse event 
SAS 
Subarachnoid space 
SD 
Standard deviation 
Ser 
Serine 
SIB 
Suicidal Ideation and Behaviour 
SoA 
Schedule of Activities 
SRM 
Study Reference Manual 


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t1/2 
Terminal half-life 
TB 
Tuberculosis 
Thr 
Threonine 
TID 
Ter in die 
Tmax 
Time to maximum observed drug concentration 
TNF(α) 
Tumour necrosis factor (α) 
TNFR1 
Tumour necrosis factor receptor-1 
TP 
Treponema pallidum 
UC 
Ulcerative colitis 
ULN 
Upper limit of normal 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
 
 
WinNonlin 
 


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12.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 1 will be performed by the local laboratory.  
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 1 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
‰Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase (AST) 
Total and direct 
bilirubin 
Creatinine 
Sodium 
Alanine 
Aminotransferase (ALT) 
Total Protein 
Glucose (fasting) 
Calcium 
Alkaline phosphatase 
Albumin 
Uric acid 
TG 
Total Cholesterol 
LDL-cholesterol 
HDL-cholesterol 
LDH 
GGT 
CK (CPK) 
Amylase 
Chloride 
Phosphorus 
CRP 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
• Urine drug screen (to include at minimum: Phencyclidines [PCP], 
Benzodiazepines [BZO], Cocaine [COC], Amphetamines [AMP], 
Tetrahydrocannabinol [THC], Opiates [OPI], Barbiturates [BAR], Trycyclic 
antidepressants [TCA]) 
• Serology (Syphilis [RPR & TP], TB, HIV antigen/antibody, HTLV-1 antibody, 
hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody) 
NOTES : 
1. Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 7. All events of ALT ≥3 × upper limit of normal (ULN) and 
bilirubin ≥ 2 × ULN (> 35% direct bilirubin) or ALT ≥ 3 × ULN and international normalized ratio (INR) > 1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 


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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 International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (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 by the investigator 
and reviewed and approved by the IRB before the study is initiated.  
• 
Any amendments to the protocol will require 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 annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB 
• 
Notifying the IRB of SAE or other significant safety findings as required by IRB 
procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
Financial Disclosure 
Investigators and sub-investigators will provide the GSK with sufficient, accurate 
financial information as requested to allow the GSK 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 legally authorized representative and answer all questions regarding 
the study.  


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• 
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 or study center.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
• 
Participants who received rescreening must be re-consented the ICF(s). 
• 
The ICF may contain a separate section that addresses the use of remaining 
mandatory samples for optional exploratory research in accordance with SOP-
GSKF-410. The investigator or authorized designee will explain to each participant 
the objectives of the exploratory research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate signature will be required to document a 
participant's agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate will not provide this separate 
signature. 
Data Protection 
• 
Participants will be assigned a unique identifier by the GSK. Any participant records 
or datasets that are transferred to the GSK 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 GSK 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 
GSK, by appropriate IRB members, and by inspectors from regulatory authorities. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the GSK 
before submission. This allows the GSK to protect proprietary information and to 
provide comments.  


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• 
The GSK will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the GSK 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. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the GSK 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 review, and 
regulatory agency inspections and provide direct access to source data documents.  
• 
The GSK or designee is responsible for the data management of this study including 
quality checking of the data.  
• 
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final Clinical 
Study Report (CSR)/ equivalent summary unless local regulations or institutional 


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policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the GSK. No records may be 
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Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available. 
• 
Definition of what constitutes source data can be found in the list of the source 
documents. 
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 GSK or investigator may include but 
are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB 
or local health authorities, the GSK's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study treatment development 


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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 assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (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. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE. 
 
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. 


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• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (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 fulfills 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, diarrhea, 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: 


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• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 
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. 


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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 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 hrs of receipt 
of the information. 
 


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Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hrs. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hrs of SAE 
entry into the eCRF. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form. 
• 
Contacts for SAE reporting can be found in Appendix 8. 
 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the GSK Medical Monitor. 
• 
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 Appendix 8. 
 


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12.5. 
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information 
Contraception Guidance 
Male participants 
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following 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  
• 
Agree to use a male condom plus an additional method of contraception with a 
failure rate of < 1% per year as described in Table 2 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 until follow up visit 
Table 2 
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  
Highly Effective Methods That Are User Independent  
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the Women of Childbearing Potential (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 treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 


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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 treatment, 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 until follow up visit.  
 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• 
Investigator will discontinue study treatment and 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 hrs of learning of the partner’s 
pregnancy.  
• 
Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 


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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 
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. 
Additional 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. 
• 
Samples will be given a code and stored securely. 
• 
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. 
• 
If particinpant chooses to stop the pharmacogenetics part of the study after giving a 
sample, GSK will not conduct any new tests on the sample. GSK will destroy the 
sample. GSK will keep and use any results generated before you stopped 
participating in the pharmacogenetics study. 
• 
GSK will only use the coded results to verify or show the quality of analyses that 
have already been reported. GSK will take steps to ensure that your coded results are 
not used in any new analyses. If new analyses are conducted then GSK will make 
sure that the subject's number will be deleted. 
• 
GSK may provide your genetic information generated from your sample for research 
with other companies or universities to learn more about other medicines, this 
immuno-inflammatory disease and other disease, only by deleting the subject 
number before it is provided, so that provided information will not be identified in 
any way and your privacy is protected.  


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• 
If GSK decides to use your sample and/or your genetic information for a different 
study, GSK will ask participant for his permission again or GSK will ask an adequate 
committee to review the study from ethical standpoint. 
 


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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 hrs 
• 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 
hrs 
• 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: 
• Viral hepatitis serology3 
• Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Obtain plasma sample for pharmacokinetic 
(PK) analysis, obtained within 24 hrs 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: 


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Liver Chemistry Stopping Criteria  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs 
• Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
• 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 immunoglobulin M (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)  
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. 


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12.8. 
Appendix 8: Country-specific requirements 
12.8.1. 
Regulatory and Ethical Considerations 
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (Ministry of Health 
and Welfare (MHW) Notification No.28 dated 27th March, 1997)” and the 
Pharmaceuticals and Medical Devices Act. 
GSK will submit the Clinical Trial Notification (CTN) to the regulatory authorities in 
accordance with Pharmaceuticals and Medical Devices Act before conclusion of any 
contract for the conduct of the study with study sites. 
12.8.2. 
Informed Consent 
Prior to participation in the study, the investigator (or subinvestigator) should fully 
inform the potential participant of the study including the written information. The 
investigator (or subinvestigator) should provide the participant  ample time and 
opportunity to inquire about details of the study. The participant  should sign and 
personally date the consent form. The participant may consider the content of the written 
information at home. The person, who conducted the informed consent discussion and the 
study collaborator giving supplementary explanation, where applicable, should sign and 
personally date the consent form. If an impartial witness is required, the witness should 
sign and personally date the consent form. The investigator (or subinvestigator) should 
retain this signed and dated form (and other written information) together with the source 
medical records, such as clinical charts (in accordance with the rules for records retention, 
if any, at each medical institution) and give a copy to the participant. 
12.8.3. 
Study Period 
JUL 2018 - SEP 2018 
12.8.4. 
Study Administrative Structure 
Sponsor Legal Registered Address: 
GlaxoSmithKline K.K. (GSK) 
Akasaka Intercity AIR, 8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052 Japan 
Study Director: 
 Head, Medicines Development, Clinical 
Pharmacology & Science Promotion Office 
Sponsor Contact Address: 
Lead Author: 
 Manager, Medicines Development, Clinical Pharmacology & Science 
Promotion Office 
Sponsor’s Emergency Contact Information (10:00-18:00, Monday to Friday, except 
national holidays and year-end and new-year holidays); 
PPD
PPD


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Medicines Development (Clinical Pharmacology), GlaxoSmithKline K.K. 
TEL: 
 (direct dialling)  
FAX: 
 
Contact Information at Night and on Holidays (Monday to Friday: 18:00-10:00, Saturday, 
Sunday, national holidays, year-end and new-year holidays) 
 (mobile: 
  
GSK Medical Monitor / Contact Address for SAE 
 
GlaxoSmithKline K.K. (GSK) 
Akasaka Intercity AIR, 8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052 Japan 
TEL: 
 (mobile)／
 (direct dialling)  
FAX: 
 
Medical Institution and Investigator 
 
SOUSEIKAI Hakata Clinic 
6-18 Tenyamatchi, Hakata-ku, Fukuoka 812-0025 Japan 
TEL: 
  
FAX: 
 
Laboratories 
Clinical Laboratory (except HTLV-1 serology and TB) 
SOUSEIKAI Hakata Clinic 
Person in charge: 
 
6-18 Tenyamachi, Hakata-ku, Fukuoka 812-0025 Japan 
TEL: 
 
FAX: 
  
HTLV-1 serology and TB (If subject meet Liver chemistry stopping criteria, include anti-
nuclear antibody, anti-smooth muscle antibody, type 1 anti-liver kidney microsomal 
antibodies, and quantitative total IgG or gamma globulins, and viral hepatitis serology 
described in Appendix 7, but except HBsAg) 
Person in charge: 
 
LSI Medience Inc. 
30-1 Shimura 3-chome, Itabashi-ku, Tokyo 174-8555, Japan  
TEL: 
 
FAX: 
 
Pharmacokinetics Measurement Facilities 
Covance Laboratories Limited 
Person in charge: 
 
Otley Road, Harrogate, North Yorkshire, HG3 1PY, UK 
TEL: 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Gx Research Administration (Sample Management , Sample Storage Facility, DNA 
Extraction Facility) 
Contact person: 
 
Q2 Solutions 
Q Squared Solutions (Quest) LLC 
27027 Tourney Road, Suite 2E 
Valencia, CA  91355 
USA 
TEL: 
 
FAX: 
 
Contract research organization 
Role: Study Monitoring 
Person in charge (Monitor Leader): 
 
Mediscience Planning Inc. 
2-8-10 Toranomon, Minato-ku, Tokyo 105-0001 Japan 
TEL: 
 
FAX: 
 
Role: Medical Writing (Protocol & Informed Consent Form) 
Person in charge: 
 
Mediscience Planning Inc. 
2-8-10 Toranomon, Minato-ku, Tokyo 105-0001 Japan 
TEL: 
 
FAX: 
 
Role: Medical Writing (Clinical Study Report) 
Person in charge: 
 
Mediscience Planning Inc. 
2-8-10 Toranomon, Minato-ku, Tokyo 105-0001 Japan 
TEL: 
 
FAX: 
 
Role: Pharmacokineic Parameter Derivation 
Person in charge: 
 
Mediscience Planning Inc. 
1-2-1 Nihonbashi hamacho, Chuo-ku, Tokyo 103-0007 Japan 
TEL: 
 
FAX: 
 
Role: Data Loading 
Person in charge: 
 
Mediscience Planning Inc. 
1-2-1 Nihonbashi hamacho, Chuo-ku, Tokyo 103-0007 Japan 
TEL: 
 
FAX: 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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12.9. 
Appendix 9: 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 3 
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 
Activities of daily life 
(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 
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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. 


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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. 
Edema cerebral 
 - 
 - 
 - 
Life-threatening 
consequences; 
urgent 
intervention 
 
A disorder characterized by swelling 
due to an excessive accumulation of 
fluid in the brain. 


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CTCAE v4.0 Term 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  CTCAE v4.0 AE Term Definition 
indicated 
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. 
Hydrocephalus 
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
Moderate symptoms; 
intervention not 
indicated 
Severe symptoms or 
neurological deficit; 
intervention indicated 
Life-threatening 
consequences; 
urgent 
intervention 
Death 
A disorder characterized by an 
abnormal increase of cerebrospinal 
fluid in the ventricles of the brain. 


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CTCAE v4.0 Term 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  CTCAE v4.0 AE Term Definition 
indicated 
indicated 
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, 
Intracranial 
Pressure (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. 


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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. 
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 


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CTCAE v4.0 Term 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  CTCAE v4.0 AE Term Definition 
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. 
Presyncope 
 - 
Present (e.g., near 
fainting) 
 - 
 - 
 - 
A disorder characterized by an 
episode of lightheadedness and 


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CTCAE v4.0 Term 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  CTCAE v4.0 AE Term Definition 
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. 


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CTCAE v4.0 Term 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  CTCAE v4.0 AE Term Definition 
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. 
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 hrs) 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). 


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CTCAE v4.0 Term 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  CTCAE v4.0 AE Term Definition 
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 
 - 


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12.10. 
Appendix 10: Protocol Amendment History 
Not applicable 
 


2017N311130_01  
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
205037 
 
1 
 
TITLE PAGE 
Protocol Title: A single-centre, randomized, double-blind, dose-ascending, placebo-
controlled study to evaluate the safety, tolerability, and pharmacokinetics of oral TID 
doses (one day) of GSK2982772 in Japanese healthy male subjects 
Protocol Number: 205037 
Short Title: Phase I study of GSK2982772 in Japanese healthy male subjects 
Compound Number: GSK2982772 
 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline K.K. (GSK) 
Akasaka Intercity AIR, 8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052 Japan 
Medical Monitor Name and Contact Information: 
 
GlaxoSmithKline K.K. (GSK) 
Akasaka Intercity AIR, 8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052 Japan 
Regulatory Agency Identifying Number(s): Not applicable 
Approval Date: 27-JUN-2018 
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 
PPD


2017N311130_01 
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205037 
 
2 
 
SPONSOR SIGNATORY: 
 
 
Kosuke Kozaiwa 
VP & Head of Medicines Development 
Development & Medical Affairs 
GlaxoSmithKline K.K. 
 
Date 
 


2017N311130_01 
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205037 
 
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TABLE OF CONTENTS 
PAGE 
1. 
SYNOPSIS ............................................................................................................... 5 
2. 
SCHEDULE OF ACTIVITIES (SOA) ......................................................................... 8 
3. 
INTRODUCTION .................................................................................................... 12 
3.1. 
Study Rationale .......................................................................................... 12 
3.2. 
Background ................................................................................................ 12 
3.3. 
Benefit/Risk Assessment ............................................................................ 13 
3.3.1. 
Risk Assessment ......................................................................... 14 
3.3.2. 
Benefit Assessment ..................................................................... 18 
3.3.3. 
Overall Benefit: Risk Conclusion .................................................. 18 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 18 
5. 
STUDY DESIGN .................................................................................................... 18 
5.1. 
Overall Design ............................................................................................ 18 
5.2. 
Number of Subjects .................................................................................... 19 
5.3. 
Sentinel Dosing........................................................................................... 19 
5.4. 
Dose Escalation Decisions ......................................................................... 20 
5.5. 
Participant and Study Completion ............................................................... 20 
5.6. 
Scientific Rationale for Study Design .......................................................... 20 
5.7. 
Dose Justification ........................................................................................ 21 
6. 
STUDY POPULATION ........................................................................................... 22 
6.1. 
Inclusion Criteria ......................................................................................... 22 
6.2. 
Exclusion Criteria ........................................................................................ 23 
6.3. 
Lifestyle Restrictions ................................................................................... 25 
6.3.1. 
Meals and Dietary Restrictions .................................................... 25 
6.3.2. 
Caffeine, Alcohol, and Tobacco ................................................... 25 
6.3.3. 
Activity ......................................................................................... 25 
6.4. 
Screen Failures........................................................................................... 25 
7. 
TREATMENTS ....................................................................................................... 26 
7.1. 
Treatments Administered ............................................................................ 26 
7.2. 
Method of Treatment Assignment ............................................................... 26 
7.3. 
Blinding ....................................................................................................... 27 
7.4. 
Preparation/Handling/Storage/Accountability .............................................. 27 
7.5. 
Treatment Compliance ................................................................................ 28 
7.6. 
Concomitant Therapy.................................................................................. 28 
7.7. 
Treatment after the End of the Study .......................................................... 28 
8. 
DISCONTINUATION CRITERIA ............................................................................. 28 
8.1. 
Discontinuation of Study Treatment ............................................................ 28 
8.1.1. 
Dose Stopping Criteria ................................................................. 28 
8.1.2. 
Liver Chemistry Stopping Criteria ................................................ 29 
8.1.3. 
QTc Stopping Criteria .................................................................. 30 
8.1.4. 
Individual Safety Stopping Criteria ............................................... 30 
8.1.5. 
Nervous System Stopping Criteria ............................................... 30 
8.2. 
Withdrawal from the Study .......................................................................... 31 


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8.3. 
Lost to Follow Up ........................................................................................ 31 
9. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 32 
9.1. 
Adverse Events........................................................................................... 32 
9.1.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 32 
9.1.2. 
Method of Detecting AEs and SAEs ............................................. 33 
9.1.3. 
Follow-up of AEs and SAEs ......................................................... 33 
9.1.4. 
Regulatory Reporting Requirements for SAEs ............................. 33 
9.1.5. 
Pregnancy ................................................................................... 33 
9.2. 
Treatment of Overdose ............................................................................... 34 
9.3. 
Safety Assessments ................................................................................... 34 
9.3.1. 
Physical Examinations ................................................................. 34 
9.3.2. 
Neurological Examinations .......................................................... 34 
9.3.3. 
Vital Signs .................................................................................... 35 
9.3.4. 
Electrocardiograms ...................................................................... 35 
9.3.5. 
Clinical Safety Laboratory Assessments ...................................... 35 
9.3.6. 
Suicidal Risk Monitoring ............................................................... 36 
9.4. 
Pharmacokinetics ....................................................................................... 36 
9.5. 
Genetics ..................................................................................................... 36 
10. STATISTICAL CONSIDERATIONS ........................................................................ 37 
10.1. Sample Size Determination ........................................................................ 37 
10.2. Sample Size Sensitivity ............................................................................... 38 
10.3. Populations for Analyses ............................................................................ 39 
10.4. Statistical Analyses ..................................................................................... 40 
10.4.1. 
Safety Analyses ........................................................................... 40 
10.4.2. 
Pharmacokinetic Analyses ........................................................... 41 
10.4.3. 
Interim Analyses .......................................................................... 41 
11. REFERENCES ....................................................................................................... 42 
12. APPENDICES ........................................................................................................ 43 
12.1. Appendix 1: Abbreviations and Trademarks ................................................ 43 
12.2. Appendix 2: Clinical Laboratory Tests ......................................................... 46 
12.3. Appendix 3: Study Governance Considerations .......................................... 47 
12.4. Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 52 
12.5. Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 57 
12.6. Appendix 6: Genetics .................................................................................. 59 
12.7. Appendix 7: Liver Safety Required Actions and Follow up 
Assessments .............................................................................................. 61 
12.8. Appendix 8: Country-specific requirements ................................................. 63 
12.8.1. 
Regulatory and Ethical Considerations ........................................ 63 
12.8.2. 
Informed Consent ........................................................................ 63 
12.8.3. 
Study Period ................................................................................ 63 
12.8.4. 
Study Administrative Structure ..................................................... 63 
12.9. Appendix 9: Nervous System Adverse Events (CTCAE Criteria) ................ 66 
12.10. Appendix 10: Protocol Amendment History ................................................. 76 
 


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1. 
SYNOPSIS 
Protocol Title: A single-centre, randomized, double-blind, dose-ascending, placebo-
controlled study to evaluate the safety, tolerability, and pharmacokinetics of oral TID 
doses (one day) of GSK2982772 in Japanese healthy male subjects 
Short Title: Phase I study of GSK2982772 in Japanese healthy male subjects 
Rationale:  
This study is the first administration of GSK2982772 to Japanese. The purpose of this 
study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral doses of 
TID doses for one day with GSK2982772 in Japanese healthy male subjects. 
GSK2982772 or placebo will be administered at 0 hr (the first dosing), 7 hr (the second 
dosing) and 14 hr (the third dosing) on Day 1 in each period. The intention of this study 
is to provide sufficient confidence in the safety of the molecule to inform progression to 
further repeat dose studies in patients. The dose range proposed in this study is based on a 
low starting dose escalating to the highest dose that is intended for the Phase 2b dose 
range study. 
Objectives and Endpoints: 
Objectives 
Endpoints 
To assess the safety and tolerability of TID 
doses for one day of GSK2982772 in Japanese 
healthy male subjects 
Adverse events (AEs) 
Change in laboratory values (clinical chemistry, 
haematology and urinalysis), 12-lead ECG and 
cardiac telemetry, vital signs (blood pressure, 
pulse rate, and body temperature) 
Physical examinations, including neurological 
examinations 
To characterise the PK profile of TID doses for 
one day of GSK2982772 in Japanese healthy 
male subjects 
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)), 
maximum observed plasma drug concentration 
(Cmax) following each dose, time to maximum 
observed plasma drug concentration (Tmax) 
following each dose, terminal half-life (t1/2) 
following the third dose, observed trough 
plasma drug concentrations (C0, C7, C14 and 
C24), where data allow 
Overall Design:  
This study will be a double-blind with respect to subjects, investigators and site staff 
(with the exception of the unblinded site pharmacist), TID oral doses for one day, 


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ascending dose, randomized, placebo-controlled, 4-way crossover study, shown as the 
table below; 
 
Group 
N 
Period 1 
Period 2 
Period 3 
Period 4 
A 
3 
Placebo, TID 
60 mg, TID 
120 mg, TID 
240 mg, TID 
B 
3 
60 mg, TID 
Placebo, TID 
120 mg, TID 
240 mg, TID 
C 
3 
60 mg, TID 
120 mg, TID 
Placebo, TID 
240 mg, TID 
D 
3 
60 mg, TID 
120 mg, TID 
240 mg, TID 
Placebo, TID 
Number of Participants:  
Sufficient Japanese healthy male subjects will be enrolled such that up to approximately 
12 subjects 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. Replacement subjects will be 
assigned to the same treatment sequence and start from the period to be replaced at the 
discretion of the GSK and in consultation with the principal investigator. 
Sentinel Dosing: 
The doses will be staggered such that for each dose, on Day 1 of Period 1, 2 and 3, 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 (AEs, clinical labs, vital signs, 12-Lead ECGs and Cardiac 
telemetry) in the judgment of the principal investigator and GSK Medical Monitor 
through at least 24 hrs after their third dose on Day 1, the remaining subjects may be 
randomized to dosing in that period.  
Treatment Groups and Duration: 
Screening 
Within 30 days prior to the first dose on Day1. 
Treatment Period 
The study will be comprised of four study periods each at least 7 days in 
duration with subjects in-house for 4 nights (through 72 hrs after the first 
dose). During each treatment period, subjects will be admitted to the unit 
the day before dosing and will be discharged after completion of the 72 hrs 
post-dose assessments.  
Each subject will receive oral TID doses of GSK2982772 in each treatment 
period. For TID dosing, GSK2982772 or placebo will be administered at 0 
hr (the first dosing), 7 hr (the second dosing) and 14 hr (the third dosing) on 
Day 1 in each period. On Day 1, subjects will fast 8hr overnight prior to first 
dose. A breakfast will be served approximately 2hr after first dose.  
Lunch and dinner will be served between 2 to 3hr prior to second and third 
doses, respectively. 
Washout Period 
Will be at least 7 days between treatment period doses for an individual 


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subject. 
Follow-up 
At least 7 days, and no greater than 14 days after last study treatment 
administration. If warranted, additional follow-up visits may be scheduled. 


2017N311130_01 
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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, are essential and required for study 
conduct. 
The Study Reference Manual (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.  
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. 
A table defining the allowed variance in timings of assessments without being considered 
a protocol deviation will be included in the SRM. 
 


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Time and Events Table for Screening and Follow-up Assessments 
Procedure 
Screening1 
Follow-up Visit2 
Notes 
Outpatient Visit 
X 
X 
 
Informed Consent 
X 
 
 
Medical/medication/drug 
/alcohol history 
X 
 
 
Demographics 
X 
 
 
Physical Examination 
X 
X 
Additional examinations may be performed, by the Investigators, as deemed necessary. 
Drug screen 
X 
 
Additional tests may be performed by the Investigators, as deemed necessary. Tests will be conducted within site specified standards. 
Syphilis, Human immunodeficiency virus 
(HIV), Human T-cell leulemia virus type 1 
(HTLV-1), Hepatitis B (Hep B) and Hepatitis 
C (Hep C) screen 
X 
 
 
Tuberculosis (TB) Test 
X 
 
Conducted at the standard practice of the site. 
X-ray Test 
X 
 
Anterior & lateral chest X-ray will be taken. 
Hema/Chem/Urinalysis tests 
X 
X 
 
Height and weight 
X 
 
 
12-lead ECG and vital signs 
X 
X 
Vital signs to include pulse rate (PR), blood pressure (BPs) and temperature. 
AE Review 
X 
X 
All Serious Adverse Effects (SAEs) will be collected from the signing of the informed consent form (ICF) until the follow-up visit at the 
time points specified. All AEs will be collected from the start of treatment until the follow-up visit at the time points specified. 
Concomitant Medication Review 
X 
X 
 
1: Within 30 days prior to the first dosing 
2: Follow-up Visit to occur at least 7 days, and no greater than 14 days after last study treatment administration. If a participant withdrew from the study after received GSK2982772 or placebo dose, the safety 
assessments listed at follow-up visit will be required.   
 


2017N311130_01 
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Detailed Time and Events Table for Days 1-4 (common Period1-4) 
Procedure 1 
Day 
 -1 
Day 1 
Pre- 
dose 
0 
20 
min 
40 
min 
1 
hr 
1.5 
hr 
2 
hr 
3 
hr 
4 
hr 
5 
hr 
7 
hr 
7 
hr 
20 
min 
7 
hr 
40 
min 
8 
hr 
8.5 
hr 
9 
hr 
10 
hr 
11 
hr 
12 
hr 
14 
hr 
14 
hr 
20 
min 
14 
hr 
40 
min 
15 
hr 
15.5 
hr 
Admission 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
X 
 
 
 
 
 
X 
 
 
 
X6 
 
 
 
 
 
 
 
 
X6 
 
 
 
 
Hema/Chem/ 
Urinalysis tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 2 
 
X 
 
 
 
 
 
X 
 
 
 
X6 
 
 
 
 
 
 
 
 
X6 
 
 
 
 
12-lead ECG 
 
X 
 
 
 
 
 
X 
 
 
 
X6 
 
 
 
 
 
 
 
 
X6 
 
 
 
 
Cardiac telemetry 3  
 
 
<============================================================================================================================================= 
PK blood sampling 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X7 
X 
X 
X 
X 
X 
X 
 
X 
X7 
X 
X 
X 
X 
Neurological 
Examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X8 
 
 
 
 
Study Treatment 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Pharmacogenetic 
Sampling (PGx) 4 
 
 
<============================================================================================================================================= 
Meals Served 
X 
 
 
 
 
 
 
X9 
 
X9 
 
 
 
 
 
 
 
X9 
 
 
 
 
 
AE Review 5 
 
<==================================================================================================================================================== 
Concomitant 
Medication Review 
 
<==================================================================================================================================================== 
Discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedure 1 
Day 2 
Day 3 
Day 4 
16 hr 
17 hr 
19 hr 
22 hr 
24 hr 
28 hr 
32 hr 
36 hr 
48 hr 
60 hr 
72 hr 
Admission 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
 
 
 
 
X 
 
 
X 
X 
 
X 
Hema/Chem/ 
Urinalysis tests 
 
 
 
 
 
 
 
 
 
 
X 
Vital signs 2 
 
 
 
 
X 
 
 
 
X 
 
X 
12-lead ECG 
 
 
 
 
X 
 
 
 
X 
 
X 
Cardiac telemetry 3 
===================================================================> 
 
 
 
 
 
 
PK blood sampling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological 
Examination 
 
 
 
 
X 
 
 
 
X 
 
X 
Study Treatment 
 
 
 
 
 
 
 
 
 
 
 
Pharmacogenetic 
Sampling (PGx) 4 
=======================================================================================================================================================> 
Meals Served 
 
 
 
 
 
X10 
 
X10 
X10 
X10 
 
AE Review 5 
=======================================================================================================================================================> 
Concomitant 
Medication Review 
=======================================================================================================================================================> 
Discharge 
 
 
 
 
 
 
 
 
 
 
X 
1: In this study, baseline is Day -1 and Day 1 pre-dose tests. 
2: Vital signs include PR, BPs and temperature. 
3: Only 24 hrs following the first dose administration 
4: A PGx blood sample will be collected at any time during the study after randomization and provided informed consent for genetic reserch. The participation is optional for each subject. 
5: All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points specified. All AEs will be collected from the start of treatment until the follow-up visit at the time points specified.  
6: Physical Examination, Vital signs and 12-lead ECG of 7hr and 14hr time point are to be performed prior to second or third dose. 
7: PK blood sampling of 7hr and 14hr time point are to be performed right prior to second or third dose. 
8: Neurological Examination of 14hr time point are to be performed prior to third dose.  
9: On Day 1, breakfast will be served approximately 2hr after the first dose, lunch will be served between 2 to 3 hr prior to second dose and dinner will be served between 2 to 3 hr prior to third dose.  
10: On Day 2-3, meal will be served per unit schedule. Mealtime will be described in SRM. 


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3. 
INTRODUCTION 
GSK2982772 is a first-in-class highly selective, RIP1 kinase inhibitor being developed 
for the treatment of inflammatory bowel disease (IBD), plaque psoriasis (PsO), 
rheumatoid arthritis (RA) and other disease conditions. 
3.1. 
Study Rationale 
The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics 
(PK) of oral doses of TID doses for one day with GSK2982772 in Japanese healthy male 
subjects. This study is the first administration of GSK2982772 to Japanese.  
3.2. 
Background 
GSK2982772 is a first-in-class, highly selective, small molecule inhibitor of RIP1 kinase. 
RIP1 is a member of the receptor-interacting Ser/Thr kinase family containing an amino-
terminal kinase domain, an intermediate domain and a carboxy-terminal death domain. 
RIP1 is a key signalling node which plays an essential role in inflammation and cell death 
in response to signals including TNF family cytokines, ligands for TLR3/TLR4, sensors 
of viral infection, and interferons [Ofengeim, 2013]. Through tight regulation by 
ubiquitylation, deubiquitylation and interaction with its receptors, RIP1 has dual roles as 
a kinase and a scaffolding protein, and serves as an upstream checkpoint for both cell 
death and survival [Ofengeim, 2013]. Detailed understanding of RIP1 kinase function has 
not been fully elucidated, but it is known that RIP1 exerts it signalling functions through 
both its catalytic kinase activity and by acting as a scaffolding protein for signalling 
complexes. Recent work has demonstrated that RIP1 catalytic kinase activity can regulate 
TNF-mediated necroptosis [Ofengeim, 2013] and noncanonical apoptosis [Wang, 2008, 
Dondelinger, 2013]. In addition, the production of certain inflammatory cytokines can be 
regulated by RIP1 kinase activity. In contrast, RIP1’s scaffolding function acts to 
facilitate other immune processes including TNF mediated classical apoptosis and 
Nuclear factor-kappaB (NF-kB)-signalling [Ofengeim, 2013, Humphries, 2015]. With 
this, an inhibitor of RIP1 kinase activity with GSK2982772 may fill a unique niche in the 
treatment of inflammatory conditions (eg. PsO, RA and IBD) through multiple 
mechanisms, including inhibition of inflammation-induced cell death (necroptosis and 
apoptosis) and inhibition of the production of certain pro-inflammatory cytokines.  
A range of nonclinical studies have been conducted to support the administration of 
GSK2982772 to humans [GlaxoSmithKline Document Number 2014N204126_04]. 
The First Time in Human (FTiH) study which was single (fed and fasted) and repeat dose 
escalation study (Study 200975) of GSK2982772 in healthy male subjects of 
predominantly White/Caucasian/European heritage in United Kingdom, 67 subjects were 
exposed to active treatment. GSK2982772 was well-tolerated up to 120 mg BID for 14 
days, with no deaths or other non-fatal SAEs being reported.  
The PK of GSK2982772 appeared approximately dose proportional over the single dose 
range 0.1 to 120 mg. Following14 days of repeat dose administration, the Cmax and 
AUC(0-t) increased approximately proportionally 20 and 60 mg QD, 60 and 120 mg BID. 


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There was no evidence of accumulation in any of the dosing regimens and trough plasma 
concentrations appeared to reach steady state from Day 2. Following oral administration 
of GSK2982772, the median time to Cmax was between 1.5 and 2.5 hr after attainment of 
Cmax. GSK2982772 concentrations decline rapidly until about 12 hrs post-dose, with a 
t1/2 of approximately 2 to 6 hrs. The majority of the systemic exposure to GSK2982772 
is observed within the first 12 hrs after administration. 
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 days repeat dose toxicology 
study in monkeys (10 mg/kg/day). Subsequently, a 13 week repeat dose 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.  
Thus, currently the study in non-Japanese (Study 205184) 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 planned Phase 2b dose range 
studies in subjects with PsO, RA and UC. Study 205184 includes dosing sessions of 120 
mg TID (1 day and 14 days), 240 mg TID (1 day and 14 days) and 360 mg BID (1 day 
and 14 days), in which all 1-day dosing regimens have been completes and GSK2982772 
was tolerated in all 1-days dosing sessions. 
Detailed information on the safety and PK of GSK2982772 in human can be found in the 
Investigators Brochure (IB) for GSK2982772 [GlaxoSmithKline Document Number 
2014N204126_04]. 
3.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK2982772 may be found in the IB. The 
following section outlines the risk assessment and mitigation strategy for this protocol. 
 


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3.3.1. 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Investigational Product (IP) [GSK2982772] 
Central nervous systemCNS) effects 
Non-clinical data: 
In the 4 week repeat dose Good 
Laboratory Practice (GLP) toxicology 
study, CNS findings were observed 
in 4/12 monkeys which were 
administered 100 or 300 mg/kg/day. 
CNS findings included uncoordinated 
movement, irregular gait, trembling, 
hunched appearance, and 
decreased activity. The clinical 
relevance of these findings in 
humans is not known. In the 13 and 
39 week repeat dose GLP toxicology 
studies, no CNS findings observed in 
monkeys at highest dose levels of 
100 and 60 mg/kg/day, respectively. 
The NOAEL for 39 week study was 
determined at 60 mg/kg/day, which 
corresponds to a gender-averaged 
Cmax 23.2 µg/mL and AUC 
182 µg･hr/mL in plasma. 
  
Clinical data: 
A FTiH study with single ascending 
and multiple ascending doses has 
been performed in 67 healthy male 
subjects to date (Study 200975). See 
IB for GSK2982772 
[GlaxoSmithKline Document Number 
2014N204126_04]. No drug-
associated CNS adverse events 
were identified and no SAEs were 
reported. See IB for GSK2982772 
[GlaxoSmithKline Document Number 
2014N204126_04]. 
In the phase IIa psoriasis study 
(Study 203167), there was one SAE 
of death via accidental overdose of 
Ecstasy/MDMA in a 19 year old male 
subject who was treated with 
GSK2982772 60 mg BID or placebo. 
There was no evidence reported 
to suggest that this event was a 
suicide. 
 
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 
signs of CNS-related effects. 
• Targeted physical examinations 
with comprehensive neurological 
assessments will be conducted at 
appropriate intervals throughout 
the study. 


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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 (Study 200975), no 
SAEs were reported. One subject 
experienced an AE herpes zoster 
27 days after receiving with placebo 
and 42 days after receiving dose with 
GSK2982772 80 mg. The blinded 
principal investigator determined this 
to be drug-related. 
In the IIa psoriasis study (Study 
203167) one subject experienced an 
AE of herpes zoster on Study Day 9 
(either 60 mg BID GSK2982772 or 
placebo). The blinded investigator 
considered the AE to be of moderate 
severity and not related to study 
drug. 
Subject Selection: 
• Subjects with recurrent, chronic or 
active infections will be excluded 
from the study. 
• Subjects will be screened for T 
Spot. 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 
8.1.4) 
 
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 
for 30 days prior to the first dose 
of GSK2982772, during study 
participation and for five half-lives 
plus 30 days (total 32 days) after 
GSK2982772 is discontinued. 
• 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 decreased 
responsiveness). 
• Investigators will be expected to 
have followed local and/or 
national guidelines with respect 
tovaccinations, including against 
influenza and pneumococcus. 
 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Respiratory effects 
Non-Clinical data: 
In the single dose Safety 
Cardiovascular and Respiratory 
Study in monkeys, a decrease in 
minute volume (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 days 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_04]. 
 
Clinical data: 
In the FTiH study, repeat doses of 
GSK2982772 up to 120 mg BID were 
administered 14 days in 36 healthy 
male subjects. 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. 
Subject Monitoring: 
• Subjects should be monitored for 
standard respiratory-related AEs. 
• Vital signs will be monitored 
during study visits. 
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 abnormal 
behaviour were reported. 
In the phase IIa psoriasis study 
(203167), one subject reported 
suicidal ideation at Day 43 via the 
Columbia Suicide Severity Rating 
Scale. This subject informed the 
investigator that he had similar 
thoughts prior to joining the study but 
had no  intention of acting on this.  
The investigator determined the 
subject was of low risk and allowed 
the subject to remain in the study. 
Subject Selection: 
• Subjects with a current history of 
Suicidal Ideation and Behaviour 
(SIB) or a history of attempted 
suicide will be excluded from the 
study. 
 
Subject Monitoring: 
• Although this drug has not been 
shown to be associated with an 
increased risk of suicidal thinking 
or behaviour when given to 
healthy volunteers, Participants 
being treated with GSK2982772 
should be monitored appropriately 
and observed closely for SIB or 
any other unusual changes in 
behaviour. 
• Families and caregivers of 
participants being treated with 
GSK2982772 should be alerted 
about the need to monitor 
participants for the emergence of 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
unusual changes in behaviour, as 
well as the emergence of SIB and 
to report such symptoms 
immediately to the study 
investigator. 
 
Reproductive Toxicity 
Non-Clinical Data: 
In the rat embryofetal development 
study, there were no maternal or 
developmental toxicity at doses ≤200 
mg/kg/day. There were maternal and 
developmental toxicity at dose of 
450 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. There 
was maternal toxicity at dose of 
≥300 mg/kg/day and no tolerability at 
dose of 600 mg/kg/day. 
 
Subject Selection: 
• Males will be included in this 
study only if they agree to use 
highly effective methods of 
contraception and avoid 
conception until last visit. 
 
Withdrawal Criteria: 
• If a female partner should become 
pregnant during the study, study 
medication should be 
discontinued. She will be followed 
to determine the outcome of the 
pregnancy.  
Drug Interaction 
Non-Clinical Data: 
In vitro studies with GSK2982772 
assessing potential drug-drug 
interactions with Cytochrome P450 
3A4 (CYP3A4) substrates and  
P-glycoprotein (P-gp) 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 P-gp substrate 
and therefore co-administration with 
concomitant medications that are P-
gp inhibitors could increase 
circulating levels of GSK2982772. 
There is a low risk that GSK2982772 
could be a perpetrator of organic 
anion transporter 3 (OAT3) 
substrates. Methotrexate(MTX) is an 
OAT3 substrate in which 
GSK2982772 could potentially impair 
the clearance of MTX. 
See Section 4.3.6 of GSK2982772 IB 
[GlaxoSmithKline Document Number 
2014N204126_04]. 
Subject Selection: 
• Subjects who are taking 
concomitant medications known 
to inhibit P-gp or CYP3A4 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. 


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3.3.2. 
Benefit Assessment 
This study is being conducted in healthy participant with no significant medical history. 
Subjects will not receive benefit from this study. However, knowledge from this study 
may contribute to the development of GSK2982772 and may benefit patients in the future. 
3.3.3. 
Overall Benefit: Risk Conclusion 
It is considered acceptable to conduct this study in healthy subjects, because whilst they 
will receive no direct medical benefit, the risks from the study treatment and procedures 
are minimal. The study will be conducted in a fully equipped clinical pharmacology unit 
with access to hospital emergency facilities.  
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. 
4. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
To assess the safety and tolerability of TID 
doses for one day of GSK2982772 in Japanese 
healthy male subjects 
Adverse events (AEs) 
Change in laboratory values (clinical chemistry, 
haematology and urinalysis), 12-lead ECG and 
cardiac telemetry, vital signs (blood pressure, 
pulse rate, and body temperature) 
Physical examinations, including neurological 
examinations 
To characterise the PK profile of TID doses for 
one day of GSK2982772 in Japanese healthy 
male subjects 
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)), 
maximum observed plasma drug concentration 
(Cmax) following each dose, time to maximum 
observed plasma drug concentration (Tmax) 
following each dose, terminal half-life (t1/2) 
following the third dose, observed trough 
plasma drug concentrations (C0, C7, C14 and 
C24), where data allow 
5. 
STUDY DESIGN 
5.1. 
Overall Design 
This study will be a double-blind with respect to subjects, investigators and site staff 
(with the exception of the unblinded site pharmacist), TID oral doses for one day, 


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ascending dose, randomized, placebo-controlled, 4-way crossover study, shown as the 
table below; 
Group 
N 
Period 1 
Period 2 
Period 3 
Period 4 
A 
3 
Placebo, TID 
60 mg, TID 
120 mg, TID 
240 mg, TID 
B 
3 
60 mg, TID 
Placebo, TID 
120 mg, TID 
240 mg, TID 
C 
3 
60 mg, TID 
120 mg, TID 
Placebo, TID 
240 mg, TID 
D 
3 
60 mg, TID 
120 mg, TID 
240 mg, TID 
Placebo, TID 
Treatment Groups and Duration: 
Screening 
Within 30 days prior to the first dose on Day1. 
Treatment Period 
The study will be comprised of four study periods each at least 7 days in 
duration with subjects in-house for 4 nights (through 72 hrs after the first 
dose). During each treatment period, subjects will be admitted to the unit the 
day before dosing and will be discharged after completion of the 72 hrs 
post-dose assessments.  
Each subject will receive oral TID doses of GSK2982772 in each treatment 
period. For TID dosing, GSK2982772 or placebo will be administered at 0 hr 
(the first dosing), 7 hr (the second dosing) and 14 hr (the third dosing) on 
Day 1 in each period. On Day 1, subjects will fast 8hr overnight prior to first 
dose. A breakfast will be served approximately 2hr after first dose. Lunch 
and dinner will be served between 2 to 3hr prior to second and third doses, 
respectively. 
Washout Period 
Will be at least 7 days between treatment period doses for an individual 
subject. 
Follow-up 
At least 7 days, and no greater than 14 days after last study treatment 
administration. If warranted, additional follow-up visits may be scheduled. 
5.2. 
Number of Subjects 
Sufficient Japanese healthy male subjects will be enrolled such that up to 12 subjects 
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. Replacement subjects will be 
assigned to the same treatment sequence and start from the period to be replaced at the 
discretion of the GSK and in consultation with the principal investigator. 
5.3. 
Sentinel Dosing 
The doses will be staggered such that for each dose, on Day 1 of Period 1, 2 and 3, 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 (AEs, clinical labs, vital signs, 12-Lead ECGs and findings 
during continuous cardiac telemetry) in the blind judgment of the principal investigator 


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and GSK Medical Monitor through at least 24 hrs after their third dose on Day 1, the 
remaining subjects may be randomized to dosing in that period.  
5.4. 
Dose Escalation Decisions 
The decision to proceed to the next dose level of GSK2982772 within the study will be 
made by principal investigator and GSK Medical Monitor per each dosing periods. 
Dose escalation decisions will be based on blind 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: all AEs, clinical laboratory values, vital signs, 12-Lead ECG up to Day 4 (at 
discharge) and findings during continuous cardiac telemetry in the previous dose (Section 
8.1.1.). 
5.5. 
Participant and Study Completion 
A participant is considered to have completed the study if he has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the SoA. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5.6. 
Scientific Rationale for Study Design 
This study will include a placebo control study, to allow for evaluation of AEs 
attributable to treatment versus those independent of treatment. 
In Study 200975, 67 subjects were exposed to active treatment. GSK2982772 was well-
tolerated, with no deaths or other non-fatal SAEs being reported. Sentinel dosing 
approach was taken in Study 200975, where two subjects receive placebo or 
GSK2982772 on Day 1 and the remaining subjects are dosed after safety evaluation at 24 
hrs of preceding two subjects. Since this study is the first study in Japanese subjects, this 
study adopts a cautious approach including sentinel dosing and will include rigorous 
safety monitoring to confirm the safety profile prior to dose-escalation of single dose of 
the next dose strength, which was the same way taken in the past non-Japanese study. 
In the 4 week repeat dose nonclinical toxicology studies, neurological related events 
(uncoordinated movement, irregular gait, trembling, hunched appearance and decreased 
activity) were observed in some rats and monkeys. On the other hand, in the 13 week 
repeat dose nonclinical toxicology studies in rats or monkeys, or in the 39 week repeat 
dose nonclinical toxicology study in monkeys, no neurological-related events were 
observed in rats or monkeys. There have been some reports of lethargy, abnormal dreams, 
and depressed mood in Study 200975 (See IB for GSK2982772 [GlaxoSmithKline 
Document Number 2014N204126_04]). This study includes neurological exams by 
considering these findings from Study 200975. 
In the currently ongoing non-Japanese healthy volunteer study (Study 205184) being 
conducted in the United Kingdom (UK), several asymptomatic arthyhmias were detected 
in 6 out of 25 subjects treated with GSK2982772 or placebo.  The study was temporarily 


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put on hold by GSK to assess the totality of these events.  A formal review by the GSK 
Internal Cardiac Safety Panel, inclusive of both internal and external cardiologists, 
determined that the arrhythmic events were not likely related to GSK2982772 
administration based on the timing and random occurrences of the events, the 
heterogeneity of the arrhythmias, the length of cardiac monitoring being performed 
during the study, and no findings in preclinical studies.  Subsequently, the protocol was 
amended to increase the number of placebo subjects to balance randomization between 
active and placebo to understand the background cardiac patterns of subjects who are 
enrolled compared to when on treatment. Approval to proceed with the study was 
received from Medicines and Healthcare products Regulatory Agency (MHRA) on 22 
March 2018. Study 200975 and Study 205184 did include telemetry, while the cardiac 
events related to the study drug were not observed in non-Japanese subkects including 
Study 205184, Since this study is the first study in Japanese subjects, telemetry will be 
planed in this study. 
GSK2982772 concentrations decline rapidly until about 12 hrs post-dose, with a t1/2 of 
approximately 2 to 3 hrs. It, therefore, is considered sufficient to allow at least 7 days 
washout between dosing periods. Also, 7 days follow up after the last dose is considered 
to be sufficient for safety evaluation. 
In the ongoing Study 205184, there are two TID dose regimens of 120 mg TID and 240 
mg TID.  This study plans also TID dose regimen, which allows to compare the PK 
between Japanese subjects and non-Japanese subjects in order to support dosing of 
GSK2982772 in Japanese patient population in the Phase 2b dose ranging studies. 
5.7. 
Dose Justification 
The initial starting dose planned is 60 mg TID and the maximum dose is 720 mg/day 
administered as 240 mg TID, which cover the dose range for the proposed Phase 2b study. 
In Study 200975, all of the administered regimens (single dose; 0.1-120 mg, repeat dose; 
20 and 60 mg QD, 60 and 120 mg BID for 14 days) appeared to be well tolerated, and no 
dose limiting AEs or safety findings were observed. There were no clinically significant 
patterns of abnormal vital sign measurements, physical and neurological examinations, 
12-lead ECG and holter ECG changes or clinical laboratory (e.g., hematology, chemistry 
or urinalysis) findings observed in healthy subjects. There were no deaths or SAEs 
reported in the study.  
Since the target dose per day currently planed in Phase IIb study is 720 mg, the dose 
regimens in Study 205184 in non-Japanese are 120 mg TID, 240 mg TID and 360 mg 
BID. For the 360 mg BID dose (single day dosing), one subject exceeded Cmax limit 
with several other subjects approaching the Cmax limit. In addtion, and the AUC(0-24) at 
360 mg was also higher than that predicted but within the limits of stopping criteria. 
Based on the data in Study 205184, 240 mg TID is considered as the maximum dose in 
this study. 
The predicted mean AUC(0-24) for the highest planned doses in the current study of 240 
mg TID (40.2 μg･h/mL) approximates parity with the mean AUC(0-24) observed at the 


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NOAEL (30 mg/kg/day) in the 13 week repeat dose toxicity study in monkey (48.4 μg･
h/mL) and is approximately 1/5th to 1/4th of the mean AUC(0-24) observed at the 
NOAEL (60 mg/kg/day) in the 39 week repeat dose toxicity study in monkey (182 ug･
h/mL). Mean Cmax values for 240 mg TID (3.21 μg/mL) doses are predicted to be 1/4th 
of the mean Cmax observed at the NOAEL in the 13 week monkey study (12.3 g/mL) 
and 1/7th of the mean Cmax  at the NOAEL in the 39 week monkey study (23.2 g/mL). 
Please see GSK2982772 IB [GlaxoSmithKline Document Number 2014N204126_04]. 
The major circulating metabolite is an N-glucuronide which accounts for approximately 
70% of drug related material in plasma. Since glucuronidation is a high capacity 
clearance mechanism it is unlikely that the kinetics of GSK2982772 will become 
saturable at the higher doses planned in this study. 
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 20 to 64 years of age inclusive, at the time of signing the 
informed consent. 
Type of Participant and Disease Characteristics 
2. Healthy as determined by the Investigators based on a medical evaluation including 
medical history, physical examination, neurological examination, laboratory tests, 
and ECG. 
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 Investigators in 
consultation with the GSK Medical Monitor 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 Investigators 
Weight 
3. Body weight  50 kg and body mass index (BMI) within the range 18.5-24.9 kg/m2 
(inclusive). 


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Sex 
4. Japanese Male 
A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and until follow up visit. 
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 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. Abnormal blood pressure as determined by the investigators 
3. Symptomatic herpes zoster within 3 months prior to screening 
4. Evidence of active or latent TB as documented by medical history and examination, 
chest X-rays (anterior and lateral), and TB testing (T Spot. TB) 
5. Alanine Aminotransferase (ALT) >1.5x upper limit of normal (ULN) 
6. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) 
7. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
8. History of active infections within 14 days of first receiving study medication. 
9. QTcF > 450 msec 
NOTES: 
• The QTc is the QT interval corrected for heart rate according to 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. 


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• For purposes of data analysis, 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). 
10. History or diagnosis of obstructive sleep apnoea, or a significant respiratory disorder. 
Childhood asthma that was fully resolved is permitted. 
11. History of active Suicidal Ideation Behaviour within the past 6 months or any history 
of attempted suicide in a participant’s lifetime. 
12. History or current evidence of febrile seizures, epilepsy, convulsions, significant 
head injury, or other significant neurologic conditions. 
Prior/Concomitant Therapy 
13. Past or intended use of over-the-counter or prescription medication including herbal 
medications within 14 days prior to dosing. 
14. Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines 
during the study 
Prior/Concurrent Clinical Study Experience  
15. History of donation of blood or blood products ≥ 400 mL within 3 months or ≥ 
200 mL within 1 month prior to screening 
16. Exposure to more than 4 new chemical entities within 12 months prior to the first 
dosing day  
17. The subject has participated in a other clinical study or other medical research within 
4 months prior to the first dosing day in the current study. 
Diagnostic assessments 
18. The subject is positive Serological test for syphilis (RPR and TP), Tuberculosis, HIV 
Antigen/Antibody, Hep B surface antigen (HbsAg), Hep C virus (HCV) antibody, or 
HTLV-1 antibody at screening. 
19. Positive pre-study drug screen  
20. Regular use of known drugs of abuse  
Other Exclusions 
21. Regular alcohol consumption within 6 months prior to the study defined as: 
• For an average weekly intake of > 14 units for males. One unit is equivalent to 
350 mL of beer, 150 mL of wine or 45 mL of 80 proof distilled spirits 
22. Smoking or history or regular use of tobacco- or nicotine-containing products within 
6 months prior to screening 
23. Sensitivity to any of the study treatments, or components thereof, or drug or other 
allergy that, in the opinion of the investigators or GSK Medical Monitor, 
contraindicates participation in the study 


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6.3. 
Lifestyle Restrictions 
6.3.1. 
Meals and Dietary Restrictions 
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice, 
pomelos, citrus fruits, grapefruit hybrids, or fruit juices from 7 days prior to the start of 
study treatment until follow-up visit. 
Once in the clinical unit subjects will not be allowed to eat anything other than the food 
provided by the study centre. 
• 
Subjects must then fast from all food and drink (except water) for 8 hrs prior to first 
dose. 
• 
Subjects must then fast from all food and drink (except water) for 8 hrs prior to any 
clinical laboratory evaluations. 
• 
Water is permitted with dosing and at all times except 1 hr pre-dose through 2 hrs 
post-dose. 
• 
On Day 1, breakfast will be served approximately 2 hr after first dose. Lunch will be 
served between 2 to 3 hr prior to second dose. Dinner will be served between 2 to 3 
hr prior to third dose. On Day 2-3, meal will be served per unit schedule. Mealtime 
will be described in SRM. 
6.3.2. 
Caffeine, Alcohol, and Tobacco 
• 
During each dosing period, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hrs 
before the start of dosing until after collection of the final PK sample. 
• 
During each dosing period, subjects will abstain from alcohol for 24 hrs before the 
start of dosing until after collection of the final PK sample. 
• 
Use of tobacco, nicotine, or nicotine-containing products (including nicotine patch) 
will not be allowed from 6-months before screening until after collection of the final 
PK sample. 
6.3.3. 
Activity 
Subjects will abstain from strenuous exercise for 48 hrs prior to each blood collection for 
clinical laboratory tests. Subjects may participate in light recreational activities during 
studies (e.g., watching television, read). 
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 


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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 
judged ineligible) may not be rescreened. 
7. 
TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
7.1. 
Treatments Administered 
Study 
Treatment 
Name 
GSK2982772  
30 mg  
GSK2982772 
120 mg  
Placebo to match 
GSK2982772 30mg 
Placebo to match 
GSK2982772 120mg 
Dosage 
formulation 
Tablet 
Tablet 
Tablet 
Tablet 
Unit dose 
strength(s)/Do
sage level(s) 
30 mg 
120 mg 
NA 
NA 
Route of 
Administration 
Oral 
Oral 
Oral 
Oral 
Dosing 
instructions 
As directed 
As directed 
As directed 
As directed 
Physical 
description 
White to almost 
white, round, film-
coated tablet 
White to almost 
white, oval, film-
coated tablet 
White to almost 
white, round, film-
coated tablet 
White to almost 
white, oval, film-
coated tablet 
Packaging and 
Labelling 
Study Treatment will 
be labelled as 
required per country 
requirement. 
Study Treatment will 
be labelled as 
required per country 
requirement. 
Study Treatment will 
be labelled as 
required per country 
requirement. 
Study Treatment will 
be labelled as 
required per country 
requirement. 
Manufacturer 
Aptuit (Italy) 
GSK (UK) 
Aptuit (Italy) 
GSK (UK) 
 
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 one of the 4 groups, according to the randomization schedule generated 
prior to the study by the Biomedical Data Sciences Department at GSK. Each participant 
will be dispensed blinded study treatment, labelled with his unique randomization 
number, throughout the study. 
Subjects will be randomized to one of four sequences (A, B, C and D), where the 
treatments in the sequences are:  


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• 
A: Placebo TID / 60 mg TID / 120 mg TID / 240 mg TID 
• 
B: 60 mg TID / Placebo TID / 120 mg TID / 240 mg TID 
• 
C: 60 mg TID / 120 mg TID / Placebo TID / 240 mg TID 
• 
D: 60 mg TID / 120 mg TID / 240 mg TID / Placebo TID 
7.3. 
Blinding 
This study will be a double-blind with respect to subjects, investigators and site staff 
(with the exception of the unblinded site pharmacist). 
Investigators will remain blinded to each participant’s assigned study treatment 
throughout the course of the study.  
A participant will be withdrawn if the participant’s treatment code is unblinded. The 
primary reason for discontinuation (the event or condition which led to the unblinding) 
will be recorded in the case report form (CRF). 
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant 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 participant’s treatment assignment, may be sent to principal 
investigator in accordance with local regulations and/or GSK policy. 
7.4. 
Preparation/Handling/Storage/Accountability 
1. The investigators or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
2. Only participants randomized 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 investigators and authorized site staff. 
3. The investigators, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study treatment 
are provided in the 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 investigators, where this is required by local laws, or is available 
upon request from GSK. 


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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 investigators 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 
enrollment 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 GSK Medical Monitor should be contacted if there are any questions regarding 
concomitant therapy. 
Participants must abstain from taking prescription or nonprescription 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 
investigators and GSK, the medication will not interfere with the study.  
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 subjects are eligible for study participation. 
8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
8.1.1. 
Dose Stopping Criteria 
The decision to proceed to the next dose level of GSK2982772 in each part of this study 
will be made by the principal investigator and GSK Medical Monitor based on safety 
results (AEs, clinical labs, vital signs, 12-Lead ECGs and findings during continuous 
cardiac telemetry) obtained in at least 6 subjects having received active treatment 
(GSK2982772) at the prior dose level.  


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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 treatment. 
• 
Two (2) or more subjects experience a severe or clinically significant non-serious AE 
(based upon principal investigator judgment) which has a reasonable possibility of 
relation to study treatment. 
• 
Two (2) or more subjects experience the same AE of moderate severity which has a 
reasonable possibility of relation to study treatment. 
• 
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 treatment. 
• 
Female partner become pregnant during the treatment period. 
8.1.2. 
Liver Chemistry Stopping Criteria 
Study treatment will be discontinued for a participant if liver chemistry stopping criteria 
are met: 


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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. 
8.1.3. 
QTc Stopping Criteria 
A subject that meets either bulleted criterion based on the average of triplicate ECG 
readings will be withdrawn from study treatment. 
See Section 9.3.4. about 12-lead ECG. 
• 
QTcF > 500 msec 
• 
QTcF increase > 60 msec from baseline 
8.1.4. 
Individual Safety Stopping Criteria 
• 
If a participant experiences a serious or severe clinically significant AE that in the 
clinical judgement of the principal investigator, after consultation with the GSK 
Medical Monitor, is possibly, probably or definitely related to investigational product. 
• 
The participant develops a serious opportunistic or atypical infection. 
• 
If any of the liver chemistry stopping criteria (See Section 8.1.2) or QTc stopping 
criteria (see Section 8.1.3) are met. 
8.1.5. 
Nervous System Stopping Criteria 
The CTCAE Nervous System disorder is a monitoring tool which provides the 
investigators 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. 


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The principal investigator and the GSK Medical Monitor will review all neurological 
events utilizing the CTCAE Nervous System disorder 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 disorder 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 disorder, which is 
also considered to be clinically significant by the principal investigator, will be 
reviewed for potential subject withdrawal. 
Note: Appendix 9 (Section 8.1.1) provides Guidance for Grading AEs that is taken from 
the CTCAE Version 4.03. 
8.2. 
Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his own request, or may be 
withdrawn at any time at the discretion of the investigators for safety, behavioral, 
compliance or administrative reasons. 
• 
If the participant withdraws consent for disclosure of future information, the GSK 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• 
If a participant withdraws from the study, he 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. 
8.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he 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: 
• 
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 investigators 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. 


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• 
Should the participant continue to be unreachable, he will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA.  
• 
Protocol waivers or exemptions are not allowed. 
• 
Immediate safety concerns should be discussed with the GSK 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 principal 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.  
• 
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 400 
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 investigators 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 (see Section 8).  
9.1.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All SAEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the SoA (Section 2).  
• 
All AEs will be collected from the start of treatment until the follow-up visit at the 
time points specified in the SoA (Section 2). 
• 
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the CRF not the AE section. 
• 
All SAEs will be recorded and reported to the GSK or designee immediately and 
under no circumstance should this exceed 24 hrs, as indicated in Appendix 4. The 


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investigators will submit any updated SAE data to the GSK within 24 hrs of it being 
available. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigators 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 
investigators must promptly notify the GSK. 
• 
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 investigators 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 investigators to the GSK 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.  
• 
GSK has a legal responsibility to notify both the local regulatory authority about the 
safety of a study treatment under clinical investigation. The GSK will comply with 
country-specific regulatory requirements relating to safety reporting to the regulatory 
authority, Institutional Review Boards (IRB), and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and GSK 
policy and forwarded to principal investigator as necessary. 
• 
An principal investigator who receives an investigator safety report describing a SAE 
or other specific safety information (e.g., summary or listing of SAE) from the GSK 
will review and then file it along with the IB and will notify the IRB, if appropriate 
according to local requirements. 
9.1.5. 
Pregnancy 
• 
Details of all pregnancies in female partners of male participants will be collected 
after the start of study treatment and until the follow-up visit. 


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• 
If a pregnancy is reported, the investigators should inform GSK within 24 hrs 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 
For this study, any dose of GSK2982772 greater than 720 mg within a 24-hr time period 
will be considered an overdose. 
GSK does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigators should: 
1. Contact the GSK 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 GSK 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 investigators 
in consultation with the GSK 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 
and weight will only be measured and recorded on screening. 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
9.3.2. 
Neurological Examinations 
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). 


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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 
• 
Axillary temperature, pulse rate, and blood pressure will be assessed. 
• 
Blood pressure and pulse measurements will be assessed 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 rate.  
9.3.4. 
Electrocardiograms 
• 
Single 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 QTcF intervals. Refer to Section 8.1.3 for QTc withdrawal criteria and additional 
QTcF readings that may be necessary. 
• 
Single ECGs will be obtained at each time point. 
• 
If QTcF is appeared the value applied the discontinuation criteria, ECG must be 
conducted two additional readings and be confirmed whether apply the 
discontinuation criteria. 
• 
Continuous cardiac telemetry will be performed at time points indicated in the SoA 
(see Section 2). Full disclosures will be reviewed in detail and the review maintained 
as part of the subject’s source documents. 
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 investigators 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 investigators to be more severe 
than expected for the participant's condition. 


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• 
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 investigators or 
GSK Medical Monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigators, the etiology should be identified and the GSK 
notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual of study site 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 SIB 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 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 SIB and to report such symptoms immediately to the study investigators. 
9.4. 
Pharmacokinetics 
• 
Blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of GSK2982772 as specified in the SoA. Instructions for the 
collection and handling of biological samples will be described in the SRM. The 
actual date and time (24-hr clock time) of each sample will be recorded. 
• 
Samples will be used to evaluate the PK of GSK2982772. Samples collected for 
analyses of GSK2982772 plasma concentration may also be used to evaluate safety 
aspects related to concerns arising during or after the study. 
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
9.5. 
Genetics 
In this study, genetics may be evaluated after review by the ethical review committee 
established by GSK in accordance with Japanese ethical guidelines for human 
genome/gene analysis research. 


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A 6 mL 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 SRM. 
10. 
STATISTICAL CONSIDERATIONS 
The objectives of this study are to evaluate safety, tolerability and PK of GSK2982772 in 
healthy Japanese subjects. No formal statistical hypotheses will be tested. Descriptive 
statistics will be used to assess safety and tolerability. An estimation approach will be 
used to address the pharmacokinetic study objectives, where point estimates and 
corresponding confidence intervals (CI) will be constructed. 
10.1. 
Sample Size Determination 
In a 4-way crossover design, total 12 subjects will be randomized in four groups with a 
randomization ratio of 1:1:1:1; 3 subjects in each group. The sample size for this study is 
based on the feasibility rather than statistical considerations. The number of subjects who 
will take a placebo, 60 mg, 120 mg, or 240 mg dose will be 12 with totalizing four groups. 
No calculations for formal power and sample size are performed.  
One of the objectives of this study is safety, where a number of safety events are of 
interest. A maximum of 12 subjects will receive each active dose and; therefore, if 0/12 
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 26.5% could not be ruled out. 
Whereas if 1/12 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 38.5% could not be 
ruled out. 
Using a Bayesian approach to determine the CI around an observed safety event, we 
would assume a flat Beta (1, 1) prior, and if we were to observe one safety event in 12 
then the posterior distribution would be Beta (2, 12), as outlined in Figure 1. Thus, we 
can 95% certain that the true probability of the safety event lies between 0.02 and 0.36. 


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0.0
0.2
0.4
0.6
0.8
1.0
0
1
2
3
4
5
1 Event in 12 Subjects
 Beta(2,12)
True Response Rate
Prior Probability Density
Posterior 95% credible interval 
 ( 0.02 ,  0.36 )
 
Figure 1 
Bayesian Approach to Determine Confidence in Safety Event 
 
Between-subject variability of Cmax and AUC(0-t) of GSK2982772 is estimated to be 
32.9% (CV%) and 23.5% (CV%), respectively (based on PK results of 60 mg BID on 
Day 1 and 120 mg BID on Day1 from Study 200975 Part B). Based on these variability 
estimates and the sample size of 12, the upper limit value of 95% CI of geometric mean 
of Cmax and AUC(0-t) is estimated to be approximately 22.6% and 15.9%, respectively. 
10.2. 
Sample Size Sensitivity 
Different safety event rates were investigated for sample size sensitivity analysis. If the 
number of subjects who completed each active dose was different, then the true incidence 
rates of safety events that could not be ruled out would change. These changes are 
outlined as below. 


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Completed N 
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 
12 
2 
48.4% 
3 
57.2% 
4 
65.1% 
11 
0 
28.5% 
1 
41.3% 
2 
51.8% 
3 
61.0% 
10 
0 
30.8% 
1 
44.5% 
2 
55.6% 
3 
65.2% 
Following table shows how the results could have variabilities with changing between-
subject estimates of variability (CV%) and number of subjects. Estimates of the upper 
limit values of 95% CI of geometric mean are described using proportions (%) of 
variability to geometric mean of PK parameters. 
N 
Estimate of between-subject variability (CV%) 
20 
30 
40 
50 
11 
14.2% 
21.8% 
29.5% 
37.3% 
12 
13.4% 
20.5% 
27.7% 
35.0% 
13 
12.7% 
19.4% 
26.2% 
33.0% 
14 
12.1% 
18.4% 
24.9% 
31.4% 
 
10.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Screened 
All subjects who have a screening visit will be included. 
Enrolled 
All subjects who passed screening and entered the study will be 
included. 
Note screening failures (who never passed screening even if 
rescreened) and subjects screened but never enrolled into the study 
(Reserve, Not Used) are excluded from the Enrolled population as 
they did not enter the study. 


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Population 
Description 
Safety analyses 
All subjects who have received at least one dose of study treatment 
will be included. This population will be used for the safety analyses. 
PK analyses 
All subjects in the Safety population for whom a PK sample has been 
obtained and analyzed will be included. This population will be used 
for the PK analyses. 
 
10.4. 
Statistical Analyses 
10.4.1. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. Safety data will be 
presented in tabular and/or graphical format and summarized descriptively according to 
GSK’s Integrated Data Standards Library (IDSL) standards. 
The tables, figures, and listings will use the Safety Population unless otherwise specified. 
AEs, changes in clinical laboratory values, 12-Lead ECGs, findings during continuous 
cardiac telemetry and vital signs will be summarized by dose group (i.e. placebo, 60 mg, 
120 mg, and 240 mg) to assess the safety and tolerability of GSK2982772. The safety and 
tolerability results will not to be formally compared between each group and comparison 
with placebo will be based on review of descriptive summaries. 


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10.4.2. 
Pharmacokinetic Analyses 
All PK analyses will be performed on the PK Population.  
Statistical Analysis Methods 
Plasma GSK2982772 concentration-time data will be analysed by non-compartmental methods with 
WinNonlin. Calculations will be based on the actual sampling times recorded during the study. 
From the plasma concentration-time data, the following PK parameters will be determined, as data 
permit: AUC(0-24), AUC(0-7), AUC(7-14) and AUC(14-24), Cmax following each dose, time to 
maximum observed plasma drug concentration (Tmax) following each dose,t1/2 following the third 
dose, observed trough plasma concentrations (C0, C7, C14 and C24). 
PK data will be presented in graphical and/or tabular form and will be summarised descriptively. 
Listings will be generated and summary statistics (n, arithmetic mean with associated 95% CI, 
standard deviation (SD), minimum, median, maximum, geometric mean with associated 95% CI, SD 
on log-scale and %CVb) will be calculated for each derived plasma PK parameter for each dose. 
The PK-dose relationship will be examined graphically by plotting derived plasma PK parameters for 
each dose group. Dose proportionality for AUC(0-24), AUC(0-7) and Cmax following the first dose 
will be assessed by using a power model as described below: 
loge (PK parameter) = μ + Si + β*loge (Dj) + εij 
where μ is the intercept, β is the slope, Si is the random effect for subject i, Dj is the dose (j = 60 mg, 
120 mg, or 240 mg), εij is the random error. Point estimates for the slope of PK parameters and their 
associated 90% CI will be presented. 
 
10.4.3. 
Interim Analyses 
A review of safety data will be conducted at the end of each period.  
The decision to proceed to higher dose strengths will be made by principal investigator 
and GSK’s Medical Monitor based on assessment of safety and tolerability at the 
preceding dose. This review can include individual subject data. 
 


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11. 
REFERENCES 
GSK2982772 Investigator’s Brochure, GlaxoSmithKline Document Number 
2014N204126_04. 
Berger S, 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. Journal of Immunology, 2014; 192:5476-80. 
Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E et al. 
RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions 
of cIAP1/2 depletion or TAK1 kinase inhibition. Cell Death and Differentiation, 
2013;20:1381-92.  
Humphries F, Yang S, Wang B, Moynagh P N. RIP kinases: key decision makers in cell 
death and innate immunity. Cell Death and Differentiation, 2015;22:225-236. 
Ofengeim D and Yuan J. Regulation of RIP1 kinase signaling at the crossroads of 
inflammation and cell death. Nature Reviews Molecular Cell Biology, 2013; 14:727-36. 
Wang L, Du F, Wang X. TNF-alpha induces two distinct caspase-8 activation pathways. 
Cell, 2008; 133(4):693-703. 
 


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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
Abbreviations 
ADL 
Activities of daily life 
AE 
Adverse event 
ALS 
Amyotrophic lateral sclerosis 
AUC 
Area under concentration-time curve 
AUC(0-7) 
Area under the concentration-time curve from time 0 to 7 hr 
AUC(7-14) 
Area under the concentration-time curve from time 7 to 14 hr 
AUC(14-24) 
Area under the concentration-time curve from time 14 to 24 hr 
AUC(0-t) 
Area under the concentration-time curve from time 0 to the time of 
the last measurable drug concentration 
AUC(0-∞) 
Area under the concentration-time curve from time 0 to infinity 
BID 
Bis in die 
BMI 
Body mass index 
BP 
Blood pressure 
CFR 
Code of Federal Regulation 
CI 
Confidence interval 
Cmax 
Maximum observed plasma drug concentration 
C0 
Plasma drug concetration at pre-dose 
C7 
Plasma drug concetration at 7 hr after dosing 
C14 
Plasma drug concetration at 14 hr after dosing 
C24 
Plasma drug concetration at 24 hr after dosing 
CNS 
Central nervous system 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTN 
Clinical Trial Notification 
CV 
Coefficient of variance 
CYP 
Cytochrome P450 
DAMP 
Damage associated molecular pattern 
e.g. 
Exempli gratia 
ECG 
Electrocardiogram 
FLAIR 
FLuid-Attenuated Inversion Recovery 
FTiH 
First Time in Human 
g 
Gram 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GLP 
Good Laboratory Practice 
GSK 
GlaxoSmithKline 
h/hr(s) 
Hour(s) 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
Hep B 
Hepatitis B 


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Hep C 
Hepatitis C 
HIV 
Human immunodeficiency virus 
HTLV-1 
Human T-cell leulemia virus type 1 
i.e. 
id est 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
INR 
International Normalized Ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
kg 
Kilogram 
loge 
Natural logarithm 
µg 
Micrograms 
mg 
Milligrams 
min 
Minute 
mL 
Milliliter 
msec 
Milliseconds 
MV 
Minute volume 
MTX 
Methotrexate 
m2 
Square metre 
NA 
Not applicable 
ng 
Nanograms 
nL 
Nanoliter 
NOS 
Not otherwise specified 
NOAEL 
No Observable Adverse Effect Level 
OAT3 
Organic anion transporter 3 
P-gp 
P-glycoprotein 
pH 
Pondus Hydrogenii 
PK 
Pharmacokinetics 
PsO 
Psoriasis 
PR 
Pulse rate 
QD 
Quaque die 
RA 
Rheumatoid arthritis 
RIP1 
Receptor-interacting serine/threonine protein-1 
RNA 
Ribonucleic acid 
RPR 
Rapid Plasma Reagin 
SAE 
Serious adverse event 
SAS 
Subarachnoid space 
SD 
Standard deviation 
Ser 
Serine 
SIB 
Suicidal Ideation and Behaviour 
SoA 
Schedule of Activities 
SRM 
Study Reference Manual 


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t1/2 
Terminal half-life 
TB 
Tuberculosis 
Thr 
Threonine 
TID 
Ter in die 
Tmax 
Time to maximum observed drug concentration 
TNF(α) 
Tumour necrosis factor (α) 
TNFR1 
Tumour necrosis factor receptor-1 
TP 
Treponema pallidum 
UC 
Ulcerative colitis 
ULN 
Upper limit of normal 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
 
 
WinNonlin 
 


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12.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 1 will be performed by the local laboratory.  
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 1 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
‰Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase (AST) 
Total and direct 
bilirubin 
Creatinine 
Sodium 
Alanine 
Aminotransferase (ALT) 
Total Protein 
Glucose (fasting) 
Calcium 
Alkaline phosphatase 
Albumin 
Uric acid 
TG 
Total Cholesterol 
LDL-cholesterol 
HDL-cholesterol 
LDH 
GGT 
CK (CPK) 
Amylase 
Chloride 
Phosphorus 
CRP 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other 
Screening 
Tests 
• Urine drug screen (to include at minimum: Phencyclidines [PCP], 
Benzodiazepines [BZO], Cocaine [COC], Amphetamines [AMP], 
Tetrahydrocannabinol [THC], Opiates [OPI], Barbiturates [BAR], Trycyclic 
antidepressants [TCA]) 
• Serology (Syphilis [RPR & TP], TB, HIV antigen/antibody, HTLV-1 antibody, 
hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody) 
NOTES : 
1. Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1 and Appendix 7. All events of ALT 3 × upper limit of normal (ULN) and 
bilirubin  2 × ULN (> 35% direct bilirubin) or ALT  3 × ULN and international normalized ratio (INR) > 1.5, if INR 
measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 


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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 International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (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 by the investigator 
and reviewed and approved by the IRB before the study is initiated.  
• 
Any amendments to the protocol will require 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 annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB 
• 
Notifying the IRB of SAE or other significant safety findings as required by IRB 
procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
Financial Disclosure 
Investigators and sub-investigators will provide the GSK with sufficient, accurate 
financial information as requested to allow the GSK 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 legally authorized representative and answer all questions regarding 
the study.  


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• 
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 or study center.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
• 
Participants who received rescreening must be re-consented the ICF(s). 
• 
The ICF may contain a separate section that addresses the use of remaining 
mandatory samples for optional exploratory research in accordance with SOP-
GSKF-410. The investigator or authorized designee will explain to each participant 
the objectives of the exploratory research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. A separate signature will be required to document a 
participant's agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate will not provide this separate 
signature. 
Data Protection 
• 
Participants will be assigned a unique identifier by the GSK. Any participant records 
or datasets that are transferred to the GSK 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 GSK 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 
GSK, by appropriate IRB members, and by inspectors from regulatory authorities. 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the GSK 
before submission. This allows the GSK to protect proprietary information and to 
provide comments.  


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• 
The GSK will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the GSK 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. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the GSK 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 review, and 
regulatory agency inspections and provide direct access to source data documents.  
• 
The GSK or designee is responsible for the data management of this study including 
quality checking of the data.  
• 
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final Clinical 
Study Report (CSR)/ equivalent summary unless local regulations or institutional 


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policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the GSK. No records may be 
transferred to another location or party without written notification to the GSK. 


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Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available. 
• 
Definition of what constitutes source data can be found in the list of the source 
documents. 
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 GSK or investigator may include but 
are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB 
or local health authorities, the GSK's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study treatment development 


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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 assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (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. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE. 
 
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. 


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• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (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 fulfills 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, diarrhea, 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: 


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• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 
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. 


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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 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 hrs of receipt 
of the information. 
 


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Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hrs. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hrs of SAE 
entry into the eCRF. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form. 
• 
Contacts for SAE reporting can be found in Appendix 8. 
 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the GSK Medical Monitor. 
• 
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 Appendix 8. 
 


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12.5. 
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information 
Contraception Guidance 
Male participants 
• 
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following 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  
• 
Agree to use method of contraception with a failure rate of < 1% per year as 
described in Table 2 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 until follow up visit 
Table 2 
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  
Highly Effective Methods That Are User Independent  
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the Women of Childbearing Potential (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 treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 


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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 treatment, 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 until follow up visit.  
 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• 
Investigator will discontinue study treatment and 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 hrs of learning of the partner’s 
pregnancy.  
• 
Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 


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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 
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. 
Additional 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. 
• 
Samples will be given a code and stored securely. 
• 
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. 
• 
If particinpant chooses to stop the pharmacogenetics part of the study after giving a 
sample, GSK will not conduct any new tests on the sample. GSK will destroy the 
sample. GSK will keep and use any results generated before you stopped 
participating in the pharmacogenetics study. 
• 
GSK will only use the coded results to verify or show the quality of analyses that 
have already been reported. GSK will take steps to ensure that your coded results are 
not used in any new analyses. If new analyses are conducted then GSK will make 
sure that the subject's number will be deleted. 
• 
GSK may provide your genetic information generated from your sample for research 
with other companies or universities to learn more about other medicines, this 
immuno-inflammatory disease and other disease, only by deleting the subject 
number before it is provided, so that provided information will not be identified in 
any way and your privacy is protected.  


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• 
If GSK decides to use your sample and/or your genetic information for a different 
study, GSK will ask participant for his permission again or GSK will ask an adequate 
committee to review the study from ethical standpoint. 
 


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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 hrs 
• 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 
hrs 
• 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: 
• Viral hepatitis serology3 
• Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• Obtain plasma sample for pharmacokinetic 
(PK) analysis, obtained within 24 hrs 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: 


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Liver Chemistry Stopping Criteria  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs 
• Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins. 
• 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 immunoglobulin M (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)  
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. 


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12.8. 
Appendix 8: Country-specific requirements 
12.8.1. 
Regulatory and Ethical Considerations 
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (Ministry of Health 
and Welfare (MHW) Notification No.28 dated 27th March, 1997)” and the 
Pharmaceuticals and Medical Devices Act. 
GSK will submit the Clinical Trial Notification (CTN) to the regulatory authorities in 
accordance with Pharmaceuticals and Medical Devices Act before conclusion of any 
contract for the conduct of the study with study sites. 
12.8.2. 
Informed Consent 
Prior to participation in the study, the investigator (or subinvestigator) should fully 
inform the potential participant of the study including the written information. The 
investigator (or subinvestigator) should provide the participant  ample time and 
opportunity to inquire about details of the study. The participant  should sign and 
personally date the consent form. The participant may consider the content of the written 
information at home. The person, who conducted the informed consent discussion and the 
study collaborator giving supplementary explanation, where applicable, should sign and 
personally date the consent form. If an impartial witness is required, the witness should 
sign and personally date the consent form. The investigator (or subinvestigator) should 
retain this signed and dated form (and other written information) together with the source 
medical records, such as clinical charts (in accordance with the rules for records retention, 
if any, at each medical institution) and give a copy to the participant. 
12.8.3. 
Study Period 
JUL 2018 - SEP 2018 
12.8.4. 
Study Administrative Structure 
Sponsor Legal Registered Address: 
GlaxoSmithKline K.K. (GSK) 
Akasaka Intercity AIR, 8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052 Japan 
Study Director: 
 Head, Medicines Development, Clinical 
Pharmacology & Science Promotion Office 
Sponsor Contact Address: 
Lead Author: 
 Manager, Medicines Development, Clinical Pharmacology & Science 
Promotion Office 
Sponsor’s Emergency Contact Information (10:00-18:00, Monday to Friday, except 
national holidays and year-end and new-year holidays); 
PPD
PPD


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Medicines Development (Clinical Pharmacology), GlaxoSmithKline K.K. 
TEL: 
 (direct dialling)  
FAX: 
 
Contact Information at Night and on Holidays (Monday to Friday: 18:00-10:00, Saturday, 
Sunday, national holidays, year-end and new-year holidays) 
 (mobile: 
  
GSK Medical Monitor / Contact Address for SAE 
 
GlaxoSmithKline K.K. (GSK) 
Akasaka Intercity AIR, 8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052 Japan 
TEL: 
 (mobile)／
 (direct dialling)  
FAX: 
 
Medical Institution and Investigator 
 
SOUSEIKAI Hakata Clinic 
6-18 Tenyamatchi, Hakata-ku, Fukuoka 812-0025 Japan 
TEL: 
  
FAX: 
 
Laboratories 
Clinical Laboratory (except HTLV-1 serology and TB) 
SOUSEIKAI Hakata Clinic 
Person in charge: 
 
6-18 Tenyamachi, Hakata-ku, Fukuoka 812-0025 Japan 
TEL: 
 
FAX: 
  
HTLV-1 serology and TB (If subject meet Liver chemistry stopping criteria, include anti-
nuclear antibody, anti-smooth muscle antibody, type 1 anti-liver kidney microsomal 
antibodies, and quantitative total IgG or gamma globulins, and viral hepatitis serology 
described in Appendix 7, but except HBsAg) 
Person in charge: 
 
LSI Medience Inc. 
30-1 Shimura 3-chome, Itabashi-ku, Tokyo 174-8555, Japan  
TEL: 
 
FAX: 
 
Pharmacokinetics Measurement Facilities 
Covance Laboratories Limited 
Person in charge: 
 
Otley Road, Harrogate, North Yorkshire, HG3 1PY, UK 
TEL: 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Gx Research Administration (Sample Management , Sample Storage Facility, DNA 
Extraction Facility) 
Contact person: 
 
Q2 Solutions 
Q Squared Solutions (Quest) LLC 
27027 Tourney Road, Suite 2E 
Valencia, CA  91355 
USA 
TEL: 
 
FAX: 
 
Contract research organization 
Role: Study Monitoring 
Person in charge (Monitor Leader): 
 
Mediscience Planning Inc. 
2-8-10 Toranomon, Minato-ku, Tokyo 105-0001 Japan 
TEL: 
 
FAX: 
 
Role: Medical Writing (Protocol & Informed Consent Form) 
Person in charge: 
 
Mediscience Planning Inc. 
2-8-10 Toranomon, Minato-ku, Tokyo 105-0001 Japan 
TEL: 
 
FAX: 
 
Role: Medical Writing (Clinical Study Report) 
Person in charge: 
 
Mediscience Planning Inc. 
2-8-10 Toranomon, Minato-ku, Tokyo 105-0001 Japan 
TEL: 
 
FAX: 
 
Role: Pharmacokineic Parameter Derivation 
Person in charge: 
 
Mediscience Planning Inc. 
1-2-1 Nihonbashi hamacho, Chuo-ku, Tokyo 103-0007 Japan 
TEL: 
 
FAX: 
 
Role: Data Loading 
Person in charge: 
 
Mediscience Planning Inc. 
1-2-1 Nihonbashi hamacho, Chuo-ku, Tokyo 103-0007 Japan 
TEL: 
 
FAX: 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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12.9. 
Appendix 9: 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 3 
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 
Activities of daily life 
(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). 


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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. 


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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. 
Edema cerebral 
 - 
 - 
 - 
Life-threatening 
consequences; 
urgent 
intervention 
 
A disorder characterized by swelling 
due to an excessive accumulation of 
fluid in the brain. 


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CTCAE v4.0 Term 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  CTCAE v4.0 AE Term Definition 
indicated 
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. 
Hydrocephalus 
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
Moderate symptoms; 
intervention not 
indicated 
Severe symptoms or 
neurological deficit; 
intervention indicated 
Life-threatening 
consequences; 
urgent 
intervention 
Death 
A disorder characterized by an 
abnormal increase of cerebrospinal 
fluid in the ventricles of the brain. 


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CTCAE v4.0 Term 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  CTCAE v4.0 AE Term Definition 
indicated 
indicated 
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, 
Intracranial 
Pressure (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. 


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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. 
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 


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CTCAE v4.0 Term 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  CTCAE v4.0 AE Term Definition 
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. 
Presyncope 
 - 
Present (e.g., near 
fainting) 
 - 
 - 
 - 
A disorder characterized by an 
episode of lightheadedness and 


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CTCAE v4.0 Term 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  CTCAE v4.0 AE Term Definition 
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. 


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CTCAE v4.0 Term 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  CTCAE v4.0 AE Term Definition 
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. 
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 hrs) 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). 


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CTCAE v4.0 Term 
Grade 1  
Grade 2  
Grade 3  
Grade 4  
Grade 5  CTCAE v4.0 AE Term Definition 
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 
 - 


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12.10. 
Appendix 10: Protocol Amendment History 
Not applicable 
 

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205037
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 205037: A single-centre, 
randomized, double-blind, dose-ascending, placebo-
controlled study to evaluate the safety, tolerability, and 
pharmacokinetics of oral TID doses (one day) of 
GSK2982772 in Japanese healthy male subjects
Compound Number 
:
GSK2982772
Effective Date 
:
11-JUL-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 205037.

This RAP is intended to describe the final 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
NA
NA
Biostatistics Group 2, Biomedical Data Sciences 
Japan
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
2018N385232_00
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
205037
2
RAP Team Approvals:
Approver
Date
Approval Method
10-JUL-2018
Pharma TMF
Lead Programmer; Statistical Programming & 
Reporting Group, Biomedical Data Sciences 
Japan
09-JUL-2018
Pharma TMF
Clinical Investigation Leader/Operational 
Science Lead; Clinical Pharmacology Office
10-JUL-2018
Pharma TMF
Data Quality Lead; Data Practice Group, 
Biomedical Data Sciences Japan
09-JUL-2018
Pharma TMF
PK Analyst; Clinical Pharmacology Office
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
11-JUL-2018
Pharma TMF
Lead Authors Line Manager; Biostatistics Group 
2, Biomedical Data Sciences Japan
11-JUL-2018
Pharma TMF
Lead Programmers Line Manager; Statistical 
Programming & Reporting Group, Biomedical 
Data Sciences Japan
2018N385232_00
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
205037
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 ................................................................................................6
2.4.
Statistical Hypotheses / Statistical Analyses .................................................7
3.
PLANNED ANALYSES ............................................................................................8
3.1.
Interim Analyses ...........................................................................................8
3.2.
Final Analyses ..............................................................................................8
4.
ANALYSIS POPULATIONS .....................................................................................8
4.1.
Protocol Deviations.......................................................................................9
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................10
5.1.
Study Treatment & Sub-group Display Descriptors.....................................10
5.2.
Baseline Definitions ....................................................................................10
5.3.
Examination of Covariates, Other Strata and Subgroups............................10
5.3.1.
Covariates and Other Strata ........................................................10
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................11
6.
STUDY POPULATION ANALYSES .......................................................................12
6.1.
Overview of Planned Study Population Analyses........................................12
6.1.1.
Details of Planned Study Population Summaries .........................13
7.
SAFETY ANALYSES .............................................................................................15
7.1.
Adverse Events Analyses ...........................................................................15
7.1.1.
Details of Planned Adverse Events Summaries ...........................15
7.2.
Clinical Laboratory Analyses.......................................................................16
7.2.1.
Details of Planned Clinical Laboratory Displays ...........................17
7.3.
Other Safety Analyses ................................................................................18
7.3.1.
Details of Planned Other Safety Displays.....................................18
8.
PHARMACOKINETIC ANALYSES.........................................................................20
8.1.
Pharmacokinetic Analyses..........................................................................20
8.1.1.
Endpoint / Variables.....................................................................20
8.1.1.1.
Drug Concentration Measures....................................20
8.1.1.2.
Derived Pharmacokinetic Parameters.........................20
8.1.2.
Summary Measure ......................................................................21
8.1.3.
Population of Interest...................................................................21
8.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................21
8.1.5.
Statistical Analyses / Methods .....................................................21
8.1.5.1.
Statistical Methodology Specification..........................21
8.1.6.
Details of Planned Pharmacokinetic Displays ..............................23
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205037
4
9.
APPENDICES........................................................................................................24
9.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................24
9.2.
Appendix 2: Schedule of Activities ..............................................................25
9.2.1.
Protocol Defined Schedule of Events...........................................25
9.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................28
9.3.1.
Study Phases ..............................................................................28
9.3.1.1.
Study Phases for Adverse Events ..............................28
9.3.1.2.
Study Phases for Concomitant Medication .................29
9.4.
Appendix 4: Data Display Standards & Handling Conventions....................30
9.4.1.
Reporting Process .......................................................................30
9.4.2.
Reporting Standards....................................................................30
9.4.3.
Reporting Standards for Pharmacokinetic....................................31
9.5.
Appendix 5: Derived and Transformed Data ...............................................32
9.5.1.
General........................................................................................32
9.5.2.
Study Population..........................................................................32
9.5.3.
Safety ..........................................................................................33
9.6.
Appendix 6: Reporting Standards for Missing Data.....................................34
9.6.1.
Premature Withdrawals................................................................34
9.6.2.
Handling of Missing Data.............................................................34
9.6.2.1.
Handling of Missing and Partial Dates ........................34
9.7.
Appendix 7: Values of Potential Clinical Importance ...................................36
9.7.1.
Laboratory Values........................................................................36
9.7.2.
ECG.............................................................................................37
9.7.3.
Vital Signs....................................................................................37
9.8.
Appendix 8: Abbreviations & Trade Marks ..................................................38
9.8.1.
Abbreviations...............................................................................38
9.8.2.
Trademarks .................................................................................38
9.9.
Appendix 9: List of Data Displays ...............................................................39
9.9.1.
Data Display Numbering..............................................................39
9.9.2.
Mock Example Shell Referencing ................................................39
9.9.3.
Deliverables.................................................................................39
9.9.4.
Study Population Tables..............................................................40
9.9.5.
Safety Tables...............................................................................41
9.9.6.
Pharmacokinetic Tables...............................................................43
9.9.7.
Pharmacokinetic Figures .............................................................44
9.9.8.
ICH Listings .................................................................................45
9.10.
Appendix 10: Example Mock Shells for Data Displays ................................49
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205037
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: 205037
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol (Dated: 07/JUN/2018).
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints

To assess the safety and tolerability of 
TID doses for one day of 
GSK2982772 in Japanese healthy 
male subjects.

Adverse events (AEs)

Change in laboratory values (clinical chemistry, 
haematology and urinalysis), 12-lead ECG, vital signs
(blood pressure, pulse rate, and body temperature)

Physical examinations, in including neurological 
examinations.

To characterise the PK profile of TID
doses for one day of GSK2982772 in 
Japanese healthy male subjects.

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)). Maximum observed plasma drug 
concentration (Cmax) following each dose, time to 
maximum observed plasma drug concentration 
(Tmax) following each dose, terminal half-life (t1/2) 
following the third dose, observed trough plasma 
drug concentrations (C0, C7, C14 and C24), where 
data allow
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205037
6
2.3.
Study Design
Overview of Study Design and Key Features
Group
N
Period 1
Period 2
Period 3
Period 4
A
3
Placebo, TID
60 mg, TID
120 mg, TID
240 mg, TID
B
3
60 mg, TID
Placebo, TID
120 mg, TID
240 mg, TID
C
3
60 mg, TID
120 mg, TID
Placebo, TID
240 mg, TID
D
3
60 mg, TID
120 mg, TID
240 mg, TID
Placebo, TID
Screening
Within 30 days prior to the first dosing.
Treatment Period
The study will be comprised of four study periods each at least 7 days in duration 
with subjects in-house for 4 nights (through 72 hours after the 1st dose). During 
each treatment period, subjects will be admitted to the unit the day before dosing 
and will be discharged after completion of the 72-hour post-dose assessments. 
Each subject will receive oral TID doses of GSK2982772 in fasted condition in 
each treatment period. For TID dosing, GSK2982772 or placebo will be 
administered using a 7 hr, 7 hr dosing interval.
Washout Period
Will be at least 7 days between treatment period doses for an individual subject.
Follow-up
At least 7 days, and no greater than 14 days after last study treatment
administration. If warranted, additional follow-up visits may be scheduled.
Design
Features

This study will be a double-blind with respect to subjects, investigator and site staff 
(with the exception of the unblinded site pharmacist), a three times daily/day, 
ascending dose, randomized, placebo-controlled, 4-way crossover study.
Dosing

The initial starting dose planned is 60 mg TID and the maximum dose is 720 mg/day 
administered as 240 mg TID, which cover the dose range of the proposed Ph2b study.

Sentinel dosing will be employed within each dosing period of the study. The doses in 
the single-ascending dose portion of the study will be staggered such that for each 
dose, 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 (AEs, clinical labs, vital 
signs and ECGs) in the judgment of the principal investigator and GSK Medical 
Monitor through approximately 24 hours after their 2nd dose on Day 1, the remaining 
subjects may be randomized to dosing in that period.

60 mg, 120 mg, and 240 mg of GSK2982772 will be administered in each sentinel 
dosing which occurred on Period 1, 2, and 3, respectively.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
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 one of the 4 groups, according to the randomization schedule 
generated prior to the study by the Biomedical Data Sciences Department at GSK. 
Each participant will be dispensed blinded study treatment, labelled with his unique 
randomization number, throughout the study.

Subjects will be randomized to one of four sequences (A, B, C, and D), where the 
treatments in the sequences are: 
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205037
7
Overview of Study Design and Key Features
o A: Placebo TID / 60 mg TID / 120 mg TID / 240 mg TID
o B: 60 mg TID / Placebo TID / 120 mg TID / 240 mg TID
o C: 60 mg TID / 120 mg TID / Placebo TID / 240 mg TID
o D: 60 mg TID / 120 mg TID / 240 mg TID / Placebo TID
o
Interim 
Analysis

No interim analysis is planned.
2.4.
Statistical Hypotheses / Statistical Analyses
The objectives of this study are to evaluate safety, tolerability and pharmacokinetics of 
GSK2982772 in healthy Japanese subjects. No formal statistical hypotheses will be 
tested. Descriptive statistics will be used to assess safety and tolerability. An estimation 
approach will be used to address the pharmacokinetic study objectives, where point 
estimates and corresponding confidence intervals will be constructed.
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3.
PLANNED ANALYSES
3.1.
Interim Analyses
A review of safety data will be conducted at the end of each period. 
The decision to proceed to higher dose strengths will be made by principal investigator 
and GSK’s Medical Monitor based on assessment of safety and tolerability at the 
preceding dose. This review can include individual subject data.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

All subjects who have a screening visit will be included

Study Population
Enrolled

All subjects who passed screening and enter the study 
will be included.

Note screening failures (who never passed screening 
even if rescreened) and subjects screened but never 
enrolled into the study (Reserve, Not Used) are 
excluded from the Enrolled poputation as they did not 
enter the study.

Study Population
Safety

All subjects who have received at least one dose of 
study treatment will be included. 

Study Population

Safety
Pharmacokinetic
(PK)

All subjects in the Safety population for whom a 
pharmacokinetic sample has been obtained and 
analyzed will be included.

PK
Refer to Appendix 9: List of Data Displays which details the population used for each display.
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4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the 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.
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.
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
[RandAll NG]
Data Displays for Reporting 
Code
Description
Description
Order in TLF 
A1
GSK2982772 60 mg
GSK2982772 60 mg
2
A2
GSK2982772 120 mg
GSK2982772 120 mg
3
A3
GSK2982772 240 mg
GSK2982772 240 mg
4
P
Placebo
Placebo
1
5.2.
Baseline Definitions
Baseline definitions are applied to each period.
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.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
Examination of Covariates, Other Strata and Subgroups
5.3.1.
Covariates and Other Strata
The list of covariates may be used in descriptive summaries and statistical analyses.
Additional covariates may also be considered.
Category
Details
Covariates
See Section 8.1.5.1, describing pharmacokinetic analyses using statistical model
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5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
9.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
9.4
Appendix 4: Data Display Standards & Handling Conventions
9.5
Appendix 5: Derived and Transformed Data
9.6
Appendix 6: Reporting Standards for Missing Data
9.7
Appendix 7: Values of Potential Clinical Importance
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Enrolled or Safety population, unless 
otherwise specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 9: List of Data Displays.
Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Subject Disposition for the Subject Conclusion Record
Y
Y
Screening Status and Reasons for Screen Failure
Y
Y
Number of Subjects Enrolled by Country and Site ID
Y
Subjects for Whom the Treatment Blind was Broken
Y
Planned and Actual Treatments
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Inclusion/Exclusion Criteria Deviations
Y
Population Analysed
Subjects Excluded from PK Population
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Y
Race and Racial Combinations
Y
Y
Age Ranges
Y
Medical Conditions and Concomitant Medications
Medical Conditions
Y
Concomitant Medications
Y
Exposure and Treatment Compliance
Exposure to Study Treatment
Y
NOTES:

Y = Yes display generated.
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6.1.1.
Details of Planned Study Population Summaries
Subject Disposition
Subject Disposition for the Subject Conclusion Record
The number and percentage of subjects who completed the study as well as subjects who 
withdrew from the study will be summarized. Reason for withdrawal will also be 
summarized for subjects who withdrew from the study. Only the total column will appear.
Screening Status and Reasons for Screen Failure
This will be based on Enrolled population. The number and percentage of subjects who 
passed screening and who failed screening and therefore were not entered into the study 
will be summarized along with the reasons for failure will be summarized for those 
subjects who failed screening. Only the total column will appear.
Number of Subjects Enrolled by Country and Site ID
This will be based on Enrolled population. The number of subjects summarized by 
Country, Site ID and Investigator name will be presented. Only the total column will 
appear. 
Protocol Deviations
Important Protocol Deviations
The number and percentage of subjects who had important protocol deviations defined as 
part of the protocol deviation management plan for the study, will be summarized. Only 
the total column will appear.
Demographic and Baseline Characteristics
Demographic Characteristics
The number and percentage of subjects or summary statistics will be provided for each 
demographic characteristic and only the total column will appear: Sex, Age (years), Age 
Group (years), Ethnicity, Race detail, Height, Weight, and Body Mass Index. Age Group 
(years) will be categorized into three ('18', '19-64', '65'). Each demographic characteristic 
will be summarized using the minimum set of summary statistics.
Race and Racial Combinations
The five-high level FDA race categories and designated Asian subcategories will be 
summarized along with all combinations of high level categories which exist in the data. 
Only the total column will appear.
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Age Ranges
The number and percentage of subjects within each age range category will be provided. 
Only the total column will appear. Age range will be categorized into: 18-64 years, 65-84 
years. This is based on the standard of EMA clinical trial results disclosure requirements.
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7.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
7.1.
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 9: List of Data Displays.
Display Type
Absolute
Summary
Individual
T
F
L
Adverse Events (AEs)
All AEs by SOC and PT
Y
Y
All AEs by Maximum Intensity
Y
Drug-Related AEs by SOC and PT
Y
Drug-Related AEs by Maximum Intensity
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT and Verbatim Text
Y
Serious and Other Significant AEs
Serious AEs
Y
AEs Leading to Withdrawal from Study 
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.1.1.
Details of Planned Adverse Events Summaries
Adverse Events (AEs)
All AEs by SOC and PT
The number and percentage of subjects with all relevant adverse events will be 
summarized by MedDRA System Organ Class and Preferred Term by treatment group. 
The counting of events and the percentages will be based on the number of subjects on 
each treatment, so subjects may appear in more than one treatment category.
All AEs by Maximum Intensity by SOC and PT
The number and percentage of subjects with adverse events by intensity (e.g., mild, 
moderate, severe) will be summarized by MedDRA System Organ Class and Preferred 
Term by treatment group. The counting of events and the percentages will be based on 
the number of subjects on each treatment, so subjects may appear in more than one 
treatment category.
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Drug-related AEs by SOC and PT
The number and percentage of subjects with all drug-related adverse events will be 
summarized by MedDRA System Organ Class and Preferred Term. The counting of 
events and the percentages will be based on the number of subjects on each treatment, so 
subjects may appear in more than one treatment category.
Drug-related AEs by Maximum Intensity by SOC and PT
The number and percentage of subjects with drug-related adverse events by intensity 
(e.g., mild, moderate, severe) will be summarized by MedDRA System Organ Class and 
Preferred Term. The counting of events and the percentages will be based on the number 
of subjects on each treatment, so subjects may appear in more than one treatment 
category.
7.2.
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 9: List of Data Displays.
Display Type
Absolute
Summary
Individual
T
F
L
Chemistry
Chemistry Changes from Baseline
Y
Chemistry Values
Y
Y
Chemistry Data Shifts from Baseline Relative to Normal Range
Y
All Chemistry Data for Subjects with any Value of PCI
Y
Chemistry Values of PCI
Y
Haematology
Haematology Changes from Baseline
Y
Haematology Values
Y
Y
Haematology Data Shifts from Baseline Relative to PCI Criteria
Y
All Haematology Data for Subjects with any Value of PCI
Y
Haematology Values of PCI
Y
Urinalysis
Urinalysis Concentration Changes from Baseline (Gravity and 
pH)
Y
Urinalysis Data (Gravity and pH)
Y
Y
Urinalysis Data (Glucose, Protein, Blood, Ketones, Bilirubin, and 
Urobilinogen)
Y
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Medical Conditions for Subjects with Liver Stopping Events
Y
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NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred 
Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.2.1.
Details of Planned Clinical Laboratory Displays
Chemistry/Haematology Laboratory Tests
Laboratory Changes from Baseline and Values
Each quantitative laboratory test and the changes in value from baseline will be 
summarized at every assessed time point using n, mean, standard deviation, median, 
minimum, and maximum by treatment group.
Laboratory Data Shifts from Baseline Relative to PCI Criteria
The number and percentage of subjects with laboratory results within each PCI criteria 
category (Low, W/in Range, High) during each planned time assessment will be 
summarized by treatment group relative to their baseline category by laboratory test, 
where PCI criteria are available. The percentages are based on the number of subjects in 
the treatment group with data for the laboratory test at the specified planned time (n). The 
worst case post-baseline is used to summarize the subjects’ overall worst case shifts 
during the post-baseline period.
Urinalysis Laboratory Tests
Urinalysis Concentration Changes from Baseline (Gravity and pH)
Gravity and pH test and the changes in value from baseline will be summarized at every 
assessed time point using n, mean, standard deviation, median, minimum, and maximum 
by treatment group.
Urinalysis Data (Glucose, Protein, Blood, Ketones, Bilirubin, and Urobilinogen)
The number and percentage of subjects with the above urinalysis results (character 
results) will be summarized by treatment group.
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7.3.
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. The details of the 
planned displays are presented in Appendix 9: List of Data Displays.
Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Neurological Examination
Neurological Examination Findings
Y
Y
ECG
ECG Findings
Y
Y
ECG Values
Y
Y
Y
All ECG Values for Subjects with any Value of PCI
Y
Cardiac Telemetry
Y
Cardiac Telemetry Abnormalities
Y
Clinically Significant Cardiac Telemetry Abnormalities
Y
Vital Signs
Vitals Values
Y
Y
Y
All Vital Signs for Subjects with any Value of PCI
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.3.1.
Details of Planned Other Safety Displays
ECG
ECG Findings
The number and percentage of subjects with ECG findings (ECG interpretation) will be 
summarized by treatment group..
ECG Values
Each ECG parameter value and the change from baseline will be summarized by 
treatment group at every assessed time point using n, mean, standard deviation, median, 
minimum, and maximum.
Cardiac Telemetry
The number and percentage of subjects with telemetry result of “normal,” “abnormal but 
clinically insignificant,” and “abnormal and clinically significant” will be summarized by 
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treatment group. The number and percentage of subjects with specific telemetry 
abnormalities will be summarized by treatment group.
Vital Signs
Vital Signs
Each vital sign parameter and the changes in value from baseline will be summarized by 
treatment group at every assessed time point using n, mean, standard deviation, median, 
minimum, and maximum.
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8.
PHARMACOKINETIC ANALYSES
8.1.
Pharmacokinetic Analyses
8.1.1.
Endpoint / Variables
8.1.1.1.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 9.4.3
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 6.3 or hihger. 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(0-7), 
AUC(7-14), 
AUC(14-24), 
AUC(0-24)
The area under the concentration-time curve will be calculated
to some fixed nominal time x (AUC(0-x), using the combination of linear and logarithmic 
trapezoidal methods (i.e., Linear Up/Log Down calculation method in Phoenix WinNonlin 
Professional).
If a sampling time deviation occurred at nominal time x (and x < t), AUC(0-x) will be 
calculated using the concentration at time x post-dose estimated by the method of
interpolation. If nominal time x > t (or if the concentration at time x was below the limit of 
quantification), then the concentration (y) at time x is estimated using lambda_z and last 
observed Ct according to the formula:
y = Ct(obser) x e-lambda_z(x-t)
Then the following equation will be used to calculate (AUC(0-x)) where t is the time of
last quantifiable plasma concentration.
AUC(0-x) = AUC(0-t) x AUC(t-x)
If lambda_z is not estimable, a partial AUC is not calculated (when x > t).
Cmax
Maximum observed plasma concentration following each dose will be obtained directly from 
the concentration-time data.
Tmax
The time to maximum observed plasma drug concentration following each dose will be 
obtained directly from the concentration-time data.
t1/2
Terminal half-life following the 3rd dose will be calculated as follows:
t1/2 = ln2 / lambda_z
C0
The plasma drug concentration at 0 hour will be obtained directly from the observed 
concentration-time data.
C7
The plasma drug concentration at 7 hours will be obtained directly from the observed 
concentration-time data.
C14
The plasma drug concentration at 14 hours will be obtained directly from the observed 
concentration-time data.
C24
The plasma drug concentration at 24 hours will be obtained directly from the observed 
concentration-time data.
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Parameter
Parameter Description
lambda_z
The first order rate constant associated with the terminal (log-linear) portion of the curve 
following the 3rd dose.
lambda_z
lower
The lower limit on time for values to be included in the calculation of lambda_z following the 
3rd dose..
lambda_z
upper
The upper limit on time for values to be included in the calculation of lambda_z following the 
3rd dose..
#pts
The number of time points used in computing lambda_z following the 3rd dose..
R-square
Square of the correlation coefficient for computing lambda_z following the 3rd dose.
NOTES:

Additional parameters may be included as required.

Lambda_z is the terminal phase rate constant.

Ct is the last observed quantifiable concentration.
8.1.2.
Summary Measure
The slope of log-transformed dose in the power model for AUC(0-24), AUC(0-7) and 
Cmax will be used as measure of the dose proportionality between dose and the PK 
parameters..
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
Intercurrent events which may affect the assessment of the safety and tolerability and the 
characterization of PK profile will not be anticipated.
8.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
8.1.5.1.
Statistical Methodology Specification
The following pharmacokinetic statistical analyses will only be performed if sufficient 
data is available (i.e. if participants have well defined plasma profiles).
Endpoint / Variables

Derived PK parameters for GSK2982772 (AUC(0-24), AUC(0-7), Cmax)
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Model Specification

Dose proportionality for AUC(0-24), AUC(0-7) and Cmax following the first (morning) dose will 
be assessed by using a power model as described below:
  loge (Yij) = μ + Si + β*loge (Dj) + εij
Yij: PK parameter (AUC(0-24), AUC(0-7), Cmax) on dose j for subject i
μ: Overall mean (intercept)
β: slope for loge transformed dose
Si: random effect for subject i following normal distribution N(0, b2)
Dj: dose effect (j= 60 mg, 120 mg, 240 mg)
ij: random error following normal distribution N(0, w2)

The model parameters will be estimated using Restricted Maximum Likelihood with the 
Newton-Raphson algorithm.

The Kenward-Roger degree of freedom approach will be used.
Model Checking & Diagnostics

If the power model has failed to converge, dose proportionality will be assessed using ANOVA.

Assessment of dose proportionality using ANOVA
o
The dose-normalized PK parameters (AUC(0-24), AUC(0-7), Cmax) will be 
calculated by dividing the PK parameters by dose.
o
The dose-normalized values will be analyzed by using the following model.
  log (Xij) = μ + Si + Dj + εij
Xij: dose-normalized PK parameter (AUC(0-24), AUC(0-7), Cmax) on the 
dose j for subject i
μ : Overall mean
Si: random effect for subject i following normal distribution N(0, b2)
Dj: dose effect (j= 60 mg, 120 mg, 240 mg)
εij: random error following normal distribution N(0, w2)
the model has dose as fixed effect and subject as random effect.
o
Point estimates and associated 90% confidence intervals for the differences 60 mg 
– 120 mg, 240 mg – 120 mg will be construced using the residual variance. These 
confidence intervals will then be exponentially back-transformed to provide point 
estimates and associated 90% confidence intervals for the ratio 60 mg/120 mg 
and 240 mg/120 mg. 
Model Results Presentation

The point estimates of the slope for each parameter and their 90% confidence intervals will be 
presented.
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8.1.6.
Details of Planned Pharmacokinetic Displays
Plasma Concentration-Time Data
The plasma concentrations at every scheduled time point will be summarized using n, 
mean, standard deviation, median, minimum, and maximum.
Derived Plasma Pharmacokinetic Parameters (non-transformed)
The plasma pharmacokinetic parameters (AUC(0-7), AUC(7-14), AUC(14-24), AUC(0-
24), Cmax, Tmax, t1/2, C0, C7, C14, C24) will be summarized using n, mean, 95% CI, 
standard deviation, median, minimum, and maximum.
Derived Plasma Pharmacokinetic Parameters (log-transformed)
For each pharmacokinetic parameters with a log-normal distribution (AUC(0-7), AUC(7-
14), AUC(14-24), AUC(0-24), Cmax, t1/2, C0, C7, C14, C24), the log-transformed 
parameters will be summarized using n, geometric mean, 95% CI of geometric mean, 
standard deviation of log-transformed data and between subject coefficient of variation 
(%CVb).
Power Model Analysis for Dose Proportionality of Pharmacokinetic Parameters AUC(0-
24), AUC(0-7) and Cmax
The analysis results will be presented as described in Section 8.1.5.1. 
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9.
APPENDICES
9.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the PDMP and the data handling will be determined prior to DBR.
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9.2.
Appendix 2: Schedule of Activities
9.2.1.
Protocol Defined Schedule of Events
Time and Events Table for Screening and Follow-up Assessments
Procedure
Screening1
Follow-up 
Visit2
Notes
Outpatient Visit
X
X
Informed Consent
X
Medical/medication/drug
/alcohol history
X
Demographics
X
Physical Examination
X
X
Additional examinations may be performed, by the Investigators, as deemed necessary (e.g., where safety or laboratory 
findings indicate).
Drug screen
X
Additional tests may be performed by the Investigators, as deemed necessary (e.g., where safety or laboratory findings 
indicate). Tests will be conducted within site specified standards.
Syphilis, Human immunodeficiency virus 
(HIV), Human T-cell leulemia virus type 1
(HTLV-1), Hepatitis B (Hep B) and
Hepatitis C (Hep C) screen
X
Tuberculosis (TB) Test
X
Conducted at the standard practice of the site.
X-ray Test
X
Anterior & lateral chest X-ray will be taken.
Hema/Chem/Urinalysis tests
X
X
Height and weight
X
12-lead ECG and vital signs
X
X
Vital signs to include pulse rate (PR), blood pressure (BPs) and temperature.
AE Review
X
X
All Serious Adverse Effects (SAEs) will be collected from the signing of the informed consent form (ICF) until the follow-up 
visit at the time points specified. All AEs will be collected from the start of treatment until the follow-up visit at the time points 
specified.
Concomitant Medication Review
X
X
1: Within 30 days prior to the first dosing
2: Follow-up Visit to occur at least 7 days, and no greater than 14 days after last study treatment administration. If a participant withdrew from the study after received GSK2982772 or placebo dose, the 
safety assessments listed at follow-up visit will be required.  
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Detailed Time and Events Table for Days 1-4 (common Period1-4)
Procedure 1
Da
y
-1
Day 1
Pre-
dose
0
20 
min
40 
min
1
hr
1.5
hr
2
hr
3
hr
4
hr
5
hr
7
hr
7 hr
20 
min
7 hr
40 
min
8
hr
8.5
hr
9
hr
10
hr
12
hr
14
hr
14 
hr
20 
min
14 
hr
40 
min
15
hr
15.5 
hr
Admission
X
Physical 
Examination
X
X
X6
Hema/Chem/
Urinalysis tests
X
Vital signs 2
X
X
X
X
12-lead ECG
X
X
X5
X
Cardiac 
telemetry 
<=====================================================================================================================================
============
PK blood 
sampling
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological 
Examination
X
X
X
Study 
Treatment
X
X
X
Pharmacogene
tic Sample 
(PGx) 3
<=====================================================================================================================================
============
Meals Served
X
X6
X7
AE Review 4
<===========================================================================================================================================
===========
Concomitant 
Medication 
Review
<===========================================================================================================================================
===========
Discharge
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Procedure 1
Day 2
Day 3
Day 4
16 hr
17 hr
19 hr
22 hr
24 hr
28 hr
32 hr
36 hr
48 hr
60 hr
72 hr
Admission
Physical 
Examination
X
X
X
X
Hema/Chem/
Urinalysis tests
X
Vital signs 2
X
X
X
12-lead ECG
X
X
X
Cardiac telemetry 
===========================================================>
PK 
blood 
sampling
X
X
X
X
X
X
X
X
X
X
X
Neurological 
Examination
X
X
X
Study Treatment
Pharmacogenetic 
Sample (PGx) 3
======================================================================================================================================>
Meals Served
X8
X8
X8
X8
X8
AE Review 4
======================================================================================================================================>
Concomitant 
Medication 
Review
======================================================================================================================================>
Discharge
X
1: In this study, baseline is Day -1 and Day 1 pre-dose tests.
2: Vital signs include PR, BPs and temperature. A 14 hr time point is to be performed prior to third dose.
3: A PGx blood sample will be collected at any time during the study after randomization. The participation is optional for each subject.
4: All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points specified. All AEs will be collected from the start of treatment until the follow-up visit at the time points 
specified. 
5: Physical Examination and 12-lead ECG of 14hr time point are to be performed prior to third dose.
6: On Day 1, lunch will be served between 2 to 3 hr prior second dose. 
7: On Day1, dinner will be served between 2 to 3 hr prior to third dose. 
8: On Day 2-3, meal will be served per unit schedule. Mealtime will be described in SRM.
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9.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
9.3.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
the date of dosing date.
Study Phase
Definition
Pre-Treatment 
Date ≤ Previous Day of Dosing Date in Period 1
Period 1
Previous Day of Dosing Date in Period 1 ≤Date < Previous Day of Dosing Date in 
Period 2
Period 2
Previous Day of Dosing Date in Period 2 ≤Date < Previous Day of Dosing Date in 
Period 3
Period 3
Previous Day of Dosing Date in Period 3 ≤Date < Previous Day of Dosing Date in 
Period 4
Period 4
Previous Day of Dosing Date in Period 4 ≤Date
9.3.1.1.
Study Phases for Adverse Events
Study Phase
Definition
Pre-Treatment
AE Onset Date and Time < Study First Dosing Date and Time
Period 1
Dosing Date and Time in Period 1 AE Onset Date and Time < Dosing Date and 
Time in Period 2
Period 2
Dosing Date and Time in Period 2 AE Onset Date and Time < Dosing Date and
Time in Period 3
Period 3
Dosing Date and Time in Period 3AE Onset Date and Time < Dosing Date and 
Time in Period 4
Period 4
Dosing Date and Time in Period 4AE Onset Date and Time
Time since Study
First Dose (min)
If study phase of the event is pre-treatment,
AE Onset Date and Time - Study First Dosing Date and Time 1
otherwise
AE Onset Date and Time – Study First Dosing Date and Time + 1 min
Time since Period 
First Dose (min)
If study phase of the AE is pre-treatment, set to missing
If study phase of the AE is period 1,
AE Onset Date and Time – Dosing Date and Time in Period 1 + 1 min
If study phase of the AE is period 2,
AE Onset Date and Time – Dosing Date and Time in Period 2 + 1 min 
If study phase of the AE is period 3,
AE Onset Date and Time – Dosing Date and Time in Period 3 + 1 min
If study phase of the AE is period 4,
AE Onset Date and Time – Dosing Date and Time in Period 4 + 1 min
Time since Last 
Dose (min)
If study phase of the AE is pre-treatment, set to missing
If study phase of the AE Study Last Dosing Start Date and Time,
AE Onset Date and Time – Study Last Dosing Start Date and Time+ 1 min 
Duration (min)
AE Resolution Date and Time – AE Onset Date and Time + 1 min
Drug-related
If relationship is marked ‘YES’ on eCRF or value is missing.
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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.
9.3.1.2.
Study Phases for Concomitant Medication
The study phase for concomitant medication will be categorized into pre-treatment, 
period 1, period 2, period 3, and period 4 based on medication start date and time.
Study Phase
Definition
Pre-Treatment
Start Date and Time < Dosing Date in Period 1
Period 1
Dosing Date in Period 1 Start Date and Time < Dosing Date in Period 2
Period 2
Dosing Date in Period 2 Start Date and Time < Dosing Date in Period 3
Period 3
Dosing Date in Period 3 Start Date and Time < Dosing Date in Period 4
Period 4
Dosing Date in Period 4 Start Date and Time 
NOTES: 

Please refer to Appendix 6: 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.
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9.4.
Appendix 4: Data Display Standards & Handling 
Conventions
9.4.1.
Reporting Process
Software

The currently supported versions of SAS software [Insert Other Software as Required] will be used.
Reporting Area
HARP Server
: N/A
HARP Compound
: N/A
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.0.
Generation of RTF Files

RTF files will be generated.
9.4.2.
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 subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings
Formats

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.

For [Insert Endpoint / Parameter] the following DP’s places will be applied:

Summary Statistics:

Listings: 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
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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.

[Insert as Required: If any publication related displays have been specified, please provide relevant 
details]
9.4.3.
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 Office function will be created according to GUI_51487. 
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_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, C14, 
C24]
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to GUI_51487.
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to [Insert document name] 
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9.5.
Appendix 5: Derived and Transformed Data
9.5.1.
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.

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    
Period Day

Calculated as the number of days from Dosing Date in each period. For study phase derivation, see 
Appendix 3.

If Study Phase of Ref Assessment or Event = Pre-Treatment or Missing
→Period Day = Missing 

If Study Phase of Ref Assessment or Event = Period X and Ref Date is on or after Dosing Date in 
Period X
→Period Day = Ref Date – Dosing Date in Period X + 1 day

If Study Phase of Ref Assessment or Event = Period X and Ref Date is before Dosing Date in 
Period X
→ Period Day = Ref Date – Dosing Date in Period X
Note: X takes a value of 1, 2, 3, 4.
9.5.2.
Study Population
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
A date and month will be imputed as ‘30th June’ as it will not be captured.

Date of Informed Consent will be used as reference date of calculation.
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9.5.3.
Safety
Laboratory Parameters
Imputation

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

The default convention for reporting of clinical laboratory units will be the international system of units 
(SI units).
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9.6.
Appendix 6: Reporting Standards for Missing Data
9.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as completion of 
all phases of the study including the last visit or the last scheduled procedure.

Withdrawn subjects may be replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be 
summarised as withdrawal visits.
9.6.2.
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 subject 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.
9.6.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject 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. 

The eCRF allows for the possibility of missing times to be recorded for AE start and end 
dates. Missing dates will be imputed using the following convention:
o
If the missing time is a start date, a '00:00' will be used for the time.
o
If the missing date is a stop date, a '23:59' will be used for the time.

The recorded missing time will be displayed in listings without imputed values.
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 eCRF allows for the possibility of missing times to be recorded for concomitant 
medications start and end dates. Missing dates will be imputed using the following 
convention:
o
If the missing time is a start date, a '00:00' will be used for the time.
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Element
Reporting Detail
o
If the missing date is a stop date, a '23:59' will be used for the time.

The recorded partial date and missing time will be displayed in listings without imputed 
values.
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9.7.
Appendix 7: Values of Potential Clinical Importance
9.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 
1
0.54
∆from BL
↓0.075
Haemoglobin 
g/L
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
White 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
Phosphorus
mmol/L
0.8
1.6
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
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9.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450 [1]
Absolute PR Interval
msec
< 110 [1]
> 220 [1]
Absolute QRS Interval
msec
< 75 [1]
> 110 [1]
Change from Baseline
Increase from Baseline QTc
msec
> 60 [1]
NOTES:
1. Represent standard ECG values of PCI for HV studies
9.7.3.
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
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9.8.
Appendix 8: Abbreviations & Trade Marks
9.8.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
ITT
Intent-To-Treat
PCI
Potential Clinical Importance 
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
TFL
Tables, Figures & Listings 
9.8.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
WinNonlin
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9.9.
Appendix 9: List of Data Displays
9.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.7
-
Safety
2.1 to 2.21
-
Pharmacokinetic
3.1 to 3.5
3.1 to 3.5
Section
Listings
ICH Listings
1 to 37
9.9.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 10: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Safety
SAF_Fn
SAF_Tn
SAF_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
9.9.3.
Deliverables
Delivery 
Description
SAC
Final Statistical Analysis Complete
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9.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1A
Summary of Subject Disposition for the Participant Conclusion 
Record
ICH E3, FDAAA, EudraCT
SAC
1.2.
Enrolled
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC
1.3.
Enrolled
NS1
Summary of Number of Participant by Country and Site ID
EudraCT/Clinical Operations
SAC
Protocol Deviation
1.4.
Safety
DV1
Summary of Important Protocol Deviations
ICH E3
SAC
Demographic and Baseline Characteristics
1.5.
Safety
DM3
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC
1.6.
Safety
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC
1.7.
Enrolled
DM11
Summary of Age Ranges
EudraCT
SAC
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9.9.5.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
2.1.
Safety
AE1CP
Summary of All Adverse Events by System Organ Class and 
Preferred Term
ICH E3
SAC
2.2.
Safety
AE5A
Summary of All Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term
ICH E3
SAC
2.3.
Safety
AE1CP
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term
ICH E3
.
SAC
2.4.
Safety
AE5A
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term and Maximum Intensity
ICH E3
.
SAC
Laboratory: Chemistry 
2.5.
Safety
LB1
Summary of Chemistry Values
SAC
2.6.
Safety
LB1
Summary of Chemistry Changes from Baseline 
ICH E3
SAC
2.7.
Safety
LB4
Summary of Chemistry Data Shifts from Baseline Relative to 
PCI Criteria
ICH E3
SAC
Laboratory: Hematology
2.8.
Safety
LB1
Summary of Hematology Values
SAC
2.9.
Safety
LB1
Summary of Hematology Changes from Baseline 
ICH E3
SAC
2.10.
Safety
LB4
Summary of Hematology Data Shifts from Baseline Relative to 
PCI Criteria
ICH E3
SAC
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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Urinalysis
2.11.
Safety
LB1
Summary of Urinalysis Data (Gravity and pH)
SAC
2.12.
Safety
LB1
Summary of Urinalysis Concentration Change from Baseline 
(Gravity and pH) 
ICH E3
SAC
2.13.
Safety
UR3b
Summary of Urinalysis Data (Glucose, Protein, Blood, Ketones, 
Bilirubin, Urobilinogen)
SAC
Neurological Examination
2.14.
Safety
NE1
Summary of Neurological Examination
SAC
ECG
2.15.
Safety
EG1
Summary of ECG Findings 
IDSL
SAC
2.16.
Safety
EG2
Summary of ECG Values
SAC
2.17.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
IDSL
SAC
2.18.
Safety
HM1
Summary of Cardiac Telemetry
IDSL
SAC
2.19.
Safety
HM2
Summary of Cardiac Telemetry Abnpormalities
IDSL
SAC
Vital Signs
2.20.
Safety
VS1
Summary of Vital Signs
IDSL
SAC
2.21.
Safety
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
SAC
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9.9.6.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.1.
PK
PK01
Summary of GSK2982772 Plasma Pharmacokinetic 
Concentration-Time Data
SAC
3.2.
PK
PK03
Summary of Derived GSK2982772 Pharmacokinetic Parameters
(non-transformed)
SAC
3.3.
PK
PK05
Summary of GSK2982772 Pharmacokinetic Parameters (log-
transformed)
SAC
3.4.
PK
PK_T1
Power Model Analysis for GSK2982772 Dose Proportionality of 
Pharmacokinetic Parameters (AUC(0-24), AUC(0-7), Cmax)
SAC
3.5.
PK
PK_T2
ANOVA Model Analysis for GSK2982772 Dose Proportionality of 
Dose-Normalized Derived Pharmacokinetic Parameters(AUC(0-
24), AUC(0-7), Cmax)
This table will be provided if the power 
model fails to converge.
SAC
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9.9.7.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.1.
PK
PK16b
Individual GSK2982772 Plasma Concentration–Time Plots by 
Subject
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
3.2.
PK
PK24
Individual GSK2982772 Plasma Concentration–Time Plots by 
Treatment
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
3.3.
PK
PK17
Mean (+SD) GSK2982772 Plasma Concentration–Time Plots
A graph on linear and semi-logarithmic 
scales will be produced.
SD will also be displayed.
SAC
3.4.
PK
PK18
Median GSK2982772 Plasma Concentration–Time Plots
A graph on linear and semi-logarithmic 
scales will be produced.
SAC
3.5.
PK
PK28
Plot of Individual (+Geometric Mean and 95% CIs) GSK2982772 
Pharmacokinetic Parameters (AUC(0-24), AUC(0-7), Cmax) 
versus Dose
SAC
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9.9.8.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
2.
Safety
ES3
Listing of Reasons for Study Withdrawal
ICH E3
SAC
3.
Safety
SD3
Listing of Reasons for Study Treatment Discontinuation
ICH E3
SAC
4.
Safety
BL2
Listing of Participants for Whom the Treatment Blind was Broken
ICH E3
SAC
5.
Safety
TA2
Listing of Planned and Actual Treatments
IDSL
SAC
Protocol Deviations
6.
Safety
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC
7.
Safety
IE4
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
ICH E3
SAC
Populations Analysed
8.
Safety
SP3A
Listing of Subjects Excluded from Any Population
ICH E3
SAC
Demographic and Baseline Characteristics
9.
Safety
DM4
Listing of Demographic Characteristics
ICH E3
SAC
10.
Safety
DM10
Listing of Race
ICH E3
SAC
Prior and Concomitant Medications
11.
Safety
MH3
Listing of Medical Conditions
IDSL
SAC
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CONFIDENTIAL
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46
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
12.
Safety
CM5
Listing of Concomitant Medications
IDSL
SAC
Exposure and Treatment Compliance
13.
Safety
EX4
Listing of Exposure Data
ICH E3
SAC
Adverse Events
14.
Safety
AE9CP
Listing of All Adverse Events
ICH E3
SAC
15.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
16.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC
Serious and Other Significant Adverse Events
17.
Safety
AE9CP
Listing of Fatal Serious Adverse Events
ICH E3
SAC
18.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
SAC
Hepatobiliary (Liver)
19.
Safety
MH2
Listing of Medical Conditions for Participants with Liver Stopping 
Events
IDSL
SAC
20.
Safety
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
IDSL
SAC
Chemistry
21.
Safety
LB6
Listing of All Chemistry Data
ICH E3
SAC
22.
Safety
LB6
Listing of All Chemistry Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC
23.
Safety
LB6
Listing of Chemistry Values of Potential Clinical Importance
SAC
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47
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Haematology
24.
Safety
LB6
Listing of All Haematology Data
ICH E3
SAC
25.
Safety
LB6
Listing of All Haematology Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC
26.
Safety
LB6
Listing of Haematology Values of Potential Clinical Importance
SAC
Urinarysis
27.
Safety
LB6
Listing of Urinarysis Data (Gravity and pH)
SAC
28.
Safety
LB14
Listing of Urinarysis Data (Glucose, Protein, Blood, Ketones, 
Bilirubin, and Urobilinogen)
SAC
Neurological Examination
29.
Safety
NE2
Listing of Neurological Examinations
IDSL
SAC
ECG
30.
Safety
EG6
Listing of ECG Findings
SAC
31.
Safety
EG4
Listing of All ECG Values
IDSL
SAC
32.
Safety
EG4
Listing of All ECG Values for Subjects with Any Value of 
Potential Clinical Importance
IDSL
SAC
33.
Safety
HM10
Listing of Clinically Significant Cardiac Telemetry Abnormalities
IDSL
SAC
Vital Signs
34.
Safety
VS5
Listing of All Vital Signs Data
IDSL
SAC
35.
Safety
VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance
IDSL
SAC
2018N385232_00


CONFIDENTIAL
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48
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetics
36.
PK
PK08
Listing of GSK2982772 Plasma Pharmacokinetic Concentration-
Time Data
IDSL
SAC
37.
PK
PK14
Listing of Derived GSK2982772 Plasma Pharmacokinetic 
Parameters
IDSL
All PK parameters in Section 8.1.1.2
will be provided in a listing
SAC
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9.10.
Appendix 10: Example Mock Shells for Data Displays
Example: PK_T1
Protocol: 205037                                                                                        Page 1 of 1
Population: PK
Table x.x
Power Model Analysis for GSK2982772 Dose Proportionality of Pharmacokinetic Parameters (AUC(0-24), AUC(0-7), 
Cmax)
Parameter
Effect
n
Slope
Point Estimate
90% CI
AUC(0-24)
Log(dose levels)
xx
xxx
(xx,xx)
AUC(0-7)
Log(dose levels)
xx
xxx
(xx,xx)
Cmax
Log(dose levels)
xx
xxx
(xx,xx)
Note: The power model was fitted to loge-transformed PK parameters with loge-transformed dose as fixed effet. 
The slope with corresponding 90% confidence interval was estimated from the power model to assess the degree 
of dose-proportionality (slope around unity indicates dose-proportionality).
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Example: PK_T2
Protocol: 205037                                                                                        Page 1 of 1
Population: PK
Table x.x
ANOVA Model Analysis for GSK2982772 Dose Proportionality of Dose-Normalized Derived Pharmacokinetic 
Parameters(AUC(0-24), AUC(0-7), Cmax)
Parameter
Treatment Comparison
Ratio of 
Adjusted Geo. 
Means
90% CI
AUC(0-24)
60 mg / 120 mg
x.xxx
(x.xxx,x.xxx)
240 mg / 120 mg
x.xxx
(x.xxx,x.xxx)
AUC(0-7)
60 mg / 120 mg
x.xxx
(x.xxx,x.xxx)
240 mg / 120 mg
x.xxx
(x.xxx,x.xxx)
Cmax
60 mg / 120 mg
x.xxx
(x.xxx,x.xxx)
240 mg / 120 mg
x.xxx
(x.xxx,x.xxx)
Note: The ANOVA
model was fitted to loge-transformed and dose-normalized PK parameters with dose as fixed 
effet. The ratios of adjusted geographic means with corresponding 90% confidence interval were estimated from 
the ANOVA
model to assess the degree of dose-proportionality (slope around unity indicates dose-
proportionality).
2018N385232_00
PPD