Clinical trial NCT02389621
Conditions: Chronic Liver Disease Thrombocytopenia
Keywords: Elective invasive procedures
Sponsor: Shionogi
Start date: 2015-06-15; Completion date: 2017-04-19
Enrollment: 215 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to compare the efficacy of lusutrombopag with placebo for the treatment of thrombocytopenia in patients with chronic liver disease who are undergoing elective invasive procedures.

Detailed description:
The study consists of 3 periods: a screening period (up to 28 days prior to randomization), a treatment period of 7 days (Days 1 to 7 during which study drug is to be administered for 4 to 7 days), and a posttreatment period (through 28 days posttreatment).

Once-daily treatment with lusutrombopag 3 mg or placebo is to commence on Day 1 and continue for up to 7 days. Platelet count is to be determined on Days 5, 6, and 7 prior to administration of study drug; if a participant meets the administration stopping criterion (ie, platelet count ≥ 50 × 10⁹/L with an increase of ≥ 20 × 10⁹/L from baseline), no additional dose of study drug is to be administered. The planned invasive procedure is to be performed in the posttreatment period between Days 9 and 14. Platelet count for determination of the need for platelet transfusion is to be determined on or after Day 8, but no more than 2 days prior to the invasive procedure; a platelet transfusion is required if the platelet count is \< 50 × 10⁹/L.

Arms: arm 1: Lusutrombopag 3 mg once daily for up to 7 days. arm 2: Placebo once daily for up to 7 days.
Interventions: intervention 1: Lusutrombopag intervention 2: Placebo
Intervention descriptions: intervention 1: Tablets for oral administration intervention 2: Tablets for oral administration

Protocol documents:
Prot_000.pdf: 
Shionogi study title 
A Phase 3 Randomised, Double-blind, Placebo-controlled Study to 
Assess the Safety and Efficacy of S-888711 (Lusutrombopag) for the 
Treatment of Thrombocytopenia in Patients with Chronic Liver 
Disease Undergoing Elective Invasive Procedures (L-PLUS 2) 
Shionogi study no. 
1423M0634 
ClinicalTrials.gov 
registration no. 
NCT02389621 
Study document 
Protocol (Edition 2 dated 03 Feb 2015) 
 
The study was conducted in its entirety under Protocol Edition 2.  


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Clinical Study Protocol: 1423M0634 
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Clinical Study Protocol 
Study Title: 
A Phase 3 Randomised, Double-blind, Placebo-controlled 
Study to Assess the Safety and Efficacy of S-888711 
(Lusutrombopag) for the Treatment of Thrombocytopenia 
in Patients with Chronic Liver Disease Undergoing 
Elective Invasive Procedures (L-PLUS 2) 
Study Number: 
1423M0634 
EudraCT Number: 
2014-004942-91
IND Number: 
104047 
Study Phase: 
3 
Product Name: 
S-888711 (Lusutrombopag) 
Sponsor: 
Shionogi & Co., Ltd. 
(Head Office) 3-1-8 Doshomachi, Chuo-ku, Osaka 541-
0045, Japan 
 
Shionogi Inc. 
300 Campus Drive 
Florham Park, NJ 07932, United States 
 
Shionogi Ltd. 
33 Kingsway 
London, WC2B 6UF, United Kingdom 
 
The study sponsor may be one or more of the above 
Shionogi companies. Throughout the protocol, the term 
“sponsor” represents the various legal entities identified in 
the “Sponsor List and Contact Information” in the 
protocol. 
 
Amendment History 
Issue Date 
Edition 1 (original) 
24 December 2014 
Edition 2 
3 February 2015 
 
Confidentiality Statement 
This document and the information contained herein or attached hereto (“Confidential 
Material”) are confidential and proprietary to Shionogi & Co., Ltd.  This Confidential 
Material should only be viewed by those individuals or companies that have been given 
prior written authorisation to do so by Shionogi & Co., Ltd. (“Authorised Users”).  This 
Confidential Material should not be made available in any form to any person or 
company, other than the Authorised Users and their respective employees or associates 
on a need-to-know basis, without the written consent from Shionogi & Co., Ltd. 


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SYNOPSIS 
Study Title: 
A Phase 3 Randomised, Double-blind, Placebo-controlled Study to Assess the Safety and 
Efficacy of S-888711 (Lusutrombopag) for the Treatment of Thrombocytopenia in 
Patients with Chronic Liver Disease (CLD) Undergoing Elective Invasive Procedures (L-
PLUS 2) 
Study Number: 
1423M0634 
Study Phase: 3 
Primary Objective: 
• To compare the efficacy of S-888711 with placebo for the treatment of 
thrombocytopenia in patients with CLD who are undergoing elective invasive 
procedures 
Secondary Objectives:  
• To assess the safety and tolerability of S-888711 treatment compared with placebo 
• To assess the platelet response following treatment with S-888711 compared with 
placebo 
• To assess the pharmacodynamics (PD) and pharmacokinetics (PK) of S-888711 
Study Design: 
This is a phase 3, multinational, randomised, double-blind, placebo-controlled study to 
assess the safety and efficacy of S-888711 for the treatment of thrombocytopenia in 
patients with CLD undergoing elective invasive procedures.  The study consists of 
3 periods:  
• Screening period: up to 28 days prior to randomisation  
• Treatment period:  7 days (Days 1 to 7) 
• Post-treatment period: through 28 days post-treatment  
The maximum study duration for each patient will be 63 days.  Potential patients who 
provide written informed consent will be screened for eligibility, and eligible patients 
will be randomised in a 1:1 ratio to either S-888711 3 mg once daily for up to 7 days or 
matched placebo control.  The randomisation will be stratified by primary invasive 
procedure (liver ablation/coagulation or other invasive procedures) and baseline platelet 
count (< 35 × 109/L or ≥ 35 × 109/L).   
Patients will begin once daily treatment with assigned study medication on Day 1 after 
randomisation and will receive study medication for up to 7 days.  A platelet count will 
be performed on Days 5, 6, and 7 prior to administration of study medication. After the 
final dose of study medication, patients will continue the protocol-specified assessments 
and procedures in the Post-treatment period.  
The planned invasive procedure will be performed in the Post-treatment period between 
Days 9 and 14.  A platelet count will be performed on or after Day 8, but no more than 
2 days prior to the elective invasive procedure, in order to assess the need for a platelet 


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transfusion before the elective invasive procedure.  A pre-operative platelet transfusion 
must be performed if the platelet count is < 50 × 109/L.  
The need for the invasive procedure will be reassessed in the event of any of the 
following: 
• Platelet count ≥ 200 × 109/L 
• Administration of an antithrombotic drug  
• In the opinion of the investigator, the procedure is no longer in the patient's best 
interest because of an adverse event (AE) or other concern  
• The patient requests cancellation of the elective procedure after randomisation 
If any of the above criteria are met and the elective procedure cannot be performed 
between Days 9 and 14, it may be performed up to Day 35 of the study.  If a patient does 
not undergo the procedure, all the relevant follow-up assessments should be performed 
and data should be collected up to Day 35.  In case the invasive procedure performed 
between Days 9 and 14 needs to be repeated, the same procedure may be performed after 
Day 15 according to the discretion of the investigator. 
Study Population: 
A total of 200 adult patients with CLD and thrombocytopenia (defined as a platelet count 
< 50 × 109/L) will be randomised into the study. 
Inclusion Criteria:  
Patients who fulfil the following criteria will be eligible for inclusion in the study:  
1. Able to understand the study and comply with all the study procedures. 
2. Willing to provide written informed consent prior to Screening. 
3. Male or female. 
4. 18 years of age or older at the time of signing informed consent. 
5. CLD limited to Child-Pugh Class A and Class B disease (see Appendix 3). 
6. Platelet count < 50 × 109/L at baseline on Day 1 prior to randomisation. 
7. Undergoing an elective invasive procedure that: 
• is likely to require administration of platelets 
• is expected to be performed between Days 9 and 14  
• does not include laparotomy, thoracotomy, craniotomy, open-heart surgery, organ 
resection, or  
• does not include partial organ resection (however, biopsy and other types of tissue 
removal will be allowed if risk of bleeding and invasiveness is considered 
comparable or lower than those procedures in the list of example procedures; see 
Appendix 4). 
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) grade of 0 or 
1 (see Appendix 5). 
9. In the opinion of the investigator, able to meet the requirements of the study. 
10. Male patients who are sterile or who agree to use an appropriate method of 


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contraception (including use of a condom with spermicide) from Screening to 
completion of the Post-treatment period. 
11. Female patients who are not postmenopausal or surgically sterile need to agree to use 
a highly effective contraception (including contraceptive implant, injectable 
contraceptive, combination hormonal contraceptive [including vaginal rings], 
intrauterine contraceptive device or vasectomised partner) from Screening to 
completion of the Post-treatment period.  Barrier method with or without spermicide, 
double barrier contraception and oral contraceptive pill are insufficient methods on 
their own. 
Exclusion Criteria: 
Patients who fulfil any of the following criteria will be excluded from the study: 
1. Any of the following diseases: 
• haematopoietic tumour 
• aplastic anaemia 
• myelodysplastic syndrome 
• myelofibrosis 
• congenital thrombocytopenia 
• drug-induced thrombocytopenia 
• generalised infection requiring treatment except for viral liver disease 
• immune thrombocytopenia. 
2. Any solid malignant tumour if: 
• the patient requires systemic chemotherapy or radiotherapy for that malignant 
tumour during the study 
• the malignant tumour is associated with nodal metastasis, distant metastasis, or 
invasion of the surrounding organs  
• The exceptions are:  
- a malignant tumour that is the treatment target of the primary invasive 
procedure 
- non-melanoma skin cancer, intramucosal cancer, or carcinoma in situ not 
requiring any treatment during the study. 
3. History of splenectomy. 
4. History of liver transplantation. 
5. Any of the following at Screening: 
• hepatic encephalopathy uncontrolled by drugs  
• ascites uncontrolled by drugs. 
6. Portal vein tumour embolism. 
7. Known to be positive for the human immunodeficiency virus. 
8. Past or present thrombosis or prothrombotic condition (eg, cerebral infarction, 


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myocardial infarction, angina pectoris, coronary artery stent placement, angioplasty, 
coronary artery bypass grafting, congestive heart failure [New York Heart 
Association {NYHA} Grade III/IV], arrhythmia known to increase the risk of 
thromboembolic events [eg, atrial fibrillation], pulmonary thromboembolism, deep 
vein thrombosis, or disseminated intravascular coagulation syndrome).  
9. History or evidence of any of the following diseases: 
• congenital thrombotic disease (eg, antithrombin deficiency, protein C deficiency, 
protein S deficiency, or coagulation factor [Factor V Leiden] mutation) 
• acquired 
thrombotic 
disease 
(eg, 
antiphospholipid 
antibody 
syndrome, 
paroxysmal nocturnal haemoglobinuria, hyperhomocysteinaemia, or increased 
factor VIII) 
• Budd-Chiari syndrome. 
10. Portal vein thrombosis based on ultrasound, computed tomography (CT), or 
magnetic resonance imaging (MRI) within 28 days prior to randomisation or a 
history of portal vein thrombosis. 
11. Absence of hepatopetal blood flow in the main trunk of the portal vein as 
demonstrated by Doppler ultrasonography within 28 days prior to randomisation. 
12. Untreated gastro-oesophageal varices that are bleeding or require treatment based on 
upper gastrointestinal endoscopy within 180 days prior to randomisation (except for 
patients in whom the primary invasive procedure is for the treatment of 
gastro-oesophageal varices). 
13. History or evidence of disease associated with a risk of bleeding (eg, coagulation 
factor deficiency or von Willebrand factor deficiency). 
14. Bleeding score at randomisation ≥ Grade 2 according to the World Health 
Organization (WHO) Bleeding Scale (see Appendix 7). 
15. Any of the following drugs or therapies within 90 days prior to randomisation: 
• anticancer drugs except for transcatheter arterial chemoembolisation (TACE) and 
lipiodolisation 
• interferon preparations 
• radiation therapy 
• exsanguination  
• other TPO receptor agonist  
• any investigational agent. 
16. Any of the following invasive procedures within 90 days prior to randomisation: 
• laparotomy, thoracotomy, craniotomy, or open-heart surgery 
• procedures involving any organ resection or any partial organ resection (tissue 
resection associated with an endoscopic examination is permitted) 
• partial splenic embolisation.  
17. Any invasive procedure (except for the treatment of gastro-oesophageal varices) 
within 14 days prior to randomisation. 


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18. Blood transfusion (except for red blood cell products and albumin preparations) 
within 14 days prior to randomisation. 
19. Patients who have received S-888711 before. 
20. Pregnant or lactating female. 
21. Patients with known or suspected ongoing, active alcohol or substance abuse. 
Patients with a recent history who the investigator feels are able to comply with the 
study procedures and medications will be allowed to participate. 
22. Considered ineligible by the investigator for any other reason. 
Test Drug, Dose, and Mode of Administration: 
Once daily oral dose of a 3 mg tablet of S-888711 
Control Drug, Dose, and Mode of Administration: 
Once daily oral dose of a matching placebo tablet  
Duration of Treatment: 
Study drug will be administered for up to 7 days.  On Days 5 to 7, the platelet count must 
be measured before administration of study drug.  If a patient meets the administration 
stopping criterion (ie, platelet count ≥ 50 × 109/L with an increase of ≥ 20 × 109/L from 
baseline), no additional dose of study drug will be administered. 
Study Endpoints: 
Primary endpoint: 
• Proportion of patients who require no platelet transfusion prior to the primary invasive 
procedure and no rescue therapy for bleeding from randomisation through 7 days after 
the primary elective procedure. 
 
Secondary endpoints: 
• Proportion of patients who require no platelet transfusion during the study 
• Proportion of responders: patients who achieve a platelet count of ≥ 50 × 109/L with 
an increase of ≥ 20 × 109/L from baseline at any time during the study 
• Duration of the platelet count defined as the number of days during which the platelet 
count was maintained as ≥ 50 × 109/L  
• Proportion of patients who require rescue therapy for bleeding at any time during the 
study 
• Frequency of platelet transfusions 
• The change from baseline in platelet count over time (time course of platelet count) 
• Safety and tolerability 
• Assessment of plasma concentrations of S-888711 
Efficacy Assessments: 
Platelet transfusions, use of rescue therapy for bleeding, and platelet counts 
Safety Assessments: 


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Physical examination, vital signs, electrocardiograms, laboratory tests (haematology, 
blood chemistry, and blood coagulation/fibrinolysis assays), imaging studies (ultrasound, 
CT, or MRI and Doppler ultrasonography), bleeding events as graded on the WHO 
Bleeding Scale, adverse events, adverse drug reactions, and adverse events of special 
interest (ie, thrombosis-related AEs). 
Pharmacokinetic Assessments: 
Blood samples to determine S-888711 plasma concentrations and PK; intensive blood 
sampling in a cohort of 20 patients and sparse blood sampling in the remainder of 
patients.  
Statistical Methods: 
Two hundred patients with CLD and thrombocytopenia who are scheduled to undergo 
elective invasive procedures will be randomised into either of two treatment groups 
(100 patients per group).  Assuming that the proportion of patients who meet the primary 
endpoint is 20% in the placebo group and 70% in the S-888711 treatment group, 100 
patients per arm will provide 99% power to detect a difference of 50% between S-888711 
and placebo groups at a two-sided significance level of 0.05.  
For the analysis of the primary endpoint, the number and proportion of patients who 
required no platelet transfusion prior to the primary invasive procedure and no rescue 
therapy for bleeding from randomisation through 7 days after the primary elective 
procedure will be calculated by treatment group.  The proportion of patients who required 
no platelet transfusion in the S-888711 group will be compared with that in the placebo 
group using the Cochran-Mantel-Haenszel test adjusted by stratification factors. 
The secondary efficacy endpoints will be summarised by treatment group, with data in 
the S-888711 group and the placebo group compared for statistical significance.  
A gatekeeping strategy will be employed for sequentially testing the important secondary 
hypotheses.  If the primary hypothesis is statistically significant, the secondary 
hypotheses will be tested in sequence.  Sequential testing for the secondary endpoints will 
be conducted in the following order: 
• Proportion of patients who require no platelet transfusion during the study 
• Proportion of responders: patients who achieve a platelet count of ≥ 50 × 109/L, with 
an increase of ≥ 20 × 109/L from baseline at any time during the study 
• Duration of the platelet count ≥ 50 × 109/L 
Treatment-emergent AEs (TEAEs) will be summarised by treatment group for the 
analyses of safety.   
Study Duration:  
The study duration for each patient is up to 63 days (Screening period, up to 28 days; 
Treatment period, 7 days; Post-treatment period, 28 days). 
 
 


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TABLE OF CONTENTS 
SYNOPSIS ...................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................ 8 
LIST OF IN-TEXT TABLES ........................................................................................ 11 
LIST OF IN-TEXT FIGURES ....................................................................................... 11 
1. 
INTRODUCTION ................................................................................................. 14 
 
Thrombocytopenia in Chronic Liver Disease Undergoing Elective Invasive 
1.1
Procedures ................................................................................................... 14 
 
Current Treatment Options ........................................................................... 14 
1.2
 
Clinical Studies with of Lusutrombopag (S-888711) .................................... 15 
1.3
 
Rationale for the Current Study .................................................................... 16 
1.4
 
Appropriateness of Conduct of the Study ..................................................... 17 
1.5
2. 
STUDY OBJECTIVES .......................................................................................... 17 
 
Primary Objective ........................................................................................ 17 
2.1
 
Secondary Objectives ................................................................................... 17 
2.2
3. 
INVESTIGATIONAL PLAN ................................................................................ 17 
 
Overall Study Design and Plan ..................................................................... 17 
3.1
 
Rationale for Study Design and Control Group ............................................ 19 
3.2
 
Study Duration ............................................................................................. 20 
3.3
 
Study Duration for Individual Patients ................................................ 20 
3.3.1
4. 
STUDY POPULATION SELECTION .................................................................. 20 
 
Study Population .......................................................................................... 20 
4.1
 
Inclusion Criteria ......................................................................................... 20 
4.2
 
Exclusion Criteria ........................................................................................ 21 
4.3
5. 
STUDY MEDICATION(S) ................................................................................... 23 
 
Description of Study Medication(s) .............................................................. 23 
5.1
 
Test Drug ........................................................................................... 23 
5.1.1
 
Placebo or Control Drug ..................................................................... 23 
5.1.2
 
Treatments to be Administered ..................................................................... 23 
5.2
 
Selection and Timing of Dose for Each Patient ............................................. 23 
5.3
 
Method of Assigning Patients to Treatment Groups ...................................... 23 
5.4
 
Blinding ....................................................................................................... 24 
5.5
 
Packaging and Labelling .............................................................................. 24 
5.6
 
Storage and Accountability .......................................................................... 25 
5.7
 
Investigational Product Retention at Study Site ............................................ 25 
5.8
 
Treatment Compliance ................................................................................. 25 
5.9
6. 
PATIENT RESTRICTIONS .................................................................................. 26 
 
Prior Therapy ............................................................................................... 26 
6.1
 
Concomitant Therapy During the Study ....................................................... 26 
6.2
 
Concomitant Therapy ......................................................................... 26 
6.2.1
7. 
STUDY PROCEDURES AND METHODS OF ASSESSMENTS ......................... 28 


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Informed Consent ......................................................................................... 28 
7.1
 
Baseline Characteristics and Eligibility Assessment ..................................... 28 
7.2
 
Baseline Characteristics ...................................................................... 28 
7.2.1
 
Medical History .................................................................................. 29 
7.2.2
 
History of Transfusion ........................................................................ 29 
7.2.3
 
Performance Status ............................................................................. 29 
7.2.4
 
Type of Chronic Liver Disease ........................................................... 29 
7.2.5
 
Severity of Liver Disorder .................................................................. 29 
7.2.6
 
Planned Invasive Procedure ................................................................ 29 
7.2.7
 
Gastro-oesophageal Varices ................................................................ 29 
7.2.8
 
Splenomegaly ..................................................................................... 30 
7.2.9
 
Presence of Ascites ............................................................................. 30 
7.2.10
 
Pregnancy Test ................................................................................... 30 
7.2.11
 
Laboratory Test (Immunological Test and Blood Thrombopoietin 
7.2.12
Concentration) .................................................................................... 30 
 
Enrolment in the Study and Dispensing Study Drug ..................................... 30 
7.3
 
Invasive Procedures ..................................................................................... 31 
7.4
 
Efficacy Assessments ................................................................................... 31 
7.5
 
Determination of the Need for Pre-operative and Platelet 
7.5.1
Transfusion Post-procedural Rescue Therapy ..................................... 31 
 
Laboratory Tests (Platelet Count) ....................................................... 32 
7.5.2
 
Pharmacokinetic Assessment ....................................................................... 32 
7.6
 
Drug Concentration Measurement ...................................................... 32 
7.6.1
 
Safety Assessment........................................................................................ 33 
7.7
 
Physical Examination ......................................................................... 33 
7.7.1
 
Portal Vein Thrombosis ...................................................................... 33 
7.7.2
 
Portal Blood Flow .............................................................................. 33 
7.7.3
 
WHO Bleeding Scale.......................................................................... 34 
7.7.4
 
Blood Pressure and Pulse Rate ............................................................ 34 
7.7.5
 
Electrocardiography ........................................................................... 34 
7.7.6
 
Laboratory Tests (Except for Platelet Count) ...................................... 34 
7.7.7
 
Adverse Events Assessments ........................................................................ 35 
7.8
 
Adverse Events Definitions ................................................................ 35 
7.8.1
 
Timing................................................................................................ 36 
7.8.2
 
Severity .............................................................................................. 36 
7.8.3
 
Relationship ....................................................................................... 37 
7.8.4
 
Expectedness ...................................................................................... 37 
7.8.5
 
Outcome ............................................................................................. 37 
7.8.6
 
Action Taken ...................................................................................... 38 
7.8.7
 
Adverse Events of Special Interest ...................................................... 38 
7.8.8
 
Clinical Laboratory Adverse Events ................................................... 38 
7.8.9
 
Serious Adverse Events ...................................................................... 39 
7.8.10


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Liver Function Abnormalities ............................................................. 40 
7.8.11
 
Special Situations-Abuse, Misuse, Overdose, and Medication Error ... 40 
7.8.12
 
Pregnancy ........................................................................................... 40 
7.8.13
 
Withdrawal of Patients from the Study Drug or Study .................................. 41 
7.9
 
Withdrawal of Patients from the Study Drug (ie, Study Medication) ... 41 
7.9.1
 
Withdrawal of Patients from the Study (ie, Study Assessment) ........... 41 
7.9.2
 
Appropriateness of Measurements ................................................................ 42 
7.10
 
Allowable Time Window ............................................................................. 42 
7.11
8. 
STATISTICAL ANALYSIS .................................................................................. 43 
 
Statistical Analysis Methods ........................................................................ 43 
8.1
 
Rationale for Target Sample Size and Stratification Factors ......................... 43 
8.2
 
Analysis Populations .................................................................................... 44 
8.3
 
Handling of Missing Data ............................................................................ 44 
8.4
 
Patient Disposition ....................................................................................... 44 
8.5
 
Demographic and Baseline Characteristics ................................................... 44 
8.6
 
Treatment and Treatment Compliance .......................................................... 44 
8.7
 
Concomitant Therapies ................................................................................ 45 
8.8
 
Endpoints ..................................................................................................... 45 
8.9
 
Primary Endpoint ............................................................................... 45 
8.9.1
 
Secondary Endpoints .......................................................................... 45 
8.9.2
 
Efficacy Analyses ........................................................................................ 45 
8.10
 
Analyses of Efficacy Endpoints .......................................................... 45 
8.10.1
 
Safety Analyses ............................................................................................ 47 
8.11
 
Adverse Events ................................................................................... 47 
8.11.1
 
Adverse Events of Special Interest ...................................................... 47 
8.11.2
 
Vital Signs .......................................................................................... 47 
8.11.3
 
Laboratory Tests ................................................................................. 47 
8.11.4
 
Electrocardiogram .............................................................................. 48 
8.11.5
 
Portal Vein Thrombosis ...................................................................... 48 
8.11.6
 
Portal Blood Flow .............................................................................. 48 
8.11.7
 
Pharmacokinetic Analysis ............................................................................ 48 
8.12
 
Interim Analysis ........................................................................................... 49 
8.13
9. 
ADMINISTRATIVE CONSIDERATIONS ........................................................... 49 
 
Investigators and Study Administrative Structure ......................................... 49 
9.1
 
Institutional Review Board Approval ........................................................... 51 
9.2
 
Ethical Conduct of the Study ........................................................................ 51 
9.3
 
Patient Information and Consent .................................................................. 51 
9.4
 
Patient Confidentiality.................................................................................. 51 
9.5
 
Study Monitoring ......................................................................................... 52 
9.6
 
Case Report Forms and Source Documents .................................................. 52 
9.7
 
Case Report Forms ............................................................................. 52 
9.7.1


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Source Documents .............................................................................. 53 
9.7.2
 
External Data ...................................................................................... 53 
9.7.3
 
Committees .................................................................................................. 53 
9.8
 
Case Review Committee ..................................................................... 53 
9.8.1
 
Independent Safety Committee ........................................................... 54 
9.8.2
 
Coordinating Committee..................................................................... 54 
9.8.3
 
Termination or Suspension of the Study ....................................................... 54 
9.9
 
Termination or Suspension of the Entire Study ................................... 54 
9.9.1
 
Termination or Suspension of the Study by Medical Institution .......... 54 
9.9.2
 
Protocol Deviations and Modifications ......................................................... 54 
9.10
 
Data Management ........................................................................................ 55 
9.11
 
Retention of Data ......................................................................................... 55 
9.12
 
Quality Control and Assurance ..................................................................... 55 
9.13
 
Publication and Disclosure Policy ................................................................ 56 
9.14
10. REFERENCE LIST ............................................................................................... 57 
 
Reference Materials ..................................................................................... 57 
10.1
 
Publications ................................................................................................. 57 
10.2
Appendix 1: 
Time and Events Schedule .................................................................. 59 
Appendix 2: 
List of Laboratory Tests...................................................................... 61 
Appendix 3: 
Child-Pugh Class ................................................................................ 62 
Appendix 4: 
List of Example Invasive Procedures .................................................. 63 
Appendix 5: 
ECOG Performance Status ................................................................. 64 
Appendix 6: 
List of P-gp and BCRP Inhibitors ....................................................... 65 
Appendix 7: 
WHO Bleeding Scale.......................................................................... 66 
Appendix 8: 
Sponsor Signatures ............................................................................. 67 
Appendix 9: 
Investigator’s Signature ...................................................................... 69 
 
LIST OF IN-TEXT TABLES 
Table 7-1: Immunological Test and Blood Thrombopoietin Concentration ................... 30 
Table 7-2: Intensive Blood Sampling ........................................................................... 32 
Table 7-3: Sparse Blood Sampling ............................................................................... 33 
Table 7-4: Routine Laboratory Tests (Except for Immunological Test, Blood 
Thrombopoietin Concentration, and Platelet Count) .................................... 35 
Table 7-5: Allowable Time Window ............................................................................ 42 
 
LIST OF IN-TEXT FIGURES 
Figure 2-1 Study Schematic .......................................................................................... 18 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADR(s) 
adverse drug reaction(s) 
AE(s) 
adverse event(s) 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-τ 
AUC over the dosing interval τ (ie, 24 hours) 
BCRP 
breast cancer resistance protein 
CI 
confidence interval 
CLD 
chronic liver disease 
Cmax 
maximum plasma concentration 
CRF 
case report form 
CRO 
Contract Research Organisation 
CT 
computed tomography 
CV% 
coefficient of variation 
ECG 
electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EIS 
endoscopic injection sclerotherapy 
EMR 
endoscopic mucosal resection 
EMS 
endoscopic metallic stenting 
EPBD 
endoscopic papillary balloon dilatation 
ESD 
endoscopic submucosal dissection 
EST 
endoscopic sphincteropapillotomy 
EUS-FNA 
endoscopic ultrasound-guided fine needle aspiration 
EVL 
endoscopic variceal ligation 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GMP 
Good Manufacturing Practice 
IB 
Investigator's Brochure 
ICH 
International Conference on Harmonisation  
IgG 
immunoglobulin G 
IRB 
institutional review board 
ITT 
intention-to-treat 
IVRS/IWRS 
interactive voice or web response system 
Lip-TAI 
lipiodolisation with anticancer drugs 
LMC 
laparoscopic microwave coagulation 
ln 
natural logarithm 
LRA 
laparoscopic radiofrequency ablation 
M-CSF 
macrophage colony-stimulating factor 
MCT 
microwave coagulation therapy 


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MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
N 
number of non-missing observations 
NYHA 
New York Heart Association 
PD 
pharmacodynamics 
PEG 
percutaneous endoscopic gastrostomy 
PEIT 
percutaneous ethanol injection therapy 
P-gp 
P-glycoprotein 
PK 
pharmacokinetics 
PMCT 
percutaneous microwave coagulation therapy 
PP 
per protocol 
PS 
performance status 
PT-INR 
prothrombin time-international normalised ratio  
RFA 
radiofrequency ablation 
SAE(s) 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SD 
standard deviation 
SMQ 
Standard MedDRA query 
SUSAR 
suspected unexpected serious adverse reaction 
TACE 
transcatheter arterial chemoembolisation 
TAE 
transcatheter arterial embolisation 
TAI 
transhepatic arterial infusion 
TEAE(s) 
treatment-emergent adverse event(s) 
TPO 
thrombopoietin 
TUL 
transurethral ureterolithotripsy 
TURBT 
transurethral resection of the bladder tumour 
ULN 
upper limit of normal 
US 
United States 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
 
Thrombocytopenia in Chronic Liver Disease Undergoing Elective 
1.1
Invasive Procedures 
Chronic liver disease (CLD) comprises a number of types of disease, including chronic 
viral hepatitis B and C, cirrhosis, hepatocellular carcinoma, alcohol-related liver disease, 
and nonalcoholic-related fatty liver disease, as well as many others.  In Europe, an 
estimated 29 million people suffer from CLD.[1]  In the United States (US), an estimated 
25.8 million ambulatory care visits were related to CLD in the 2006 to 2010 period,[1] 
and an estimated 31,903 deaths were attributed to CLD in 2010.[2]  Overall, CLD is 
recognised as a major public health problem and an important cause of morbidity and 
mortality in both Europe and the US,[1,3,4] and its prevalence is increasing.[4]  
Thrombocytopenia is a common complication in patients with CLD and has been reported 
in up to 76% of patients with this condition[5].  Furthermore, severe thrombocytopenia in 
liver disease can be associated with significant morbidity.[6] Thrombocytopenia is 
associated with an increased risk of clinically significant bleeding, such as cerebral or 
other internal haemorrhage, as well as petechiae, purpura, and mucosal bleeding.  
Moderate liver disease-related thrombocytopenia is defined as a platelet count 
< 100 × 109/L, with severe thrombocytopenia defined by a platelet count of 
< 50 × 109/L.[6]  Clinically significant spontaneous bleeding does not typically occur 
until platelet counts are < 10-20 × 109/L[6]; however, patients with CLD may undergo 
invasive treatments, such as percutaneous therapies, trans-catheter arterial embolization, 
and trans-hepatic arterial infusion chemotherapy for CLD-related pathologies.  As all 
invasive procedures are associated with some degree of bleeding, patients with CLD are 
at an increased risk of potentially serious bleeding events if their platelet count is < 50 
× 109/L.  
Thrombocytopenia in patients with CLD is multifactorial in origin.  Possible causes 
include decreased production and/or decreased activity of the haematopoietic growth 
factor thrombopoietin (TPO), suppression of platelet production in the bone marrow due 
to the underlying liver disease (eg, chronic hepatitis C infection), or use of anti-cancer 
agents, use of interferon-based therapy as an antiviral treatment, and the splenic 
sequestration of platelets.  Of these, platelet sequestration in the spleen and decreased 
TPO production in the liver are the major mechanisms for thrombocytopenia in patients 
with liver cirrhosis.[6] As platelets are essential to haemostasis, the risk of clinically 
significant bleeding is increased in patients with CLD.  
 
Current Treatment Options 
1.2
Treatment options for thrombocytopenia in CLD may be directed at the disease 
underlying the thrombocytopenia or at the thrombocytopenia itself.  Patients with platelet 
counts below 50 × 109/L may benefit from prophylactic platelet transfusions prior to any 
invasive procedures; however, no specific guidelines on the use of prophylactic platelet 
transfusions in patients with CLD are available and currently there is no consensus on the 
appropriate threshold for administering such transfusions.[6] Thus, clinicians may rely on 
currently available general guidelines, which recommend prophylactic administration of 
platelets to maintain a platelet count of >50 × 109/L in patients undergoing many invasive 
procedures.[7] Furthermore, several complications are associated with this intervention, 


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including febrile non-haemolytic and allergic reactions, the need for hospitalisation, iron 
overload with chronic transfusions and the risk of infections.[8]  In addition, platelet 
transfusions do not ensure a haemostatic platelet level may be a limitation.[9,10]   
Thus, alternative therapeutic options to platelet transfusions would be desirable for 
patients with thrombocytopenia and CLD.  TPO is a cytokine that stimulates proliferation 
and differentiation of megakaryocytic progenitor cells from haematopoietic stem cells, 
stimulates megakaryocyte maturation and regulates platelet production.  It plays a central 
role in regulating thrombopoiesis, and decreases in TPO production or activity in patients 
with CLD suggest that TPO mimetics may stimulate platelet production.[11,12]  Thus, 
TPO serves as a rational therapeutic target to stimulate platelet production and provides 
an alternative to platelet transfusion in patients with CLD. 
Currently, two TPO mimetics have been approved in the US and European Union (EU), 
romiplostim and eltrombopag for the treatment of immune thrombocytopenia.  These 
have both been shown to increase platelet counts in healthy subjects and in patients with 
immune thrombocytopenia. Additionally, eltrombopag has been approved for the 
treatment of thrombocytopenia in patients with chronic hepatitis C to allow the initiation 
and maintenance of interferon-based therapy.  Eltrombopag was shown to increase 
platelet counts in ≥75% of patients with hepatitis C-associated thrombocytopenia and 
compensated liver disease after 4 weeks of treatment, with significantly more patients 
than placebo-treated patients completing 12 weeks of antiviral therapy.[13]   
An orally administered agent that reduces the need for platelet transfusions and has an 
acceptable safety profile would provide clinical benefit for patients with CLD who are 
undergoing elective invasive procedures.  Shionogi has developed S-888711 to fulfil this 
unmet clinical need. 
 
Clinical Studies with of Lusutrombopag (S-888711) 
1.3
S-888711 is an orally active, small-molecule TPO receptor agonist that acts on the 
transmembrane domain of human TPO receptors, activates the signal transduction 
pathway in the same manner as endogenous TPO, and leads to an upregulation of platelet 
production.   
Following single (0.1 to 50 mg) and multiple (once daily for 14 days; 0.25 to 2 mg) 
dosing, S-888711 increased platelet production in a plasma-exposure dependent manner.  
Furthermore, S-888711, at the doses and regimens investigated, was safe and well 
tolerated.  The maximum plasma concentration (Cmax) and the area under the plasma 
concentration-time curve (AUC) for S-888711 increased dose-proportionally, with plasma 
S-888711 concentrations reaching steady state within 7 days of the initial dose.  Further 
studies showed that the pharmacokinetics (PK) of S-888711 were unlikely to be affected 
by food, race, most concomitant drugs, or hepatic function.  
Two open-label, phase 2 studies (Studies 1017M0623 and 1112M0625) conducted in 
Japan were designed to investigate the optimal dose of S-888711, administered once daily 
for 7 days, in thrombocytopenic patients with CLD who were scheduled to undergo 
percutaneous liver ablation (including liver coagulation).  The efficacy, safety, and PK of 
S-888711 as a pre-treatment for percutaneous liver ablation were assessed at doses of 
0.25, 0.5, 1, 1.5, and 2 mg/day (Study 1017M0623) or 2.5, 3, and 4 mg/day (Study 
1112M0625).  The data demonstrated that doses of ≥ 2 mg/day were required to increase 
platelet counts in thrombocytopenic patients to levels above 50 × 109/L to perform 
percutaneous liver ablation.  


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Consequently, a double-blind, phase 2b, dose-finding study (Study 1208M0626) 
conducted in Japan evaluated 3 doses of S-888711 (2, 3, and 4 mg) to determine the 
optimal dose for future studies.  The data showed that 80.0% (12/15), 81.3% (13/16), and 
93.3% (14/15) of patients in the 2, 3, and 4 mg groups, respectively, received no platelet 
transfusion prior to percutaneous liver ablation compared to 20.0% (3/15) of 
placebo-treated patients.  In patients who received no platelet transfusion, mean 
maximum platelet counts were 59 × 109/L, 73.8 × 109/L, 94.8 × 109/L, and 103.8 × 109/L 
in the placebo, and 2, 3, and 4 mg S-888711 groups, respectively.  These data suggest that 
platelet counts increased with increasing doses of S-888711.  For patients with a platelet 
count ≥ 50 × 109/L, the increased platelet count duration without a platelet transfusion 
was 20 days or more for all S-888711 treatment groups.  All patients, with the exception 
of one in the 4 mg group, experienced adverse events (AEs) during the study.  There was 
no increased incidence of thrombus-related AEs with increasing dose of S-888711 (6.7% 
[1/15], 6.7% [1/15], 0% [0/16], and 13.3% [2/15] in the placebo, and 2, 3, and 4 mg 
S-888711 groups, respectively).   
A randomised, double-blind, phase 3 study (Study 1304M0631) conducted in Japan 
compared 3 mg of S-888711 to placebo as a treatment for thrombocytopenia in patients 
with CLD undergoing elective invasive procedures.  The list of allowed invasive 
procedures in this study was broadened from the phase 2 study to allow inclusion of many 
other procedures.  The primary endpoint was the proportion of patients who received no 
platelet transfusion prior to the primary invasive procedure.  A statistically significantly 
greater proportion of patients in the S-888711 3 mg group than in the placebo group 
(79.2% [38/48] versus 12.5% [6/48]; P < 0.0001) received no platelet transfusion prior to 
the invasive procedure.  In patients who received no platelet transfusion, mean maximum 
platelet counts were 90.2 × 109/L and 66.7 × 109/L in the S-888711 3 mg and placebo 
groups, respectively.  A 'responder' was defined as a patient with a platelet count of ≥ 
50 × 109/L with an increase of ≥ 20 × 109/L from baseline.  The adjusted mean number 
of days on which the responder criterion was met in patients without platelet transfusion 
was significantly greater in the S-888711 3 mg group than in the placebo group (12.39 
versus 0.74 days; P < 0.0001).  Overall, AEs were reported at a comparable incidence in 
both treatment groups (93.8% [45/48] and 100% [48/48] in the S-888711 and placebo 
groups, respectively).  Importantly, thrombotic events were reported for 1 (2.1%) patient 
in each treatment group.  
In summary, the data indicate that Cmax and AUC values increased in a dose proportional 
manner across the dose range 0.25 to 4 mg.  Furthermore, no significant safety concerns 
were raised.   
 
Rationale for the Current Study 
1.4
This phase 3, multinational, randomised, double-blind, placebo-controlled study is 
designed to assess the efficacy and safety of S-888711 3 mg for the treatment of 
thrombocytopenia in patients with CLD prior to undergoing an elective invasive 
procedure.  The study will be conducted to test the hypothesis that in patients with 
thrombocytopenia and CLD, relative to placebo, treatment with S-888711 3 mg once 
daily for up to 7 days prior to an elective invasive procedure is associated with a higher 
proportion of patients who do not require platelet transfusion prior to the procedure nor 
rescue therapy for bleeding from randomisation through 7 days after the procedure. 


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Appropriateness of Conduct of the Study 
1.5
The 3 mg dose of S-888711 selected was based on data from the Japanese studies (see 
Section 3.2) with a requirement to avoid pre-operative platelet transfusions while 
ensuring patient safety.  Study design features necessary for ensuring individual patient 
safety have been incorporated.  Inclusion of patients who are at high risk of spontaneous 
bleeding or thrombosis is not permitted and measures included minimising the numbers 
of patients being dosed who have rapid rises in platelet counts.  In addition, patients will 
have their hepatic circulation imaged pre-dosing/pre-procedure and will be excluded if 
there is any evidence of portal vein thrombosis.  
Further details on the rationale for the study design, including selection of the 3 mg dose 
and choice of control group are provided in Section 3.2. 
An Independent Safety Committee will periodically review elements of the study data 
(see Section 9.8.2).   
2. 
STUDY OBJECTIVES 
 
Primary Objective 
2.1
The primary objective of the study is: 
• To compare the efficacy of S-888711 with placebo for the treatment of 
thrombocytopenia in patients with CLD who are undergoing elective invasive 
procedures. 
 
Secondary Objectives 
2.2
The secondary objectives of the study are: 
• To assess the safety and tolerability of S-888711 treatment compared with placebo. 
• To assess the platelet response following treatment with S-888711 compared with 
placebo. 
• To assess the pharmacodynamics (PD) and PK of S-888711. 
3. 
INVESTIGATIONAL PLAN 
 
Overall Study Design and Plan 
3.1
This is a phase 3, multinational, randomised, double-blind, placebo-controlled study to 
assess the safety and efficacy of S-888711 for the treatment of thrombocytopenia in 
patients with CLD undergoing elective invasive procedures.  A schematic of the study 
design is provided in Figure 2-1.  
The study consists of 3 periods:  
• Screening period: up to 28 days prior to randomisation  
• Treatment period: 7 days (Days 1 to 7) 
• Post-treatment period: through 28 days post-treatment  
The maximum study duration for each patient will be 63 days.  Potential patients who 
provide written informed consent will be screened for eligibility, and eligible patients will 
be randomised in a 1:1 ratio to either S-888711 3 mg once daily for up to 7 days or 


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matched placebo control.  The randomisation will be stratified by primary invasive 
procedure (liver ablation/coagulation or other invasive procedures) and baseline platelet 
count (< 35 × 109/L or ≥ 35 × 109/L).  
Patients will begin once daily treatment with assigned study medication on Day 1 after 
randomisation and will receive study medication for up to 7 days.  A platelet count will be 
performed on Days 5, 6, and 7 prior to administration of study medication. After the final 
dose of study medication, patients will continue the protocol-specified assessments and 
procedures in the Post-treatment period.  
The planned invasive procedure will be performed in the Post-treatment period between 
Days 9 and 14.  A platelet count will be performed on or after Day 8, but no more than 
2 days prior to the elective invasive procedure in order to assess the need for a platelet 
transfusion before the planned elective procedure.  A pre-operative platelet transfusion 
must be performed if the platelet count is < 50 × 109/L.  Patients may be admitted to the 
study centre for the elective invasive procedure if required. 
The need for the invasive procedure will be reassessed in the event of any of the 
following: 
• Platelet count ≥ 200 × 109/L 
• Administration of an antithrombotic drug  
• In the opinion of the investigator, the procedure is no longer in the patient's best 
interest because of an AE or other concern  
• The patient requests cancellation of the elective procedure after randomisation 
If any of the above criteria are met and the elective procedure cannot be performed 
between Days 9 and 14, it may be performed up to Day 35 of the study.  If a patient does 
not undergo the procedure, all the relevant follow-up assessments should be performed 
and data should be collected up to Day 35.  In case the invasive procedure performed 
between Days 9 and 14 needs to be repeated, the same procedure may be performed after 
Day 15 according to the discretion of the investigator. The overall schedule of events for 
the study is provided in Appendix 1.  
 
Figure 2-1 
Study Schematic 
 
Screening
Period 
(Up to 28 days) 
 
Treatment Period 
(7 days) 
Post-treatment Period 
(28 days) 
 
 
 
 
 
 
Informed consent 
Randomisation and 
initial dose of study drug 
(Day 1) 
 
Final study day
(Day 35)
 
S-888711 3 mg once daily
Up to 7 days 
Placebo once daily
Up to 7 days 
 
 
Invasive 
procedure 
(Days 9 to 14) 


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Rationale for Study Design and Control Group 
3.2
This study will be conducted to test the hypothesis that in patients with thrombocytopenia 
and CLD, relative to placebo, treatment with S-888711 3 mg once daily for up to 7 days 
prior to an elective invasive procedure is associated with a higher proportion of patients 
who do not require platelet transfusion prior to the procedure nor rescue therapy for 
bleeding from randomisation through 7 days after the procedure.  
The list of potential invasive procedures included in this study were selected based on the 
phase 3 study completed in Japan (Study 1304M0631).  In that study, a number of 
invasive procedures were permitted, unless they were associated with a high degree of 
invasiveness and high risk of bleeding, such as laparotomy, thoracotomy, craniotomy, 
open-heart surgery, and organ resection.  
The dose of S-888711 selected for this phase 3 study is 3 mg based upon results from the 
phase 2b and phase 3 studies conducted in Japan.  In the phase 2b study S-888711 doses 
of 2 mg, 3 mg, and 4 mg were evaluated.  All three doses were effective.  The 2 mg dose 
was eliminated from further study as the number of days on which the criterion for 
responder was met (least squares mean ± standard error) with the 2 mg dose was less 
(8.36 ± 1.73 days) than that observed with the 3 mg and 4 mg doses (11.59 ± 1.84 days 
and 13.88 ± 1.85 days, respectively) and thus would afford the clinician less flexibility if 
a patient’s condition or schedule necessitated delay of the elective procedure.  The 4 mg 
dose was eliminated from further study due to concern that increases in platelet counts 
might exceed 200 × 109/L, as the platelet count had increased to 195 × 109/L in one 
patient in the 3 mg group who had a platelet count of 45 × 109/L at screening and 
65 × 109/L at baseline.  In the phase 3 study, the proportion of patients who required no 
platelet transfusion prior to the planned invasive procedure was significantly greater in 
the S-888711 3 mg group than in the placebo group: 79.2% (38/48 patients) in the 3 mg 
group and 12.5% (6/48 patients) in the placebo group (P < 0.0001).  The incidence of 
thrombotic events was the same in the S-888711 3 mg and placebo groups: 2.1%.  No PK 
or PD differences were observed between white and Japanese subjects in phase 1 studies 
that would suggest a different S-888711 dose is required in these populations.  PK 
modelling and PK/PD modelling based on data in white and Japanese subjects (including 
Japanese patients with thrombocytopenia and CLD who were undergoing elective 
invasive procedures) were performed, and platelet count profiles were simulated by using 
the PK/PD model.  Results support an S-888711 dose of 3 mg as the optimal daily dose 
regardless of ethnicity. 
As per the previous phase 2 and 3 studies, the dosage of S-888711 will be once daily 
administration for up to 7 days.  The study duration (excluding Screening) will be 35 days 
(7 days for the Treatment period followed by a 28-day Post-treatment period).  This was 
based on the assessment of the post-treatment change in platelet counts.  The planned 
invasive procedure will be performed between Days 9 and 14 because an adequate 
increase in platelet counts is assumed in this period based on the results of Studies 
1208M0626 and 1304M0631, which indicate that mean platelet count increases extend 
out to around 20 days.  


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Study Duration 
3.3
 
Study Duration for Individual Patients 
3.3.1
The study duration for each patient is up to 63 days (Screening period, up to 28 days; 
Treatment period, 7 days; Post-treatment period, through 28 days). 
4. 
STUDY POPULATION SELECTION 
 
Study Population 
4.1
A total of 200 adult patients with CLD and thrombocytopenia (defined as a platelet count 
< 50 × 109/L) will be randomised into the study provided they fulfil all of the eligibility 
criteria. 
 
Inclusion Criteria 
4.2
Patients who fulfil the following criteria will be eligible for inclusion into the study:  
1. Able to understand the study and comply with all the study procedures. 
2. Willing to provide written informed consent prior to Screening. 
3. Male or female. 
4. 18 years of age or older at the time of signing informed consent. 
5. CLD limited to Child-Pugh Class A and Class B disease (see Appendix 3). 
6. Platelet count < 50 × 109/L at baseline on Day 1 prior to randomisation. 
7. Undergoing an elective invasive procedure that: 
• 
is likely to require administration of platelets 
• 
is expected to be performed between Days 9 and 14  
• 
does not include laparotomy, thoracotomy, craniotomy, open-heart surgery, 
organ resection, or  
• 
does not include partial organ resection (however, biopsy and other types of 
tissue removal will be allowed if risk of bleeding and invasiveness is considered 
comparable or lower than those procedures in the list of example procedures; see 
Appendix 4). 
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) grade of 0 or 
1 (see Appendix 5). 
9. In the opinion of the investigator, able to meet the requirements of the study. 
10. Male patients who are sterile or who agree to use an appropriate method of 
contraception (including use of a condom with spermicide) from Screening to 
completion of the Post-treatment period. 
11. Female patients who are not postmenopausal or surgically sterile need to agree to use 
a highly effective contraception (including contraceptive implant, injectable 
contraceptive, combination hormonal contraceptive [including vaginal rings], 
intrauterine contraceptive device, or vasectomised partner) from Screening to 


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completion of the Post-treatment period.  Barrier method with or without spermicide, 
double barrier contraception and oral contraceptive pill are insufficient methods on 
their own. 
 
Exclusion Criteria 
4.3
Patients who fulfil any of the following criteria will be excluded from the study: 
1. Any of the following diseases: 
• 
haematopoietic tumour 
• 
aplastic anaemia 
• 
myelodysplastic syndrome 
• 
myelofibrosis 
• 
congenital thrombocytopenia 
• 
drug-induced thrombocytopenia 
• 
generalised infection requiring treatment except for viral liver disease 
• 
immune thrombocytopenia. 
2. Any solid malignant tumour if: 
• 
the patient requires systemic chemotherapy or radiotherapy for that malignant 
tumour during the study 
• 
the malignant tumour is associated with nodal metastasis, distant metastasis, or 
invasion of the surrounding organs  
• 
The exceptions are:  
- 
a malignant tumour that is the treatment target of the primary invasive 
procedure 
- 
non-melanoma skin cancer, intramucosal cancer, or carcinoma in situ not 
requiring any treatment during the study. 
3. History of splenectomy. 
4. History of liver transplantation. 
5. Any of the following at Screening: 
• 
hepatic encephalopathy uncontrolled by drugs  
• 
ascites uncontrolled by drugs. 
6. Portal vein tumour embolism. 
7. Known to be positive for the human immunodeficiency virus. 
8. Past or present thrombosis or prothrombotic condition (eg, cerebral infarction, 
myocardial infarction, angina pectoris, coronary artery stent placement, angioplasty, 
coronary artery bypass grafting, congestive heart failure [New York Heart 
Association {NYHA} Grade III/IV], arrhythmia known to increase the risk of 
thromboembolic events [eg, atrial fibrillation], pulmonary thromboembolism, deep 
vein thrombosis, or disseminated intravascular coagulation syndrome). 


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9. History or presence of any of the following diseases: 
• 
congenital thrombotic disease (eg, antithrombin deficiency, protein C deficiency, 
protein S deficiency, or coagulation factor [Factor V Leiden] mutation) 
• 
acquired thrombotic disease (eg, antiphospholipid antibody syndrome, 
paroxysmal nocturnal haemoglobinuria, hyperhomocysteinaemia, or increased 
factor VIII) 
• 
Budd-Chiari syndrome. 
10. Portal vein thrombosis based on ultrasound, computed tomography (CT), or magnetic 
resonance imaging (MRI) within 28 days prior to randomisation or a history of portal 
vein thrombosis. 
11. Absence of hepatopetal blood flow in the main trunk of the portal vein as 
demonstrated by Doppler ultrasonography within 28 days prior to randomisation.  
12. Untreated gastro-oesophageal varices that are bleeding or require treatment based on 
upper gastrointestinal endoscopy within 180 days prior to randomisation (except for 
patients in whom the primary invasive procedure is for the treatment of 
gastro-oesophageal varices). 
13. History or presence of disease associated with a risk of bleeding (eg, coagulation 
factor deficiency or von Willebrand factor deficiency). 
14. Bleeding score at randomisation ≥ Grade 2 according to the World Health 
Organization (WHO) Bleeding Scale (see Appendix 7). 
15. Any of the following drugs or therapies within 90 days prior to randomisation: 
• 
anticancer drugs except for transcatheter arterial chemoembolisation (TACE) 
and lipiodolisation 
• 
interferon preparations 
• 
radiation therapy 
• 
exsanguination  
• 
other TPO receptor agonist 
• 
any investigational agent. 
16. Any of the following invasive procedures within 90 days prior to randomisation: 
• 
laparotomy, thoracotomy, craniotomy, or open-heart surgery 
• 
procedures involving any organ resection or any partial organ resection (tissue 
resection associated with an endoscopic examination is permitted) 
• 
partial splenic embolization.  
17. Any invasive procedure (except for the treatment of gastro-oesophageal varices) 
within 14 days prior to randomisation. 
18. Blood transfusion (except for red blood cell products and albumin preparations) 
within 14 days prior to randomisation. 
19. Patients who have received S-888711 before. 
20. Pregnant or lactating female. 


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21. Patients with known or suspected ongoing, active alcohol or substance abuse.  
Patients with a recent history who the investigator feels are able to comply with the 
study procedures and medications will be allowed to participate. 
22. Considered ineligible by the investigator for any other reason. 
5. 
STUDY MEDICATION(S) 
 
Description of Study Medication(s) 
5.1
 
Test Drug 
5.1.1
Laboratory code: 
S-888711 
USAN, INN: 
Lusutrombopag 
Chemical name: 
(2E)-3-{2,6-dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2- 
methoxyphenyl}-1,3-thiazol-2-yl)carbamoyl]-phenyl}-2- 
methylprop-2-enoic acid 
Constituent 
ingredients, 
content, and dosage form: 
Slight red to light red, round shaped film-coated tablet 
containing 3 mg of S-888711 per tablet, 
 
 
 
Placebo or Control Drug 
5.1.2
Name of test drug: 
Placebo 
Constituent 
ingredients, 
content, and dosage form: 
Tablet matching the S-888711 tablet but lacking the active 
ingredient, m
. 
 
Treatments to be Administered 
5.2
One S-888711 3 mg tablet or matching placebo tablet will be taken once daily.  Study 
drug will be administered for up to 7 days.  On Days 5 to 7, the platelet count must be 
measured before administration of study drug.  If a patient meets the administration 
stopping criterion (ie, platelet count ≥ 50 × 109/L with an increase of ≥ 20 × 109/L from 
baseline), no additional dose of study drug will be administered. 
 
Selection and Timing of Dose for Each Patient 
5.3
Patients will be randomly assigned to either of the two treatment groups and the treatment 
group assigned will not be changed during the Treatment period.  Administration of the 
study drug on Day 2 will be performed at 12 hours or longer after administration on Day 
1.  The study drugs will be administered at the same time of the days between Days 2 and 
7 to the extent possible. 
 
Method of Assigning Patients to Treatment Groups 
5.4
The treatments will be randomized to subject identification numbers by the interactive 
voice or web response system (IVRS/IWRS) provider in a 1:1 fashion to either of the two 
treatment groups (S-888711 3 mg/day for up to 7 days or placebo for up to 7 days).  
Randomisation will be stratified by the primary invasive procedure and the platelet count 
at baseline as follows:  


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• Primary invasive procedure: liver ablation/coagulation or other invasive procedures 
• Platelet counts at baseline: < 35 × 109/L or ≥ 35 × 109/L 
The study drug assigned from the interactive voice or web response system (IVRS/IWRS) 
on the day of randomisation is the study drug to be dosed between Days 1 and 4.  Before 
dosing on Days 5 to 7, the investigator will submit to IVRS/IWRS a platelet count.  Study 
drug on Days 5 to 7 will then be assigned on each day from IVRS/IWRS.  Once the study 
medication is stopped, no submission of data on platelet counts to the IVRS/IWRS system 
is necessary. However platelet counts should still be collected on the CRF.  
 
Blinding 
5.5
The study will be conducted in a double-blind manner using a placebo matching the 
active drug in appearance, labelling, and packaging.  An IVRS/IWRS will be used for 
central patient randomisation and study drug assignment.  IVRS/IWRS will assign drug 
identifiers according to a randomisation schedule.  Only an unblinded Contract Research 
Organisation (CRO) or designee will have the authority to assign the drug identifiers.  All 
patients, the investigator, all study personnel, and data analysts will be blinded to the 
treatment assigned at randomisation until database lock.  The randomisation schedule will 
be kept confidential and will not be accessible to anyone until unblinding, except for Drug 
Supply Management staff, IVRS/IWRS Clinical Coordinator(s), IVRS/IWRS vendor staff, 
unblinded statistician on the Independent Safety Committee, and for reporting suspected 
unexpected serious adverse reaction (SUSAR) as required by local regulation. 
Unblinding, at the investigator's request, should occur only in the event of an emergency 
or an AE where details of the treatment assigned are required to determine an appropriate 
course of therapy.  In such cases, the investigator or qualified designee is to contact the 
IVRS/IWRS.  Prior to unblinding, and if the situation allows it, the investigator should try 
to contact the sponsor in order to obtain additional information about the investigational 
product.  If this is impractical, the investigator must notify the sponsor as soon as possible, 
without revealing the treatment assignment of the unblinded patient.  The investigator 
must document the patient identification and the date and time for breaking the blind, as 
well as clearly explaining the reasons for breaking the code.   
Treatment assignment may be determined from plasma drug concentrations; therefore, 
these data will be reported to the sponsor after the database is locked. 
If the Independent Safety Committee (see Section 9.8.2) requires emergency codes due to 
a medical emergency or for any other issues arising during the study, the required 
information will be reported to them according to the procedures outlined in a separate 
document.  
 
Packaging and Labelling 
5.6
Study drug will be supplied in a Patient Medication Box containing 1 Tablet Card.  The 
Tablet Card for Days 1 to 4 will contain 4 tablets.  Separate Tablet Cards for Days 5, 6, 
and 7 will contain 1 tablet each and will be assigned by the IVRS/IWRS for each day.  
The treatment label will include a study reference code, drug identifier, quantity of dosage 
units, and lot number at a minimum, as well as other pertinent information according to 
local regulations.  The expiry or use-by date will be shown on the label and stored in the 
IVRS/IWRS, and printable blinded assignment reports are available to site personnel.  
S-888711 should not be used after the expiry or use-by date.  


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All packaged and labelled supplies will be formally released in accordance with both 
Good Manufacturing Practice (GMP) and Good Clinical Practice (GCP) guidelines.  
 
Storage and Accountability 
5.7
S-888711 and matching placebo tablets should be stored in their original package at room 
temperature (15°C to 30°C [59°F to 86°F]), with daily minimum and maximum 
temperature logs maintained at the study sites.  
Study medication accountability is the responsibility of the investigator who should 
ensure that all study drugs are stored and dispensed according to local regulations.  All 
drug supplies must be kept in a secure, locked area, with access limited to those 
authorised by the investigator.  
The investigator, pharmacist, or designee will maintain accurate records for the receipt of 
and condition of all study drugs, date of receipt, when and how much study drug is 
dispensed and used by each patient in the study, and any reasons for departure from the 
protocol-dispensing regimen. All patients are required to bring used and unused Tablet 
Cards to each study visit for compliance assessments. 
Unless otherwise notified, all study drug supplies (both used and unused Tablet Cards) 
must be saved for study medication accountability.  Drug accountability records will be 
available at each monitoring visit for verification by the sponsor’s monitor.  At study 
completion, a final reconciliation of all study drugs will be performed.  Study drug must 
not be used for any purpose other than in the current study.  
 
Investigational Product Retention at Study Site 
5.8
At the end of the study, all unused study drug and used (empty) Tablet Cards will be 
returned or disposed of as instructed by the sponsor.  Transmittal forms will be provided 
and must be included with all returns. If any S-888711 supplies are to be destroyed at the 
investigational site, the institution/investigator(s) must obtain prior approval by Shionogi 
and final reconciliation must be completed by the unblinded monitor prior to destruction.  
After such destruction, the institution/investigator(s) must notify Shionogi, in writing, of 
the method, date, and location of destruction. 
 
Treatment Compliance 
5.9
The investigator or designee will instruct each patient to record daily drug compliance 
and the time they took study medication in their study drug booklet.  These data will be 
checked and recorded on the case report form (CRF).  In addition, the drug identifier, the 
date, and the number of tablets actually taken will be recorded on the CRF.  Patients will 
bring all used and unused Tablet Cards to each study visit to check compliance and for 
the purpose of drug accountability.  Based on compliance checks, if any study drug has 
not been taken by a patient, they will be counselled about the importance of taking study 
drug. 
In the event that a subject is withdrawn for compliance reasons (e.g. missed doses or 
visits), the investigator will promptly notify the sponsor or designee and will make every 
effort to complete the early termination assessments.  The investigator must register all 
subject discontinuations in the IVRS/IWRS system. 


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6. 
PATIENT RESTRICTIONS 
 
Prior Therapy 
6.1
Prior therapies are defined as therapies taken prior to randomisation into the study.   
Restrictions regarding the prior therapy are specified in the exclusion criteria (see 
Section 4.3) and summarised below. 
• Any of the following drugs or therapies within 90 days prior to randomisation: 
− 
anticancer drugs except for TACE and lipiodolisation 
− 
interferon preparations 
− 
radiation therapy 
− 
exsanguination  
− 
other TPO receptor agonist  
− 
any investigational agent  
• Any of the following invasive procedures within 90 days prior to randomisation: 
− 
laparotomy, thoracotomy, craniotomy, or open-heart surgery 
− 
procedures involving any organ resection or any partial organ resection (tissue 
resection associated with an endoscopic examination is permitted) 
− 
partial splenic embolisation  
• Any invasive procedure (except for the treatment of gastro-oesophageal varices) within 
14 days prior to randomisation 
• Blood transfusion (except for red blood cell products and albumin preparations) within 
14 days prior to randomisation 
• S-888711 
 
Concomitant Therapy During the Study 
6.2
 
Concomitant Therapy 
6.2.1
Concomitant therapies are defined as any drug or substance administered between 
randomisation and the end of study or withdrawal from the study.  Restricted and 
prohibited concomitant therapies are specified in the exclusion criteria and in Sections 
6.2.1.1 and 6.2.1.2. 
The following information on all therapies (including prescription drugs, over-the-counter 
drugs, and procedures) from randomisation until completion of the Post-treatment period 
(or early termination) will be recorded on the CRF by the investigator or designee:   
• Name of used drug or procedure 
• Route of administration (if a drug is administered)  
• Duration of treatment  
• Reason for use 


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6.2.1.1 
Restricted Therapy 
Use of vitamin K from Screening to completion of the Post-treatment period is permitted 
for patients who have received vitamin K for at least 28 days prior to randomisation; 
however, a change in vitamin K dose is not permitted during the study.  
If taking P-glycoprotein (P-gp) inhibitors or breast cancer resistance protein (BCRP) 
inhibitors (see Appendix 6), the dose must be stable for 7 days prior to randomisation and 
during the Treatment period and extra vigilance should be given to patients whose platelet 
counts increase ≥ 50 × 109/L with an increase of  ≥ 20 × 109/L.  
6.2.1.2 
Prohibited Therapy 
Use of the following therapies is not permitted from the day of Screening until 
completion of the Post-treatment period: 
• Platelet preparations (except for use prior to the invasive procedure and as rescue 
therapy).  Note that patients who receive a platelet transfusion prior to the invasive 
procedure (based on the determination of platelet count pre-operatively) may receive 
subsequent platelet transfusions. 
• Blood preparations and alternatives to blood, except for platelet preparations, red 
blood cell preparations, and albumin preparations (eg, whole blood cell preparations; 
human immunoglobulin preparations other than those targeting specific infections, 
such as antitetanic globulin and hepatitis B immune globulin; coagulation factor 
products; fibrinogen other than fibrinogen for tissue adhesion; antithrombin III; fresh 
frozen plasma; and recombinant coagulation factor product) unless needed as rescue 
therapy for bleeding  
• Anticancer drugs, except for those used in patients in whom the primary invasive 
procedure is TACE or lipiodolisation, and patients in whom the primary invasive 
procedure is liver ablation/coagulation with TACE or lipiodolisation planned after 
completion of study assessments on Day 8  
• Interferon products 
• Macrophage colony-stimulating factor (M-CSF) products 
• Granulocyte CSF (G-CSF) products 
• Erythropoietin 
• TPO receptor agonists other than the study drug 
• Antithrombotic agents (heparin, aspirin, dipyridamole, ticlopidine, urokinase, etc.) 
except for use as rescue therapy  
• Desmopressin products 
• Monoethanolamine oleate 
• Other investigational products 
• Radiotherapy 
• Exsanguination 
• Any invasive procedures except for the primary invasive procedure in the study 
The following therapies can be concomitantly used after assessment on Day 8 provided 


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that the primary invasive procedure is liver ablation/coagulation:  
− 
TACE 
− 
Lipiodolisation with anticancer drugs (ie, Lip-TAI) 
− 
transcatheter arterial embolisation (TAE) excluding Lipiodol infusion for 
marking 
6.2.1.3 
Rescue Therapy 
Use of the following therapies is permitted as rescue therapy for bleeding events, 
independent of platelet count:  
• Platelet preparations 
• Other blood preparations, including red blood cells and plasma 
• Volume expanders 
Antithrombotic drugs may be administered as rescue therapy for thrombotic events when 
the platelet count is ≥ 200 × 109/L or when, in the opinion of the investigator, formation 
of a thrombus is highly suspected. 
7. 
STUDY PROCEDURES AND METHODS OF ASSESSMENTS 
 
Informed Consent 
7.1
The nature of the study will be fully explained to each patient by the investigator or 
designee using the institutional review board (IRB)-approved informed consent form.  
Patients who agree to participate in the study must voluntarily sign the informed consent 
form prior to the initiation of any study-related procedures.  Informed consent will be 
obtained from all patients and they cannot be entered into the study until they have signed 
and dated the informed consent form.  A copy of the signed and dated informed consent 
form will be given to the patient, and the investigator should retain the original document.   
The investigator or designee is responsible for ensuring that patients understand the risks 
and benefits of participation in the study, and should be available to answer any questions 
patients may have throughout the study.  In addition, they should share with patients, in a 
timely manner, any new information that may affect patient willingness to continue in the 
study. 
 
Baseline Characteristics and Eligibility Assessment 
7.2
The following information will be collected during the Screening period.  In addition, 
safety assessments conducted at Screening, as well as at specified time points throughout 
the study, are detailed in Section 7.7. 
 
Baseline Characteristics 
7.2.1
The following baseline characteristics will be recorded on the CRF: date of birth, sex, 
race, ethnicity, patient identification number, date informed consent signed, height, 
weight, and whether pregnant/lactating (for females only).  


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Medical History 
7.2.2
Any concomitant disease (including the type of medical history of CLD) at Screening will 
be recorded on the CRF.   
For medical history, any of the followings will be recorded on the CRF: 
• any diseases controlled by drugs irrespective of symptoms 
• hepatic encephalopathy, jaundice, or other signs along with CLD (Note: splenomegaly, 
ascites, and gastro-oesophageal varices will be recorded on the CRF separately.  See 
the Section 7.2.8 to 7.2.10) 
• history of hepatectomy, drug allergy, food allergy, pollinosis. 
 
History of Transfusion 
7.2.3
Details of transfusion history (eg, whole blood, red blood cell, platelet, other transfusions, 
or unknown) will be recorded on the CRF. 
 
Performance Status 
7.2.4
Performance status will be assessed according to the ECOG PS (see Appendix 5), and the 
date of assessment and grade will be recorded on the CRF.   
 
Type of Chronic Liver Disease 
7.2.5
The type of medical history of CLD (hepatitis C, hepatitis B, alcoholic hepatitis, 
non-alcoholic hepatitis, autoimmune hepatitis, other hepatitis) will be recorded on the 
CRF.   
 
Severity of Liver Disorder 
7.2.6
Severity of liver disorder will be assessed according to the Child-Pugh class, and the date 
of assessment and assessment of each item will be recorded on the CRF.   
 
Planned Invasive Procedure 
7.2.7
The planned invasive procedure will be recorded on the CRF.   
If the planned invasive procedure is not included in the list of invasive procedures (see 
Appendix 4), the investigator or designee should contact the Medical Monitor (see 
Section 9.1) to discuss the enrolment of such a patient based upon invasiveness and 
bleeding risk of the procedure and which is comparable to the permitted surgeries on the 
provided list (see Appendix 4).  
 
Gastro-oesophageal Varices 
7.2.8
During the Screening period, should an upper gastrointestinal endoscopy be performed to 
assess any gastro-oesophageal varices, the date of endoscopy and the presence or absence 
of gastro-oesophageal varices will be recorded on the CRF.  If gastro-oesophageal varices 
are present, details on whether the planned invasive procedure is for the treatment of these 
will be recorded on the CRF.  If the planned invasive procedure is not for the treatment of 
gastro-oesophageal varices, bleeding status or the requirement of treatment will be 
recorded on the CRF.  If an endoscopy has been performed within 180 days of 


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randomisation, results from that assessment can be used.  
 
Splenomegaly 
7.2.9
During the Screening period, diagnostic imaging (ultrasonography, CT, or MRI) will be 
performed to assess the presence or absence of splenomegaly.  The test date and method, 
and the presence or absence of splenomegaly will be recorded on the CRF.  If 
ultrasonography, CT, or MRI has been performed within 28 days of randomisation, that 
image can be used for the assessment of splenomegaly. 
 Presence of Ascites 
7.2.10
During the Screening period, diagnostic imaging (ultrasonography, CT, or MRI) will also 
be used to assess the presence of ascites.  The test date and method, and the presence or 
absence of ascites will be recorded on the CRF.   
 Pregnancy Test 
7.2.11
For women of childbearing potential, a urine pregnancy test will be performed during the 
Screening period before dosing at Day 1 and at the end of the study at Day 35 (or early 
termination of assessment, if applicable) for the investigator or designee to assess 
pregnancy status at the beginning and the end of the trial.  For women of childbearing 
potential who withdraw from the study, a pregnancy test will also be performed. The test 
will not be required for women of non-childbearing potential, ie, those who meet any of 
the following criteria:  
• Postmenopausal women (ie, those in whom at least 1 year has elapsed since their last 
regular menstrual period) 
• Women who have undergone hysterectomy, bilateral oophorectomy, or sterilisation. 
 Laboratory Test (Immunological Test and Blood Thrombopoietin 
7.2.12
Concentration) 
Laboratory tests, including immunological tests and blood TPO concentration 
measurements, will be performed during the Screening period (see Table 7-1).  Full 
details of all laboratory tests are provided in Appendix 2. 
Blood samples will be collected by the investigator or designee at the pre-specified time 
points.  All samples will be sent to the central laboratory for processing.  Full details of 
the sample collection, handling, labelling, storage, and shipping procedures will be 
specified in a separate manual.  
Table 7-1: 
Immunological Test and Blood Thrombopoietin Concentration 
Test 
Items Evaluated 
Immunological 
platelet-associated IgG, antiplatelet antibody, Helicobacter pylori antibody IgG 
Other 
TPO 
Abbreviation: immunoglobulin G (IgG). 
 
Enrolment in the Study and Dispensing Study Drug 
7.3
Upon obtaining the informed consent, the investigator or designee will contact the 


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IVRS/IWRS and provide the requested identifying information for the subject to register 
them into the IVRS/IWRS. Once assigned to a patient, the randomisation number will not 
be reused.  If the patient's enrolment is accepted, the patient will be start Screening 
procedures but must not begin the study medication before randomisation.  If the patient 
fails to be randomised for any reason, the IVRS/IWRS must be notified that the subject 
was not randomised.  The investigator or designee will input the reason for not being 
randomised into the IVRS/IWRS.  Once a patient is randomised the investigator, designee, 
or site pharmacist will dispense study drug as specified in Section 5.  Full details of the 
randomisation processes are provided in a separate manual.  The date of randomisation 
and the assigned patient identification number will be entered on the CRF. 
 
Invasive Procedures 
7.4
The planned invasive procedure will be performed in the Post-treatment period 
between Days 9 and 14.  The need for the invasive procedure will be reassessed in the 
event of the following: 
• Platelet count ≥ 200 × 109/L 
• Administration of an antithrombotic drug  
• In the opinion of the investigator, the procedure is no longer in the patient's best 
because of an AE or other concern  
• The patient requests cancellation of elective procedure after randomisaton 
If any of the above criteria are met and the elective procedure cannot be performed 
between Days 9 and 14, it may be performed up to Day 35 of the study.  If a patient does 
not undergo a procedure, all relevant follow-up assessments should be performed and data 
should be collected up to Day 35.  In case the invasive procedure performed between 
Days 9 and 14 needs to be repeated, the same procedure may be performed after Day 15 
according to the discretion of the investigator. 
Information on whether to perform the planned invasive procedure, details of the 
procedure performed (eg, percutaneous radiofrequency ablation [RFA]/microwave 
coagulation therapy [MCT], laparoscopic RFA/MCT, endoscopic variceal ligation [EVL], 
endoscopic injection sclerotherapy [EIS], TACE, TAE, or other), the date performed, the 
initiation time of the procedure, and whether the procedure was performed within the 
specified period will be recorded on the CRF.  If the planned invasive procedure is not 
performed within the specified period or is not performed at all, the reason will be 
recorded on the CRF. 
 
Efficacy Assessments 
7.5
 
Determination of the Need for Pre-operative and Platelet Transfusion 
7.5.1
Post-procedural Rescue Therapy 
A platelet count will be performed on or after Day 8, but no more than 2 days prior to the 
elective invasive procedure, in order to assess the need for a pre-operative platelet 
transfusion before the planned elective procedure.  
The date of this platelet count, the time of measurement, the measured value, and, if 
applicable, the date and the initiation time of the platelet transfusion, the dose (units) 
transfused, and the reason for the transfusion will be recorded on the CRF.   


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Laboratory Tests (Platelet Count) 
7.5.2
A blood sample for a platelet count will be collected at Screening, and this will be used to 
determine whether the patient is considered eligible to enter the study and proceed to 
randomisation.  Blood samples for the platelet count will be collected and analysed 
locally on Days 1 (ie, before randomisation to confirm eligibility into the study), 5 to 8, 
10, 12, 14, 17, 21, 28, and 35 (or at drug withdrawal and/or early termination of 
assessment, if applicable) using standard methods at each participating site.  Full details 
of all laboratory tests are provided in Appendix 2. 
The date of platelet count performed, the time of each measurement, and the measured 
value will be recorded on the CRF.   
Platelet counts are measured for the assessment of efficacy.  However, the investigator or 
designee will assess whether any abnormal changes from baseline (Day 1) are considered 
to be clinically significant (see Section 7.8.9), and any clinically significant results should 
be recorded as AEs by the investigator or designee.  The reference ranges provided by 
each participating site will be used to assess whether values are normal (ie, within the 
reference range) or abnormal (ie, outside the reference range).   
If the platelet count has not returned to baseline level at the final post-treatment 
assessment on Day 35, appropriate follow-up review will be performed until the platelet 
count returns to baseline levels or the investigator or designee considers that no further 
review is warranted.  
 
Pharmacokinetic Assessment 
7.6
 
Drug Concentration Measurement 
7.6.1
All patients will undergo blood sampling for the PK assessment of S-888711.  At least 20 
patients will undergo intensive blood sampling (Table 7-2) and the remaining patients 
will undergo sparse blood sampling (Table 7-3).  The actual time and date of all blood 
collections will be recorded on the CRF. 
Table 7-2: 
Intensive Blood Sampling 
Study Day 
Blood Sampling Time 
Allowance 
Day 5 
• Pre-dose 
• Within 
60 
minutes 
before 
administration 
• 2 hours after dose 
• 4 hours after dose 
• 6 hours after dose 
• 8 hours after dose 
• ± 15 minutes after dose 
Day 6 
• 24 hours after Day 5-dose 
• ± 60 minutes after Day 5-dose, but 
before Day 6-dose 
Day 7 
• 48 hours after Day 5-dose 
• Simultaneous 
sampling 
with 
platelet count determination 
 


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Table 7-3: 
Sparse Blood Sampling 
Study Day 
Blood Sampling Time 
Allowance 
Day 5 
• Pre-dose 
• Within 
60 
minutes 
before 
administration 
• 2 to 4 hours after dose 
• Within the specified time window 
(ie, 2 to 4 hours after dose) 
Day 6  
• 24 hours after Day 5-dose 
• Simultaneous 
sampling 
with 
platelet count determination 
Day 7 
• 48 hours after Day 5-dose 
• Simultaneous 
sampling 
with 
platelet count determination 
 
Blood samples for the PK assessment will be collected by the investigator or designee at 
the pre-specified time points.  All samples will be sent to the central laboratory for 
processing.  Full details of the sample collection, handling, labelling, storage, and 
shipping procedures will be specified in a separate manual. 
 
Safety Assessment 
7.7
 
Physical Examination 
7.7.1
The investigator or designee will perform a physical examination during the Screening 
period, on Days 1 (before the initial administration), 5 to 8, 10, 12, 14, 21, 28, and 35 (or 
at drug withdrawal and/or early termination of assessment, if applicable).  Clinically 
significant findings on physical examination will be recorded as an AE on the CRF.  
 
Portal Vein Thrombosis 
7.7.2
Portal vein thrombosis will be assessed by the investigator or designee using diagnostic 
imaging (ultrasonography, CT, or MRI) during the Screening period, and between 3 and 
10 days after the planned invasive procedure* in the Post-treatment period (Days 12 to 
21).  For assessment in the Screening period, the investigation should be arranged as close 
to randomisation as possible.  However, for patients in whom gastro-oesophageal varices 
are treated, portal vein thrombosis will be confirmed using imaging performed after the 
treatment.   
The imaging date and method, and the presence or absence of portal vein thrombosis will 
be recorded on the CRF.  The independent safety committee will assess portal vein 
thrombosis (see Section 9.8.2). 
* Even if the planned invasive procedure is postponed.  In addition, if any additional invasive procedures 
are performed, diagnostic imaging should also be performed before and after the additional procedure for 
post-assessment of the initial and additional procedures. 
 
Portal Blood Flow 
7.7.3
The direction of portal blood flow (hepatofugal, hepatopetal, stasis) will be assessed by 
the investigator or designee using Doppler ultrasonography during the Screening period, 
and between 3 and 10 days after the planned invasive procedure* in the Post-treatment 
period (Days 12 to 21).  The test date and the results will be recorded on the CRF.   


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* Even if the planned invasive procedure is postponed.  In addition, if any additional invasive procedures 
are performed, diagnostic imaging should also be performed before and after the additional procedure for 
post-assessment of the initial and additional procedures. 
 
WHO Bleeding Scale 
7.7.4
The severity of bleeding will be assessed according to the WHO Bleeding Scale (see 
Appendix 7)[15] during the Screening period, on Days 1 and 8, between 3 and 10 days 
after the invasive procedure (Days 12 to 21), and on Day 35 (or early termination of 
assessment, if applicable).  The date of the assessment and the grade will be recorded on 
the CRF.   
 
Blood Pressure and Pulse Rate 
7.7.5
Resting blood pressure (systolic blood pressure and diastolic blood pressure in supine 
position) and pulse rate will be measured during the Screening period, and on Days 1 (ie, 
immediately before S-888711 administration), 5, 8, 10, 12, 14, 21, 28, and 35 (or at drug 
withdrawal and/or early termination of assessment, if applicable).  
The test date and the results will be recorded on the CRF.  
The investigator or designee will assess whether any abnormal changes from baseline 
(Day 1) are considered to be clinically significant (see Section 7.8.9), and any clinically 
significant results should be recorded as AEs by the investigator or designee.   
 
Electrocardiography 
7.7.6
Electrocardiography (ECG) will be performed during the Screening period and on Day 35 
(or at drug withdrawal and/or early termination of assessment, if applicable).     
All ECG traces will be evaluated by the investigator or designee and categorised as 
normal or abnormal.  The date of the ECG and any abnormality observed should be 
recorded on the CRF.  Any abnormal traces will be reviewed by the investigator or 
designee for clinical significance (see also Section 7.8.9), with any clinically significant 
findings recorded as an AE on the CRF.   
 
Laboratory Tests (Except for Platelet Count) 
7.7.7
A list of clinical laboratory tests is shown in Table 7-4.  Full details of all laboratory tests 
are provided in Appendix 2. Central Laboratory tests (except for platelet count) will be 
performed during the Screening period, and on Days 1 (ie, immediately before the first 
dose of study drug), 8*, 14, and 35 (or at drug withdrawal and/or early termination of 
assessment, if applicable).   
Blood samples will be collected by the investigator or designee at the pre-specified time 
points.  All samples will be sent to the central laboratory for processing.  Full details of 
the sample collection, handling, labelling, storage, and shipping procedures will be 
specified in a separate manual.   
The reference ranges provided by the central laboratory will be used to assess whether 
values are normal (ie, within the reference range) or abnormal (ie, outside the reference 
range).    
Any abnormal changes from baseline (Day 1) will be assessed by the investigator or 
designee for clinical significance (see Section 7.8.9), with any clinically significant 


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findings recorded as an AE on the CRF.   
* If laboratory tests are measured at drug withdrawal, laboratory tests on Day 8 are not necessary. 
 
Table 7-4: 
Routine Laboratory Tests (Except for Immunological Test, Blood 
Thrombopoietin Concentration, and Platelet Count) 
Test 
Items Evaluated 
Haematology (except 
for platelet count) 
Red blood cell count, white blood cell count, haemoglobin, and 
haematocrit 
Blood chemistry 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate 
dehydrogenase, gamma glutamyl transferase, alkaline phosphatase, total 
bilirubin, bilirubin direct, indirect bilirubin, total protein, albumin, blood 
urea nitrogen, serum creatinine, sodium, potassium, chloride, and calcium 
Blood 
coagulation/ 
fibrinolysis assay  
Prothrombin time (international normalised ratio value), activated partial 
thromboplastin time, antithrombin III activitya, fibrinogena, fibrin 
degradation productsa, D-dimera, protein C activitya, free protein S antigena
and von Willebrand factor activitya 
a 
Only at Screening. 
 
Adverse Events Assessments 
7.8
 
Adverse Events Definitions 
7.8.1
An AE is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product, including an investigational 
drug and which does not necessarily have to have a causal relationship with this treatment.  
The definition covers also medication errors and uses outside what is foreseen in the 
protocol, including misuse and abuse of the investigational medicinal product. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with use of an 
investigational product, regardless of whether it is considered related to the 
investigational product.  
AEs include events spontaneously reported by the patient and events elicited from 
non-leading questions, as well as abnormal findings on physical examination, vital signs, 
ECG, or laboratory tests at each visit during the study.  AEs include any new occurrences 
of an event or events that have increased in severity or frequency from Screening, as well 
as abnormal results from any diagnostic procedures, including any laboratory test 
abnormalities.  Treatment-emergent AEs (TEAEs) are defined in Section 7.8.2.  Any 
medical history reported as ongoing at the time of informed consent will be considered an 
AE if it worsens during the course of the study. 
A serious adverse event (SAE) is defined by regulations as any AE occurring at any dose 
that results in any of the following outcomes: 
• death 
• is life-threatening condition 
• requires hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity 


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• consists of a congenital anomaly/birth defect 
• is a medically important event 
Important medical events that do not result in death, are not life threatening, or do not 
require hospitalisation may be considered as SAEs when, based upon appropriate medical 
judgment, they may jeopardise the patient and may require medical intervention to 
prevent one of the outcomes listed above.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalisation, or the 
development of drug dependency or drug abuse.  The investigator or designee will 
determine the seriousness of all AEs. 
 
Timing 
7.8.2
AEs (both serious and non-serious) will be collected throughout the study from the time 
of informed consent until the patient’s final follow-up visit or 28 days after the last dose 
of study medication, whichever is the later (or at drug withdrawal and/or early 
termination of assessment, if applicable).   
The investigator or designee is responsible for assessing AEs.  AEs should be fully 
investigated, and details of the onset and outcome dates, severity, seriousness, 
relationship to study drug, action taken with regards to study drug, concomitant drugs or 
therapies taken as a result of the AE, and outcome will be recorded on the CRF.  The 
onset of the AEs will be recorded on the CRF as before or after the initiation of the 
primary invasive procedure. 
Reported AEs (both serious and non-serious) will be followed up until recovery, or until 
the patient’s final follow-up visit or 28 days after the last dose of study medication, 
whichever is the later (or at drug withdrawal and/or early termination of assessment, if 
applicable).  Any AEs reported after the first dose of S-888711 or placebo will be 
considered as TEAEs.  
Any SAE assessed as causally related to the study drug and is ongoing 28 days after the 
last dose of study medication will be followed until resolution, stabilisation, the condition 
becomes chronic, or the patient is lost to follow-up.   
After the follow-up assessment, the necessary information will be recorded on the CRF.  
If a patient ceases to visit the hospital during the study, a follow-up interview will be 
performed by telephone or other appropriate method.  The reason for discontinuation and 
the results of the follow-up assessment will be recorded on the CRF. 
Further details of the follow-up of platelet counts are provided in Section 7.5.2. 
 
Severity 
7.8.3
The severity of an AE will be graded by the investigator or designee according to the 
following definitions: 
• Mild: A finding or symptom is minor and does not interfere with usual daily activities. 
• Moderate: The event is discomfort and causes interference with usual daily activity or 
affects clinical status. 
• Severe: The event causes interruption of the patient's usual daily activities or has a 


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clinically significant effect. 
 
Relationship 
7.8.4
The relationship of an AE to study drug should be determined by the investigator or 
designee according to the following criteria.  Causal relationship assessment to drug 
treatments is required for purposes of reporting AEs.  To promote consistency, the 
following guidelines should be taken into considerations along with good clinical and 
scientific judgment when determining the relationship of drug treatments to an AE: 
Related: 
An AE which can be reasonably explained that the study drug caused the 
AE.  For example, the occurrence of the AE cannot be explained by other 
causative factors, can be explained by pharmacological effect of the study 
drug such as similar event had been reported previously, or increase/decrease 
of the dose effect the occurrence or seriousness of the AE. 
Not 
Related: 
An AE which cannot be reasonably explained that the study drug caused the 
AE. 
 
Expectedness 
7.8.5
An expected treatment-related TEAE is any adverse drug reaction (ADR) consistent with 
the current Investigator's Brochure (IB) for S-888711. 
An adverse reaction is ‘unexpected’ if its nature and severity are not consistent with the 
information about the medicinal product in question set out in the IB. 
 
Outcome 
7.8.6
Outcome will be defined as: 
• Recovered/resolved; 
• Recovering/resolving; 
• Not recovered/not resolved; 
• Recovered/resolved with sequelae; 
• Fatal; 
• Unknown. 
If the outcome was recovered, recovered with sequelae, or fatal, the date on which that 
outcome occurred will be recorded in the patient's CRF as the AE stop date.   
AEs should be followed until recovery, or until the patient’s final follow-up visit or 
30 days after the last dose of study medication, whichever is the later.  If the outcome was 
recovering, not recovered, or unknown at this time, the date on which the investigator or 
designee confirmed that follow-up investigations were finished will be recorded in the 
patient’s CRF as the date of last assessment, and the reason for completion of follow-up 
of the AE will be entered in the comment box. 


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Action Taken 
7.8.7
Action taken will be defined as: 
• Drug withdrawn;  
• Dose not changed; 
• Not applicable. 
 
Adverse Events of Special Interest 
7.8.8
7.8.8.1 
Thrombotic/Thromboembolic Complications 
The investigator or designee will assess all thrombotic/thromboembolic events, with 
particular attention given to, but not limited to, the following AEs: 
• Portal vein thrombosis 
• Mesenteric vein thrombosis 
The 
investigator 
or 
designee 
should 
carefully 
monitor 
patients 
with 
thrombotic/thromboembolic events, as defined above, as well as those who experience 
AEs that have the potential to be classified as above. 
 
Clinical Laboratory Adverse Events 
7.8.9
For any abnormal laboratory test results (haematology, blood chemistry, or urinalysis, 
blood coagulation/fibrinolysis assay) or other safety assessments (eg, physical 
examination and vital signs) that worsen from baseline, the investigator or designee will 
assess whether the changes are considered clinically significant.  Abnormal laboratory 
test results are defined as those that are outside of the reference range.  Test results that 
are abnormal at baseline and worsen during the study will also be assessed by the 
investigator or designee must for clinically significant changes.  Any test results 
considered clinically significant by the investigator or designee should be recorded as 
AEs.  If an abnormal laboratory finding is associated with a disease or organ toxicity, the 
investigator or designee will report only the disease or organ toxicity as an AE.   
The following laboratory test results will be considered as clinically significant by the 
investigator or designee: 
• Those leading to any of the outcomes included in the definition of an SAE. 
• Those requiring withdrawal of study drug. 
• Those leading to initiation of concomitant drug treatment or other therapy. 
• Those requiring additional diagnostic testing or other medical or surgical intervention. 
In all other circumstances, the investigator or designee will use their discretion in 
assessing clinical significance.  The investigator or designee should not consider 
withdrawal from study drug due to an increase in platelets as clinically significant.   


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 Serious Adverse Events 
7.8.10
7.8.10.1 Reporting Serious Adverse Events 
All AEs must be fully recorded in the patient notes throughout the study from the time of 
informed consent until the patient’s final follow-up visit and the data after randomisation 
will be transcribed into the patients’ CRF.  AEs resulting from concurrent illnesses, 
concomitant medications, or progression of disease must also be collected and reported to 
the sponsor or designee.  AEs would not include information recorded as medical history 
at screening, for pre-planned procedures for which the underlying condition was known 
and no worsening occurred. 
Quintiles Drug Safety Department will be responsible for collection of all safety 
information on behalf of the sponsor. 
All SAEs with date of onset after the end of trial visit or 28 days after the last dose, 
whichever is later, must be reported to Quintiles Drug Safety Department in detail on the 
SAE form within 24 hours of the investigator first becoming aware of the event.  The 
investigator will be requested to complete a separate paper SAE reporting form in 
addition to the information on the CRF.  The investigator site must fax the SAE report to 
Quintiles Drug Safety according to the instructions on the SAE form; a dedicated phone 
number is available for any queries on completing the SAE form, and country specific 
SAE reporting phone and fax numbers will be specified in a separate document.  
Quintiles Drug Safety will forward details of the SAE to the sponsor. 
All SAEs must be reported regardless of causal relationship to study drug.  Follow-up 
information on each SAE may be requested by the sponsor.   
When reporting the SAEs, the investigator should record the diagnosis whenever possible.  
If no diagnosis is available at the time of reporting, individual signs and symptoms can be 
reported. 
Contact Information on Reporting the Completed SAE Form 
Medical Monitor: 
24 hour emergency number if the Medical Monitor cannot be reached within 2 hours: 
 24 hour Urgent Medical Contact (Contact directly, on mobile/office phone, for urgent 
issues: Tel: 
 
Quintiles Emergency SAE Fax Number: 
 
If the sponsor requires follow-up information, the investigator should provide new 
information to them using the SAE form and fax it to the number provided above.  
Discharge summaries, consultant reports, autopsy reports, or other relevant documents 
must be evaluated by the investigator, with all relevant information included on the 
follow-up SAE form.  Copies of these reports may also be requested by the sponsor. 
Appropriate remedial measures should be taken by the investigator using their best 
medical judgment to treat the SAE.  These measures and the patient’s response should be 
recorded.  Clinical, laboratory, and diagnostic measures should be used by the 
investigator, as needed, to adequately determine the aetiology of the SAE.  
Any SAEs occurring after the AE assessment period (see Section 7.8.2) that the 
investigator considers related to study drug must be reported to the sponsor. 


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The investigator will be responsible for reporting all SAEs to the IRB, as well as to the 
sponsor.  The sponsor will be responsible for reporting all SAEs to the regulatory 
authorities as required by the applicable regulatory requirements. 
 Liver Function Abnormalities 
7.8.11
When liver function abnormalities meet any of the following criteria (Hy's law) the 
investigator or designee must report these abnormalities to the sponsor using the specified 
form within 24 hours. 
• AST or ALT > 3 × upper limit of normal (ULN) and total bilirubin > 2 × ULN 
• AST or ALT > 3 × ULN and prothrombin time-international normalised ratio 
(PT-INR) > 1.5 
 Special Situations-Abuse, Misuse, Overdose, and Medication Error 
7.8.12
The investigator must report all cases of abuse, misuse, overdose and medication error (as 
defined below) to the sponsor's medical monitor via fax using a Special Situations Report 
Form as soon as possible.  If there are any associated SAEs, the investigator will also 
complete an SAE Form. 
• Abuse: persistent or sporadic, intentional excessive use of an investigational 
product(s), which is accompanied by harmful physical or psychological effects. 
• Misuse: Intentional and inappropriate use of an investigational product(s) other than as 
directed or indicated at any dose.   
• Overdose: intentional or unintentional intake of a dose of investigational product(s) 
higher than the assigned dose in the protocol.  
• Medication Error: any unintended error in the prescribing, dispensing, or 
administration of an investigational product(s).  Cases of patients missing doses of 
investigational product(s) do not need to be reported as a medication error. 
 Pregnancy 
7.8.13
All patients (males and females) who are participating in the study must agree to use an 
appropriate method of contraception (see Section 4.2), from Screening to completion of 
the Post-treatment period, excluding male patients who have been surgically sterilised 
or female patients who are postmenopausal or have undergone hysterectomy, bilateral 
oophorectomy, or sterilisation. 
If a female patient becomes pregnant during the study, she must be instructed to 
discontinue study drug and inform the investigator immediately.  All pregnancies 
occurring between the time of patient consent through to study completion must be 
reported by the investigator to the sponsor within 24 hours by faxing the Pregnancy Form.  
Any pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE, as appropriate.  Spontaneous abortions must be reported as an 
SAE.  The outcome of the pregnancy should be followed by the study site and it must be 
reported to the sponsor by faxing the Pregnancy Form.  All pregnancies confirmed after 
the Post-treatment period but within 3 months of the last dose of study drug should be 
reported to the sponsor or designee and followed to completion.  At the end of the 
pregnancy (ie, birth, miscarriage, abortion), the outcome should be reported to the 


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sponsor. 
In addition, the investigator (or designee) must attempt to collect pregnancy information 
on any female partners of male patients who become pregnant during the study.  
Pregnancy information must be reported to the sponsor as described above. 
 
Withdrawal of Patients from the Study Drug or Study  
7.9
 
Withdrawal of Patients from the Study Drug (ie, Study Medication) 
7.9.1
The investigator or designee will withdraw a patient from study medication for any of the 
following reasons: 
• Platelet count ≥ 50 × 109/L, with an increase of ≥ 20 × 109/L from baseline (ie, the 
administration stopping criterion). 
• Occurrence of a thrombosis-related AE.  
• If a serious or intolerable AE occurs and the investigator believes the patient 
should be withdrawn from the study medication because of that AE. 
• The patient requests to be withdrawn from the study medication. 
• The patient is proved to be ineligible for the study after participation in the study 
has begun. 
• The investigator determines that the patient should be withdrawn from the study 
medication due to other reasons. 
 
Even after withdrawal from study medication, study assessments in the Treatment period 
(Days 1 to 7) and the Post-treatment period (Days 8 to 35) will be performed on schedule, 
as specified in the study protocol.  
 
Withdrawal of Patients from the Study (ie, Study Assessment) 
7.9.2
The investigator or designee will withdraw a patient from study assessment for any of the 
following reasons: 
• The patient requests to be withdrawn from the study. 
• The patient is lost to follow-up. 
• The investigator determines that the patient should be withdrawn from the study 
due to other reasons. 
 
In the event of withdrawal from study medication or termination of the study assessments, 
the investigator or designee will promptly notify the sponsor or designee, and will make 
every effort to determine the reason for withdrawal and to complete the assessments 
required at drug withdrawal/early termination of the study.  The reason for 
withdrawal/termination and the date of withdrawal/termination will be recorded on the 
CRF.  However, assessments at early termination of the study are not mandatory for 
patients who are withdrawn from the study without study drug administration.  Follow-up 
of AEs will be performed in accordance with the specifications in Section 7.8.2.  For 
patients withdrawn due to an AE, information related to the AE will also be followed. 


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Appropriateness of Measurements 
7.10
The primary endpoint in the study will be the proportion of patients who did not require a 
platelet transfusion prior to the primary invasive procedure and who did not receive 
rescue therapy for bleeding from randomisation through 7 days after the primary elective 
procedure.  This is considered to be an appropriate primary endpoint because the desired 
effect of S-888711 is to increase the patient's platelet count and thereby avoid the need for 
a platelet transfusion for the prevention of bleeding prior to the scheduled invasive 
procedures.  The criteria for assessing whether a patient needs a platelet transfusion are 
not consistent with actual clinical practice.  In this study, a platelet count of < 50 × 109/L 
will be used as the criterion to determine whether a pre-operative platelet transfusion is 
needed.  This will allow the efficacy of S-888711 to be evaluated appropriately, by 
referencing the Guideline for Use of Blood Preparations.[12] As a secondary variable, the 
time course of the platelet count will be assessed to provide comprehensive efficacy data. 
Safety assessments will consist of those typical in clinical trials.  In addition, in order to 
assess the effect of S-888711 on bleeding, the incidence of bleeding-related AEs will be 
calculated.  The risk of thrombus formation due to an increase in platelet count due to 
S-888711 will also be assessed by monitoring the incidence of thrombosis-related AEs. 
PK assessments will consist of measurements of the plasma concentration of S-888711 in 
order to assess the time profile of plasma drug concentrations.  
 
Allowable Time Window 
7.11
All measurements and assessments will be performed according to the schedule provided 
in Appendix 1.  If, for unavoidable reasons, study measurements and assessments are not 
possible at the specified time points, they should be performed within an allowable time 
window (see Table 7-5).  Data collected outside of the allowable time window will be 
handled as missing data for that study visit. 
Table 7-5: 
Allowable Time Window 
Timing 
Study Day 
Allowance 
Screening  
After obtaining consent and 
before randomisation 
After 
obtaining 
consent 
and 
within 
28 days prior to randomisationa 
Randomisation 
Before 
initiation 
of 
study 
medication 
Within 7 days before initiation of study 
medication  
Before initiation of study 
medication 
Day 1 
Within 7 days before initiation of study 
medicationb 
Treatment period  
Days 1-7 
±0 day 
Post-treatment period 
Day 8 
±0 day 
Day 10 
±1 day 
Days 12 and 14 
+1 day 
Days 17 and 21 
−1 day to +2 days  
Day 28 
±2 days  
Day 35 
−2 day to +7 days  
At drug withdrawal 
- 
Within 2 days after the next day of final 
administration 
At early termination of 
study assessment 
- 
Within 7 days after the day of early 
termination of study assessment 
a The result of the upper gastrointestinal endoscopy for the assessment of gastro-oesophageal varices can 
be used if the test is performed within 180 days before randomisation.  The diagnostic imaging 


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(ultrasonography, CT, or MRI) for the assessment of splenomegaly can be used if the diagnostic 
imaging is performed within 28 days before randomisation.  The diagnostic imaging (ultrasonography, 
CT, or MRI) for the assessment of portal vein thrombosis should be arranged as close to randomisation 
as possible; however, if gastro-oesophageal varices are treated, confirmation should be made after the 
treatment.   
b Data obtained within 7 days before initiation of study medication can be used as baseline data (Day 1). 
8. 
STATISTICAL ANALYSIS 
 
Statistical Analysis Methods 
8.1
Statistical and PK analyses will be performed by the sponsor (Shionogi & Co., Ltd.).  Full 
details of the statistical analyses will be specified in the Statistical Analysis Plan (SAP), 
which will be finalised before unblinding of the study data.   
In principle, summary statistics, including the number of patients, arithmetic mean, 
standard deviation (SD), median, and minimum and maximum values will be calculated 
for continuous variables.  The number and proportion of patients in each category will be 
calculated for categorical variables.   
Unless otherwise noted, all statistical tests will be performed at a 0.05 (two-sided) 
significance level.   
In general, all tabulations will be presented by treatment group.  Individual patient data, 
PK data, and any derived data will be summarised by treatment group and listed by 
patient.  All the analyses and listings will be performed using Statistical Analysis 
Software (SAS) (Version 9.2 or higher) and/or WinNonlin (Version 6.2.1 or higher). 
 
Rationale for Target Sample Size and Stratification Factors 
8.2
Two hundred patients with CLD and thrombocytopenia who are scheduled to undergo 
elective invasive procedures will be randomised into either of two treatment groups 
(100 patients per group).  
In the phase 3 study (Study 1304M0631) conducted in Japan, the proportion of patients 
who required no platelet transfusion prior to the primary invasive procedure was 79.2% in 
S-888711 3 mg group for up to 7 days and 12.5% in the placebo group.  The difference of 
proportion of patients was 66.7% and its 95% confidence interval (CI) was [51.9%, 
81.5%].  Based on the results, it was assumed that the difference in the primary endpoint 
to be obtained in this study is 50% between S-888711 and placebo groups.  Assuming that 
the proportion of patients who meet the primary endpoint is 20% in the placebo group and 
70% in the S-888711 group, 100 patients per arm will provide 99% power to detect a 
difference of 50% between S-888711 and placebo groups at a two-sided significance level 
of 0.05.   
With 100 patients per arm, from the safety point of view, the sample size will assure at 
least 95% probability to detect an AE with an incidence of 3% or more. 
Since the risk of bleeding is different for each elective procedure, primary invasive 
procedure has been selected as a stratification factor as per the phase 3 Japanese study 
(Study 1304M0631).  Furthermore, in the Japanese study, the proportion of patients in the 
3 mg group who received no platelet transfusion prior to the primary invasive procedure 
was relatively low in the group whose platelet count at baseline was < 35 × 109/L (57.1%, 
4/7 patients) compared to the group whose platelet count at baseline was ≥ 35 × 109/L 


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(82.9%, 34/41 patients).  Thus, for the current study, platelet count at baseline has been 
selected as an additional stratification factor 
 
Analysis Populations 
8.3
The following analysis populations are defined:  
Intention-to-Treat (ITT) Population will include all randomised patients.  Any 
mis-randomised patients will be analysed according to the treatment randomised to.  This 
population is the primary population for the analysis of efficacy. 
Safety Analysis Population will include all randomised patients who actually receive at 
least 1 dose of the study drug.  This population will be analysed according to the 
treatment that patients actually received, rather than the treatment to which they were 
randomised.  This population is the primary population for the analysis of safety. 
Per Protocol (PP) Population will include all randomised patients who have no major 
protocol deviations pertaining to the efficacy evaluation.  This population will be used in 
a sensitivity analysis.   
Pharmacokinetic Concentration Population will include all patients who undergo 
plasma PK sampling and who have at least one evaluable PK assay result for S-888711.  
This population will be used for the concentration listing, as well as for plotting the 
concentration-time data. 
Pharmacokinetic Parameter Population will include all patients with at least one 
PK parameter estimated in the intensive PK sampling group.  This population will be used 
for PK parameter listing and summary. 
 
Handling of Missing Data 
8.4
Unless otherwise noted, missing data will not be imputed.  All analyses will be performed 
using actual observations.   
 
Patient Disposition 
8.5
The number and proportion of patients who completed and prematurely discontinued the 
study will be calculated by treatment group for all randomised patients.  In addition, 
reasons leading to discontinuation will be summarised by treatment group.  The number 
and proportion of patients included in each analysis population will also be calculated for 
all randomised patients. 
 
Demographic and Baseline Characteristics 
8.6
Demographics and baseline characteristics will be tabulated using summary statistics for 
the ITT population. 
 
Treatment and Treatment Compliance 
8.7
The number of days of study drug dosing will be tabulated using summary statistics in 
each treatment group for the safety analysis population. 


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Concomitant Therapies 
8.8
Concomitant drugs will be coded using the WHO Drug Dictionary.   
 
Endpoints 
8.9
 
Primary Endpoint 
8.9.1
The primary endpoint is the proportion of patients who require no platelet transfusion 
prior to the primary invasive procedure and no rescue therapy for bleeding from 
randomisation through 7 days after the primary elective procedure.  The following 
patients will also be considered as failures for the primary endpoint: 
• Patients who withdrew from the study before receiving the primary invasive procedure 
• Patients who did not receive the invasive procedure 
 
Secondary Endpoints 
8.9.2
The secondary efficacy endpoints are as follows: 
• Proportion of patients who require no platelet transfusion during the study 
• Proportion of responders: patients who achieve a platelet count of ≥ 50 × 109/L with an 
increase of  ≥ 20 × 109/L from baseline at any time during the study 
• Duration of the platelet count defined as the number of days during which the platelet 
count was maintained as ≥ 50 × 109/L  
• Proportion of patients who require rescue therapy for bleeding at any time during the 
study 
• Frequency of platelet transfusions 
• The change from baseline in platelet count over time (time course of platelet count) 
• Safety and tolerability 
• Assessment of plasma concentrations of S-888711 
 
Efficacy Analyses 
8.10
The ITT population is the primary population for the analyses of efficacy.  The PP 
population will be used for sensitivity analyses of the primary endpoint.   
 Analyses of Efficacy Endpoints 
8.10.1
8.10.1.1 Primary Endpoint Analysis 
The number and proportion of patients who required no platelet transfusion prior to the 
primary invasive procedure and no rescue therapy for bleeding from randomisation 
through 7 days after the primary elective procedure will be calculated by treatment group.  
The proportion of patients who required no platelet transfusion in the S-888711 group 
will be compared with that in the placebo group using the Cochran-Mantel-Haenszel test 
adjusted by the stratification factors. 


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8.10.1.2 Secondary Endpoint Analysis 
A gatekeeping strategy will be employed for sequentially testing the important secondary 
hypotheses.  If the primary hypothesis is statistically significant, the secondary 
hypotheses will be tested in sequence at a level of 0.05 (two-sided).  Sequential testing for 
the secondary endpoints will be conducted in the following order: 
• The comparison between S-888711 and placebo on the proportion of patients who 
require no platelet transfusion during the study 
• The comparison between S-888711 and placebo on the proportion of responders: 
patients who achieve a platelet count of ≥ 50 × 109/L, with an increase of ≥ 20 × 109/L 
from baseline at any time during the study 
• The comparison between S-888711 and placebo for the duration of platelet count ≥ 50 
× 109/L  
8.10.1.2.1 Proportion of Patients Requiring no Platelet Transfusion During the Study  
The number and proportion of patients who required no platelet transfusion during the 
study will be calculated by treatment group.  The proportion of patients who required no 
platelet transfusion in the S-888711 group will be compared with that in the placebo 
group using the Cochran-Mantel-Haenszel test adjusted by the stratification factors. 
8.10.1.2.2 Proportion of Responder Rate 
The number and proportion of patients who meet the criteria for a responder at least once 
during the study (ie, 'Responders') will be calculated for each treatment group.  The 
responder rate in the S-888711 group will be compared with that in the placebo group 
using the Cochran-Mantel-Haenszel test, with consideration of stratification factors. 
The number and proportion of 'Responders' will be calculated at each scheduled time 
point.  
8.10.1.2.3 Duration of the Increase in Platelet Count 
Median and quartiles for the duration of increased platelet count will be calculated in each 
treatment group with or without platelet transfusions.  The duration will be compared 
between the S-888711 group and placebo group using Wilcoxon rank sum test. 
8.10.1.2.4 Proportion of Patients who Required Rescue Therapy 
The number and proportion of patients who required rescue therapy will be calculated for 
each treatment group.  
8.10.1.2.5 Frequency of Platelet Transfusion and Dose (Unit) Transfused During the Study 
Summary statistics for the number and dose (unit) of platelet transfusions during the study 
will be calculated for patients who received a platelet transfusion.  
8.10.1.2.6 Time Course of Platelet Count  
Summary statistics for platelet count will be calculated at each scheduled time point in 
each treatment group.  Summary statistics for the change in platelet count from baseline 
will also be calculated. 


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Summary statistics for the maximum platelet count and the maximum change in platelet 
count of each patient will be calculated by treatment group. 
 
Safety Analyses 
8.11
Safety analyses will be performed for the safety population. 
 Adverse Events 
8.11.1
AEs will be classified by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) Version 18.0 or higher.  Of the AEs 
reported on the CRF, TEAEs will be used for the analyses of safety.  The definition of a 
TEAE is provided in Section 7.8.2.   
The number of patients who experience at least 1 TEAE, death, other treatment-emergent 
SAEs, significant TEAEs, and TEAEs leading to withdrawal will be counted for each 
treatment group.  The number of TEAEs, counted by cases reported, will also be 
presented.  Treatment-related TEAEs will be summarised in the same manner as the 
overall summary of TEAEs.   
A summary of TEAE by MedDRA system organ class and preferred term will be 
presented for each treatment group, including the percentage of patients.  The summary of 
TEAEs by severity will also be presented by system organ class and preferred term.  
The number and proportion of patients who experience bleeding-related TEAEs will be 
calculated by treatment group.  Bleeding-related TEAEs are defined as TEAEs which 
were classified as “haemorrhage terms (except laboratory terms)” using Standard 
MedDRA Queries (SMQ). 
 Adverse Events of Special Interest 
8.11.2
• Thrombotic/thromboembolic complications 
The number and percentage of patients who have a thrombotic/thromboembolic AE or 
that may have the potential to be classified as a thrombotic/thromboembolic AE will be 
summarised by treatment group.  Thrombotic/thromboembolic AEs include, but are not 
limited to, portal vein thrombosis and mesenteric vein thrombosis.  The definition of 
thrombotic/thromboembolic AEs is described as AEs which are classified as follows 
using the SMQ: “embolic and thrombotic events, arterial”, “embolic and thrombotic 
events, venous”, or “embolic and thrombotic events, vessel type unspecified and mixed 
arterial and venous”.  
 Vital Signs 
8.11.3
Summary statistics for vital signs, measured after randomisation, and their changes from 
baseline will be calculated at each scheduled time point by treatment group.  Baseline will 
be the value obtained on Day 1 (before initiation of study medication).  If the value on 
Day 1 is missing and the value obtained before randomisation was obtained within 7 days 
of initiation of study medication, that value can be used as a baseline measurement. 
 Laboratory Tests  
8.11.4
Summary statistics for laboratory tests, measured after randomisation, and their changes 


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from baseline will be calculated at each scheduled time point by treatment group.  
Baseline will be the value obtained on Day 1 (before initiation of study medication).  If 
the value on Day 1 is missing and the value obtained before randomisation was obtained 
within 7 days of initiation of study medication, that value can be used as a baseline 
measurement. 
 Electrocardiogram 
8.11.5
The number and proportion of patients with an abnormal ECG finding will be calculated 
at each scheduled time point. 
 Portal Vein Thrombosis 
8.11.6
The number and proportion of patients who experienced portal vein thrombosis will be 
counted. 
 Portal Blood Flow 
8.11.7
Summary statistics by category for the direction of portal blood flow (ie, hepatofugal, 
hepatopetal, stasis) will be counted for patients who underwent Doppler ultrasonography 
at each scheduled time point. 
 
Pharmacokinetic Analysis 
8.12
Plasma S-888711 concentrations will be listed by nominal sampling time and sampling 
design group (intensive PK sampling or sparse PK sampling).  Plasma S-888711 
concentrations for patients who completed at least 5 days of study drug administration 
will be summarised by nominal sampling time and sampling design group.  Summary 
statistics will include the number of non-missing observations (N), arithmetic mean 
(Mean), SD, and coefficient of variation (CV%, calculated by SD/Mean × 100), 
geometric mean and coefficient of variation for geometric mean (CV% Geometric Mean), 
and median, minimum, and maximum values at each sampling time.  The CV% 
Geometric Mean will be calculated according to a formula CV% Geometric Mean = 
[exp(sd2)-1]1/2 × 100, where sd is the standard deviation for natural logarithm 
(ln)-transformed data.  Time course profiles for plasma concentration data will be 
presented graphically.  Based on plasma concentration data on Days 5 and 6 and using 
non-compartmental methods, the following PK parameters will be calculated, whenever 
possible, for each patient who completed at least 5 days of study drug administration in 
the intensive PK sampling group:   
Cmax (ng/mL): 
Maximum plasma concentration  
Tmax (hr): 
Time to Cmax 
AUC0-τ (ng·hr/mL): AUC over the dosing interval τ (ie, 24 hours), calculated by the 
trapezoidal method (Linear Up/Log Down Trapezoidal Method) 
CL/F (L/hr): 
Apparent 
total 
clearance 
estimated 
according 
to: 
CL/F=Dose/AUC0-τ 
The estimated PK parameters will be summarised with N, Mean, SD, CV%, geometric 
mean, CV% Geometric Mean, median, minimum, and maximum values.  The Tmax will be 
summarised with N, Mean, SD, CV%, median, minimum, and maximum values. 


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Specification of the PK parameters for analysis and the level of statistical significance, 
together with procedures for accounting for missing, unused or spurious data, procedures 
for reporting deviations from the original statistical plan, and the selection of patients to 
be included in the analyses population(s) will be presented in the report and/or the PK 
analysis plan, as appropriate. 
PK parameters to be reported will be detailed in the PK analysis plan.  Other parameters 
may be added if appropriate. 
Non-compartmental PK calculations will be performed by using WinNonlin Version 6.2.1 
or higher. 
Population PK and PK/PD analyses will be planned and reported separately. 
 
Interim Analysis 
8.13
No interim analyses are planned for this study. 
9. 
ADMINISTRATIVE CONSIDERATIONS 
 
Investigators and Study Administrative Structure 
9.1
Sponsor 
list 
and 
contact 
information 
In Eastern and Western Europe, and Australia: 
Shionogi Ltd. 
33 Kingsway, London, WC2B 6UF, United Kingdom 
Tel: 
  
 
In North and South America, and Asia:  
Shionogi Inc. 
300 Campus Drive 
Florham Park, NJ 07932, USA 
Tel: 
Sponsor's Representative: 
 
33 Kingsway, London, WC2B 6UF, United Kingdom 
Tel: 
 
Sponsor's Study Manager: 
 
33 Kingsway, London, WC2B 6UF, United Kingdom 
Tel: 
0 
Medical Officer: 
  
33 Kingsway, London, WC2B 6UF, United Kingdom 
Tel: 
0 
Sponsor’s 
Chief 
Medical 
Officer: 
 
Shionogi & Co., Ltd. 


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 12F, Hankyu Terminal Bldg.,  
1-4, Sh ba a 1-chome, Kita-ku, Osaka 530-0012, Japan
Tel: 
 
Sponsor’s 
Global 
Project 
Leader: 
 
Shionogi & Co., Ltd. 
) 12F, Hankyu Terminal Bldg.,  
1-4, Sh ata 1-chome, Kita-ku, Osaka 530-0012, Japan
Tel: +
 
Investigator and Study Centre: 
Multicentre global study  
Medical Monitor: 
  
Tel: 
 
IVRS/IWRS:  
Cenduit Europe 
Binningerstrasse 95, CH-4123 Allschwil, Switzerland  
Tel: 
 
Central Laboratory: 
Quintiles Laboratories Europe 
Robert Stewart, Alba Campus, Rosebank, Livingston, 
West Lothian, Scotland, EH54 7EG, UK 
Bioanalytical Laboratory: 
inVentiv Health Clinical Lab 
301D College Road East 
Princeton, NJ 08540, USA 
Tel: 
 
CRO (for study monitoring 
and its quality control):  
Quintiles 
 
Quintiles Hungary Ltd. 
H-1117 Budapest, Budfoki ut 91-93, Hungary 
Tel: 
 
Email: 
 
 
 
Quintiles Italy LTd. 
Via Roma, 108 – Edificio F – Scala 2  
Cassina De’ Pecchi 20060, Italy 
Tel: 
 
Email: 
  
Emergency Contact: 
Medical Monitor: 
) 
The following additional number is also available for 


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urgent contact: 
Tel: 
 
 
Institutional Review Board Approval 
9.2
The IRB will safeguard the rights, safety, and well-being of patients in the study by 
reviewing the following study documentation: protocol, informed consent form, written 
information on patient recruitment procedures (if applicable), other written information 
given to patients, IB, safety updates, annual progress reports (if applicable), and any 
significant revisions to these documents.  These documents will be provided to the IRB 
by the investigator or the sponsor.  The IRB will be appropriately constituted in 
accordance with International Conference on Harmonisation (ICH) GCP, and local 
requirements, as applicable.  The study will commence only after the IRB has given full 
approval and the investigator has received the document being approved.   
Amendments to the protocol will be subject to the same requirements as the initial review.  
The investigator will submit periodic reports and updates to the IRB, as required, and will 
inform the IRB of any reportable AEs. 
 
Ethical Conduct of the Study 
9.3
The study will be conducted in accordance with all appropriate regulatory requirements 
and under the IRB-approved protocol.  The study will be conducted in accordance with 
current ICH GCP, all appropriate patient privacy requirements, and the ethical principles 
outlined in the Declaration of Helsinki.   
 
Patient Information and Consent 
9.4
The investigator will generate an informed consent form for the study.  The sponsor will 
provide the investigators with a proposed informed consent form that complies with ICH 
GCP guidelines and applicable regulatory requirements.  The informed consent form will 
include all the elements required by ICH GCP plus any additional elements required due 
to local regulations.  The informed consent form will be reviewed and approved by the 
appropriate IRB before use.  The sponsor must agree to any changes to the proposed 
informed consent form suggested by the investigator prior to submission to the IRB, and 
the IRB-approved version must be provided to the site monitor following IRB approval.  
Prior to each patient entering the study, the investigator or designee will explain the 
nature, purpose and methods, reasonably anticipated benefits and potential hazards of the 
study to them in simple terms using the IRB-approved informed consent form.  The 
method of obtaining and documenting informed consent will comply with ICH GCP and 
all applicable regulatory requirement(s). 
 
Patient Confidentiality 
9.5
Patient privacy must adhere to all applicable data privacy laws and regulations.  In order 
to maintain patient privacy, all CRFs, study drug accountability records, study reports, 
and communications will identify the patient by their patient number.  The investigator 
will grant site monitor(s) and auditor(s) of the sponsor or designee, as well as regulatory 
authority(ies), access to all source documents for verification of data collected on the 
CRFs and for verification of the data collection process.  The patient’s confidentiality will 


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be maintained and will not be made publicly available to the extent permitted by the 
applicable laws and regulations.  Appropriate consent and authorisations for use and 
disclosure and/or transfer (if applicable) of protected information must be obtained. 
Patient data collected on the CRF during the study will be documented in an anonymous 
manner and patients will only be identified by a patient identification number.  In the 
event that it is necessary to identify a patient for safety or regulatory reasons, the sponsor 
and investigator are required to keep this information confidential. 
 
Study Monitoring 
9.6
The sponsor and designated study monitors will monitor the study to ensure that it is 
conducted in accordance with ICH GCP requirements and the IRB-approved protocol.  
Study monitoring will be performed by a representative of the sponsor (site monitor) 
through on-site monitoring visits as frequently as necessary and through frequent 
communications (e-mail, letter, telephone, and fax).  The site monitor will review data 
recorded on the CRFs, verify the CRF entries directly against the source documents, 
collect any safety/efficacy information on patients, verify that amounts of unused study 
drug are accurate, and check retention of source documents and essential documents.   
 
Case Report Forms and Source Documents 
9.7
 
Case Report Forms 
9.7.1
The term CRF should be understood to refer to either a paper form or an electronic data 
record or both, depending on the data collection method used in this study.  The sponsor 
or designee will supply CRFs for each randomised patient.  Historical information and 
study data, specified in the protocol, will be recorded on the CRFs by the investigator or 
designee.  All patient data from each study visit must be collected on source documents 
and must be promptly entered on the CRFs in accordance with the specific instructions 
given.  CRF entries will be performed by an investigator or designee, and the study 
coordinator who are authorised to complete such documentation.  It is the investigator’s 
responsibility to ensure completion and to review and approve all CRFs.  CRFs must be 
signed by the investigator.  These signatures serve to attest that the information contained 
on the CRFs is true.  At all times, the investigator has final personal responsibility for the 
accuracy and authenticity of all clinical and laboratory data entered onto the CRFs.  
Patient source documents are the physician’s patient records maintained at the trial site.  
In most cases, the source documents will be the hospital's or the physician’s chart and 
information collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, Shionogi 
and the investigator must prospectively document which items will be recorded in the 
source documents and for which items the CRF will stand as the source document. 
If queries are generated by the sponsor or designee to the participating medical 
institutions for resolution, the CRF data will be changed or a response will be recorded in 
accordance with the specific instructions given.   
A list of reference ranges for all laboratory tests to be undertaken will be part of the 
documentation collected prior to study initiation.  These should be updated if they are 
changed during the study.  If a central laboratory has been used to perform any or all of 
the tests, it is essential that all reference ranges for the laboratory tests analysed at that 


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laboratory should be collected.   
 
Source Documents 
9.7.2
Source documentation supporting the CRF data should indicate the patient’s participation 
in the study, and should document the dates and details of all study procedures, AEs, and 
patient status.  However, the following data can be directly recorded on the CRF:  
• severity, seriousness, outcome, causal relationship to the study drug of AEs 
• reason for withdrawal  
• reason for use of concomitant therapy 
• any comments inserted into CRF 
The items listed below are only recorded on the CRF (ie, items automatically-calculated 
by the electronic data capture [EDC] system): 
• age at informed consent 
• total score and class of Child-Pugh 
• body mass index 
The investigator must maintain source documents, such as laboratory reports, complete 
medical history, and physical examination reports.  All source documents should be 
accessible for verification by the site monitor, auditor, the IRB, or for inspections by the 
regulatory authorities.  Direct access to these documents must be guaranteed by the 
investigator or designee, or the study coordinator, who must provide support at all times 
for these activities.  The nature and location of all sources of original data required to 
complete the CRF will be identified by the sponsor and the site staff.  If electronic records 
are maintained at the medical institution, the method of verification must be specified in 
documents within that medical institution.   
 
External Data  
9.7.3
The following data will not be included in the CRF.  Those will be separately reported.   
• laboratory data (expect for platelet count) 
• plasma S-888711 concentrations 
 
Committees 
9.8
 
Case Review Committee  
9.8.1
Prior to database lock, the sponsor, together with the medical officer, will review all data 
reported on the CRFs for all patients under blind conditions.  At the case review 
committee meeting, the sponsor will decide which patients will be included in the 
analysis populations based on the definition of each population (see Section 8.3) and each 
patient's results.  The case review committee will also evaluate whether medical decisions 
made by the investigators were appropriate for important data affecting the safety and 
efficacy endpoints.   


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Independent Safety Committee  
9.8.2
An Independent Safety Committee will review results of thrombotic/thromboembolic 
events and report back to the sponsor.  The procedures for review, including maintaining 
the blind, and for management of the committee will be specified in a separate document. 
 
Coordinating Committee  
9.8.3
Not applicable to this study.  
 
Termination or Suspension of the Study 
9.9
 
Termination or Suspension of the Entire Study 
9.9.1
The sponsor may prematurely terminate or suspend the study at any time for the 
following reasons:   
• Ensuring the safety of the patients is difficult due to safety concerns (eg, occurrence of 
many serious ADRs) 
• Achieving the purpose of the study is considered impossible (eg, inadequate 
recruitment of patients) 
If the study is prematurely terminated or suspended, the sponsor should promptly inform 
the investigators.  The investigator or designee should promptly inform the participating 
patients and change the study medication to other appropriate therapy(ies).   
For withdrawal criteria for individual patients, see Section 7.9. 
 
Termination or Suspension of the Study by Medical Institution 
9.9.2
The investigator may prematurely terminate or suspend the study at their medical 
institution with the agreement of the sponsor.  This may be done at any time during the 
study if they consider that ensuring patient safety during the study is difficult due to 
safety concerns (eg, occurrence of many SAEs). 
The sponsor may request that the investigator prematurely terminates or suspends the 
study at their medical institution at any time during the study if major 
violations/deviations of the protocol, other procedures, or ICH GCP have not been 
improved. 
If the study is prematurely terminated or suspended, the investigator or designee should 
promptly inform the corresponding IRB and any participating patients, and should change 
the study medication to other appropriate therapy(ies).   
 
Protocol Deviations and Modifications 
9.10
The investigator will conduct the study in compliance with the protocol provided by the 
sponsor, which has received approval/favourable opinion by the IRB and the regulatory 
authority(ies).  Modifications to the protocol should not be performed without agreement 
of both the investigator and the sponsor.  Changes to the protocol will require written IRB 
approval/favourable opinion prior to implementation, except when a modification is 
needed to eliminate an immediate hazard(s) to the patients.   
The investigator or designee should document any deviation from the protocol, together 


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with the reason for such a deviation.  If the investigator deviates from the protocol or a 
protocol amendment in order to eliminate an immediate hazard(s) to the patients, they 
should submit a record of the deviation to the sponsor, the medical institution, and the 
IRB immediately.  The IRB will provide an expedited review and grant 
approval/favourable opinion if appropriate.  After the investigator has obtained 
approval/favourable opinion from the IRB, they should obtain written agreement for the 
change from the sponsor. 
When deviations from the protocol are required to eliminate an immediate hazard(s) to 
patients, the investigator will contact the sponsor, if circumstances permit, to discuss the 
planned course of action.  Any deviations from the protocol must be fully documented on 
the source documentation. 
 
Data Management 
9.11
The sponsor (Shionogi & Co., Ltd.) will be responsible for data management and data 
analysis.  These procedures are specified in a separate document. 
 
Retention of Data 
9.12
To enable evaluations and/or audits from regulatory authorities or Shionogi, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRF, hospital records), all original signed 
informed consent forms, source documents, and detailed records of treatment disposition.  
The study documents should be retained by the investigator according to ICH GCP, local 
regulations, or as specified in the Clinical Study Agreement, whichever is longer.  The 
investigator and study centre should take measures to prevent accidental or premature 
destruction of these documents. 
If the sponsor is granted manufacturing and marketing approval for the drug, they will 
promptly notify the head of the study centre and the investigator. 
Records will be retained for one of the following periods of time (whichever is longest):  
• at least 2 years after the last marketing application approval 
• 2 years after formal discontinuation of the clinical development of the investigational 
product 
If the investigator relocates, retires, or for any reason withdraws from the study, Shionogi 
should be prospectively notified.  The study documents must be transferred to an 
acceptable designee, such as another investigator, another institution, or to Shionogi.  The 
investigator must obtain Shionogi’s written permission before disposing of any records, 
even if the retention requirements have been met. 
 
Quality Control and Assurance 
9.13
The sponsor will implement and maintain quality control and quality assurance 
procedures with written standard operating procedures to ensure that the study is 
conducted and data are generated, documented, and reported in compliance with the 
protocol, ICH GCP, and all applicable regulatory requirements.  This study will be 
conducted in accordance with the provisions of the Declaration of Helsinki and all 
revisions thereof, in accordance with ICH GCP, and as required by applicable regulatory 
requirements. 


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Necessary training for the study will be provided to investigators and any other required 
study centre personnel by the sponsor or appropriate designee prior to study initiation. 
 
Publication and Disclosure Policy 
9.14
All information on S-888711 supplied by the sponsor to the investigator is privileged and 
confidential.  The investigator agrees to use this information to perform the study and will 
not use it for any other purposes without consent from the sponsor.  It is understood that 
there is an obligation to provide the sponsor with complete data obtained during the 
course of the study.  Information obtained from the clinical trial will be used for the 
development of S-888711 and may be disclosed to regulatory authority(ies), other 
investigators, corporate partners, or consultants as required. 
The sponsor will retain ownership of all data.  All proposed publications based on the 
study will be subject to the sponsor's approval requirements which will be detailed in the 
Clinical Study Agreement 
The key design elements of this protocol will be posted in a publicly accessible database.  


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10. 
 REFERENCE LIST 
 
Reference Materials 
10.1
S-888711 Investigator's Brochure Version 8 
 
Publications 
10.2
1. 
Roberts HW, Utuama OA, Klevens M, Teshale E, Hughes E, Jiles R. The 
contribution of viral hepatitis to the burden of chronic liver disease in the United 
States. Am J Gastroenterol. 2014;109(3):387-93. 
2. 
Murphy SL, Xu J, Kochanek KD. Deaths: Final data for 2010. National Vital 
Statistics 
Reports. 
2013;61(4). 
www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_04.pdf Accessed on 20 Jun 2014. 
3. 
Blachier M, Leleu H, Peck-Radosavljevic M, Valla D-C, Roudot-Thoraval F. 
The burden of liver disease in Europe: a review of available epidemiological data. 
J Hepatol. 2013;58(3):593-608. 
4. 
Rahimi RS, Rockey DC. Complications and outcomes in chronic liver disease. 
Curr Opin Gastroenterol. 2011;27(3):204-9. 
5. 
Afdhal N, McHutchison J, Brown R, et al. Thrombocytopenia associated with 
chronic liver disease. J Hepatol. 2008;48(6):1000–7.  
6. 
Hayashi H, Beppu T, Shirabe K, Maehara Y, Baba H. Management of 
thrombocytopenia due to liver cirrhosis: a review. World J Gastroenterol. 
2014;20(10):2595-605. 
7. 
American National Red Cross. A Compendium of Transfusion Practice 
Guidelines. 2010. 
8. 
Blumberg N, Heal JM, Phillips GL. Platelet transfusions: trigger, dose, benefits, 
and risks. F1000 Med Rep. 2010;2:5. Published online Jan 27, 2010. doi: 
10.3410/M2-5. 
9. 
Klingemann HG, Self S, Banaji M, Deeg HJ, Doney K, Slichter SJ, et al. 
Refractoriness to random donor platelet transfusions in patients with aplastic 
anaemia: A multivariate analysis of data from 264 cases. Br J Haematol. 
1987;66:115-21. 
10. 
Legler TJ, Fischer I, Dittmann J, Simson G, Lynen R, Humpe A, et al. Frequency 
and causes of refractoriness in multiply transfused patients. Ann Hematol. 
1997;74:185-9. 
11. 
Goulis J, Chau TN, Jordan S, Mehta AB, Watkinson A, Rolles K, et al. 
Thrombopoietin concentrations are low in patients with cirrhosis and 
thrombocytopenia and are restored after orthotopic liver transplantation. Gut. 
1999;44:754-8. 
12. 
Eissa LA, Gad LS, Rabie AM, El-Gayar AM. Thrombopoietin level in patients 
with chronic liver diseases. Ann Hepatol. 2008;7:2227-36. 
13. 
McHutchison GJ, Dusheiko G, Shiffman LM, et al. Eltrombopag for 
Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C. N 
Engl J Med. 2007;357(22):716-24. 


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14. 
Afdhal NH, Giannini EG, Tayyab G, et al. Eltrombopag before procedures in 
patients 
with 
cirrhosis 
and 
thrombocytopenia. 
N 
Engl 
J 
Med. 
2012;367(8):716-24. 
15. 
Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer 
treatment. Cancer. 1981;47(1):207-14. 
16. 
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection 
of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646-9.  
17. 
The 
Eastern 
Cooperative 
Oncology 
Group. 
http://www.ecog.org/general/perf_stat.html. Accessed on 20 Jun 2014. 
18. 
FDA draft guidance. Drug Interaction Studies   Study Design, Data Analysis, 
Implications for Dosing, and Labelling Recommendations. February 2012. 
 


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Appendix 1: 
Time and Events Schedule  
 
Screening
Treatment Period
Post-treatment Period (Invasive Procedure, Days 9 to 14)
With- 
drawala 
Unsche 
duledb 
Study Day 
From 
Day 
−28 
Day 1
Day 
2 
Day
 3
Day
 4
Day 
5 
Day 
6 
Day 
7 
Day  
8 
Day  
9 
Day 
10
Day 
11
Day 
12
Day
13
Day 
14
Day 
17
Day 
21
Day 
28
Day 
35 
Pre-
dosing
Post-
dosing
Informed consent
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography (including body weight 
and height) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrolment (IVRS/IWRS) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation (IVRS/IWRS) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug assignment (IVRS/IWRS) 
 
 
 
 
 
 
Xc
(X)c
(X)c
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Type of CLD and severity of liver 
disorder (Child-Pugh) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gastro-oesophageal varicesd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Splenomegaly and severity of ascitese 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine)
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Physical examination 
X 
X 
 
 
 
 
X
X
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Xb 
Portal vein thrombosis assessment f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg
 
 
 
 
X 
Xb 
Portal blood flow (direction) h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xg
 
 
 
 
X 
Xb 
WHO Bleeding Scale 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Xg
 
 
 
X 
X 
 
Blood pressure, pulse rate 
X 
X 
 
 
 
 
X
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Xb 
Electrocardiography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Xb 
Platelet count (local laboratory)  
X 
X 
 
 
 
 
Xi
Xi
Xi
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Xb 
Haematology except for platelet count  
(central laboratory) 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Xb 
Blood chemistry 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Xb 


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Screening
Treatment Period
Post-treatment Period (Invasive Procedure, Days 9 to 14)
With- 
drawala 
Unsche 
duledb 
Study Day 
From 
Day 
−28 
Day 1
Day 
2 
Day
 3
Day
 4
Day 
5 
Day 
6 
Day 
7 
Day  
8 
Day  
9 
Day 
10
Day 
11
Day 
12
Day
13
Day 
14
Day 
17
Day 
21
Day 
28
Day 
35 
Pre-
dosing
Post-
dosing
Blood coagulation/fibrinolysis assayj 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
Xb 
Immunological tests/other tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of study medication 
 
 
X 
X
X
X
Xc,k
Xc,k
Xc,k
 
 
 
 
 
 
 
 
 
 
 
 
 
Invasive procedure 
 
 
 
 
 
 
 
 
 
 
 
 
Xl
 
 
 
 
 
 
 
 
 
Sampling 
for 
plasma 
drug 
concentration (Sparse PK)m 
 
 
 
 
 
 
X
X
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sampling 
for 
plasma 
drug 
concentration (Intensive PK)n 
 
 
 
 
 
 
X
X
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
Applied to both study medication withdrawn and study assessment withdrawn, except for a patient with drug withdrawn because of the administration stopping criterion 
(ie, platelet count ≥ 50 × 109/L with an increase of ≥ 20 × 109/L from baseline). 
b 
Only necessary assessments will be performed. 
c 
If platelet count on Day 5, 6 or Day 7 is ≥ 50 × 109/L with an increase of ≥ 20 × 109/L from baseline, a patient must stop taking study medication.  
d 
Confirmed by upper gastrointestinal endoscopy.  If data on upper gastrointestinal endoscopy are obtained within 180 days before randomisation, the data can be used. 
e 
Confirmed by ultrasonography, CT, or MRI.  If ultrasonography, CT, or MRI is performed within 28 days before randomisation, the image can be used for assessing the 
presence or absence of splenomegaly.    
f 
Confirmed by ultrasonography, CT, or MRI in the Screening period and after the invasive procedure.  The Screening investigation should be arranged as close to 
randomisation as possible.  However, if gastro-oesophageal varices are treated, portal vein thrombosis will be confirmed with the image obtained after the treatment.     
g 
Performed within 3 to 10 days after the invasive procedure.  When any additional invasive procedure is performed, the assessment of bleeding events as graded on the 
WHO Bleeding Scale, portal vein thrombosis, and portal blood flow will be performed before and after the invasive procedure. 
h 
Confirmed by Doppler ultrasonography (at Screening, the investigation should be as close to randomisation as possible). 
i 
Blood samples will be collected before study medication. 
j 
Antithrombin III activity, fibrinogen, fibrin degradation products, D-dimer, Protein C activity, free protein S antigen, von Willebrand factor activity will be performed 
only at Screening.  Prothrombin time (international normalised ratio value) and activated partial thromboplastin time will be performed at Screening, Day 1, Day 8, 
Day 14, and Day 35. 
k  Administered after platelet count is confirmed and drug assignment.  
l  
Performed between Days 9 and 14.  
m  All patients except for Intensive PK; pre-dose, 2 to 4 hours post-dose on Day 5, and pre-dose on Days 6 and 7.  
n 
At least 20 patients; pre-dose, 2, 4, 6, 8 hours post-dose on Day 5, pre-dose on Days 6 and 7.   


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Appendix 2: 
List of Laboratory Tests 
Test 
Items Evaluated 
Haematology 
Platelet count 
Haematology 
(except for platelet 
count) 
Red blood cell count, white blood cell count, haemoglobin, and haematocrit 
Blood chemistry 
Aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, gamma 
glutamyl transferase, alkaline phosphatase, total bilirubin, bilirubin direct, indirect 
bilirubin, total protein, albumin, blood urea nitrogen, serum creatinine, sodium, 
potassium, chloride, and calcium 
Blood coagulation/ 
fibrinolysis assay  
Prothrombin time (international normalised ratio value), activated partial 
thromboplastin time, antithrombin III activitya, fibrinogena, fibrin degradation 
productsa, D-dimera, protein C activitya, free protein S antigena, and von Willebrand 
factor activitya 
Immunologicala 
Platelet-associated IgG, antiplatelet antibody, Helicobacter pylori antibody IgG  
Othera 
Thrombopoietin 
a Only at Screening. 
 


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Appendix 3: 
Child-Pugh Class 
Child-Pugh Class[16] 
Point 
Measurement 
1 point 
2 points 
3 points 
Hepatic encephalopathy  
None 
Grade I-II (or 
suppressed with 
medication) 
Grade 
III-IV 
(or 
refractory) 
Ascites  
None 
Mild 
Moderate to Severe 
Serum bilirubin (µmol/L [mg/dL])  
<34 (<2.0) 
34 – 50 (2.0 - 3.0) 
>50 (>3.0) 
Serum albumin (g/L)  
>35 
28 - 35 
<28 
Prothrombin 
time-international 
normalised ratio value (PT-INR)  
<1.71 
1.71 - 2.30 
>2.30 
Points for each measurement are totalled and the total score is used for determination of classification: Class A, 5 to 6 
points; Class B, 7 to 9 points; Class C, 10 to 15 points. 
 


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Appendix 4: 
List of Example Invasive Procedures 
Region 
Type of Surgery 
Liver 
• radiofrequency ablation (RFA) 
• percutaneous microwave coagulation therapy (PMCT) 
• percutaneous ethanol injection therapy (PEIT) 
• transcatheter arterial embolisation (TAE)/transhepatic arterial infusion 
(TAI)/transcatheter arterial chemoembolisation (TACE) 
• endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) 
• laparoscopic radiofrequency ablation (LRA) 
• laparoscopic microwave coagulation (LMC) 
Biliary-pancreas  
• endoscopic metallic stenting (EMS) 
• endoscopic sphincteropapillotomy (EST) 
• endoscopic papillary balloon dilatation (EPBD) 
• endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) 
Gastrointestinal tract 
• endoscopic polypectomy 
• endoscopic submucosal dissection (ESD) 
• endoscopic mucosal resection (EMR) 
• percutaneous endoscopic gastrostomy (PEG) 
• endoscopic variceal ligation (EVL) 
• endoscopic injection sclerotherapy (EIS) 
• endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) 
Urinary system 
• transurethral resection of the bladder tumour (TURBT) 
• transurethral ureterolithotripsy (TUL) 
Other regions 
• percutaneous needle biopsy 
• laparoscopy 
• arthroscopic surgery 
• endoscopy with possible biopsy 
• various paracenteses 
• tooth extraction 


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Appendix 5: 
ECOG Performance Status 
ECOG Performance Status[17] 
Grade 
ECOG Performance Status 
0  
Fully active, able to carry on all pre-disease performance without restriction  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work  
2  
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and about 
more than 50% of waking hours  
3  
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours  
4  
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair  
5 
Dead 


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Appendix 6: 
List of P-gp and BCRP Inhibitors 
List of P-gp and BCRP Inhibitors[18] 
P-gp Inhibitor 
BCRP Inhibitor 
Amiodarone, azithromycin, captopril, carvedilol, 
clarithromycin, conivaptan, cyclosporine, diltiazem, 
dronedarone, erythromycin, felodipine, itraconazole, 
ketoconazole, lopinavir, and ritonavir, quercetin, 
quinidine, ranolazine, ticagrelor, verapamil 
Cyclosporine, elacridar (GF120918), eltrombopag, 
gefitinib 
 
 


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Appendix 7: 
WHO Bleeding Scale 
WHO Bleeding Scale[15] 
Grade 
WHO Bleeding Scale 
0 
No bleeding 
1 
Petechial bleeding 
2 
Mild blood loss (clinically significant) 
3 
Gross blood loss, requiring transfusion (severe) 
4 
Debilitating blood loss, retinal or cerebral, associated with fatality 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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Appendix 9: 
Investigator’s Signature 
 
INVESTIGATOR SIGNATURE 
Study Title: 
A Phase 3 Randomised, Double-blind, Placebo-controlled Study to 
Assess the Safety and Efficacy of S-888711 (Lusutrombopag) for the 
Treatment of Thrombocytopenia in Patients with Chronic Liver 
Disease Undergoing Elective Invasive Procedures (L-PLUS 2) 
Study Number: 
1423M0634 
I agree with the content of this protocol and the confidential nature of the documentation 
made as part of this study.  I also acknowledge that the sponsor of the study has the right 
to discontinue the study at any time.  I have read the protocol and understand it and will 
work according to it and according to the principles of GCP, applicable laws and 
regulations, and the Declaration of Helsinki. 
 
 
 
 
 
 
Principal Investigator 
Date 
 
 
Name and Qualifications: 
 
 
 
Institution and Address:  
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Shionogi study title 
A Phase 3 Randomised, Double-blind, Placebo-controlled Study to 
Assess the Safety and Efficacy of S-888711 (Lusutrombopag) for 
the Treatment of Thrombocytopenia in Patients with Chronic Liver 
Disease Undergoing Elective Invasive Procedures (L-PLUS 2) 
Shionogi study no. 
1423M0634 
ClinicalTrials.gov 
registration no. 
NCT02389621 
Study document 
Statistical analysis plan 
 


STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3 Randomised, Double-blind, Placebo-controlled Study to 
Assess the Safety and Efficacy of S-888711 (Lusutrombopag) for 
the Treatment of Thrombocytopenia in Patients with Chronic Liver 
Disease Undergoing Elective Invasive Procedures (L-PLUS 2)
Study Number:
1423M0634
Study Phase:
3
Product Name:
S-888711 (Lusutrombopag)
Sponsor:
Shionogi & Co., Ltd., Shionogi Inc., Shionogi Ltd.
Issue Date:
5 June 2017 (Version 2.0)
Confidentiality Statement
This document and the information contained herein or attached hereto (“Confidential 
Material”) are confidential and proprietary to Shionogi & Co., Ltd. This Confidential 
Material should only be viewed by those individuals or companies that have been given 
prior written authorisation to do so by Shionogi & Co., Ltd. (“Authorised Users”). This 
Confidential Material should not be made available in any form to any person or 
company, other than the Authorised Users and their respective employees or associates 
on a need-to-know basis, without the written consent from Shionogi & Co., Ltd.




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AMENDMENT HISTORY
Version
Date
Author
Remarks
1.0
17 Apr 2015 
First version
2.0
5 Jun 2017 
Major revisions are as follows. 
y Added an ITT analysis for the 
duration of the increase in platelet 
count (see Sections 6.2 and 9.2.3).
y Added a sensitivity analysis for the 
primary endpoint based on platelet 
count at platelet transfusion 
assessment.
y Removed summary of significant 
TEAEs from Section 10.1.
y Revised the descriptions to clarify 
the definition or data handling. 
y Added Appendix 3.


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TABLE OF CONTENTS
SIGNATURE PAGE ...........................................................................................................2 
AMENDMENT HISTORY .................................................................................................3 
TABLE OF CONTENTS .....................................................................................................4 
LIST OF TABLES ...............................................................................................................5 
ABBREVIATIONS .............................................................................................................6 
1. 
INTRODUCTION .......................................................................................................7 
2. 
STUDY OVERVIEW ..................................................................................................7 
3. 
STUDY OBJECTIVES ................................................................................................8 
3.1 
Primary Objective ..............................................................................................8 
3.2 
Secondary Objective(s) ......................................................................................8 
4. 
STUDY DESIGN ........................................................................................................8 
4.1 
Schedule of Assessments ...................................................................................8 
4.2 
Study Blinding and Randomization ...................................................................8 
4.3 
Determination of Sample Size ...........................................................................9 
5. 
ANALYSIS POPULATIONS .....................................................................................9 
5.1 
Intention-to-Treat (ITT) Population ...................................................................9 
5.2 
Per Protocol (PP) Population .............................................................................9 
5.3 
Safety Analysis Population ..............................................................................10 
6. 
OVERALL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING ...10 
6.1 
Statistical Reporting .........................................................................................10 
6.2 
Statistical Testing .............................................................................................10 
6.3 
Analysis Visit ...................................................................................................11 
6.4 
Handling of Missing Data ................................................................................11 
6.5 
Definition .........................................................................................................12 
6.5.1 
Study Day...............................................................................................12 
6.5.2 
Baseline ..................................................................................................12 
6.5.3 
Last Observation ....................................................................................12 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................12 
7.1 
Patient Disposition and Withdrawals ...............................................................12 
7.2 
Demographic and Baseline Characteristics .....................................................12 
8. 
STUDY CONDUCT ..................................................................................................13 
8.1 
Protocol Deviation ...........................................................................................13 
8.2 
Treatment Exposure .........................................................................................13 
8.3 
Concomitant Medication ..................................................................................13 
9. 
EFFICACY ................................................................................................................14 
9.1 
Primary Endpoint .............................................................................................14 


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9.1.1 
Primary Analysis ....................................................................................15 
9.1.2 
Sensitivity Analysis ...............................................................................15 
9.2 
Secondary Endpoints .......................................................................................16 
9.2.1 
Proportion of Patients Requiring no Platelet Transfusion During the 
Study ......................................................................................................16 
9.2.2 
Proportion of Responders ......................................................................17 
9.2.3 
Duration of the Increase in Platelet Count .............................................17 
9.2.4 
Proportion of Patients who Required Rescue Therapy ..........................18 
9.2.5 
Frequency of Platelet Transfusion and Dose (Unit) Transfused 
During the Study ....................................................................................18 
9.2.6 
Time Course of Platelet Count ...............................................................18 
10. SAFETY ....................................................................................................................19 
10.1 
Adverse Events ................................................................................................19 
10.2 
Adverse Events of Special Interest ..................................................................21 
10.3 
WHO Bleeding Scale .......................................................................................21 
10.4 
Vital Signs ........................................................................................................21 
10.5 
Electrocardiography .........................................................................................21 
10.6 
Laboratory Tests ..............................................................................................21 
10.7 
Portal Vein Thrombosis and Portal Blood Flow ..............................................22 
11. INTERIM ANALYSES .............................................................................................23 
12. PROGRAMMING CONVENTIONS ........................................................................23 
13. CHANGES FROM PROTOCOL ..............................................................................23 
Appendix 1 
Time and Events Schedule .....................................................................24 
Appendix 2 
Testing Procedure for Primary and Important Secondary Endpoints ....26 
Appendix 3 
Calculation p-value and Confidence Interval for 
Cochran-Mantel-Haenzel Test ...................................................................................27 
Appendix 4 
CTCAE Term and Criteria for Classification ........................................29 
LIST OF TABLES
Table 1 
Analysis Visit Windows ...........................................................................11 
Table 2 
Demographic and Baseline Characteristics ..............................................13 
Table 3 
Priority of Categories ................................................................................20 
Table 4 
List of Laboratory Tests ............................................................................22 
Table 5 
Displayed Digits of Statistics....................................................................23 


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ABBREVIATIONS
AE(s)
adverse event(s)
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body mass index
CI
confidence interval
CLD
chronic liver disease
CMH
Cochran-Mantel-Haenszel
CRO
Contact Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
ECG
Electrocardiography
ECOG
Eastern Cooperative Oncology Group
EIS
endoscopic injection sclerotherapy
EVL
endoscopic variceal ligation
ICSA
Individual Clinically Significant Abnormalities
ITT
intention-to-treat
IVRS/IWRS
Interactive Voice or Web Response System
MCT
microwave coagulation therapy
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PK
pharmacokinetics
PP
per protocol
PT-INR
prothrombin time-international normalized ratio 
RFA
radiofrequency ablation
SAE(s)
serious adverse event(s)
SAP
statistical analysis plan
SMQ
standard MedDRA queries
SUSAR
suspected unexpected serious adverse reaction
TACE
transcatheter arterial chemoembolization
TAE
transcatheter arterial embolization
TEAE(s)
treatment-emergent adverse event(s)
WHO
World Health Organization


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1.
INTRODUCTION
This “Statistical Analysis Plan (SAP)” presents details, including technical matters, of the 
efficacy and safety analyses described in Section “8. STATISTICAL ANALYSIS” of the 
protocol 1423M0634 for the clinical trial entitled “A Phase 3 Randomised, Double-blind, 
Placebo-controlled Study to Assess the Safety and Efficacy of S-888711 
(Lusutrombopag) for the Treatment of Thrombocytopenia in Patients with Chronic Liver 
Disease (CLD) Undergoing Elective Invasive Procedures (L-PLUS2)”. Details of output 
(or mock-ups of tables, listings and figures) from analyses in this SAP, will be included 
in the document prepared separately. Details of the analyses of pharmacokinetics (PK)
and pharmacokinetics/pharmacodynamics will also be described in a separate document. 
All the analyses described in this SAP will be performed in the Biostatistics Dept., 
Shionogi & Co., Ltd. 
2.
STUDY OVERVIEW
This is a phase 3, multinational, randomized, double-blind, placebo-controlled study to 
assess the safety and efficacy of S-888711 for the treatment of thrombocytopenia in 
patients with CLD undergoing elective invasive procedures. The study consists of 3 
periods:  
x
Screening period: up to 28 days prior to randomization  
x
Treatment period: up to 7 days (Days 1 to 7) 
x
Post-treatment period: through 28 days post-treatment  
The maximum study duration for each patient will be 63 days. Potential patients who 
provide written informed consent will be screened for eligibility, and eligible patients
will be randomized in a 1:1 ratio toeither S-888711 3 mg once daily for up to 7 days or 
matched placebo control. The randomization will be stratified by primary invasive 
procedure (liver ablation/coagulation or other invasive procedures) and baseline platelet 
count (< 35 × 109/L or ≥ 35 × 109/L). 
Patients will begin once daily treatment with assigned study medication on Day 1 after 
randomization and will receive study medication for up to 7 days. A platelet count will be 
performed on Days 5, 6, and 7 prior to administration of study medication. After the final 
dose of study medication, patients will continue the protocol-specified assessments and 
procedures in the Post-treatment period.  
The planned invasive procedure will be performed in the Post-treatment period between 
Days 9 and 14. A platelet count will be performed on or after Day 8, but no more than 
2 days prior to the elective invasive procedure in order to assess the need for a platelet 
transfusion before the planned elective procedure. A preoperative platelet transfusion 
must be performed if the platelet count is < 50 × 109/L.


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Study Schematic
3.
STUDY OBJECTIVES
Primary Objective
3.1
The primary objective of this study is to compare the efficacy of S-888711 with placebo 
for the treatment of thrombocytopenia in patients with CLD who are undergoing elective 
invasive procedures.
Secondary Objective(s)
3.2
The secondary objectives of the study are:
x
To assess the safety and tolerability of S-888711 treatment compared with 
placebo.
x
To assess the platelet response following treatment with S-888711 compared with 
placebo.
x
To assess the pharmacodynamics (PD) and PK of S-888711.
4.
STUDY DESIGN
Schedule of Assessments
4.1
Schedule of assessments is shown in Appendix 1.
Study Blinding and Randomization
4.2
The study will be conducted in a double-blind manner using a placebo matching the 
active drug in appearance, labelling and packaging. An IVRS/IWRS will be used for 
central patient randomization and study drug assignment. IVRS/IWRS will assign drug 
identifiers according to a randomization schedule. Only an unblinded Contract Research 
Organization (CRO) or designee will have the authority to assign the drug identifiers. All 
patients, the investigator, all study personnel, and data analysts will be blinded to the 


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treatment assigned at randomization until database lock. The randomization schedule will
be kept confidential and will not be accessible to anyone until unblinding, except for 
Drug Supply Management staff, IVRS/IWRS Clinical Coordinator(s), IVRS/IWRS 
vendor staff, unblinded statistician on the Independent Safety Committee, and for 
reporting suspected unexpected serious adverse reaction (SUSAR) as required by local 
regulation.
Eligible patients will be randomized to one of the two treatment groups (S-888711 3 
mg/day for up to 7 days, or placebo for up to 7 days) in a ratio of 1:1. Randomization will
be stratified by the primary invasive procedure and the platelet count at baseline as 
follows: 
x
Primary invasive procedure: liver ablation/coagulation or other invasive 
procedures
x
Platelet count at baseline: < 35 × 109/L or ≥ 35 × 109/L
Determination of Sample Size
4.3
Two hundred patients with CLD and thrombocytopenia who are scheduled to undergo 
elective invasive procedures will be randomized into either of two treatment groups (100
patients per group). 
In the phase 3 study (Study 1304M0631) conducted in Japan, the proportion of patients 
who required no platelet transfusion prior to the primary invasive procedure was 79.2% 
in the S-888711 3 mg group and 12.5% in the placebo group. The difference in the
proportion of patients was 66.7% and its 95% confidence interval (CI) was [51.9%, 
81.5%]. Based on the results, it was assumed that the difference in the primary endpoint 
to be obtained in this study is 50% between S-888711 and placebo groups. Assuming that 
the proportion of patients who meet the primary endpoint is 20% in the placebo group 
and 70% in the S-888711 treatment group, 100 patients per arm will provide 99% power 
to detect a difference of 50% between S-888711 and placebo groups at a two-sided 
significance level of 0.05. 
With 100 patients per arm, from the safety point of view, the sample size will assure at 
least 95% probability to detect an adverse event (AE) with an incidence of 3% or more.
5.
ANALYSIS POPULATIONS
Intention-to-Treat (ITT) Population
5.1
Intention-to-Treat (ITT) Population will include all randomized patients. Patients will be 
analyzed according to the treatment to which they were randomized. This population is
the primary population for the analysis of efficacy.
Per Protocol (PP) Population
5.2
Per Protocol (PP) Population will include all randomized patients who have no major
protocol deviations pertaining to the efficacy evaluation. These deviations will be 


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determined prior to unblinding of the study data. This population will be used in a 
sensitivity analysis of the primary endpoint.
Safety Analysis Population
5.3
Safety Analysis Population will include all randomized patients who actually receive at 
least 1 dose of the study drug. Patients will be analyzed by the treatment they actually 
received, rather than by the designated treatment to which they were randomized. If 
patients received both S-888711 and placebo, they will be considered as the S-888711
group. This population is the primary population for the analysis of safety.
6.
OVERALL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING
Statistical Reporting
6.1
In principle, summary statistics, including the number of patients, arithmetic mean, 
standard deviation (SD), median, and minimum and maximum values, will be calculated 
for continuous variables. The number and proportion of patients in each category will be 
calculated for categorical variables.
In general, all tabulations will be presented by treatment group. Individual patient data 
and any derived data will be summarized by treatment group and listed by patient. All the 
analyses and listings will be performed using SAS Version 9.2 or higher.
Statistical Testing
6.2
Unless otherwise noted, all statistical tests will be performed at a two-sided significance 
level of 0.05.
A gatekeeping procedure will be employed for sequentially testing the important 
secondary endpoints (see Appendix 2). If the primary endpoint is statistically significant, 
the secondary endpoints will be tested at the 0.05 level (two-sided) in sequence.
Sequential testing for the secondary endpoints will be conducted in the following order:
x
The comparison between S-888711 and placebo in the proportion of patients who 
require no platelet transfusion during the study
x
The comparison between S-888711 and placebo in the proportion of responders: 
patients who achieve a platelet count of ≥ 50 × 109/L, with an increase of ≥ 20 × 
109/L from baseline at any time during the study
x
The comparison between S-888711 and placebo in the duration of platelet count ≥ 
50 × 109/L
x
The comparison between S-888711 without platelet transfusion and placebo with 
platelet transfusion in the duration of platelet count ≥ 50 × 109/L


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Analysis Visit
6.3
Analysis visit windows are defined as shown in Table 1 to determine the analysis value 
for each study visit. Measurements collected outside of the visit window will be 
considered missing for that study visit. For all patients with multiple values within a visit 
window, the value obtained closest to the target study day will be used. In the case of 
multiple observations equidistant to the study visit date, the later one will be used, unless 
otherwise noted. Only for screening visit, the earliest one will be used for analysis if 
multiple values were obtained within 28 days prior to randomization.
In regard to “after the invasive procedure”, which is the analysis visit for WHO Bleeding 
Scale, Portal Vein Thrombosis, and Portal Blood Flow, the allowance is within 3 days to 
10 days after the first invasive procedure. In the case of multiple observations equidistant 
to the study visit date, the earlier one will be used, unless otherwise noted.
Table 1
Analysis Visit Windows
Study Day for Analysis
Allowance
Screening
Within 28 days prior to randomization
Day 1 (Baseline)
Within 7 days before initiation of study medication
Days 5-7
r0 day
Day 8
r0 day
Day 10
±1 day
Days 12 and 14
+1 day
Days 17 and 21
−1 day to +2 days 
Day 28
±2 days 
Day 35
−2 day to +7 days 
Handling of Missing Data 
6.4
Unless otherwise noted, missing values will not be imputed. All analyses will be 
performed using actual observations.
If a patient received platelet transfusion on the same day as an invasive procedure but the 
time of either platelet transfusion or invasive procedure was missing, the patient will be 
considered as he/she underwent the invasive procedure after receiving platelet 
transfusion.
If a patient had a platelet transfusion and platelet count on the same day but the time of 
either platelet transfusion or collection of blood sample for platelet count was missing, 
the patient will be considered as he/she received the platelet transfusion after collection 
of the blood sample for platelet count.


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Definition
6.5
Study Day
6.5.1
Study Day 1 corresponds to the date of initial dose of the study drug. Other study days 
are defined relative to Study Day 1. Screening will be expressed as Day -28 for 
descriptive purpose. 
Baseline
6.5.2
The baseline value is defined as a value obtained on Day 1 before administration of the 
initial dose of study drug. If this value is missing, the most recent value obtained prior to 
Day 1 within the 7 preceding days will be used as the baseline value. Regarding body 
weight, height, and body mass index (BMI), the measurement at screening visit will be 
used as the baseline value.
Last Observation
6.5.3
Last observation will refer to the last nonmissing observation after baseline which is 
within the analysis visit window and used in the analysis (see Section 6.3) or is within 
7 days after the day of early termination of study assessment. 
7. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
 
Patient Disposition and Withdrawals
7.1
The number and proportion of patients who completed the study (which is defined as 
completing both the treatment period and the posttreatment period) and the number and 
proportion of patients who prematurely discontinued from the study will be calculated by 
treatment group for all randomized patients. Withdrawals in the treatment and the 
posttreatment periods and the reasons leading to discontinuation will also be summarized.
The number of patients who were administered at least one dose of study drug and the 
number and proportion of patients who completed 7 days of dosing period will be 
calculated by treatment group for all randomized patients. The reason for the 
discontinued administration of study drug (i.e., administration for less than 7 days) will 
be summarized by treatment group for all randomized patients who completed and did 
not complete the study, respectively. 
The number and proportion of patients in each analysis population will be summarized by 
treatment group, as well as the reasons for exclusion from ITT, PP and Safety 
Populations. 
 
Demographic and Baseline Characteristics
7.2
Demographics and baseline characteristics shown in Table 2 will be tabulated by 
treatment group for the ITT population. Summary statistics will be calculated for 
continuous variables, and the frequency and proportion of patients in each category will 
be obtained for categorical variables. 


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Table 2
Demographic and Baseline Characteristics
Continuous Variable
age, height, weight, BMI, platelet count at baseline
Categorical Variable
sex, race, ethnicity,
presence or absence of any transfusion history,
presence or absence of history of CLD due to:
- hepatitis B,
- hepatitis C,
- alcoholic hepatitis,
- non-alcoholic hepatitis,
- autoimmune hepatitis,
Child-Pugh class,
WHO Bleeding Scale,
planned invasive procedure (liver ablation/coagulation, other),
platelet count at baseline (< 35 × 109/L, ≥ 35 × 109/L),
platelet count at randomization (< 35 × 109/L, ≥ 35 × 109/L)
ECOG performance status,
presence or absence of gastro oesophageal varices,
presence or absence of splenomegaly,
presence or absence of ascites
Details of medical history will be summarized by treatment group. The reported medical 
history terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 18.0 or higher.
8.
STUDY CONDUCT
Protocol Deviation
8.1
Protocol deviations/violations will be provided in a patient data listing. Major protocol 
deviations will be specified in the “Blinded Data Review Plan” and its final list will be 
determined based on blinded data review prior to database lock. The number and 
proportion of patients with major protocol deviations will be summarized by treatment 
group. The summary will be based on all randomized patients.
Emergency unblinding information will be listed, if needed.
Treatment Exposure
8.2
The number of days of study drug dosing will be tabulated using summary statistics by 
treatment group for the safety analysis population.
Concomitant Medication
8.3
Concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary (version Mar2015 B2 or higher), and summarized based on the safety
analysis population.


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The number and proportion of patients who received at least one dose of concomitant 
medication during the study will be calculated by treatment group, with details of 
concomitant medications with WHO Drug Dictionary preferred term. Patients for whom 
a particular preferred term was reported more than once will be counted only once for 
that preferred term.
The number and proportion of patients who received at least one session of concomitant 
therapy during the study will be calculated by treatment group, with details of 
concomitant therapy names. Patients for whom a particular concomitant therapy was 
reported more than once will be counted only once for that therapy.
9.
EFFICACY
Unless otherwise specified, efficacy analyses will be performed for the ITT population㸬
Primary Endpoint
9.1
The primary endpoint is the proportion of patients who require no platelet transfusion 
prior to the primary invasive procedure and no rescue therapy for bleeding from the date 
of randomization until 7 days after the primary elective procedure. The patients will be 
determined as a success for the primary endpoint if all of the following conditions are 
satisfied:
x
Patients received no platelet transfusion from the date of randomization through at 
least 7 days after the primary invasive procedure (i.e., the first invasive procedure 
in the study)
x
Patients received no rescue therapy for bleeding (including any of the following)
from the date of randomization through 7 days after the primary invasive 
procedure

Platelet preparations

Other blood preparations, including red blood cells and plasma

Volume expanders
x
Patients underwent an invasive procedure
In contrast, the following patients will be considered as failures for the primary endpoint
if any of the following conditions is satisfied:
x
Patients received at least one platelet transfusion prior to the primary invasive 
procedure
x
Patients received at least one rescue therapy for bleeding from the date of 
randomization through 7 days after the primary invasive procedure
x
Patients withdrew from the study before undergoing the primary invasive 
procedure
x
Patients did not undergo an invasive procedure


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Primary Analysis
9.1.1
The number and proportion of patients who required no platelet transfusion prior to the 
primary invasive procedure and no rescue therapy for bleeding from the date of 
randomization through 7 days after the primary elective procedure will be calculated by
treatment group. The primary endpoint will be presented along with 95% confidence 
intervals (CIs), which will be calculated with the Clopper-Pearson method.
The proportion of patients who required no platelet transfusion in the S-888711 group 
will be compared with that in the placebo group using the Cochran-Mantel-Haenszel 
(CMH) test adjusted by the stratification factors, i.e., the four strata: 
x
Platelet count at randomization < 35 × 109/L and liver ablation/coagulation
x
Platelet count at randomization < 35 × 109/L and other invasive procedure
x
Platelet count at randomization ≥ 35 × 109/L and liver ablation/coagulation
x
Platelet count at randomization ≥ 35 × 109/L and other invasive procedure.
In addition, the differences in the primary endpoint and its 95% CI using Wald method 
(see Appendix 3) will be calculated.
9.1.1.1
Subgroup Analysis
The primary endpoint will be analyzed separately for the following subgroups:
x
Platelet count at baseline: < 35 × 109/L, ≥ 35 × 109/L
x
Received primary invasive procedure: Percutaneous RFA/MCT, Laparoscopic 
RFA/MCT, EVL, EIS, TACE, TAE, other, and not performed
x
Sex: male, female
x
Age: < 65 years, ≥ 65 years
x
Baseline body weight: < 75 kg, ≥ 75 kg
x
Race: White, NonWhite
x
Child-Pugh class: A, B, C
The number and proportion of patients will be calculated by treatment group. The 
proportion of patients will be reported and will be compared between the S-888711 and 
placebo groups by Fisher’s exact test. In addition, the interaction between subgroup
(except received invasive procedure and Child-Pugh class C) and treatment group will be
tested with Breslow-Day test.
Sensitivity Analysis
9.1.2
The following sensitivity analyses for the primary endpoint will be performed for the ITT 
population, unless otherwise noted.


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1) PP Population
The primary efficacy analysis will be repeated for PP population.
2) Handling of Withdrawal
For classification of patients into success and failure, the primary endpoint will be 
modified as follows to explore the impact of missing data, withdrawals, or 
patients who did not undergo an invasive procedure.

Patients who withdrew from the study before undergoing the primary invasive 
procedure but whose last observation of platelet count was ≥ 50 × 109/L with 
an increase of ≥ 20 × 109/L from baseline will be classified as success, if 
he/she did not receive platelet transfusion and rescue therapy for bleeding.

Patients who did not undergo an invasive procedure but whose platelet count 
was ≥ 50 × 109/L with an increase of ≥ 20 × 109/L from baseline at least once
within 14 days after randomization will be classified as success, if he/she did 
not receive platelet transfusion and rescue therapy for bleeding.
3) Patients Data Based Analysis
For classification of patients into success and failure, the primary endpoint will be 
modified as follows based on platelet count at platelet transfusion assessment.

Patents whose platelet count was ≥50 × 109/L at platelet transfusion 
assessment will be considered as success regardless of preoperative platelet 
transfusion, if he/she (1) underwent invasive procedure, (2) did not receive 
platelet transfusion within 7 days after the primary invasive procedure, and (3) 
did not receive rescue therapy for bleeding from the date of randomization 
through 7 days after the primary invasive procedure. If platelet count at 
platelet transfusion assessment was missing, the patients will be considered as 
failure.
Secondary Endpoints
9.2
The following analyses for secondary endpoints will be conducted in the ITT population.
Proportion of Patients Requiring no Platelet Transfusion During the 
9.2.1
Study
A secondary endpoint is the proportion of patients who required no platelet transfusion 
during the study. A patient will be considered as success for this endpoint if he/she 
required no platelet transfusion and received the invasive procedure during the study.  
All other patients will be considered as failures.
9.2.1.1
Analysis
The number and proportion of patients who required no platelet transfusion during the 
study will be calculated by treatment group. The proportions will be presented along with 
95% CIs. The proportion of patients who required no platelet transfusion during the study
in the S-888711 group will be compared with that in the placebo group using the CMH 
test adjusted by the stratification factors. In addition, the differences in the secondary 
endpoint and its 95% CI will be calculated.


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Proportion of Responders
9.2.2
A responder will be defined as the patient who achieved the following criterion, that is a
platelet count of ≥ 50 × 109/L with an increase of ≥ 20 × 109/L from baseline without 
platelet transfusion at least once during the study. All patients in the ITT population will 
be classified into either responder or nonresponder for evaluating the proportion of 
responders during the study. A patient who had platelet transfusion will be considered as 
a responder if he/she achieved the responder criterion before receiving the first platelet 
transfusion. However, a patient will be considered as nonresponder if their platelet count 
met the responder criterion only after platelet transfusion.
In evaluating the proportion of responders at each scheduled time point (Day 5, 6, 7, 8, 10, 
12, 14, 17, 21, 28, and 35), a patient will be counted as a responder if all of the following 
conditions are satisfied:
x
Patients achieved a platelet count of ≥ 50 × 109/L with an increase of ≥ 20 × 109/L 
from baseline at the evaluation point.
x
Patients received no platelet transfusion through the evaluation point.
Missing platelet count at each scheduled time point will not be imputed.
9.2.2.1
Analysis
The number and proportion of responders during the study will be calculated by 
treatment group. The responder rates will be presented along with 95% CIs, which will be 
calculated with the Clopper-Pearson method. The proportion of responders during the 
study in the S-888711 group will be compared with that in the placebo group using the 
CMH test adjusted by the stratification factors. In addition, the differences in the 
responder rate and its 95% CI will be calculated.
The number and proportion of responders will be calculated by treatment group at each 
time point. This analysis will be performed for the ITT population with observed values.
Duration of the Increase in Platelet Count
9.2.3
The duration of the increase in platelet count will be defined as the number of days 
during which the platelet count was maintained as ≥ 50 × 109/L, and it will be calculated 
based on the platelet count at scheduled time points (Days 1, 5, 6, 7, 8, 10, 12, 14, 17, 21, 
28, and 35). The detail of the calculation is as follows.
Let (ݔ௜, ݕ௜) be the observed value at scheduled time point i, where i = 1, 2, ..., c and c (≤ 
12) can be different for each patient. For i > 1, ݔ௜is the day from initial administration 
of the study drug to Visit i defined as (the measurement date at Visit i) – (date of initial 
dose of the study drug) + 1, and ݕ௜is the observed platelet count [× 109/L], respectively. 
The baseline value represents (ݔଵ, ݕଵ), where ݔଵ= 1. Let ܮ௜be the line connecting 
(ݔ௜, ݕ௜) and (ݔ௜ାଵ, ݕ௜ାଵ), and (ݖ௜, 50) be the intersection point between ܮ௜and 
ݕ= 50. Then, the duration of the platelet count will be calculated as ܦ= σ ݀௜
௜
, where 


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݀௜= ൞
ݔ௜ାଵെݔ௜,
if ݕ௜൒50 and ݕ௜ାଵ൒50
ݔ௜ାଵെݖ௜,
if ݕ௜< 50 and ݕ௜ାଵ൒50
ݖ௜െݔ௜,
if ݕ௜൒50 and ݕ௜ାଵ< 50
0,
if ݕ௜< 50 and ݕ௜ାଵ< 50
.
If there is a missing assessment at Visit (i+1), ܮ௜should be the line connecting (ݔ௜, ݕ௜)
and (ݔ௜ାଶ, ݕ௜ାଶ), where (ݔ௜ାଶ, ݕ௜ାଶ) represents the next visit with data available.
9.2.3.1
Analysis
Median and quartiles for the duration of the increase in platelet count will be calculated 
by treatment group with or without platelet transfusions. The duration in the S-888711
group will be compared with that in the placebo group using van Elteren test stratified 
with platelet transfusion during the study. In addition, to explore an efficacy of S-888711
compared to platelet transfusion, the duration in the S-888711 group without platelet 
transfusion will be compared with that in the placebo group with platelet transfusion 
using Wilcoxon rank sum test.
Proportion of Patients who Required Rescue Therapy
9.2.4
The number and proportion of patients who received rescue therapy for bleeding events
during the study will be calculated for each treatment group. Platelet preparations, other 
blood preparations including red blood cells and plasma, and volume expanders will be 
considered as rescue therapy for bleeding events.
The number and proportion of patients who received antithrombotic drugs for thrombotic
events during the study will be summarized similarly.
Frequency of Platelet Transfusion and Dose (Unit) Transfused 
9.2.5
During the Study
The number and proportion of patients who received platelet transfusion during the study 
will be calculated for each treatment group, and the reasons for platelet transfusion will 
be summarized. For the patients who received at least one platelet transfusion, the
number of platelet transfusions during the study will be summarized by treatment group.
Average dose (unit/bags) of platelet transfusion will be calculated for each patient and 
then summarized by treatment group if appropriate. If the total amount of transfused 
platelets is able to be estimated for patients, it will be performed with reference to a 
minimum contents based on a guidance on platelet preparations in each country taking 
into account the method for collection (apheresis/pooled).
Time Course of Platelet Count 
9.2.6
Unless otherwise specified, the following analyses will be performed for patients who 
received and who didn’t receive platelet transfusions.


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Summary statistics for platelet count will be calculated at each scheduled time point 
(Days 1, 5, 6, 7, 8, 10, 12, 14, 17, 21, 28, and 35) by treatment group. Summary statistics 
for the change in platelet count from baseline will also be calculated.
The time course of the median, 25% and 75% quartile of platelet count will be 
graphically displayed by treatment group. Reference line which shows y = 50 × 109/L 
will be drawn in the figure. In addition, the time course of the mean and standard 
deviation of platelet count change from baseline will be graphically displayed by 
treatment group. Reference line which shows y = 20 × 109/L will be drawn in the figure.
Summary statistics for the maximum platelet count and the maximum change in platelet 
count of each patient will be calculated by treatment group. Baseline value will not be 
included in this analysis.
For the patients who received no platelet transfusion, the time point at which each patient 
showed the maximum platelet count will be summarized by treatment group. If maximum 
platelet count for the patient is observed at more than one time point, the earliest time 
point will be used in this analysis.
10. SAFETY
Safety analyses will be performed for the safety analysis population.
Adverse Events
10.1
Adverse events will be classified by system organ class and preferred term using the 
Medical Dictionary for Regulatory Activities (MedDRA) Version 18.0 or higher. Unless 
otherwise specified, treatment-emergent adverse events (TEAEs), that is any AEs 
reported after initiation of treatment with S-888711 or placebo, will be used for the 
analyses of safety.
The number of patients who experienced at least 1 TEAE and corresponding incidence 
will be calculated by treatment group. The incidence of TEAEs will be reported along 
with 95% CIs, which will be calculated with Clopper-Pearson method. The number of 
TEAEs, counted by cases reported, will also be presented. Death, treatment-emergent 
serious adverse events (SAEs), TEAEs leading to withdrawal of the study drug, and 
treatment-related AEs will be summarized in the same manner as the overall summary of 
TEAEs. The definitions of death, treatment-emergent SAEs, TEAEs leading to 
withdrawal of the study drug, and treatment-related AEs are shown below.
Term
Definition
Death
TEAEs with “Fatal” in terms of outcome.
Treatment-emergent SAEs
TEAEs with “Serious” in terms of seriousness
TEAEs leading to withdrawal of the 
study drug
TEAEs with “Drug withdrawn” in terms of the action taken 
for study drug.
Treatment-related AEs
TEAEs with “Related” in terms of the causal relationship with 
study drug.


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The number of patients who experienced TEAEs and corresponding incidence will be 
calculated by system organ class (SOC) and preferred term (PT) for each treatment group.
In the calculation, a patient who experienced a particular TEAE more than once will be 
counted only once within a SOC and PT. Treatment-emergent SAEs, TEAEs leading to 
withdrawal of the study drug, and treatment-related AEs will be summarized in a similar 
manner.
The number of patients who experienced TEAEs in each category of severity and 
outcome will be counted by SOC and PT for each treatment group, and the corresponding 
incidence in each category will be calculated. For patients who experienced a particular 
TEAE more than once in different categories, the patient will be counted only once using 
the highest priority category shown in Table 3. Treatment-related AEs will be 
summarized in a similar manner. 
Table 3
Priority of Categories
Priority
Category
Severity
Outcome
1
Severe
Fatal
2
Moderate
Recovered/resolved with sequelae
3
Mild
Not recovered/not resolved
4
Recovering/resolving
5
Recovered/resolved
6
Unknown
For the patients who underwent invasive procedure in safety analysis population, the 
summary of TEAEs before and after the primary invasive procedure will be presented by 
SOC and PT for each treatment group. In the calculation of the number of patients and 
corresponding incidence, a patient who experienced a particular TEAE more than once 
will be counted only once. Treatment-related AEs will be summarized in a similar 
manner.
The number of patients who experienced bleeding-related TEAEs and corresponding 
incidence will be calculated by SOC and PT for each treatment group. A patient who 
experienced a particular TEAE more than once will be counted only once within a SOC 
and PT. Bleeding-related TEAEs will be defined as TEAEs which were classified as 
“haemorrhage terms (except laboratory terms)” using Standard MedDRA Queries 
(SMQ).


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 Adverse Events of Special Interest
10.2
Thrombotic/thromboembolic events will be considered as adverse events of special 
interest in this study. The definition of thrombotic/thromboembolic TEAEs is described 
as TEAEs which are classified as follows using the SMQ: 
x
“embolic and thrombotic events, arterial”
x
“embolic and thrombotic events, venous” 
x
“embolic and thrombotic events, vessel type unspecified and mixed arterial and 
venous”.
The number of patients who experienced thrombotic/thromboembolic TEAEs and 
corresponding incidence will be calculated by SOC and PT for each treatment group. A 
patient who experienced a particular TEAE more than once will be counted only once 
within a SOC and PT. 
 WHO Bleeding Scale
10.3
For each WHO Bleeding Scale, the number and proportion of patients will be calculated 
by treatment group at each scheduled time point (Days 1, 8, 35, after the primary invasive 
procedure and last observation). 
 Vital Signs
10.4
For systolic blood pressure, diastolic blood pressure, and pulse rate, summary statistics of 
observations and their changes from baseline will be calculated at each scheduled time
point (Days 1, 5, 8, 10, 12, 14, 21, 28, 35 and last observation) by treatment group.
 Electrocardiography
10.5
The number and proportion of patients with an abnormal ECG finding will be calculated
by treatment group at Day 35 and last observation. 
 Laboratory Tests 
10.6
For laboratory tests listed in Table 4, summary statistics of observations and their 
changes from baseline will be calculated at each scheduled time point (Days 1, 8, 14, 35 
and last observation) by treatment group.  


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Table 4 
List of Laboratory Tests
Test
Items Evaluated
Haematology 
(except for platelet count)
Red blood cell count, white blood cell count, haemoglobin, and 
haematocrit
Blood Chemistry
Aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), lactate dehydrogenase, gamma glutamyl transferase, 
alkaline phosphatase, total bilirubin, bilirubin direct, indirect 
bilirubin, total protein, albumin, blood urea nitrogen, serum 
creatinine, sodium, potassium, chloride, and calcium
Blood Coagulation/Fibrinolysis Assay 
Prothrombin time-international normalized ratio (PT-INR), 
activated partial thromboplastin time
Individual clinically significant abnormalities (ICSA) will be summarized based on 
criteria which are determined by reference to Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0 (see Appendix 4). For each CTCAE term shown in 
Appendix 4, the number and proportion of patients with a laboratory test result classified
as grade 2 or more will be calculated at each scheduled time point (Days 1, 8, 14, 35) by 
treatment group. In addition, the number and proportion of patients with a laboratory test 
result classified as grade 2 or more at least once after the initiation of study drug will be 
calculated. For the term “hyponatremia”, the number and proportion of patients with a 
laboratory test result classified as grade 3 or more will be summarized because the term 
doesn’t have criteria for grade 2. The upper limit of normal range for PT-INR is regarded 
as 1 if it will not be specified by the central laboratory. 
The number and proportion of patients who met the following criteria for liver function 
abnormalities will be calculated at each scheduled time point (Days 1, 8, 14, 35) by 
treatment group. The number and proportion of patients with liver function abnormalities 
after the initiation of study drug will also be calculated.
x
AST or ALT ≥ 3 × upper limit of normal (ULN) and total bilirubin ≥2 × ULN
x
AST or ALT ≥ 3 × ULN and PT-INR ≥ 1.5 
x
AST/ALT ≥ 3 
 Portal Vein Thrombosis and Portal Blood Flow
10.7
For the patients who underwent diagnostic imaging in safety analysis population, the 
number and proportion of patients who experienced portal vein thrombosis at screening
and after the primary invasive procedure will be calculated by treatment group. The 
patients who underwent an invasive procedure more than once will be regarded as having
portal vein thrombosis if they experienced it at least once after the primary invasive 
procedure. If a patient received an invasive procedure and underwent assessment of 
portal vein thrombosis on the same day, the assessment will be considered as being after 
invasive procedure (see Section 6.3). 


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For the patients who underwent Doppler ultrasonography in safety analysis population, 
summary statistics by category for the direction of portal blood flow (i.e., hepatofugal, 
hepatopetal, stasis) at screening and after the primary invasive procedure will be 
calculated by treatment group. If a patient received an invasive procedure and underwent 
Doppler ultrasonography on the same day, the assessment will be considered as being 
after invasive procedure (see Section 6.3).
11. INTERIM ANALYSES
No interim analyses are planned for this study.
12. PROGRAMMING CONVENTIONS
In principle, displayed digits of calculated summary statistics and percentages will be
defined in Table 5.
Table 5
Displayed Digits of Statistics
Statistics
Displayed Digits
Number
Integer
Mean, Standard Deviation, 25% 
quartile, 75% quartile and 
Median
Rounded to decimal places that are greater than those of the raw 
data by 1. For data were rounded off to eight decimal places, the 
required statistics are to be calculated and then rounded off to two 
decimal places.
Maximum and Minimum
Displayed by respective displayed digits of the raw data. For data 
rounded off to eight decimal places, required statistics are to be 
calculated and then rounded off to one decimal place.
Percentage (%)
Rounded to one decimal place.
P-value
Rounded off to four decimal places. Values less than 0.0001 will be 
reported as <.0001.
13. CHANGES FROM PROTOCOL
x
An analysis using the van Elteren is added in order to compare the duration of the 
increase in platelet count between S-888711 and placebo group for the ITT
population (see Section 9.2.3)
x
Summary of significant TEAEs is removed because this event was not defined in 
the protocol.


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Appendix 1
Time and Events Schedule
Screening
Treatment Period
Post-treatment Period 
(Invasive Procedure, Days 9 to 14)
With-
drawalaUnsche
duledb
Study Day
From 
Day 
−28
Day 1
Day 
2 
Day
 3 
Day
 4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10
Day 
11
Day 
12
Day
13
Day 
14
Day 
17
Day 
21
Day 
28
Day 
35
Pre-
dosing
Post-
dosing
Informed consent
X
Inclusion/exclusion criteria
X
Demography (including body 
weight and height)
X 
Medical history
X
Enrolment (IVRS/IWRS)
X
Randomisation (IVRS/IWRS)
X
Drug assignment (IVRS/IWRS)
Xc
(X)c (X)c
Concomitant medication
ECOG performance status
X
Type of CLD and severity of liver 
disorder (Child-Pugh)
X 
Gastro-oesophageal varicesd
X
Splenomegaly and severity of 
ascitese
X 
Pregnancy test (urine)
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb
Portal vein thrombosis 
assessment f
X 
Xg
X
Xb
Portal blood flow (direction) h
X 
Xg
X 
Xb
WHO Bleeding Scale
X
X
X
Xg
X
X
Blood pressure, pulse rate
X
X
X
X
X
X
X
X
X
X
X
Xb
Electrocardiography
X
X
X
Xb
Platelet count (local laboratory) 
X 
X 
Xi
Xi
Xi
X 
X 
X 
X 
X 
X 
X 
X 
X
Xb
Haematology except for platelet 
count  (central laboratory)
X 
X 
X 
X 
X 
X 
Xb


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Screening
Treatment Period
Post-treatment Period 
(Invasive Procedure, Days 9 to 14)
With-
drawalaUnsche
duledb
Study Day
From 
Day 
−28
Day 1
Day 
2
Day
3
Day
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
9
Day 
10
Day 
11
Day 
12
Day
13
Day 
14
Day 
17
Day 
21
Day 
28
Day 
35
Pre-
dosing
Post-
dosing
Blood chemistry
X
X
X
X
X
X
Xb
Blood coagulation/fibrinolysis 
assayj
X
X
X
X
X
X
Xb
Immunological tests/other tests
X
Adverse events
Administration of study 
medication
X
X
X
X
Xc,k
Xc,k
Xc,k
Invasive procedure
Xl
Sampling for plasma drug 
concentration (Sparse PK)m
X
X
X
Sampling for plasma drug 
concentration (Intensive PK)n
X
X
X
a
Except for a patient with drug withdrawn because of the administration stopping criterion (ie, platelet count ≥ 50 × 109/L with an increase of ≥ 20 × 109/L from baseline).
b
Only necessary assessments will be performed.
c
If platelet count on Day 5, 6 or Day 7 is ≥ 50 × 109/L with an increase of ≥ 20 × 109/L from baseline, a patient must stop taking study medication. 
d
Confirmed by upper gastrointestinal endoscopy.  If data on upper gastrointestinal endoscopy are obtained within 180 days before randomisation, the data can be used.
e
Confirmed by ultrasonography, CT, or MRI. If ultrasonography, CT, or MRI is performed within 28 days before randomisation, the image can be used for assessing the 
presence or absence of splenomegaly. 
f
Confirmed by ultrasonography, CT, or MRI in the Screening period and after the invasive procedure.  The Screening investigation should be arranged as close to 
randomisation as possible.  However, if gastro-oesophageal varices are treated, portal vein thrombosis will be confirmed with the image obtained after the treatment.    
g
Performed within 3 to 10 days after the invasive procedure.  When any additional invasive procedure is performed, the assessment of bleeding events as graded on the WHO 
Bleeding Scale, portal vein thrombosis, and portal blood flow will be performed before and after the invasive procedure.
h
Confirmed by Doppler ultrasonography (at Screening, the investigation should be as close to randomisation as possible).
i
Blood samples will be collected before study medication.
j
Antithrombin III activity, fibrinogen, fibrin degradation products, D-dimer, Protein C activity, free protein S antigen, von Willebrand factor activity will be performed only at 
Screening.  Prothrombin time (international normalised ratio value) and activated partial thromboplastin time will be performed at Screening, Day 1, Day 8, Day 14, and Day 
35.
k
Administered after platelet count is confirmed and drug assignment. 
l
Performed between Days 9 and 14. 
m
All patients except for Intensive PK; pre-dose, 2 to 4 hours post-dose on Day 5, and pre-dose on Days 6 and 7.
n
At least 20 patients; pre-dose, 2, 4, 6, 8 hours post-dose on Day 5, pre-dose on Days 6 and 7.


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Appendix 2
Testing Procedure for Primary and Important 
Secondary Endpoints
S-888711 for up to 7 days vs. Placebo
Testing the Primary Efficacy Endpoint:
The null hypothesis is that there is no difference between S-888711 for up to 7 days and 
placebo groups regarding the proportion of patients, who require no platelet transfusion prior to 
the primary invasive procedure and no rescue therapy for bleeding from randomization until 7 
days after the primary elective procedure.
↓
if rejecteda
Testing the Secondary Efficacy Endpoint 1:
The null hypothesis is that there is no difference between S-888711 for up to 7 days and 
placebo groups regarding the proportion of patients who require no platelet transfusion during 
the study.
↓
if rejecteda
Testing the Secondary Efficacy Endpoint 2:
The null hypothesis is that there is no difference between S-888711 for up to 7 days and 
placebo groups regarding the proportion of patients who achieve a platelet count of ≥ 50 × 
109/L with an increase of ≥ 20 × 109/L from baseline at any time during the study.
Ў
if rejecteda
Testing the Secondary Efficacy Endpoint 3:
The null hypothesis is that there is no difference between S-888711 and placebo groups 
regarding the duration of the platelet count ≥ 50 × 109/L.
↓
if rejecteda
Testing the Secondary Efficacy Endpoint 4:
The null hypothesis is that there is no difference between S-888711 for up to 7 days without 
platelet transfusion and placebo with platelet transfusion groups regarding the duration of the 
platelet count ≥ 50 × 109/L.
[a] If superiority of S-888711 to placebo is demonstrated at the two-sided significance level of 0.05, then 
the next hypothesis will be tested.


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Appendix 3
Calculation p-value and Confidence Interval for 
Cochran-Mantel-Haenzel Test
Let ݔ௜௝and ݊௜௝denote the number of responders and the total number of patients in 
treatment ݅and stratum ݆, respectively, where ݅=1,2 represents the treatment group 
(S-888711 or Placebo) and ݆= 1,2,3,4 represents the stratum, the following 2 × 2
contingency table shows the total number of subjects and the number of responders in 
each treatment arm at stratum ݆.
Category
S-888711
Placebo
Response
ݔଵ௝
ݔଶ௝
No Response
݊ଵ௝െݔଵ௝
݊ଶ௝െݔଶ௝
Total
݊ଵ௝
݊ଶ௝
The proportion of patients with response (ߨ୧୨) in treatment ݅and stratum ݆can be 
estimated by:
ߨො௜௝= ݔ௜௝݊௜௝
Τ
and the stratum-specific proportion difference (݀௝) is estimated by:
݀መ௝= ߨොଵ௝െߨොଶ௝.
The adjusted estimate of the difference in the rate of responders between the two 
treatment groups (݀௔ௗ௝) is given as:
݀መ௔ௗ௝= ෍
ݓ௝݀௝
ସ
௝ୀଵ
using the CMH weights defined as ݓ௝= ൬
௡భೕ௡మೕ
௡భೕା௡మೕ൰൜σ
௡భೕ௡మೕ
௡భೕା௡మೕ
ସ
௝ୀଵ
ൠ
൘
.
Hence, the 2-sided stratified 95% Wald-type confidence intervals of ݀௔ௗ௝based on the
CMH weights is constructed as:
݀መ௔ௗ௝± ݖఈ/ଶVar൫݀መ௔ௗ௝൯,
where the variance of ݀ୟୢ୨is given as:
Var൫݀መ௔ௗ௝൯= ඨ෍
ݓෝ௝
ଶቆߨොଵ௝(1 െߨොଵ௝)
݊ଵ௝
+ ߨොଶ௝(1 െߨොଶ௝)
݊ଶ௝
ቇ
ସ
௝ୀଵ
,


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and ݖఈଶ
Τ
is the 97.5th percentile of the standard normal distribution.
Two-sided p-value will be obtained by:
2 × ቊ1 െߔቆቤ
݀መ௔ௗ௝
ܸܽݎ൫݀መ௔ௗ௝൯ቤቇቋ,
where ߔis the cumulative distribution of standard normal distribution.


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Appendix 4 
CTCAE Term and Criteria for Classification*
CTCAE Term
Grade
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Blood and lymphatic system disorders 
Anemia
10.0 g/dL ≤HGB < LLN
8.0 g/dL ≤HGB < 10.0 g/dL
HGB < 8.0 g/dL
---
---
Investigations
Activated partial thromboplastin 
time prolonged
ULN < APTT ≤ 1.5×ULN
1.5×ULN < APTT ≤2.5×ULN
APTT > 2.5×ULN
---
---
Alanine aminotransferase increased
ULN < ALT ≤ 3.0×ULN
3.0×ULN < ALT ≤5.0×ULN
5.0×ULN < ALT ≤
20.0×ULN
ALT > 20.0×ULN
---
Alkaline phosphatase increased
ULN < ALP ≤ 2.5×ULN
2.5×ULN < ALP ≤ 5.0×ULN
5.0×ULN < ALP ≤ 
20.0×ULN
ALP > 20.0×ULN
---
Aspartate aminotransferase 
increased
ULN < AST ≤ 3.0×ULN
3.0×ULN < AST ≤ 5.0×ULN
5.0×ULN AST ≤ 
20.0×ULN
AST > 20.0×ULN
---
Blood bilirubin increased
ULN < T. Bil ≤ 1.5×ULN
1.5×ULN < T. Bil ≤ 3.0×ULN
3.0×ULN < T.Bil ≤ 
10.0×ULN
T.Bil> 10.0×ULN
---
Creatinine increased
BL < CREAT ≤1.5×BL㸪
or  
ULN < CREAT ≤ 1.5×ULN
1.5×BL < CREAT ≤ 3.0×BL㸪
or  
1.5×ULN < CREAT ≤ 3.0×ULN
CREAT > 3.0×BL㸪
or
3.0×ULN < CREAT ≤ 
6.0×ULN
CREAT > 6.0×ULN
---
GGT increased
ULN < γ-GTP ≤ 2.5×ULN
2.5×ULN < γ-GTP ≤ 5.0×ULN
5.0×ULN < γ-GTP ≤ 
20.0×ULN
γ-GTP > 20.0×ULN
---
Hemoglobin increased
In the case BL ≤ ULN, 
ULN < HGB ≤ULN + 2 g/dL㸪
In the case BL > ULN, 
BL < HGB ≤ BL + 2 g/dL
In the case BL ≤ ULN,
ULN + 2 g/dL< HGB ≤ ULN + 4
g/dL㸪
In the case BL > ULN,
BL + 2 g/dL < HGB ≤ BL + 4 g/dL
In the case BL ≤ ULN,
HGB > ULN + 4 g/dL㸪
In the case BL > ULN,
HGB > BL + 4 g/dL
---
---
INR increased
ULN *< PT-INR ≤1.5×ULN* 
1.5×ULN* < PT-INR ≤ 2.5×ULN*
PT-INR* > 2.5×ULN*
---
---
White blood cell decreased
3×103/µL ≤ WBC < LLN
2×103 /µL ≤ WBC < 3×103/μL
1×103/µL ≤ WBC < 
2×10^3/μL
WBC < 1×103/μL
---
*
Classification criteria are determined by reference to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [Published: May 28, 2009].


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CTCAE Term
Grade
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Metabolism and nutrition disorders 
Hypercalcemia
ULN < Ca ≤ 11.5 mg/dL
11.5 mg/dL < Ca ≤ 12.5 mg/dL
12.5 mg/dL < Ca ≤ 13.5
mg/dL
Ca > 13.5 mg/dL
---
Hyperkalemia
ULN < K ≤ 5.5 mEq/L
5.5 mEq/L < K ≤ 6.0 mEq/L
6.0 mEq/L < K ≤ 7.0 
mEq/L
K > 7.0 mEq/L
---
Hypernatremia
ULN < Na ≤ 150 mEq/L
150 mEq/L < Na ≤ 155 mEq/L
155 mEq/L < Na ≤ 160
mEq/L
Na > 160 mEq/L
---
Hypoalbuminemia
3 g/dL ≤ ALB < LLN
2 g/dL ≤ ALB < 3 g/dL
ALB < 2 g/dL
---
---
Hypocalcemia
8.0 mg/dL ≤ Ca < LLN
7.0 mg/dL ≤Ca < 8.0 mg/dL
6.0 mg/dL ≤ Ca < 7.0
mg/dL
Ca < 6.0 mg/dL
---
Hypokalemia
3.0 mEq/L ≤ K <LLN
3.0 mEq/L ≤ K <LLN
2.5 Eq/L ≤ K < 3.0 mEq/L
K < 2.5 mEq/L
---
Hyponatremia
130 mEq/L ≤Na <LLN
---
120 mEq/L ≤ Na < 130 
mEq/L
㸺120 mEq/L
---
ALB = Albumin; APTT = Activated partial thromboplastin time; BL = Baseline value; CREAT = Creatinine; FIBRINO = Fibrinogen; HGB = Hemoglobin; LLN = Lower limit of 
normal range; PT-INR = International normalized ratio of prothrombin time; T.Bil = Total bilirubin; ULN = Upper limit of normal range
*:
ULN for International normalized ratio of prothrombin time (PT-INR) is regarded as 1 if it will not be specified by the central laboratory.