Clinical trial NCT04132050
Conditions: Idiopathic Thrombocytopenic Purpura
Sponsor: Kissei Pharmaceutical Co., Ltd.
Start date: 2019-12-24; Completion date: 2023-09-25
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the efficacy, safety and pharmacokinetics of R788 compared with placebo, and to investigate the safety and efficacy of long term dosing of R788 in patients with chronic idiopathic thrombocytopenic purpura.

Detailed description:

Arms: arm 1: Patients are administered R788 for 24 weeks (double-blind period), followed by R788 for up to 52 weeks (open-label period). Patients who have completed open-label period and meet the criteria are eligible to continue R788 treatment over a 3 year period (extension - period). arm 2: Patients are administered Placebo for 24 weeks (double-blind period), followed by R788 for up to 28 weeks (open-label period). Patients who have completed open-label period and meet the criteria are eligible to continue R788 treatment over a 3 year period (extension - period).
Interventions: intervention 1: R788 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral administration intervention 2: Oral administration

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
- 1 -
Protocol 
Title of study: 
A Phase 3 Study in Patients with Chronic Idiopathic 
Thrombocytopenic Purpura in R788 
Protocol No.: 
R788-1301 
Version: 
1.0 
Date of preparation/revision: 
August 28, 2019 
Sponsor: 
Kissei Pharmaceutical Co., Ltd. 
3-1-3, Koishikawa, Bunkyo-ku, Tokyo
TEL: 03-5684-3533  FAX: 03-5804-8560
Confidentiality Statement 
This confidential document belongs to the sponsor. Unpublished information contained in this 
document may not be disclosed without the written approval of the sponsor. 
This is the translated version of the Statistical Analysis Plan written in Japanese. 
NCT number: 
NCT04132050


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
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Protocol Synopsis 
Title of study: 
A Phase III Study in Patients with Chronic Idiopathic Thrombocytopenic Purpura in R788 
(Protocol No.: R788-1301) 
Study phase: 
Phase III 
Study objectives: 
1. Primary objective 
To investigate the increase in platelet count in patients with chronic idiopathic thrombocytopenic purpura 
(ITP) after oral administration of R788 for 24 weeks in a placebo-controlled, double-blind manner (Period 
I). 
2. Secondary objectives 
1) To evaluate the following efficacy of R788 in patients with chronic ITP 
• Maintenance of platelet count during long-term treatment with R788 
• Increase in platelet count during Period II for patients who received placebo in Period I 
• Improving of quality of life (QOL) 
2) To investigate the safety of R788 in patients with chronic ITP 
3) To investigate the pharmacokinetics of R788 in patients with chronic ITP (Period I). 
3. Exploratory objective 
To investigate the time course of platelet count in patients with chronic ITP during interruption of R788 
(Non-dosing (ND) period) 
Endpoints: 
1. Primary endpoint 
Achievement of stable platelet response (subjects who achieve a platelet count of ≥ 50000/μL on at least 4 of the 
6 visits from Weeks 14 to 24 are considered as a responder and the percentage of responders will be evaluated) 
 
2. Secondary endpoints 
1) Achievement rate of a platelet count of ≥ 50000/μL at the specified evaluation time point 
2) Achievement rate of a platelet count of ≥ 30000/μL at the specified evaluation time points and platelet 
count increase at least 20000/μL above baseline (for subjects with a baseline platelet count of 
< 15000/μL) 
3) Achievement rate of overall response (subjects who achieve a platelet count of ≥ 50000/μL during at 
least 1 of the 6 visits from Weeks 2 to 12 are considered as a responder and the percentage of 
responders will be evaluated)  
4) Number of times when a platelet count of ≥ 50000/μL in the 6 visits from Weeks 2 to 12 
5) Number of times when a platelet count of ≥ 50000/μL in the 12 visits from Weeks 2 to 24 
6) Duration of maintained platelet count since first achievement of a platelet count ≥ 50000/μL after 
administration of the study drug 
7) Percentage of subjects who maintained platelet count for 12 weeks since achievement of a platelet 
count ≥ 50000/μL within 12 weeks after administration of the study drug in Periods I and II (only for 
subjects who transition to Period II after being treated with placebo in Period I) 
8) Summary statistics of platelet count 
9) Distribution of platelet count 
10) Individual courses in platelet count 
11) QOL assessment (Short form 36 [SF-36]) 
 
3. Safety endpoints 
1) Incidence of adverse events and adverse drug reactions 
2) Laboratory tests (hematology, serum chemistry, and urinalysis) 
3) Immunoglobulin test 
4) ITP Bleeding Score 
5) Eastern Cooperative Oncology Group (ECOG) Performance Status 
6) Vital signs 
7) 12-lead electrocardiogram (ECG) 
 
4. Pharmacokinetic endpoints 
Plasma concentration of R406 (active substance) 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
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Subjects: 
Patients with chronic ITP who meet all of the following inclusion criteria and do not meet any of the 
exclusion criteria are eligible. 
1. Inclusion criteria 
1) Japanese patients (defined as Japanese whose all relatives within the second degree are Japanese) who 
give written informed consent to participate in the study 
2) Patients at least 20 years of age (at the time of informed consent) 
3) Patients diagnosed with ITP according to the ITP diagnostic criteria (revised in 1990) by the Study 
Group on Idiopathic Hematopoietic Disorders of the Ministry of Health, Labour and Welfare at least 6 
months before acquisition of consent 
4) Patients with a platelet count average of < 30000/μL at Screen A, Screen B, and Day 1. Each platelet 
count should not exceed 35000/μL. 
5) Patients who have used and failed or who were intolerant at least 1 of the following typical regimen 
for the treatment of ITP before informed consent 
• Corticosteroids 
• Thrombopoietin (TPO) receptor agonists (eltrombopag olamine or romiplostim) 
• Rituximab 
• Intravenous immunoglobulin 
6) Patients with ECOG performance status of 0 or 1 at Screening A and Day 1 
7) Patients who do not use treatment for ITP or patients whose concurrent treatment may consist of either 
corticosteroids (equivalent to 10 mg/day prednisolone or less), azathioprine, or danazol. The dose of 
the concurrent medication must have been stable for at least 2 weeks prior to Day 1 and must be 
expected to remain stable throughout Period I. 
8) Patients who can discontinue or have already discontinued the following ITP drugs for at least the 
following periods prior to Day 1, if applicable 
• Cyclosporine or mycophenolate mofetil: 2 weeks 
• Eltrombopag olamine: 2 weeks 
• Romiplostim: 3 weeks 
• Alkylating agent: 8 weeks 
• Rituximab or other anti-CD20 monoclonal antibodies: 24 weeks 
9) Patients who are negative for H. pylori or who have completed H. pylori eradication therapy 
 
2. Exclusion criteria 
1) Patients with thrombocytopenia associated with other diseases (eg, lymphoma, chronic lymphocytic 
leukemia, viral infection, autoimmune disease, thyroid disease, human immunodeficiency virus, 
hepatitis, or myelodysplasia), induced or alloimmune thrombocytopenia, antiphospholipid antibody 
syndrome, or liver cirrhosis 
2) Patients who are suspected cyclic thrombocytopenia 
3) Patients with autoimmune hemolytic anemia 
4) Patients with a history of or active clinically significant, respiratory, gastrointestinal (pancreatitis), 
renal, hepatic, neurological, psychiatric, musculoskeletal, genitourinary, dermatological, or other 
disorders that could affect the conduct of the study or the absorption, distribution, metabolism, or 
excretion of the study drug 
5) Patients complicated with any major cardiovascular event including but not limited to myocardial 
infarction, unstable angina, cerebrovascular accident, pulmonary embolism, or New York Heart 
Association Class III or IV heart failure, or with a history of such events within 6 months prior to Day 
1 
6) Patients with systolic blood pressure ≥ 140 mmHg or diastolic blood pressure of ≥ 90 mmHg at 
Screening A, Screening B, or Day 1 whether or not the subject is receiving anti-hypertensive treatment 
7) Patients with conditions with increased thrombus formation, such as factor V Leiden mutation, active 
protein C resistance, congenital antithrombin III deficiency, and lupus anticoagulant, or patients 
complicated with coagulopathy, such as arterial or venous thromboembolism, or history of 
coagulopathy within 6 months prior to Screening A 
8) Patients who cannot discontinue anticoagulants at least 30 days prior to Screening A because of a 
history of venous thromboembolism at least 6 months prior to Screening A, or patients with a D-dimer 
assay result out of the normal range at Screening A in spite of the discontinuance of anticoagulants at 
least 30 days prior to Screening A 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
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9) Patients with an ITP Bleeding Score of Grade 2 at any site at Screen A or Day 1 
10) Patients with 1 or more of the following laboratory abnormalities at Screening A, Screening B, or Day 
1: 
• White blood cell count < 2500/μL 
• Neutrophil count < 1500/μL 
• Lymphocyte count < 750/μL 
• Hemoglobin < 10 g/dL 
11) Patients with 1 or more of the following laboratory abnormalities at Screening A: 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 × the upper limit of 
normal (ULN) 
• Total bilirubin > 2.0 mg/dL 
• Estimated glomerular filtration rate (eGFR) < 30 mL/min 
12) Patients with significant infection, acute infection such as influenza, or active inflammatory response 
during the screening period 
13) Patients with acute gastrointestinal symptoms (eg, nausea, vomiting, diarrhea, or abdominal pain) 
during the screening period 
14) Patients with increased the dose of, or added, prescription drugs within the 2 weeks prior to Day 1. 
Except for prescription drugs for which the investigator has determined that the assessment of efficacy 
and safety of the study drug is not affected. 
15) Patients who tested positive or the lower limit of quantitation for at least 1 of the following 
immunological tests at Screening A 
• Human immunodeficiency virus (HIV) antigen 
• HIV antibodies 
• Hepatitis B surface (HBs) antigen 
• Anti-HBs (excluding HBs antibody monopositive cases due to hepatitis B (HB) vaccination or 
hepatitis B virus (HBV) DNA levels below the lower limit of quantification) 
• Anti-hepatitis B core (HBc) (unless HBV DNA levels are below the lower limit of quantification) 
• Hepatitis C virus (HCV) RNA quantification 
16) Patients who has received any transfusion or blood products between 2 weeks prior to Screening A 
and Day 1 
17) Patients who have used at least 1 of the following drugs during the screening period 
• Platelet transfusion 
• Intravenous immunoglobulin 
• Intravenous methylprednisolone 
• Oral dexamethasone (unless equivalent to 10 mg/day prednisolone or less) 
• Oral prednisolone (unless dosage is 10 mg/day or less) 
18) Patients with allergy or sensitivity to any of the components of the study drug 
19) Patients who underwent splenectomy within 12 weeks prior to Day 1 
20) Patients who has had major surgery within 4 weeks prior to Day 1 or has a surgical wound that is not 
fully healed. 
21) Patients who are scheduled to undergo surgery for whom use of rescue therapy is planned from the 
time of informed consent to the end of the follow-up period. 
22) Patients with malignancy or a history of malignancy within 5 years before obtaining informed 
consent. 
23) Patients with a history of severe drug hypersensitivity. 
24) Patients with concomitant or past history of alcoholism. 
25) Patients with concomitant or past history of drug abuse (defined as illicit drug use). 
26) Patients with psychiatric disorders, such as depression, schizophrenia, or dementia. 
27) Pregnant patients, breast-feeding patients, patients who wish to become pregnant during the period 
from informed consent to 30 days after the last dose of the study drug, or women who are not willing 
to use appropriate methods of contraception. 
28) Patients who have received other study drugs within 12 weeks before acquisition of consent. 
29) Other patients whom the investigator judges to be inappropriate for the study. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
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Study design: 
A placebo-controlled, multicenter, randomized, double-blind, parallel-group study (Period I) and a 
multicenter, open-label study (Periods II and III). 
 
Structure of the study: 
1) Screening period 
Screening period is defined as 4 weeks from Screening A to before the administration of the study drug on 
Day 1. 
2) Period I 
Period I is defined as 24 weeks from after the administration of the study drug on Day 1 to Week 24. 
3) Period II 
• The day at the beginning of study drug administration in Period II is Week 24 for subjects who 
complete Period I. Period II is defined as 28 weeks from Weeks 24 to 52. 
• The day at the beginning of study drug administration in Period II is early transition (ET) Day 1 for 
early transition subjects (subjects who meet all the “Transition criteria to Period II for subjects who 
withdraw from Period I”). Period II is defined as 28 weeks from ET Day 1 to ET Week 28. 
4) Non-dosing period 
Non-dosing period is defined as maximum 4 weeks from Week 52 or ET Week 28 to Day 1 of Period III. 
5) Period III 
Period III is defined as the period from Day 1 of Period III to the date of marketing approval of R788. 
6) Follow-up period 
• Follow-up period is defined as 2 weeks from Week 52 or ET Week 28 to the tests at the end of the 
follow-up period for subjects who complete Period II and are not willing to participate in the Non-
dosing period and Period III. 
• Follow-up period is defined as 2 weeks from the Withdrawal Visit to the tests at the end of the follow-
up period for subjects who withdraw from Period I and do not transition to Period II, those who 
withdraw from Period II, and those who withdraw from Period III. 
• Follow-up period is defined as the period until 2 weeks after Week 52 or ET Week 28 for subjects who 
withdraw from the Non-dosing period before ND Week 2. 
• No follow-up period is established for subjects who withdraw from the Non-dosing period at ND Week 
2 or later or subjects who continue Period III until the date of marketing approval of R788. 
 
Screening 
period 
4 weeks 
Period I (double-blind) 
24 weeks 
Period II (open-label) 
28 weeks 
 
Non-
dosing 
period 
Up to 4 
weeks 
Period III (open-
label) 
Until market 
authorization 
 
 
 
 
 
 
 
Follow-
up period 
2 weeks 
 
 
 
 
*: Subjects who meet all the "Transition criteria to Period II for subjects who withdraw from Period I" 
Figure 1 
Structure of Study 
 
Transition: 
1) Transition to Period II 
The following subjects transition to Period II. 
• Subjects who completed Period I 
• Early transition subjects (subjects who meet all the "Transition criteria to Period II for subjects who 
withdraw from Period I") 
R788 group 
Placebo group 
R788 group 
Period II 
Early transition 
subjects* 
R788 group 
No study 
drug 
No study 
drug 
No study 
drug 
Willing  
to 
Not 
willing to 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
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2) Transition criteria to Period II for subjects who withdraw from Period I 
(1) Subjects who meet any of the following criteria and withdraw from Period I due to "2) Lack of 
efficacy (inadequate response)" in "Withdrawal criteria (withdrawal in individual subjects)" 
• Subjects with a platelet count of ≥ 15000/μL on Day 1: 
a) Platelet count of < 50000/μL after Week 12 despite the increased dose to 150 mg bid for more 
than 4 weeks. 
b) Platelet count of < 50000/μL after Week 12 because of the inability to increase the dose to 
150 mg bid due to possible poor tolerability. 
• Subjects with platelet count of < 15000/μL on Day 1: 
a) Platelet count increase of < 20000/μL from Day 1 after Week 12 despite the increased dose to 
150 mg bid for more than 4 weeks. 
b) Platelet count increase of < 20000/μL from Day 1 after Week 12 because of the inability to 
increase the dose to 150 mg bid due to possible poor tolerability. 
(2) Subjects with systolic blood pressure of < 140 mmHg and diastolic blood pressure of < 90 mmHg on 
ET Day 1 whether or not the subject is receiving antihypertensive treatment 
(3) Subjects without the following laboratory abnormalities on ET Day 1: 
• White blood cell count < 2000/μL 
• Neutrophil count < 1000/μL 
• Lymphocyte count < 750/μL 
• Hemoglobin < 10 g/dL 
(4) Subjects without the following laboratory abnormalities on the last laboratory test before ET Day 1 
• ALT or AST > 1.5 × ULN 
• Total bilirubin > 1.5 × ULN 
• eGFR < 30 mL/min 
(5) Subjects who do not have significant infection, an acute infection such as influenza, or inflammatory 
process on ET Day 1. 
(6) Subjects who have not received blood or blood products within the 2 weeks prior to ET Day 1 
(intravenous immunoglobulin or platelet transfusion are allowed if used for rescue therapy). 
3) Transition to Non-dosing period 
Subjects who provide written informed consent to participate in the Non-dosing period and Period III 
transition to the Non-dosing period. However, subjects with platelet count of < 50000/μL at Week 52 or at 
ET Week 28 may skip the Non-dosing period and transition to Period III at the discretion of the 
investigator. 
4) Transition to Period III 
The following subjects transition to Period III. 
• Subjects who completed the Non-dosing period 
• Subjects receiving any rescue therapy during the Non-dosing period 
• Subjects who have platelet count of < 50000/μL during the Non-dosing period and need to transition to 
Period III before completing the Non-dosing period, as judged by the investigator 
Study drugs: 
Test drug 
1) Product Code: R788 
2) International nonproprietary name (INN): fostamatinib 
3) Content and dosage formulation: 
R788 100 mg Tablets: orange-colored round film-coated tablets containing 100 mg of fostamatinib per 
tablet 
R788 150 mg Tablets: orange-colored oval film-coated tablets containing 150 mg of fostamatinib per 
tablet 
4) Storage: Store in a tightly closed container at room temperature. 
 
Control drug 
1) Content and dosage formulation: 
R788 100 mg Tablets placebo: orange-colored round film-coated tablets containing 0 mg of fostamatinib 
per tablet 
R788 150 mg Tablets placebo: orange-colored oval film-coated tablets containing 0 mg of fostamatinib 
per tablet 
R788 100 mg Tablets cannot be distinguished from R788 100 mg Tablets placebo. R788 150 mg Tablets 
cannot be distinguished from R788 150 mg Tablets placebo. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
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2) Storage: Store in a tight container at room temperature. 
 
Dose and administration method: 
1) Screening period 
No study drug is administered. 
2) Period I 
R788 or the matching placebo is administered orally for 24 weeks. The initial dose should be 100 mg bid 
and the dose should be adjusted during Period I in accordance with “Dosing adjustments.” Morning and 
evening doses should be at least 8 hours apart and should be taken at approximately the same time each 
day, with or without food during Period I. 
3) Period II 
R788 is orally administered for 28 weeks. 
(1) Subjects who completed Period I 
The study drug for Period I is continued until the visit at Week 24 and the study drug for Period II is 
initiated after the visit at Week 24 (if study drug in Period II is initiated as twice daily, subjects who 
took the study drug for Period I in the morning on the day of the visit start the study drug for Period 
II from the evening of the same day). The dose and administration at the start of the study drug for 
Period II is as follows. 
• If platelet count at Week 24 is ≥ 50000/μL, study drug in Period II is initiated with the last dose and 
administration in Period I 
• If platelet count at Week 24 is < 50000/μL and last dose and administration in Period I is 150 mg 
bid, study drug in Period II is initiated with 100 mg bid 
• If platelet count at Week 24 is < 50000/μL and last dose and administration in Period I is 100 mg qd, 
150 mg qd, or 100 mg bid, study drug in Period II is initiated with the last dose and administration in Period 
I 
(2) Early transition subjects 
The study drug for Period II is initiated after the visit on ET Day 1 (if study drug in Period II is 
initiated as twice daily, subjects who took the study drug for Period I in the morning on the day of the 
visit start the study drug for Period II from the evening of the same day). The dose and administration 
at the start of the study drug for Period II is as follows. 
• If the last dose and administration in Period I is 100 mg bid or 150 mg bid, study drug in Period II 
is initiated with 100 mg bid 
• If the last dose and administration in Period I is 100 mg qd or 150 mg qd, study drug in Period II is 
initiated with the last dose and administration in Period I 
The dose should be adjusted during Period II in accordance with “Dosing adjustments.” Morning and 
evening doses should be at least 8 hours apart and should be taken at approximately the same time 
each day, with or without food during the Period II. 
4) Non-dosing period 
No study drug is administered. 
5) Period III 
The study drug is administered orally until market authorization of R788 in Japan. The study drug for 
Period III is initiated with the last dose and administration of study drug in Period II and is started after 
the visit on Day 1 of Period III. The dose should be adjusted during Period III in accordance with “Dose 
adjustments.” Morning and evening doses should be at least 8 hours apart and should be taken at 
approximately the same time each day, with or without food during the Period III. 
6) Follow-up period 
No study drug is administered. 
 
Dosing adjustments 
1) Dose escalation for subjects not responding 
(1) Period I 
If the platelet count at Week 4 or after is below 50000/μL and the study drug has been well tolerated, 
the dose of study drug should be increased from 100 mg bid to 150 mg bid at the discretion of the 
investigator. 
(2) Period II 
• Subjects who completed Period I: 
If the platelet count after the study drug for Period II is initiated remains below 50000/μL and the 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
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study drug has been well tolerated, the dose of study drug should be increased from 100 mg bid to 
150 mg bid at the discretion of the investigator. 
• Early transition subjects: 
If the platelet count at ET Week 4 or after is below 50000/μL and the study drug has been well 
tolerated, the dose of study drug should be increased from 100 mg bid to 150 mg bid at the 
discretion of the investigator. 
(3) Period III 
If the platelet count is below 50000/μL and the study drug has been well tolerated, the dose of study 
drug should be increased from 100 mg bid to 150 mg bid at the discretion of the investigator. 
2) Dose adjustment due to adverse events 
If the following adverse events or abnormal results of laboratory tests, abnormal findings, and abnormal 
symptoms associated with adverse events are observed and any of the dose adjustment criteria is met, the 
dose of the study drug should be adjusted. 
• Increases in ALT, AST, or bilirubin 
• Neutrophil count decreased 
• Onset of diarrhea 
• Increase in blood pressure 
Additionally, if any other severe or serious adverse events with a potential relationship to the study drug 
are observed, the dose of the study drug should be adjusted at the discretion of the investigator. 
 
If adverse events or abnormal results of laboratory tests, abnormal findings, and abnormal symptoms 
associated with adverse events which result in dose reduction of study drug recover, the dose of study 
drug can be re-escalated by 1 dose level in accordance with Table 1 based on the investigator’s decision. 
If adverse events or abnormal results of laboratory tests, abnormal findings, and abnormal symptoms 
associated with adverse events which leads to interruption of study drug recover, the study drug is 
restarted at 1 lower dose level than that before the interruption. After resuming the study drug, the dose of 
study drug can be re-escalated by 1 dose level in accordance with Table 1 based on the investigator’s 
decision. 
Table 1 
Dosing Adjustments 
Dose reduction 
Dose before dose 
escalation/reduction 
Dose escalation 
Dose level 
−4 
Dose level 
−3 
Dose level 
−2 
Dose level 
−1 
Dose 
level 
+1 
Dose 
level 
+2 
Dose 
level 
+3 
Interruption 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruption 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruption 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruption 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
 
3) Dose adjustment due to excessive elevation of platelet count 
(1) Period I 
If excessive platelet count increase is observed, the investigator should respond in accordance with 
Table 2. The doses/regimens of allowed ITP therapies (corticosteroids, azathioprine, or danazol) 
should not be changed. If platelet count is above 250000/μL even after the dose of the study drug is 
adjusted, the dose of allowed ITP therapy is reduced according to “Allowed ITP therapies”. 
Table 2 
Actions Taken with the Study Drug for Excessive Elevation of Platelet Count in Period 
I 
 
Action 
1) Platelet counts > 250000/μL 
• Reduce the dose of the study drug by 1 dose level until the platelet count 
falls to ≤ 250000/μL. 
• Monitor platelet count until platelet count falls to < 200000/μL (the 
frequency of additional measurements will be determined by the 
investigator). 
• If the excessive elevation of platelet count is improved, the dose of study 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
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drug can be re-escalated by 1 dose level based on the investigator’s decision. 
2) Platelet counts > 150000/μL and 
≤ 250000/μL 
• Continue the study drug at full dose. 
• Monitor the platelet count until stable to assure it does not exceed 
250000/μL (the frequency of additional measurements will be determined by 
the investigator). 
 
(2) Periods II and III 
If excessive platelet count increase is observed, the investigator should respond in accordance with 
"Allowed ITP therapies". If platelet count is above 250000/μL even after the dose of allowed ITP therapy 
is adjusted, reduce the dose of the study drug by 1 dose level until the platelet count falls to ≤ 250000/μL 
(see Table 1) and measure the platelet count until it falls to < 200000/μL. If the excessive elevation of 
platelet count is improved, the dose of study drug can be re-escalated by 1 dose level based on the 
investigator’s decision. 
Concomitant therapies: 
1) Concomitant therapies 
Drugs for various symptoms with ITP and drugs used at the start of the screening period for 
complications should not change the doses/regimens as much as possible until the end of the follow-up 
period or market authorization. It is acceptable to change the doses/regimens of concomitant medications 
for safety, such as the occurrence of adverse events. 
2) Prohibited concomitant medications 
The concomitant use of the medications listed in Table 3 is prohibited from 2 weeks before Day 1 to the 
end of the follow-up period or market authorization. 
Table 3 
Prohibited Concomitant Medications 
Classification 
Principal drugs 
1) Strong cytochrome P450 (CYP) 3A4 
inhibitors 
Itraconazole, indinavir sulfate ethanol adduct, clarithromycin, cobicistat, 
diltiazem hydrochloride, nelfinavir mesilate, voriconazole, ritonavir 
containing preparation 
2) Study drugs other than R788 
Any study drugs other than R788 
 
3) Prohibited ITP concomitant medications 
The concomitant use of the medications listed in Table 4 is prohibited from the period specified in 
"Washout" before Day 1 (Table 8) to the end of the follow-up period or market authorization. 
Table 4 
Prohibited ITP concomitant medications  
Classification 
Principal drugs 
ITP medications other than the allowed 
ITP therapies or ITP medications specified 
as rescue therapies 
Cyclosporine, mycophenolate mofetil, eltrombopag olamine, 
romiplostim, rituximab or other anti CD20 monoclonal antibodies, 
alkylating agents 
 
4) Restricted medications 
Medications listed in Table 5 should be administered with attention to subject safety from 2 weeks before 
Day 1 to the end of the follow-up period or market authorization. 
Table 5 
Restricted Medications 
Classification 
Principal drugs 
1) Moderate CYP3A4 inhibitors 
Atazanavir sulfate, aprepitant, amiodarone hydrochloride, istradefylline, 
imatinib mesylate, erythromycin, crizotinib, cyclosporine, ciprofloxacin 
hydrochloride, cimetidine, tofisopam, fluconazole, fluvoxamine maleate, 
verapamil hydrochloride, fosamprenavir calcium hydrate, fosfluconazole, 
miconazole 
2) CYP3A4 inducers 
Etravirine, efavirenz, enzalutamide, carbamazepine, St. John’s wort, 
nevirapine, barbiturates, phenytoin, bosentan hydrate, mitotane, 
modafinil, rifabutin, rifampicin, rufinamide 
3) P-glycoprotein (P-gp) substrates 
Digoxin 
4) Hydroxymethylglutaryl (HMG)-CoA 
reductase inhibitors 
Simvastatin, rosuvastatin, atorvastatin, pitavastatin 
 
5) Allowed ITP therapies 
(1) Screening period and Period I 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
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Subjects are allowed to use only one of the specific therapies for ITP: corticosteroids (equivalent to 
10 mg/day prednisolone or less), azathioprine, or danazol, throughout the screening period and Period 
I. Dosage of these allowed ITP therapies should not be changed from at least 2 weeks before Day 1 to 
any of the following visit. Tapering of the allowed ITP therapies will not be permitted, even if platelet 
count exceeds 50000/μL. New treatments allowed for ITP should not be added from at least 2 weeks 
before Day 1. 
• Withdrawal Visit (subjects who withdraw from Period I and do not transition to Period II) 
• ET Day 1 (subjects who withdraw from Period I and transition to Period II) 
• Week 24 (except for the above) 
However, if platelet count is above 250000/μL even after the dose of the study drug is adjusted in 
accordance with "Dose adjustment due to excessive elevation of platelet count" (Table 2), reduce the 
dose of the allowed ITP therapy until the platelet count falls to ≤ 250000/μL and measure the platelet 
count until it falls to < 200000/μL. 
(2) Period II 
The same drug as in Period I can be used as ITP therapy in Period II with the same doses/regimens as 
in Period I. Consideration can be given to tapering the dose of allowed ITP therapy in subjects whose 
platelet count is stable at ≥ 50000/μL during Period II (including the start of Period II) at the 
discretion of the investigator. New treatments for ITP should not be added. If excessive platelet count 
increase is observed during Period II (including the start of Period II), the investigator should respond 
in accordance with Table 6. 
(3) Non-dosing period 
The same drug as in Period II can be used as ITP therapy in Non-dosing period with the same 
doses/regimens as used at the end of Period II. Doses/regimens of these allowed ITP therapies should 
not be changed until any of the following visit. New treatments for ITP should not be added. If 
excessive platelet count increase is observed during Non-dosing period, the investigator should 
respond in accordance with Table 6. 
• Period III Day 1 (subjects who transition to Period III) 
• Withdrawal Visit (subjects who withdraw from the Non-dosing period) 
(4) Period III 
The same drug as in Non-dosing period can be used as ITP therapy in Period III with the same 
doses/regimens as used at the end of Non-dosing period. Consideration can be given to tapering the 
dose of allowed ITP therapy in subjects whose platelet count is stable at ≥ 50000/μL during Period III 
(including the start of Period III) at the discretion of the investigator. New treatments for ITP should 
not be added. If excessive platelet count increase is observed during Period III (including the start of 
Period III), the investigator should respond in accordance with Table 6. 
(5) Follow-up period 
Doses/regimens of the allowed ITP therapy at the completion of Period II or at the Withdrawal Visit 
should not be changed during the follow-up period. New treatments for ITP should not be added. 
However, if excessive platelet count increase is observed, the investigator should respond in 
accordance with Table 6. 
Table 6 
Actions Taken for Allowed ITP Therapy for Excessive Elevation of Platelet Count 
 
Action 
1) Platelet counts > 250000/μL 
• Reduce the dose of the allowed ITP therapy. 
• Monitor platelet count until platelet count falls to < 200000/μL (the 
frequency of additional measurements will be determined by the 
investigator). 
• If the excessive elevation of platelet count is improved, the dose of 
allowed ITP therapies can be re-escalated based on the investigator’s 
decision. 
2) Platelet counts > 150000/μL and 
≤ 250000/μL 
• Leave the dose of the allowed ITP therapy unchanged. 
• Monitor the platelet count until stable to assure it does not exceed 
250000/μL (the frequency of additional measurements will be 
determined by the investigator). 
 
6) Rescue therapy 
Rescue therapy may be used at the discretion of the investigator from the start of the study drug in Period 
I to the end of the follow-up period or market authorization for subjects who meet any one or both of the 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 11 - 
following conditions. 
• Platelet count < 50000/μL and at immediate risk of bleeding or with clinically significant bleeding or 
wet purpura. 
• Platelet count < 50000/μL and requires urgent or emergent surgery. 
The drugs listed in Table 7 can be used for rescue therapy. The investigator should determine the dose and 
administration of rescue therapy with reference to Table 7. 
Table 7 
Rescue Therapy 
Drug 
Doses/regimens 
Platelet transfusion 
10 to 20 units/dose 
Intravenous immunoglobulin 
400 mg/kg/day for 5 consecutive days 
Intravenous methylprednisolone 
1 g/day for 3 consecutive days 
Oral dexamethasone 
Up to 40 mg/day for 1 to 2 days 
Oral prednisolone 
Up to 1 mg/kg/day for 1 to 3 days 
 
7) Washout 
Prior to start of the study drug administration in Period I, the use of all ITP medications except the 
allowed ITP therapies are prohibited during the specific period as shown in Table 8. 
Table 8 
Washout Period 
Drug 
Prohibited period prior to 
study drug administration 
Cyclosporine or mycophenolate mofetil 
2 weeks 
Eltrombopag olamine 
2 weeks 
Romiplostim 
3 weeks 
Alkylating agents 
8 weeks 
Rituximab or other anti-CD20 monoclonal antibodies 
24 weeks 
  
Study assessments/procedures and time points: 
See the study schedule table. 
Number of subjects 
Twenty-four subjects (16 in the Period I R788 group and 8 in the Period I placebo group) 
 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 12 - 
Study Schedule Table for Period I 
 
Informed 
consent 
Screening period 
Period I 
Withdrawal Follow-up 
period 
 
— 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 Visit 11 Visit 12  Visit 13 Visit 14 Visit 15 
— 
The end of 
follow-up 
 
— 
Screening 
A 
Screening 
B 
Day 1 
Week 2 
Week 4 
Week 6 
Week 8 Week 10 
Week  
12 a) 
Week  
14 a) 
Week  
16 a) 
Week  
18 a) 
Week  
20 a) 
Week  
22 a) 
Week 24 
— 
2 weeks 
after 
Withdrawal 
Visit 
Allowance (days) 
— 
−31 to −25 −17 to −11 
1 
12 to 18 26 to 32 40 to 46 54 to 60 68 to 74 82 to 88 
96 to  
102 
110 to  
116 
124 to 
130 
138 to 
144 
152 to 
158 
166 to  
172 
— 
±7 
Informed consent 
●b) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
● 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
● 
● 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration 
First 
Second 
 
Third 
 
 
 
 
 
 
 
Early transition to 
Period II allowed 
 
 
 
 
 
Study drug dispensed 
 
 
 
●c) 
 
 
 
 
 
●d) 
 
 
 
 
 
● 
 
 
Study drug compliance 
 
 
 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
ITP Bleeding Score 
 
● 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
ECOG Performance Status 
 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
● 
● 
Height and weight 
 
 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGe) 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
● 
● 
Vital signs 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Hematology 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Serum chemistry 
 
● 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Urinalysis 
 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
 
● 
● 
● 
D-dimer assayf) 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prothrombin time-
international normalized 
ratio/activated partial 
thromboplastin time 
(PT-INR/APTT) 
 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulin test 
 
● 
 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
● 
● 
Immunological test 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testg) 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
● 
● 
● 
Pharmacokinetics 
(before administration 
of the study drug) 
 
 
 
 
●h) 
 
●h) 
 
 
 
 
 
 
 
 
 
●j) 
 
Pharmacokinetics 
(after administration of 
the study drug) 
 
 
 
 
●h) 
●i) 
●h) 
●i) 
●i) 
●i) 
●i) 
●i) 
●i) 
●i) 
●i) 
●i) 
 
SF-36k) 
 
 
 
● 
 
● 
 
 
 
● 
 
 
 
 
 
● 
● 
● 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant meds 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 13 - 
a) 
If the subject withdraws from Period I and transition to Period II, in principle, the study procedures on ET Day 1 will be performed on the same day as the last visit in Period I. When the study procedures on ET 
Day 1 are performed on the same day as the last visit for Period I, the procedures overlapping on ET Day 1 with the last visit of Period I may be omitted when the procedures on ET Day 1 are performed. If the 
procedures on ET Day 1 cannot be performed on the same day as the last visit of Period I, all procedures on ET Day 1 must be performed within 1 week from the last visit of Period I. All procedures on ET Day 1 
should be performed on the same day. 
b) 
Written informed consent must be obtained before starting Screening A (before performing any test specified in this study) or washout of ITP drugs, whichever comes earlier. 
c) 
The dose of 100 mg of the study drug is administered at study institutions and this must be the only administration of the study drug on Day 1, irrespective of the time of administration. 
d) 
The need of dispensing the study drug is decided, considering the number of tablets to be taken before the next visit. 
e) 
In principle, the 12-lead ECG is taken before vital signs, laboratory tests, immunoglobulin test, immunological test (Screening A only), pregnancy test (women of childbearing potential only), and pharmacokinetics 
(only at Week 24 and at the Withdrawal Visit). 
f) 
D-dimer assay is performed if the patient has a history of venous thromboembolism more than 6 months prior to Screening A. 
g) 
Pregnancy testing should be performed for all female subjects of childbearing potential no matter with or without contraception. 
h) 
In principle, the subject should visit the hospital in the morning without administration of the study drug for the morning and blood sample is collected. Study drug is administered at the study site and blood sample 
is collected again 1 to 4 hours after taking the study drug. 
i) 
In principle, the study drug is administered in the morning 1 to 4 hours before blood sampling and blood sample is collected during morning at the study institution. 
j) 
The time of the last study drug administration before blood sampling to the date of blood sampling are not specified. 
k) 
SF-36 assessment is performed prior to other procedures and assessments. However, when all procedures on ET Day 1 are performed on the same day as the last visit of Period I, SF-36 assessments are performed 
prior to other procedures and assessments on ET Day 1. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 14 - 
Study Schedule for Period II (for subjects who completed Period I) 
 
Period I 
Period II 
Withdrawal 
Follow-up period 
 
Visit 15 
Visit 16 
Visit 17 
Visit 18 
Visit 19 
Visit 20 
Visit 21 
Visit 22 
— 
The end of 
follow-up 
 
Week 24 
Week 28 
Week 32 
Week 36 
Week 40 
Week 44 
Week 48 
Week 52 
— 
Week 52 or 
2 weeks after 
Withdrawal Visita) 
Allowance (days) 
166 to 172 
190 to 204 
218 to 232 
246 to 260 
274 to 288 
302 to 316 
330 to 344 
358 to 372 
— 
±7 
Informed consent 
 
 
 
 
 
 
 
●b) 
 
 
Registration 
● 
 
 
 
 
 
 
 
 
 
Study drug dispensed 
● 
● 
● 
● 
● 
● 
● 
 
 
 
Study drug compliance 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
ITP Bleeding Score 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
ECOG Performance Status 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
12-lead ECGc) 
● 
 
 
 
 
 
 
● 
● 
● 
Vital signs 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Hematology 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Serum chemistry 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Urinalysis 
● 
● 
 
 
● 
 
 
● 
● 
● 
Immunoglobulin test 
● 
 
 
 
 
 
 
● 
● 
● 
Pregnancy testd) 
● 
 
 
 
● 
 
 
● 
● 
● 
Pharmacokinetics 
●e) 
 
 
 
 
 
 
 
 
 
SF-36f) 
● 
 
 
 
 
 
 
● 
● 
● 
Adverse events 
 
 
 
 
 
 
 
 
 
 
Concomitant meds 
 
 
 
 
 
 
 
 
 
 
a) 
The tests at the end of the follow-up period are not performed for subjects who want to participate in the Non-dosing period and Period III and provide written informed consent. 
b) 
Written informed consent is obtained from subjects who want to participate in the Non-dosing period and Period III. 
c) 
In principle, the 12-lead ECG is taken before vital signs, laboratory tests, immunoglobulin test, pregnancy test (women of childbearing potential only), and pharmacokinetics (Week 24 only). 
d) 
Pregnancy testing should be performed for all female subjects of childbearing potential no matter with or without contraception. 
e) 
In principle, study drug is administered in the morning 1 to 4 hours before blood sampling and blood sample is collected during morning at the study institution. 
f) 
SF-36 assessment is performed prior to other procedures and assessments. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 15 - 
Study Schedule for Period II (for early transition subjects) 
 
Period I 
Period II 
Withdrawal 
Follow-up period 
 
ET 
Visit 1 
ET 
Visit 2 
ET 
Visit 3 
ET 
Visit 4 
ET 
Visit 5 
ET 
Visit 6 
ET 
Visit 7 
ET 
Visit 8 
— 
The end of 
follow-up 
 
ET 
Day 1 a) 
ET 
Week 4 
ET 
Week 8 
ET 
Week 12 
ET 
Week 16 
ET 
Week 20 
ET 
Week 24 
ET 
Week 28 
— 
ET Week 28 or 
2 weeks after 
Withdrawal Visitb) 
Allowance (days) 
1 
22 to 36 
50 to 64 
78 to 92 
106 to 120 
134 to 148 
162 to 176 
190 to 204 
— 
±7 
Informed consent 
 
 
 
 
 
 
 
●c) 
 
 
Inclusion/exclusion 
● 
 
 
 
 
 
 
 
 
 
Registration 
● 
 
 
 
 
 
 
 
 
 
Study drug dispensed 
● 
● 
● 
● 
● 
● 
● 
 
 
 
Study drug compliance 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
ITP Bleeding Score 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
ECOG Performance Status 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
12-lead ECGd) 
● 
 
 
 
 
 
 
● 
● 
● 
Vital signs 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Hematology 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Serum chemistry 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Urinalysis 
● 
● 
 
 
● 
 
 
● 
● 
● 
Immunoglobulin test 
● 
 
 
 
 
 
 
● 
● 
● 
Pregnancy teste) 
● 
 
 
 
● 
 
 
● 
● 
● 
SF-36f) 
● 
 
 
 
 
 
 
● 
● 
● 
Adverse events 
 
 
 
 
 
 
 
 
 
 
Concomitant meds 
 
 
 
 
 
 
 
 
 
 
a) 
If the subject withdraws from Period I and transition to Period II, in principle, the study procedures on ET Day 1 will be performed on the same day as the last visit in Period I. When the study procedures on ET 
Day 1 are performed on the same day as the last visit for Period I, the procedures overlapping on ET Day 1 with the last visit of Period I may be omitted when the procedures on ET Day 1 are performed. If the 
procedures on ET Day 1 cannot be performed on the same day as the last visit of Period I, all procedures on ET Day 1 must be performed within 1 week from the last visit of Period I. All procedures are performed 
on the same day. 
b) 
The tests at the end of the follow-up period are not performed for subjects who want to participate in the Non-dosing period and Period III and provide written informed consent. 
c) 
Written informed consent is obtained from subjects who want to participate in the Non-dosing period and Period III. 
d) 
In principle, the 12-lead ECG is taken before vital signs, laboratory tests, immunoglobulin test, and pregnancy test (women of childbearing potential only). 
e) 
Pregnancy testing should be performed for all female subjects of childbearing potential no matter with or without contraception. 
f) 
SF-36 assessment is performed prior to other procedures and assessments. However, when all procedures on ET Day 1 are performed on the same day as the last visit of Period I, SF-36 assessments are performed 
prior to other procedures and assessments on ET Day 1. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 16 - 
Study Schedule for Non-dosing Period and Period III 
 
Period II 
Non-dosing perioda) 
Period III 
Withdrawalb) 
Follow-up period 
 
Visit 22 or 
ET Visit 8 
Non-dosing period 
Visit 1 
Period III 
Visit 1 
Period III 
Visit 2 to 
market 
authorization 
— 
The end of 
follow-up 
 
Week 52 or 
ET Week 28 
Non-dosing period 
Week 2 c) 
Period III 
Day 1 d) 
From Period III 
Week 8 
— 
2 weeks after 
Withdrawal Visite) 
Allowance (days) 
1 
12 to 18 
26 to 32 
Period III 
Every 8 weeks ± 14 
from Day 1 
— 
±7 
Informed consent 
●f) 
 
 
 
 
 
Study drug dispensed 
 
 
● 
● 
 
 
Study drug compliance 
● 
 
 
● 
● 
 
ITP Bleeding Score 
● 
● 
● 
● 
● 
● 
ECOG Performance 
Status 
● 
● 
● 
● 
● 
● 
12-lead ECGg) 
● 
● 
● 
 
 
 
Vital signs 
● 
● 
● 
● 
● 
● 
Hematology 
● 
● 
● 
● 
● 
● 
Serum chemistry 
● 
● 
● 
● 
● 
● 
Urinalysis 
● 
● 
● 
● 
● 
● 
Immunoglobulin test 
● 
● 
● 
 
 
 
Pregnancy testh) 
● 
● 
● 
● 
● 
● 
SF-36i) 
● 
● 
● 
 
 
 
Adverse events 
 
 
 
 
 
 
Concomitant Medsj) 
 
 
 
 
 
 
a) 
Subjects with platelet count of < 50000/μL at Week 52 or at ET Week 28 may skip the Non-dosing period and transition to Period III at the discretion of the investigator. The study procedures for Day 1 of Period 
III are immediately performed irrespective of the allowance of visit for subjects who transition from the Non-dosing period to Period III before completing the Non-dosing period. 
b) 
The tests on the Withdrawal Visit are not performed for subjects who withdraw from the Non-dosing period. 
c) 
The study procedures for ND Week 2 are not performed for subjects who skip the Non-dosing period and transition to Period III, or transition from the Non-dosing period to Period III before performing the study 
procedures for ND Week 2. 
d) 
When the study procedures on Day 1 of Period III are performed on the same day as those for ND Week 2, the procedures overlapping on Day 1 of Period III with ND Week 2 may be omitted when the procedures 
on Day 1 of Period III are performed. The study procedures for Day 1 of Period III are omitted for subjects who skip the Non-dosing period and transition to Period III. 
e) 
The tests at the end of the follow-up period are performed at Week 52 or 2 weeks after ET Week 28 for subjects who withdraw from the Non-dosing period before ND Week 2. The tests at the end of the follow-up 
period are not performed for subjects who withdraw from the Non-dosing period at ND Week 2 or later. 
f) 
Written informed consent is obtained from subjects who want to participate in the Non-dosing period and Period III. 
g) 
In principle, the 12-lead ECG is taken before vital signs, laboratory tests, immunoglobulin test, and pregnancy test (women of childbearing potential only). 
h) 
Pregnancy testing should be performed for all female subjects of childbearing potential no matter with or without contraception. 
i) 
SF-36 assessment is performed prior to other procedures and assessments. 
j) 
Only the use of ITP drugs is checked during Period III or later. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 17 - 
TABLE OF CONTENTS 
1. History and Background of Study Plan ................................................................. 22 
1.1 Idiopathic Thrombocytopenic Purpura .............................................................. 22 
1.2 Treatment of ITP ............................................................................................... 22 
1.3 Development History of R788 ........................................................................... 24 
1.4 Summary of Expected Adverse Drug Reactions and Benefits .......................... 28 
2. Title of Study and Study Phase ............................................................................. 30 
2.1 Title of Study ..................................................................................................... 30 
2.2 Study Phase ..................................................................................................... 30 
3. Objective ............................................................................................................... 30 
3.1 Primary Objective ............................................................................................. 30 
3.2 Secondary Objectives ....................................................................................... 30 
3.3 Exploratory Objective ....................................................................................... 30 
4. Endpoints .............................................................................................................. 30 
4.1 Efficacy Endpoints ............................................................................................ 30 
4.2 Safety Endpoints .............................................................................................. 32 
4.3 Pharmacokinetic endpoint ................................................................................ 32 
5. Subjects ................................................................................................................ 32 
5.1 Inclusion Criteria ............................................................................................... 32 
5.2 Exclusion Criteria .............................................................................................. 34 
5.3 Withdrawal in Individual Subjects ..................................................................... 36 
6. Consent of Subjects.............................................................................................. 38 
6.1 Time to Collect Informed Consent .................................................................... 38 
6.2 Collection of Consent ....................................................................................... 38 
7. Study Drugs .......................................................................................................... 39 
7.1 Test and Control Drugs ..................................................................................... 39 
7.2 Packaging Form of Study Drugs ....................................................................... 40 
7.3 Labeling ............................................................................................................ 40 
7.4 Drug Accountability ........................................................................................... 40 
8. Study Method ....................................................................................................... 40 
8.1 Study Design .................................................................................................... 40 
8.2 Structure of the Study ....................................................................................... 40 
8.3 Transition to Period II ........................................................................................ 41 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 18 - 
8.4 Transition to Non-dosing Period ....................................................................... 43 
8.5 Transition to Period III ....................................................................................... 43 
8.6 Dose and Administration ................................................................................... 43 
8.7 Concomitant Medications ................................................................................. 49 
8.8 Randomization and Blinding ............................................................................. 53 
8.9 Number of Subjects .......................................................................................... 55 
9. Guidance to and Management of Subjects ........................................................... 55 
10. Study Assessments and Procedures .................................................................. 57 
10.1 Demographics ................................................................................................ 57 
10.2 Administration State ........................................................................................ 57 
10.3 Concomitant Medications ............................................................................... 58 
10.4 Efficacy Endpoints .......................................................................................... 58 
10.5 Laboratory Tests ............................................................................................. 58 
10.6 Immunoglobulin Test ....................................................................................... 59 
10.7 Immunological Test ......................................................................................... 59 
10.8 Eastern Cooperative Oncology Group (ECOG) Performance Status ................... 59 
10.9 Vital Signs ....................................................................................................... 59 
10.10 Height and Weight ........................................................................................ 60 
10.11 12-lead ECG ................................................................................................. 60 
10.12 Pregnancy Test ............................................................................................. 60 
10.13 ITP Bleeding Score ....................................................................................... 60 
10.14 Pharmacokinetics ......................................................................................... 60 
10.15 Adverse Events ............................................................................................. 61 
10.16 Evaluation of Diarrhea .................................................................................. 65 
11. Schedule of Study Assessments and Procedures............................................... 65 
11.1 Collection of Informed Consent ....................................................................... 65 
11.2 Screening Period ............................................................................................ 65 
11.3 Period I ........................................................................................................... 66 
11.4 Period II (Subjects Who Completed Period I) ................................................. 71 
11.5 Period II (Early Transition Subjects) ................................................................ 73 
11.6 Non-dosing Period .......................................................................................... 75 
11.7 Period III ......................................................................................................... 75 
11.8 At Withdrawal .................................................................................................. 76 
11.9 Follow-up Period ............................................................................................. 77 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 19 - 
12. Security of Study................................................................................................. 78 
12.1 Management of Adverse Events ..................................................................... 78 
12.2 Management of Serious Adverse Events ........................................................ 78 
12.3 Management of Pregnant Women .................................................................. 78 
12.4 Management of Abnormal Liver Function Test Values .................................... 79 
12.5 Collection and Provision of Safety Information ............................................... 79 
13. Discontinuation/suspension of Study .................................................................. 80 
13.1 Discontinuation/suspension of Part of the Study or the Entire Study .............. 80 
13.2 Discontinuation Criteria (Discontinuation/suspension of Part of the 
Study or the Entire Study) ................................................................................ 80 
13.3 Procedure for Discontinuation/suspension ..................................................... 80 
14. Statistical Analysis .............................................................................................. 81 
14.1 Analysis Sets .................................................................................................. 81 
14.2 Analysis Group ............................................................................................... 81 
14.3 Disposition of Subjects ................................................................................... 82 
14.4 Demographic and Other Baseline Characteristics .......................................... 82 
14.5 Efficacy ........................................................................................................... 82 
14.6 Safety ............................................................................................................. 86 
14.7 Pharmacokinetics ........................................................................................... 87 
14.8 Timing of Analysis ........................................................................................... 87 
15. Agreement on and Amendment to the Protocol .................................................. 88 
15.1 Agreement on the Protocol ............................................................................. 88 
15.2 Amendment to the Protocol ............................................................................ 88 
15.3 Protocol Deviations ......................................................................................... 88 
16. Direct access to Source Documents ................................................................... 88 
16.1 Source Documents ......................................................................................... 88 
16.2 Direct Access .................................................................................................. 88 
16.3 Consistency of a Case Report From with the Source Documents .................. 89 
17. Quality Control and Assurance for the Study ...................................................... 89 
18. Ethics .................................................................................................................. 89 
18.1 Compliance with GCP .................................................................................... 89 
18.2 Subject Confidentiality Considerations ........................................................... 89 
18.3 Compensation to Subjects .............................................................................. 89 
19. Data Handling and Records Retention ............................................................... 90 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 20 - 
19.1 Case Report from Creation and Submission .................................................. 90 
19.2 External Data .................................................................................................. 90 
19.3 Records Retention .......................................................................................... 90 
20. Payment ............................................................................................................. 91 
21. Publication Policy................................................................................................ 91 
22. Study Organization ............................................................................................. 91 
23. Protocol Revision History .................................................................................... 91 
24. References ......................................................................................................... 92 
 
 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 21 - 
List of Abbreviations and Terms 
Abbreviation or term 
Description 
AIHA 
Autoimmune hemolytic anemia 
ATP 
Adenosine triphosphate 
AUC0-∞ 
Area under the plasma concentration-time curve from zero (0) hours to infinity (∞) 
AUC0-t 
Area under the plasma concentration-time curve from zero (0) hours to last 
quantifiable concentration 
AUCss 
Area under the plasma concentration-time curve during any dosing interval at steady 
state 
AUCτ 
Area under the plasma concentration-time curve from zero to the end of the dosing 
interval 
BCR 
B-cell receptor 
14C 
Carbon-14 labeled 
Cmax 
Maximum plasma concentration 
Cmax, ss 
Maximum plasma concentration at steady state 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
ECOG 
Eastern Cooperative Oncology Group 
GCP 
Good Clinical Practice 
HCG 
Human chorionic gonadotropin 
H. pylori 
Helicobacter pylori 
ICH 
The International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for human use 
ITP 
Idiopathic thrombocytopenic purpura 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometer 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
P-gp 
P-glycoprotein 
PT-INT/APTT 
Prothrombin time-international normalized ratio/activated partial thromboplastin time 
PT 
Preferred term 
RA 
Rheumatoid arthritis 
Rac 
Accumulation ratio 
SF-36 
Short form 36 
SOC 
System organ class 
SYK 
Spleen tyrosine kinase 
TPO 
Thrombopoietin 
t1/2 
Terminal elimination half-life 
t1/2, ss 
Terminal elimination half-life at steady state 
tmax 
Time to reach maximum plasma concentration 
tmax, ss 
Time to reach maximum plasma concentration at steady state 
UGT 
UDP-glucuronosyltransferase 
 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 22 - 
1. History and Background of Study Plan 
1.1 Idiopathic Thrombocytopenic Purpura 
ITP is an autoimmune disorder characterized by the development of antibodies to platelet 
membrane proteins and binding of them to platelets or megakaryocyte, which enhances platelet 
destruction in reticuloendothelial cells in the spleen and suppresses platelet production in bone 
marrow, thereby causing thrombocytopenia.1) Although patients with ITP develop 
thrombocytopenia, they often have normal or increased numbers of megakaryocytes, which are 
the precursors cells of platelets in the bone marrow.1) Therefore, ITP is thought to be the main 
condition in which thrombocytopenia results from increased destruction of platelets rather than 
inhibition of platelet production, but the etiology of ITP remains unknown and the mechanism 
of antibody production has not been determined.1) 
The clinical symptom of ITP show various hemorrhagic manifestations on the skin and mucous 
membrane mainly as the purpura.2) A platelet count of < 10000/μL is associated with an 
increased risk of serious bleeding episodes.2) Severe mucosal bleeding may be fatal because it 
may lead to gastrointestinal bleeding or intracranial hemorrhage.3) In Japan, ITP has been 
specified as a designated intractable disease by the “Act on Medical Care for Patients with 
Intractable Diseases” (Act No. 50, 2014). The health administration report from the Ministry of 
Health, Labour and Welfare in 2017 showed that there were 17618 patients who had a certificate 
for receiving specific medical expenses (for the designated intractable disease).4) The annual 
incidence of newly diagnosed patients in Japan was reported to be 2.4 per 100000 people.2) 
1.2 Treatment of ITP 
Based on the scientific verification by accumulated therapeutic experience of ITP and long-
term follow-up of its clinical course, not all thrombocytopenia in patients with ITP needs to be 
treated, and this therapeutic concept is getting consensus internationally.5) It is revealed that 
platelet count recovered spontaneously in 5% to 10% of untreated patients with ITP, and that 
ITP patients with a platelet count of ≥ 30000/μL were not greatly different from the general 
population in life prognosis. It has been shown that the non-treatment follow-up is not 
necessarily a negative factor for ITP patients with a platelet count of ≥ 30000/μL from the 
perspective of long-term prognosis considering both death by ITP-induced hemorrhage and 
death by adverse drug reactions.5) Based on this view, the therapeutic goal for ITP is not to 
restore platelet count to a normal level, but to maintain platelet count at a level at which serious 
bleeding can be prevented (platelet count ≥ 30000/μL, or ≥ 50000/μL if possible).6) 
The Japanese ITP treatment reference guide in 20125) recommends that, after definite diagnosis 
is made, patients with ITP should be subjected to the examination for Helicobacter pylori (H. 
pylori) infection, and that positive patients should be treated with eradication therapy. Drug 
therapy is initiated to patients at risk of bleeding who had no platelet response to eradication 
therapy or who are negative for H. pylori infection. As the first line therapy, corticosteroids are 
used to suppress an excessive immune response and prevent peripheral platelet destruction. A 
splenectomy is considered as the second-line therapy to prevent platelet destruction as with 
corticosteroids in patients responding poorly to the first-line therapy or in patients who cannot 
tolerate the first-line therapy. In addition to immunosuppressive agents such as azathioprine and 
rituximab, TPO receptor agonists that stimulate platelet production in the bone marrow are 
widely used as the third line treatment. 


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The first-line corticosteroid therapy has increased platelet count to ≥ 30000/μL in 
approximately 80% of patients and to ≥ 100000/μL in approximately 50% of them.5) However, 
corticosteroids need dose reduction because their long-term use may cause adverse drug 
reactions. Therefore, ITP often recurs during dose reduction even in responders. Splenectomy 
is considered when the maintenance dose of steroids is high.3),5) 
The second-line splenectomy provides platelet responses for approximately 80% of patients 
who received it. However, because of the recurrence in approximately 20% of them, 
approximately 60% have permanent platelet response.5) Although splenectomy is a highly 
effective treatment, earlier studies have reported postoperative complications, such as portal 
vein thrombosis, reduced protection against Streptococcus pneumoniae, Neisseria meningitidis, 
and Haemophilus influenzae by splenectomy, risk of serious post-splenectomy infection,5) and 
increased frequency of sepsis and thrombosis.7) Splenectomy was performed in approximately 
0.7% (715) of ITP patients requiring treatment in 10 years from 2005 to 2014. The rate of 
patients undergoing splenectomy has shown a gradually decrease in recent years.7) 
As third-line TPO receptor agonists, romiplostim (Romiplate® Subcutaneous Injection), which 
is an injection preparation, and eltrombopag olamine (Revolade® Tablets), which is an oral 
preparation, have been used in Japan. TPO receptor agonists bind to TPO receptors, which are 
factors stimulating megakaryocyte growth and platelet production, to accelerate 
megakaryocytic maturation, thereby stimulating platelet production. Although they have an 
effect to increase platelets in patients with refractory chronic ITP, they have been reported to 
result in treatment discontinuance by adverse events in approximately one third of patients8) 
and eventually lead to the loss of therapeutic effect in approximately 30% of responders.9) 
Furthermore, it was reported that, given their mechanism of action, they cannot cure ITP and 
require long-term use as symptomatic therapy, and that they caused adverse drug reactions, 
including increased reticulin fibers in the bone marrow, serious thrombosis, and reduction in 
platelet count below the baseline level, leading to exacerbated bleeding tendency after 
discontinuation.5) 
Rituximab, an anti-CD 20 monoclonal antibody, was approved for insurance coverage for 
chronic ITP in June 2017 in response to the requests for approval of unapproved and off-label 
drugs with high medical need. In the Japanese clinical study of rituximab, the percentage of 
patients achieving the primary endpoint of a platelet count at Week 24 of ≥ 50000/μL was 30.8% 
(two-sided 95% confidence interval, 14.3% to 51.8%). Although it was lower than the 
predetermined threshold (20%, lower limit of the 95% confidence interval), it shows that the 
drug has a certain level of efficacy.10) The mean duration of response to rituximab is 10.5 months, 
showing a long-term sustained effect, but relapse has been reported to occur in 10.5% of 
patients.5) The investigation of the safety of rituximab has reported that it reactivated the 
hepatitis B virus and only infrequently caused progressive multifocal leukoencephalopathy, and 
it is therefore recommended that the drug be used carefully.11) 
In summary, in the early phase of ITP treatment, the administration of high-dose corticosteroids 
and splenectomy have been performed to suppress the destruction of platelets in the periphery, 
and rituximab or TPO receptor agonists and others have been used in patients with insufficient 
response. However, based on the abundant evidence on efficacy, TPO receptor agonists are now 
widely used to promote platelet production. Under these circumstances, a new drug that inhibits 
the increased destruction of platelets, the main pathology of ITP, and is positioned as a radical 
therapy is expected. 


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1.3 Development History of R788 
R788 (nonproprietary name: fostamatinib) is a prodrug product of an orally available small-
molecule tyrosine kinase inhibitor developed by Rigel Pharmaceuticals, Inc. (hereinafter 
referred to as Rigel) in the United States. R788 is metabolized to its active substance, R406, 
through the cleavage of the phosphate group by alkaline phosphatase in the apical brush border 
membrane of gastrointestinal cells. R406 inhibits splenic tyrosine kinase (SYK), one of the 
tyrosine kinases involved in Fcγ receptor activation and B-cell receptor signaling, thereby 
inhibiting platelet phagocytosis and destruction by macrophages. The effect of R406 on B cells 
may also inhibit antiplatelet antibody production. 
For the overseas development of R788, Rigel obtained the approval for the treatment of 
thrombocytopenia in adult patients with chronic ITP who have had an insufficient response to 
a previous treatment in April 2018 and launched it in May 2018 in the United States. In Europe, 
the application for marketing approval for the same indication was received in October 2018 
and approval review is ongoing. Rigel is currently developing the product for the indication of 
autoimmune hemolytic anemia (AIHA) in Europe and the United States. In addition, R788 was 
designated as an orphan drug for ITP in 2015 and for AIHA in 2018 in the United States. 
Outside of Japan, 28 Phase I clinical studies (including 2 studies in Japanese patients), 1 Phase 
II clinical study in ITP patients, and 3 Phase III clinical studies in ITP patients have been 
conducted. In addition to these clinical studies, R788 was once developed for indications other 
than ITP and AIHA. The safety data from at least 4600 patients are available, including Japanese 
patients with rheumatoid arthritis (RA). 
This study is planned to investigate the efficacy, safety, and pharmacokinetics of the oral 
administration of R788 for 24 weeks and the safety and efficacy of the long-term administration 
of R788 in Japanese patients with chronic ITP. 
1.3.1 Nonclinical studies 
1.3.1.1 Primary pharmacodynamics 
The key aspects of the pharmacology are summarized below. 
 
R406 inhibited Fcε receptor-dependent human mast cell degranulation and release of lipid 
and cytokine mediators of inflammation. 
 
R406 showed a reversible adenosine triphosphate (ATP) competitive inhibition of SYK. 
 
R406 specifically inhibited phosphorylation of of the SYK substrate linker of activated T-
cells and downstream molecules of SYK activity. 
 
R406 inhibited Fcγ receptor-dependent human mast cell, macrophage, and neutrophil 
responses. 
 
R406 inhibited B-cell receptor (BCR) mediated responses in primary human B cells. 
 
R788 treatment mitigated clearance of platelets and red blood cells in murine models of 
immune autoantibody-mediated thrombocytopenia and AIHA. 
1.3.1.2 Secondary pharmacodynamics 
R406 was highly selective in biochemical assays of 326 molecular targets across various 


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enzymes, receptors, and transporters. The most potent activity was as an antagonist of human 
adenosine A3 receptors. R406 was profiled in broad kinase panels utilizing different 
biochemical assays indicating a range of potential activities, some of which have been 
confirmed or identified by relevant cell-based assays. Using cell-based assays, R406 inhibits 
the kinase activity of RET proto-oncogene, vascular endothelial growth factor receptor-2, FMS-
related tyrosine kinase 3, Janus kinase 1/3, and KIT proto-oncogene receptor tyrosine kinase 
within 5-fold of R406 activity against the SYK assay. 
1.3.1.3 Safety pharmacology 
R406 was well tolerated in safety pharmacology studies (considering the central nervous system 
[CNS], respiratory system, and cardiovascular system). Mild behavioral abnormality (e.g., 
hypoactivity) were observed at 50 mg/kg of R406 in the rat CNS study, and a slight reduction 
in heart rate at 50 mg/kg and a trend towards increased blood pressure were observed at 50 
mg/kg in the monkey cardiovascular study. Data from anesthetized rat studies suggested that 
R788-induced increase in blood pressure elevation from increased vascular resistance. Data 
from other investigative studies suggested that impaired vasorelaxation due to inhibition of 
vascular endothelial growth factor-induced endothelial nitric oxide release may contribute to 
this effect. In conscious telemetered rats, there was a direct relationship between plasma 
concentrations of R406 and increased blood pressure. Increased blood pressure persisted 
throughout the 28-day treatment period and blood pressure returned to the baseline level after 
treatment discontinuation. Increased blood pressure was resolved with standard 
antihypertensive drugs including nifedipine (calcium antagonist), atenolol (β-blocker), and 
captopril (angiotensin-converting enzyme inhibitor). 
1.3.1.4 Pharmacokinetics 
1) 
Absorption 
The results from in vivo pharmacokinetic studies showed that there is negligible systemic 
or portal exposure to R788 following oral administration. In vivo conversion of R788 to 
R406 is rapid, extensive and most likely to be catalyzed by intestinal alkaline phosphatases. 
R406 bioavailability from R788 dosing ranged from approximately 40 to 80% in various 
species. Consistent with the high bioavailability, approximately 73% of the radioactivity 
was recovered in urine and bile following oral 14C-R788 dosing to monkeys. Oral absolute 
bioavailability for R788 in humans was 55%. 
2) 
Distribution 
R406 was highly bound to plasma proteins in mice (98.6%), rats (97.9%), rabbits (99.5%), 
monkeys (98.5%), and humans (98.3%). 14C-R406 had a mean binding to purified human 
serum albumin of 96.3% over the concentration range of 100 to 4000 ng/mL. It showed a 
mean binding to purified alpha 1-acid glycoprotein of 75.5% over the same concentration 
range. In in vitro studies, 14C-R406 was distributed preferentially into not monocytes but 
red blood cells (2.6-fold). The volume of distribution of R406 was approximately 0.3 to 
1.2 L/kg in all the animal species, suggesting extravascular distribution of R406. A 
quantitative whole body autoradiography study in rats showed that, with the exception of 
the CNS, drug-derived radioactivity was widely distributed to tissues of pigmented and 
albino rats 4 hours after oral dosing of 20 mg/kg of 14C-R788. For most tissues, the 
maximum concentrations were observed at 1 hour post-dose. Radioactivity levels in the 


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majority of tissues were below the quantitation limit at 24 hours; however, the eyes (uveal 
tract), the liver, and the contents of the small intestine had low levels of radioactivity at 
168 hours post-dose. 
3) 
Metabolism 
Purified bovine alkaline phosphatase and human intestinal microsomes rapidly converted 
R788 to R406. The major metabolite formed in hepatic microsomes from humans and all 
animal species was para-O-demethylated R406 (R529). CYP3A4 was identified as the 
human CYP450 isoform primarily involved in this biotransformation. Direct 
N-glucuronidation of R406, primarily mediated by UDP-glucuronosyltransferase (UGT) 
1A9 in humans, was also observed in vitro. The major metabolites in plasma from all 
species were glucuronide and sulfate conjugates of R529. 
4) 
Excretion 
Clearance of R406 averaged 16.9, 13.4, 73.5, and 1.99 mL/min/kg in rats, monkeys, mice, 
and rabbits, respectively, and the terminal half-life averaged 1.51, 3.09, 0.58, and 
3.41 hours, respectively. Mass balance studies were performed in rats using 14C-R406 and 
in mice, monkeys, rabbits, and humans with 14C-R788. In all species, fecal elimination of 
drug-related material was the primary route of excretion (80% to 84% of the dose). Urinary 
excretion was highest in humans (19.3% of the dose) and ranged from 3% to 10% of the 
dose in all other species. 
1.3.1.5 Toxicology 
Toxicology studies in rats and monkeys (doses: ≤ 100 mg/kg/day of R788) for 4 to 26 weeks 
and 4 to 39 weeks, respectively, identified lymphohematopoietic and liver function test 
abnormalities (mild and fully reversible), and reproductive and/or developmental liabilities in 
rats and rabbits. Consistent with bone growth plate effects in rats in the general toxicity study, 
similar findings were observed in the carcinogenicity studies in rat and mouse and the 1-month 
juvenile study in rabbits (doses: 12.5 to 50 mg/kg/day). A related finding of odontodysplasia 
was also observed in the rat 2-year carcinogenicity study. There were no adverse effects on any 
male reproductive parameters in rats at doses up to 40 mg/kg/day. 
There was no evidence for mutagenic or clastogenic effects in genotoxicity studies, nor 
carcinogenic potential in mouse and rat carcinogenicity studies. R788 promoted no remarkable 
adverse effects on host response in murine immunological host resistance models 
(Streptococcus, Listeria, and Influenza viruses). 
1.3.2 Clinical studies 
Outside of Japan, 28 Phase I clinical studies (including 2 studies for Japanese), 1 Phase II 
clinical study in ITP patients, and 3 Phase III clinical studies in ITP patients have been 
conducted. In addition to these clinical studies, clinical studies for indications other than ITP, 
such as AIHA and RA, have been conducted. 
1.3.2.1 Phase I study in healthy White and Japanese subjects after single and 
multiple ascending doses (D4300-007) 
The pharmacokinetics and safety of R788 (parent compound) and R406 (major active 
metabolite) were evaluated in 12 healthy White subjects with R788 150 mg, each 6 healthy 


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Japanese subjects with R788 50, 100, or 200 mg, and 12 healthy Japanese subjects with R788 
150 mg, respectively, administered orally in a single dose in a fasted state (Day 1 of the study 
drug administration), followed by repeated oral administration in a fasted state for 7 days (Day 
2–3 of the study drug administration: untreated, Day 4–9 of the study drug administration: bid 
[50, 100, and 200 mg groups] or qd [150 mg group], and Day 10 of the study drug 
administration: qd). Two subjects (50, 100, and 200 mg groups) or four subjects (150 mg group) 
in each treatment group received placebo. There were no major differences in the 
pharmacokinetics of R406 between Japanese and White subjects, and the pharmacokinetics in 
Japanese and White subjects were considered similar. 
Table 1.3.2.1-1 
Plasma Pharmacokinetic Parameters of R406 (Single Dose) 
Treatment 
group 
Cmax 
(ng/mL) 
tmax a) 
(hr) 
AUC0-∞ 
(ng•hr/mL) 
AUC0-t 
(ng•hr/mL) 
AUCτ b) 
(ng•hr/mL) 
t1/2 
(hr) 
50 mg 
Japanese 
163 
(36.5) 
3 
(1, 4) 
2170 
(14.9) 
2090 
(15.7) 
1080 
(29.8) 
15.2 
(22.2) 
100 mg 
Japanese 
338 
(39.8) 
3 
(1.5, 6) 
4150 
(33) 
3960 
(30.4) 
2080 
(24.9) 
15.9 
(40.3) 
150 mg 
Japanese 
626 
(39) 
1.5 
(1, 4) 
5870 
(27.6) 
5730 
(27.1) 
4500 
(31.6) 
12.6 
(34.9) 
150 mg 
White 
431 
(47.7) 
1.5 
(0.5, 4) 
4620 
(32.8) 
4480 
(32.9) 
3400 
(34.1) 
12.7 
(42.8) 
200 mg 
Japanese 
395 
(38.8) 
1.5 
(1, 4) 
4430 c) 
(32.1) 
4300 c) 
(32.8) 
2260 
(44.9) 
14.8 c) 
(9.56) 
Data show the geometric mean (geometric CV%) of 6 subjects (50, 100, and 200 mg) or 12 subjects (150 mg). 
a) Median (min, max), b) AUC0-12 (bid) or AUC0-24 (qd), c) 5 subjects 
 
Table 1.3.2.1-2 
Plasma Pharmacokinetic Parameters of R406 (7-day Repeated 
Dose, Steady State) 
Treatment 
group 
Cmax, ss 
(ng/mL) 
tmax, ss a) 
(hr) 
AUC0-t 
(ng•
hr/mL) 
AUCss 
(ng•
hr/mL) 
t1/2, ss 
(hr) 
Rac(Cmax)b) 
Rac(AUC)c) 
50 mg 
Japanese 
340 
(16.7) 
2 
(1.5, 4) 
4900 
(16.9) 
2570 
(12.5) 
16.5 
(19.8) 
2.09 
(38) 
2.39 
(35.4) 
100 mg 
Japanese 
615 
(31.1) 
2 
(1.5, 4) 
8930 
(44.8) 
4610 
(31) 
16 
(35.1) 
1.82 
(36.7) 
2.22 
(18.1) 
150 mg 
Japanese 
643 
(37) 
4 
(1, 6) 
7480 
(34.7) 
5900 
(33.5) 
14.3 
(30.6) 
1.01 
(38.4) 
1.26 
(25.3) 
150 mg 
White 
520 
(45.2) 
2 
(1, 4) 
6670 
(46.8) 
4980 
(37.9) 
12.7 
(45.4) 
1.21 
(59.4) 
1.46 
(39.6) 
200 mg 
Japanese 
1730 
(20.4) 
1.5 
(1, 4) 
26500 
(33.5) 
14100 
(19.4) 
12.3 
(17.5) 
4.51 
(48.9) 
6.55 
(52.1) 
 
 
 
 
 
 
 
 
Data show the geometric means (geometric CV%) of 5 subjects (200 mg), 6 subjects (50 and 100 mg), 11 subjects (150 mg, 
Japanese), or 12 subjects (150 mg, White). 
a) Median (min, max), b) Rac(Cmax) (Cmax, ss of 7-day repeated dose /Cmax of single dose), c) Rac(AUC) (AUCss over 7-day 
repeated dose /AUCτ of single dose) 
 
There were no serious adverse events or withdrawals due to adverse events. No major 
differences in incidence of adverse events or adverse drug reactions were observed between 
Japanese and White subjects. 


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1.3.2.2 Overseas Phase III clinical studies (C788-047 and C788-048 studies) and 
overseas long-term extension study (C788-049 study) in patients with ITP 
The overseas Phase III clinical studies in patients with ITP included 2 double-blind, randomized, 
placebo-controlled studies (C788-047 and C788-048 studies) and 1 open-label, long-term 
extension study (C788-049 study) in patients with persistent/chronic ITP were conducted. The 
C788-047 and C788-048 studies were identically designed clinical studies to evaluate the 
efficacy and safety of R788 administered for 24 weeks as compared to placebo in patients with 
persistent/chronic ITP. Subjects who discontinued the study after Week 12 based on the platelet 
count criteria were able to enter the C788-049 study (when the baseline platelet count was 
< 15000/μL), as with the subjects who completed 24 weeks of treatment in the C788-047 or 
C788-048 study. 
The analysis of the primary efficacy endpoint of the C788-047 and C788-048 studies showed 
that the achievement rate of stable platelet response in subjects treated with R788 (18%) was 
consistent between the studies. The difference from the placebo group was statistically 
significant in the C788-047 study, while no significant difference was observed in the C788-
048 study in which there was one responder in the placebo group. 
In the C788-049 study, the achievement rate of stable response in subjects randomized to 
placebo in the C788-047 or C788-048 study was compared with the achievement rate of stable 
response in these patients after the treatment with R788 (predetermined within-subject and 
between-study comparison). The stable response was met when the platelet count was increased 
to ≥ 50000/μL within 12 weeks after the start of treatment and increased platelet count was 
maintained for the subsequent 12 weeks. A total of 44 subjects who were randomized to the 
placebo group enrolled to the C788-049 study; one subject was a responder in the C788-048 
study and the other 43 were non-responders. One subject met the criteria for stable response 
during the treatment with placebo in the C788-048 study, while 10 of these 44 subjects (22.7%) 
met the criteria for stable response in the C788-049 study, indicating a consistent response rate 
as compared to the subjects treated with R788 in the C788-047 and C788-048 studies. 
1.4 Summary of Expected Adverse Drug Reactions and Benefits 
1.4.1 Expected adverse drug reactions 
The integrated safety analysis of 2 overseas Phase III clinical studies (C788-047 and C788-048 
studies) in 150 patients with persistent/chronic ITP (102 in the R788 group and 48 in the placebo 
group) showed that adverse events occurred in 83.3% (85/102) of the R788 group and 75.0% 
(36/48) of the placebo group. Common adverse events with an incidence of ≥ 5% in the R788 
group included diarrhea, hypertension, and nausea (Table 1.4.1-1). 
Treatment-related adverse events occurred in 58.8% (60/102) of the R788 group and 27.1% 
(13/48) of the placebo group. Common treatment-related adverse events with an incidence of 
≥ 5% in the R788 group included diarrhea in 26.5% (27/102), hypertension in 15.7% (16/102), 
nausea in 14.7% (15/102), ALT increased in 9.8% (10/102), dizziness in 8.8% (9/102), and AST 
increased in 6.7% (7/102). 
Serious adverse events occurred in 12.7% (13/102) in the R788 group and 20.8% (10/102) in 
the placebo group. Treatment-related serious adverse event occurred in 3.9% (4/102) in the 
R788 group (febrile neutropenia, diarrhea, pneumonia, and hypertensive crisis) and 2.1% (1/48) 


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in the placebo group (menorrhagia). Serious bleeding-related adverse events were reported in 
4.9% (5/102) in the R788 group and 10.4% (5/48) in the placebo group. 
The integrated safety analysis of the C788-047, C788-048, and C788-049 studies showed that 
the occurrence of adverse events was comparable between the C788-047 and C788-048 studies 
and C788-049 study, and that there were no new safety-related trends during extended treatment. 
Table 1.4.1-1 
Incidence of Common Adverse Events (≥ 5%) in C788-047 and 
C788-048 Studies 
Adverse events 
R788 
(N = 102) 
Placebo 
(N = 48) 
Mild 
% 
Moderat
e 
% 
Severe 
% 
Total 
% 
Mild 
% 
Moderate 
% 
Severe 
% 
Total 
% 
Diarrheaa) 
21 
10 
1 
31 
13 
2 
0 
15 
Hypertensionb) 
17 
9 
2 
28 
10 
0 
2 
13 
Nausea 
16 
3 
0 
19 
8 
0 
0 
8 
Dizziness 
8 
2 
1 
11 
6 
2 
0 
8 
ALT increased 
5 
6 
0 
11 
0 
0 
0 
0 
AST increased 
5 
4 
0 
9 
0 
0 
0 
0 
Respiratory infectionc) 
7 
4 
0 
11 
6 
0 
0 
6 
Rashd) 
8 
1 
0 
9 
2 
0 
0 
2 
Abdominal paine) 
5 
1 
0 
6 
2 
0 
0 
2 
Fatigue 
4 
2 
0 
6 
0 
2 
0 
2 
Chest pain 
2 
3 
1 
6 
2 
0 
0 
2 
Neutropeniaf) 
3 
2 
1 
6 
0 
0 
0 
0 
a) Includes diarrhea and frequent bowel movements. 
b) Includes hypertension, blood pressure increased, diastolic blood pressure abnormal, and diastolic blood pressure increased. 
c) Includes upper respiratory tract infection, respiratory tract infection, lower respiratory tract infection, and viral upper 
respiratory tract infection. 
d) Includes rash, rash erythematous and rash macular. 
e) Includes abdominal pain and abdominal pain upper. 
f) Includes neutropenia and neutrophil count decreased. 
 
1.4.2 Expected benefits 
The efficacy of R788 including increased platelet count was confirmed in the overseas Phase 
III clinical studies in patients with persistent/chronic ITP (C788-047 and C788-048 studies). 
R788 is expected to increase platelet count in patients with chronic ITP in this study. 
2. Title of Study and Study Phase 
2.1 Title of Study 
A Phase III Study in Patients with Chronic Idiopathic Thrombocytopenic Purpura in R788 
2.2 Study Phase 
Phase III 


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3. Objective 
3.1 Primary Objective 
To investigate the increase in platelet count in patients with chronic ITP after oral administration 
of R788 for 24 weeks in a placebo-controlled, double-blind manner (Period I). 
3.2 Secondary Objectives 
1) 
To evaluate the efficacy of R788 in patients with chronic ITP for the following points: 
 
Maintenance of platelet count during long-term treatment with R788 
 
Increase in platelet count during Period II for patients who received placebo in 
Period I 
 
Improving of QOL 
2) 
To investigate the safety of R788 in patients with chronic ITP 
3) 
To investigate the pharmacokinetics of R788 in patients with chronic ITP (Period I). 
3.3 Exploratory Objective 
To investigate the time course of platelet count in patients with chronic ITP during interruption 
of R788 (Non-dosing period) 
4. Endpoints 
4.1 Efficacy Endpoints 
4.1.1 Efficacy endpoints 
4.1.1.1 Primary endpoint 
Achievement rate of stable platelet response (subjects who achieve a platelet count of 
≥ 50000/μL on at least 4 of the 6 visits from Weeks 14 to 24 are considered as a responder and 
the percentage of responders will be evaluated) 
4.1.1.2 Secondary efficacy endpoints 
1) 
Achievement rate of a platelet count of ≥ 50000/μL at the specified evaluation time point 
2) 
Achievement rate of a platelet count of ≥ 30000/μL at the specified evaluation time points 
and platelet count increase at least 20000/μL above baseline (for subjects with a baseline 
platelet count of < 15000/μL) 
3) 
Achievement rate of overall response (subjects who achieve a platelet count of ≥ 50000/μL 
during at least 1 of the 6 visits from Weeks 2 to 12 are considered as a responder and the 
percentage of responders will be evaluated) 
4) 
Number of times when a platelet count of ≥ 50000/μL in the 6 visits from Weeks 2 to 12 
5) 
Number of times when a platelet count of ≥ 50000/μL in the 12 visits from Weeks 2 to 24 


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6) 
Duration of maintained platelet count since first achievement of a platelet count 
≥ 50000/μL after administration of the study drug 
7) 
Percentage of subjects who maintained platelet count for 12 weeks since achievement of 
a platelet count ≥ 50000/μL within 12 weeks after administration of the study drug in 
Periods I and II (only for subjects who transition to Period II after being treated with 
placebo in Period I) 
8) 
Summary statistics of platelet count 
9) 
Distribution of platelet count 
10) Individual courses in platelet count 
11) QOL assessment (SF-36) 
4.1.2 Rationale for efficacy endpoints 
1) 
Primary endpoint 
The achievement rate of stable platelet response was the primary endpoint used in the 
overseas Phase III clinical studies (C788-047 and C788-048 studies). The primary 
endpoint in the overseas Phase III clinical studies was set to allow the evaluation of the 
persistence of efficacy and ensure the feasibility of visits by subjects, with reference to the 
endpoints used for clinical studies of TPO receptor agonists. The endpoint was set by 
considering the background of the endpoint in the overseas Phase III clinical studies and 
comparing Japanese and non-Japanese clinical study results. 
2) 
Secondary efficacy endpoints 
The endpoints of 1), 2), and 6) to 11) were set to allow the comparison of Japanese and 
non-Japanese clinical study results because they were evaluated in the overseas Phase III 
clinical studies (C788-047 and C788-048 studies) or the overseas long-term extension 
study (C788-049 study). The endpoint of 3) was set as a clinically significant evaluation 
indicator for evaluating the effect to increase platelet count during the early treatment stage 
(Weeks 2 to 12) because it was evaluated in the analysis after unblinding in the overseas 
Phase III clinical studies (C788-047 and C788-048 studies) and correlated with the 
reduced incidence of bleeding-related adverse events and reduced use of rescue therapy.12) 
The endpoints of 4) and 5) were set as secondary endpoints to evaluate the frequency of 
the effect to increase platelet count during the early treatment stage and Period I, 
respectively. 
4.2 Safety Endpoints 
4.2.1 Safety endpoints 
1) 
Incidence of adverse events and adverse drug reactions 
2) 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
3) 
Immunoglobulin test 
4) 
ITP Bleeding Score 
5) 
ECOG Performance Status 


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6) 
Vital signs 
7) 
12-lead ECG 
4.2.2 Rationale for safety endpoints 
In addition to general safety endpoints, an immunoglobulin test was set, considering the action 
mechanism of R788. The ITP Bleeding Score was also set as a safety endpoint, considering the 
characteristics of the target disease. 
4.3 Pharmacokinetic endpoint 
4.3.1 Pharmacokinetic endpoint 
Plasma concentration of R406 (active substance) 
4.3.2 Rationale for pharmacokinetic endpoint 
The pharmacokinetic endpoint was set to evaluate pharmacokinetics and the relationship 
between pharmacokinetics and efficacy or safety during the extended treatment with R788 in 
Japanese patients with chronic ITP. 
5. Subjects 
Patients with chronic ITP who meet all the following inclusion criteria and do not meet any of 
the exclusion criteria are eligible. 
5.1 Inclusion Criteria 
5.1.1 Inclusion criteria 
1) 
Japanese patients (defined as Japanese whose all relatives within the second degree are 
Japanese) who give written informed consent to participate in the study 
2) 
Patients at least 20 years of age (at the time of informed consent) 
3) 
Patients diagnosed with ITP according to the ITP diagnostic criteria (revised in 1990)1) by 
the Study Group on Idiopathic Hematopoietic Disorders of the Ministry of Health, Labour 
and Welfare at least 6 months before acquisition of consent 
4) 
Patients with a platelet count average of < 30000/μL at Screen A, Screen B, and Day 1. 
Each platelet count should not exceed 35000/μL. 
5) 
Patients who have used and failed or who were intolerant at least 1 of the following typical 
regimen for the treatment of ITP before informed consent 
 
Corticosteroids 
 
TPO receptor agonists (eltrombopag olamine or romiplostim) 
 
Rituximab 
 
Intravenous immunoglobulin 
6) 
Patients with ECOG performance status of 0 or 1 at Screening A and Day 1 


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7) 
Patients who do not use treatment for ITP or patients whose concurrent treatment may 
consist of either corticosteroids (equivalent to 10 mg/day prednisolone or less), 
azathioprine, or danazol. The dose of the concurrent medication must have been stable for 
at least 2 weeks prior to Day 1 and must be expected to remain stable throughout Period I. 
8) 
Patients who can discontinue or have already discontinued the following ITP drugs for at 
least the following periods prior to Day 1, if applicable 
 
Cyclosporine or mycophenolate mofetil: 2 weeks 
 
Eltrombopag olamine: 2 weeks 
 
Romiplostim: 3 weeks 
 
Alkylating agent: 8 weeks 
 
Rituximab or other anti-CD20 monoclonal antibodies: 24 weeks 
9) 
Patients who are negative for H. pylori or who have completed H. pylori eradication 
therapy 
5.1.2 Rationale for inclusion criteria 
1) 
This criterion was set according to the ethical principles based on the Declaration of 
Helsinki and Good Clinical Practice (GCP). 
2) 
This criterion was set to specify the age at which the informed consent of the subject alone 
was legally valid. 
3) 
This criterion was set to include patients with chronic ITP. 
4) 
This criterion was set with reference to the treatment goal in the “Reference Guide for 
Management of Adult Idiopathic Thrombocytopenic Purpura (ITP) 2012 Version.” 
5) 
This criterion was set to include patients who did not respond adequately to standard ITP 
drugs or for whom standard ITP drugs were not considered tolerated. 
6) 
This criterion was set to ensure the safety of subjects. 
7), 8) These criteria were set to appropriately evaluate the efficacy of R788. 
9) 
This criterion was set with reference to the “Flow of Adult ITP Treatment” in the 
“Reference Guide for Management of Adult Idiopathic Thrombocytopenic Purpura (ITP) 
2012 Version.” 
5.2 Exclusion Criteria 
5.2.1 Exclusion criteria 
1) 
Patients with thrombocytopenia associated with other diseases (eg, lymphoma, chronic 
lymphocytic leukemia, viral infection, autoimmune disease, thyroid disease, human 
immunodeficiency virus, hepatitis, or myelodysplasia), induced or alloimmune 
thrombocytopenia, antiphospholipid antibody syndrome, or liver cirrhosis 
2) 
Patients who are suspected cyclic thrombocytopenia 
3) 
Patients with autoimmune hemolytic anemia 
4) 
Patients with a history of or active clinically significant, respiratory, gastrointestinal 


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(pancreatitis), renal, hepatic, neurological, psychiatric, musculoskeletal, genitourinary, 
dermatological, or other disorders that could affect the conduct of the study or the 
absorption, distribution, metabolism, or excretion of the study drug 
5) 
Patients complicated with any major cardiovascular event including but not limited to 
myocardial infarction, unstable angina, cerebrovascular accident, pulmonary embolism, or 
New York Heart Association Class III or IV heart failure, or with a history of such events 
within 6 months prior to Day 1 
6) 
Patients with systolic blood pressure ≥ 140 mmHg or diastolic blood pressure of 
≥ 90 mmHg at Screening A, Screening B, or Day 1 whether or not the subject is receiving 
anti-hypertensive treatment 
7) 
Patients with conditions with increased thrombus formation, such as factor V Leiden 
mutation, active protein C resistance, congenital antithrombin III deficiency, and lupus 
anticoagulant, or patients complicated with coagulopathy, such as arterial or venous 
thromboembolism, or history of coagulopathy within 6 months prior to Screening A 
8) 
Patients who cannot discontinue anticoagulants at least 30 days prior to Screening A 
because of a history of venous thromboembolism at least 6 months prior to Screening A, 
or patients with a D-dimer assay result out of the normal range at Screening A in spite of 
the discontinuance of anticoagulants at least 30 days prior to Screening A. 
9) 
Patients with an ITP Bleeding Score of Grade 2 at any site at Screen A or Day 1 
10) Patients with 1 or more of the following laboratory abnormalities at Screening A, 
Screening B, or Day 1: 
 
White blood cell count < 2500/μL 
 
Neutrophil count < 1500/μL 
 
Lymphocyte count < 750/μL 
 
Hemoglobin < 10 g/dL 
11) Patients with 1 or more of the following laboratory abnormalities at Screening A: 
 
ALT or AST > 1.5 × ULN 
 
Total bilirubin > 2.0 mg/dL 
 
eGFR < 30 mL/min 
12) Patients with significant infection, acute infection such as influenza, or active 
inflammatory response during the screening period 
13) Patients with acute gastrointestinal symptoms (eg, nausea, vomiting, diarrhea, or 
abdominal pain) during the screening period 
14) Patients with increased the dose of, or added, prescription drugs within the 2 weeks prior 
to Day 1. Except for prescription drugs for which the investigator has determined that the 
assessment of efficacy and safety of the study drug is not affected. 
15) Patients who tested positive or the lower limit of quantitation for at least 1 of the following 
immunological tests at Screening A 
 
HIV antigen 


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 
HIV antibodies 
 
HBs antigen 
 
Anti-HBs (excluding HBs antibody monopositive cases due to HB vaccination or 
HBV DNA levels below the lower limit of quantification) 
 
Anti-HBc (unless HBV DNA levels are below the lower limit of quantification) 
 
HCV RNA quantification 
16) Patients who has received any transfusion or blood products between 2 weeks prior to 
Screening A and Day 1 
17) Patients who have used at least 1 of the following drugs during the screening period 
 
Platelet transfusion 
 
Intravenous immunoglobulin 
 
Intravenous methylprednisolone 
 
Oral dexamethasone (unless equivalent to 10 mg/day prednisolone or less) 
 
Oral prednisolone (unless dosage is 10 mg/day or less) 
18) Patients with allergy or sensitivity to any of the components of the study drug 
19) Patients who underwent splenectomy within 12 weeks prior to Day 1 
20) Patients who has had major surgery within 4 weeks prior to Day 1 or has a surgical wound 
that is not fully healed. 
21) Patients who are scheduled to undergo surgery for whom use of rescue therapy is planned 
from the time of informed consent to the end of the follow-up period. 
22) Patients with malignancy or a history of malignancy within 5 years before obtaining 
informed consent. 
23) Patients with a history of severe drug hypersensitivity. 
24) Patients with concomitant or past history of alcoholism. 
25) Patients with concomitant or past history of drug abuse (defined as illicit drug use). 
26) Patients with psychiatric disorders, such as depression, schizophrenia, or dementia. 
27) Pregnant patients, breast-feeding patients, patients who wish to become pregnant during 
the period from informed consent to 30 days after the last dose of the study drug, or women 
who are not willing to use appropriate methods of contraception. 
28) Patients who have received other study drugs within 12 weeks before acquisition of 
consent. 
29) Other patients whom the investigator judges to be inappropriate for the study. 
5.2.2 Rationale for exclusion criteria 
1) to 3) 
These criteria were set to exclude patients ineligible for the study. 


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4), 14), 16), 17), 19) These criteria were set to exclude the matters that might affect the 
efficacy evaluation of R788. 
5) to 13), 15), 18), 
20) to 25), 28) 
These criteria were set to ensure the safety of subjects. 
26) 
This criterion was set to eliminate the effect on the efficacy evaluation 
of R788 and compliance with the protocol. 
27) 
Animal studies have reported that R788 has embryofetal toxicity and 
migrates into breast milk. This criterion was set to avoid the 
administration of R788 in pregnant or lactating patients. 
5.3 Withdrawal in Individual Subjects 
5.3.1 Withdrawal criteria (withdrawal in individual subjects) 
1) 
Adverse events 
 
If the investigator judges that the adverse event requires withdrawal from the study. 
 
If the subject does not wish to continue the study due to the adverse event. 
2) 
Lack of efficacy (inadequate response) 
 
If the investigator determines that there is an unacceptable risk for the subject to 
continue due to lack of efficacy of the study drug. The lack of efficacy of the study 
drug will be determined with reference to the following. 
(1) Period I 
 
Subjects with a platelet count of ≥ 15000/μL on Day 1: 
a) 
Platelet count of < 50000/μL after Week 12 despite the increased dose to 
150 mg bid for more than 4 weeks. 
b) 
Platelet count of < 50000/μL after Week 12 because of the inability to 
increase the dose to 150 mg bid due to possible poor tolerability. 
 
Subjects with platelet count of < 15000/μL on Day 1: 
a) 
Platelet count increase of < 20000/μL from Day 1 after Week 12 despite the 
increased dose to 150 mg bid for more than 4 weeks. 
b) 
Platelet count increase of < 20000/μL from Day 1 after Week 12 because of 
the inability to increase the dose to 150 mg bid due to possible poor 
tolerability. 
 
Requirement for rescue therapy from Week 10 to platelet test at Week 24. 
(2) Periods II and III 
 
Subjects who complete Period I: 
a) 
Platelet count remains < 50000/μL despite the increase dose to 150 mg bid 
for more than 4 weeks after the start of the study treatment in Period I. 


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b) 
Platelet count remains < 50000/μL because of the inability to increase the 
dose to 150 mg bid due to possible poor tolerability. 
 
Subjects who meet all the “8.3.1 Transition criteria to Period II for subjects who 
withdraw from ” (hereinafter referred to as early transition subjects): 
a) 
Platelet count remains < 50000/μL after ET Week 12 despite the treatment 
with 150 mg bid for at least 4 weeks after the start of the study treatment in 
Period II. 
b) 
Platelet count remains at < 50000/μL after ET Week 12 because of the 
inability to increase the dose to 150 mg bid after the start of the study 
treatment in Period II due to possible poor tolerability. 
However, the study drug may be continued in both subjects who complete Period I and 
early transition subjects if the investigator judges that tangible clinical benefit from the 
use of study drug is evident, with reference to the following a) to c). 
a) 
If the platelet count is obviously increased (eg, if the platelet count increases 
20000/μL or more from Day 1 and the platelet count is 30000/μL or more) 
b) 
Reduction in bleeding events 
c) 
Reduction in rescue therapy 
3) 
Subjects' voluntary request to discontinue the study (discontinuation due to adverse events 
is classified as 1) and discontinuation due to lack of efficacy is classified as 2)). 
4) 
Significant protocol deviations during the study period 
 
If GCP violations are found 
 
If it is found that the subject of the protocol, inclusion criteria, or exclusion criteria 
are not met after case registration 
 
If the investigator judges that the subject does not comply with the protocol and 
causes health damage to the subject due to continuation of the study 
5) 
Pregnancy 
6) 
Termination of the entire study 
7) 
Discontinuation of the study at the study institution in question 
8) 
Unobservable or loss to follow-up 
 
If the subject cannot be contacted and the continuation of the study becomes 
impossible 
9) 
In addition, if the investigator judges that discontinuation of the study is necessary (the 
reason is recorded in the Case Report Form [CRF] in detail) 
5.3.2 Actions to be taken against withdrawal in individual subjects 
When any subject meets the criteria specified in “5.3.1 Withdrawal criteria (withdrawal in 
individual subjects)” during the study period, the investigator will immediately decide to 
withdraw the subject from the study. The test items specified for the Withdrawal Visit will be 
measured and evaluated and the date and reason for withdrawal will be recorded in the CRF. 


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The date when withdrawal is decided by the investigator is considered as the date of withdrawal. 
When any subject withdraws from the study due to the onset of an adverse event, the 
investigator will immediately take appropriate measures and follow the subject as specified in 
“10.15.9 Follow-up.” 
5.3.3 Investigation of subjects who do not visit study institutions 
When any subject becomes unable to visit the study institution on the scheduled date, the 
investigator or clinical research coordinator will immediately investigate the reason and 
subsequent process. 
6. Consent of Subjects 
6.1 Time to Collect Informed Consent 
Written informed consent must be obtained before starting Screening A (before performing any 
test specified in this study) or washout of ITP drugs, whichever comes earlier. Written informed 
consent will be obtained again at Week 52 or ET Week 28 for subjects who want to participate 
in the Non-dosing period and Period III. 
6.2 Collection of Consent 
The investigator will prepare the patient information leaflet and informed consent form with 
reference to the materials and information provided by the sponsor for preparing the patient 
information leaflet (eg, reference samples of patient information and consent forms) and will 
submit them to Institutional Review Board (IRB) for approval. 
The investigator will select subjects suitable for the objective of the study from ethical and 
scientific perspectives. Patients who are unable to consent will be excluded from the subjects. 
Adequate attention should be paid to the voluntary participation of subjects when they may be 
unfairly disadvantaged by not participating in the study. 
The investigator will provide the candidates with sufficient explanation about the study using 
the patient information leaflet before enrolling them in the study. The investigator will give 
each candidate an opportunity to ask questions, fully answer the questions, and confirm that 
he/she fully understands the explanation before collecting his/her written informed consent 
(consent form) to voluntarily participate in the study. The investigator who gives the 
explanation will enter the date and affix his/her name and seal or sign it. The subject enters the 
date and signs it. The clinical research coordinator who gives a supplementary explanation will 
also enter the date and affix his/her name and seal or sign it, if applicable. 
The investigator will hand the patient information leaflet and a copy of the consent form to each 
subject and retain the original consent form at the study institution. 


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7. Study Drugs 
7.1 Test and Control Drugs 
7.1.1 Test drug 
1) 
Product Code: R788 
2) 
INN: fostamatinib 
3) 
Content and dosage formulation: 
 
R788 100 mg Tablets: orange-colored round film-coated tablets containing 100 mg 
of fostamatinib per tablet 
 
R788 150 mg Tablets: orange-colored oval film-coated tablets containing 150 mg 
of fostamatinib per tablet 
4) 
Storage: Store in a tightly closed container at room temperature. 
7.1.2 Control drug 
1) 
Content and dosage formulation: 
 
R788 100 mg Tablets placebo: orange-colored round film-coated tablets containing 
0 mg of fostamatinib per tablet 
 
R788 150 mg Tablets placebo: orange-colored oval film-coated tablets containing 
0 mg of fostamatinib per tablet 
R788 100 mg Tablets cannot be distinguished from R788 100 mg Tablets placebo. R788 
150 mg Tablets cannot be distinguished from R788 150 mg Tablets placebo. 
2) 
Storage: Store in a tight container at room temperature. 
7.1.3 Rationale for the control drug 
With reference to the “Choice of Control Groups and Related Issues in Clinical Trials” 
(PMSB/ELD Notification No. 136 dated February 27, 2001), placebo was selected as the 
control drug to control all potential effects (natural history of the disease, expectations of the 
subject or physician, effects of participation in the study, use of other treatments, and subjective 
elements of assessment) other than the pharmacological action of the test drug on actual or 
apparent disease progression. 
7.2 Packaging Form of Study Drugs 
Sixty tablets will be filled per bottle for R788 100 mg Tablets or placebo for R788 100 mg 
Tablets and R788 150 mg Tablets or placebo for R788 150 mg Tablets. 
7.3 Labeling 
The details of labeling are specified in the procedure specified elsewhere. 


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7.4 Drug Accountability 
The study drug administrator will appropriately control and store the study drugs in accordance 
with the written procedure specified elsewhere. 
8. Study Method 
8.1 Study Design 
A placebo-controlled, multicenter, randomized, double-blind, parallel-group study (Period I) 
and a multicenter, open-label study (Periods II and III). 
8.2 Structure of the Study 
1) 
Screening period 
Screening period is defined as 4 weeks from Screening A to before the administration of 
the study drug on Day 1. 
2) 
Period I 
Period I is defined as 24 weeks from after the administration of the study drug on Day 1 
to Week 24. 
3) 
Period II 
 
The day at the beginning of study drug administration in Period II is Week 24 for 
subjects who complete Period I. Period II is defined as 28 weeks from Weeks 24 
to 52. 
 
The day at the beginning of study drug administration in Period II is ET Day 1 for 
early transition subjects. Period II is defined as 28 weeks from ET Day 1 to ET 
Week 28. 
4) 
Non-dosing period 
Non-dosing period is defined as maximum 4 weeks from Week 52 or ET Week 28 to Day 
1 of Period III. 
5) 
Period III 
Period III is defined as the period from Day 1 of Period III to the date of marketing 
approval of R788. 
6) 
Follow-up period 
 
Follow-up period is defined as 2 weeks from Week 52 or ET Week 28 to the tests 
at the end of the follow-up period for subjects who complete Period II and are not 
willing to participate in the Non-dosing period and Period III. 
 
Follow-up period is defined as 2 weeks from the Withdrawal Visit to the tests at 
the end of the follow-up period for subjects who withdraw from Period I and do 
not transition to Period II, those who withdraw from Period II, and those who 
withdraw from Period III. 
 
Follow-up period is defined as the period until 2 weeks after Week 52 or ET Week 


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28 for subjects who withdraw from the Non-dosing period before ND Week 2. 
 
No follow-up period is established for subjects who withdraw from the Non-dosing 
period at ND Week 2 or later or subjects who continue Period III until the date of 
marketing approval of R788. 
Screening 
period 
4 weeks 
Period I (double blind) 
24 weeks 
Period II (open label) 
28 weeks 
 
Non-
dosing 
period 
Up to 4 
weeks 
Period III (open label) 
Until market 
authorization 
 
 
 
 
 
 
 
Follow-up 
period 
2 weeks 
 
 
 
 
*: Subjects who meet all the “8.3.1 Transition criteria to Period II for subjects who withdraw from ” 
Figure 8.2-1 
Structure of Study 
 
8.3 Transition to Period II 
The following subjects transition to Period II. 
 
Subjects who completed Period I 
 
Early transition subjects (subjects who meet all the “8.3.1 Transition criteria to Period II 
for subjects who withdraw from ”) 
8.3.1 Transition criteria to Period II for subjects who withdraw from Period I 
1) 
Subjects who meet any of the following criteria and withdraw from Period I due to “2) 
Lack of efficacy (inadequate response)” in “5.3.1 Withdrawal criteria (withdrawal in 
individual subjects)” 
 
Subjects with a platelet count of ≥ 15000/μL on Day 1: 
a) 
Platelet count of < 50000/μL after Week 12 despite the increased dose to 
150 mg bid for more than 4 weeks. 
b) 
Platelet count of < 50000/μL after Week 12 because of the inability to 
increase the dose to 150 mg bid due to possible poor tolerability. 
 
Subjects with platelet count of < 15000/μL on Day 1: 
a) 
Platelet count increase of < 20000/μL from Day 1 after Week 12 despite the 
increased dose to 150 mg bid for more than 4 weeks. 
b) 
Platelet count increase of < 20000/μL from Day 1 after Week 12 because of 
R788 group 
Placebo group 
R788 group 
Period II 
Early transition 
subjects* 
R788 group 
No study 
drug 
No study 
drug 
No study 
drug 
Willing  
to 
Not 
willing to 
R788 group 
Placebo group 
R788 group 
Period II 
Early transition 
subjects* 
R788 group 
No study 
drug 
No study 
drug 
No study 
drug 
Willing  
to 
Not 
willing to 


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the inability to increase the dose to 150 mg bid due to possible poor 
tolerability. 
2) 
Subjects with systolic blood pressure of < 140 mmHg and diastolic blood pressure of 
< 90 mmHg on ET Day 1 whether or not the subject is receiving antihypertensive 
treatment 
3) 
Subjects without the following laboratory abnormalities on ET Day 1: 
 
White blood cell count < 2000/μL 
 
Neutrophil count < 1000/μL 
 
Lymphocyte count < 750/μL 
 
Hemoglobin < 10 g/dL 
4) 
Subjects without the following laboratory abnormalities on the last laboratory test before 
ET Day 1 
 
ALT or AST > 1.5 × ULN 
 
Total bilirubin > 1.5 × ULN 
 
eGFR < 30 mL/min 
5) 
Subjects who do not have significant infection, an acute infection such as influenza, or 
inflammatory process on ET Day 1. 
6) 
Subjects who have not received blood or blood products within the 2 weeks prior to ET 
Day 1 (intravenous immunoglobulin or platelet transfusion are allowed if used for rescue 
therapy). 
8.3.2 Rationale for transition criteria to Period II for subjects who withdraw from 
Period I 
1) 
This criterion was set to include subjects who withdraw from Period I due to lack 
of efficacy. 
2) to 5) These criteria were set to ensure the safety of subjects. 
6) 
This criterion was set to exclude the matters that might affect the efficacy 
evaluation of R788. 
8.4 Transition to Non-dosing Period 
Subjects who provide written informed consent to participate in the Non-dosing period and 
Period III transition to the Non-dosing period. However, subjects with platelet count of 
< 50000/μL at Week 52 or at ET Week 28 may skip the Non-dosing period and transition to 
Period III at the discretion of the investigator. 
8.5 Transition to Period III 
The following subjects transition to Period III. 
 
Subjects who completed the Non-dosing period 


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 
Subjects receiving any rescue therapy during the Non-dosing period 
 
Subjects who have platelet count of < 50000/μL during the Non-dosing period and need 
to transition to Period III before completing the Non-dosing period, as judged by the 
investigator 
8.6 Dose and Administration 
8.6.1 Dose and administration 
Dose and administration method are shown in Figure 8.6.1-1 and Figure 8.6.1-2. 
1) 
Screening period 
No study drug is administered. 
2) 
Period I 
R788 or matching placebo is administered orally for 24 weeks. On Day 1, 100 mg of the 
study drug will be administered at the study institution. This must be the only 
administration of the study drug on Day 1, irrespective of the time of administration. The 
study drug will be administered twice daily beginning on the next day and the dose will 
be adjusted according to “8.6.2 Dose adjustment” during Period I. Morning and evening 
doses should be at least 8 hours apart and should be taken at approximately the same time 
each day, with or without food during Period I. In principle, subjects will visit the study 
institution in the morning without taking the study drug and take the study drug at the 
study institution in the morning to measure drug concentration at Weeks 2 and 6. In 
principle, subjects will take the study drug at 1 to 4 hours before visiting the study 
institution in the morning at Week 4 and Weeks 8 to 24. 
3) 
Period II 
R788 is orally administered for 28 weeks. 
(1) Subjects who completed Period I 
The study drug for Period I is continued until the visit at Week 24 and the study drug 
for Period II is initiated after the visit at Week 24 (if study drug in Period II is initiated 
as twice daily, subjects who took the study drug for Period I in the morning on the day 
of the visit start the study drug for Period II from the evening of the same day). The dose 
and administration at the start of the study drug for Period II is as follows. 
 
If platelet count at Week 24 is ≥ 50000/μL, study drug in Period II is initiated with 
the last dose and administration in Period I. 
 
If platelet count at Week 24 is < 50000/μL and last dose and administration in 
Period I is 150 mg bid, study drug in Period II is initiated with 100 mg bid. 
 
If platelet count at Week 24 is < 50000/μL and last dose and administration in 
Period I is 100 mg qd, 150 mg qd, or 100 mg bid, study drug in Period II is initiated 
with the last dose and administration in Period I. 
(2) Early transition subjects 
The study drug for Period II is initiated after the visit on ET Day 1 (if study drug in 
Period II is initiated as twice daily, subjects who took the study drug for Period I in the 


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morning on the day of the visit start the study drug for Period II from the evening of the 
same day). The dose and administration at the start of the study drug for Period II is as 
follows. 
 
If the last dose and administration in Period I is 100 mg bid or 150 mg bid, study 
drug in Period II is initiated with 100 mg bid. 
 
If the last dose and administration in Period I is 100 mg qd or 150 mg qd, study 
drug in Period II is initiated with the last dose and administration in Period I. 
The dose should be adjusted during Period II in accordance with “8.6.2 Dose 
adjustment.” Morning and evening doses should be at least 8 hours apart and should be 
taken at approximately the same time each day, with or without food during the Period 
II. 
4) 
Non-dosing period 
No study drug is administered. 
5) 
Period III 
The study drug is administered orally until market authorization of R788 in Japan. The 
study drug for Period III is initiated with the last dose and administration of study drug in 
Period II and is started after the visit on Day 1 of Period III. The dose should be adjusted 
during Period III in accordance with “8.6.2 Dose adjustment.” Morning and evening doses 
should be at least 8 hours apart and should be taken at approximately the same time each 
day, with or without food during the Period III. 
6) 
Follow-up period 
No study drug is administered. 
 
Period I (double blind) 
24 weeks 
Period II (open label) 
28 weeks 
Non-dosing 
period 
Up to 4 weeks 
Period III 
(Open label) 
Until market 
authorization 
Day 1 or later 
Week 4 or later 
Week 24 
After the start of 
the study 
treatment in 
Period II 
 
Day 1 or later in 
Period III 
 
 
 
 
 
 
This does not apply to cases when dose is adjusted according to “8.6.2.2 Dose adjustment due to adverse events” or “8.6.2.3 
Dose adjustment due to excessive elevation of platelet count.” 
100 mg 
bida) 
100 mg 
bid 
150 mg 
bid 
100 mg 
bid 
100 mg 
bid 
150 mg 
bid 
100 mg 
bid 
150 mg 
bid 
Platelet < 50000/μL 
 and study drug is well 
tolerated 
Platelet < 50000/μL 
Platelet ≥ 50000/μL 
Platelet < 50000/μL 
 and study drug is well 
tolerated 
150 mg 
bid 
100 mg 
bid 
Administration of the 
study drug will be started 
initiated with the last dose 
and administration in 
Period II. 
No study 
drug 
No study 
drug 
150 mg 
bid 
100 mg 
bida) 
100 mg 
bid 
150 mg 
bid 
100 mg 
bid 
100 mg 
bid 
150 mg 
bid 
100 mg 
bid 
150 mg 
bid 
Platelet < 50000/μL 
 and study drug is well 
tolerated 
Platelet < 50000/μL 
Platelet ≥ 50000/μL 
Platelet < 50000/μL 
 and study drug is well 
tolerated 
150 mg 
bid 
100 mg 
bid 
The study drug is initiated 
with the last dose and 
administration in Period 
II. 
No study 
drug 
No study 
drug 
150 mg 
bid 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 45 - 
a) The dose of 100 mg of the study drug is administered at study institutions and this must be the only administration of the 
study drug on Day 1, irrespective of the time of administration. 
Figure 8.6.1-1 
Dose and Administration Method for Subjects Who Complete 
Period I 
 
Period I (double blind) 
24 weeks 
Period II (open label) 
28 weeks 
Non-dosing 
period 
Up to 4 weeks 
Period III 
(Open label) 
Until market 
authorization 
Day 1 or later 
Week 4 or later 
ET Day 1 
ET Week 4 or 
later 
 
Day 1 or later in 
Period III 
 
 
 
 
 
 
This does not apply to cases when dose is adjusted according to “8.6.2.2 Dose adjustment due to adverse events” or “8.6.2.3 
Dose adjustment due to excessive elevation of platelet count.” 
a) The dose of 100 mg of the study drug is administered at study sites and this must be the only administration of the study 
drug on Day 1, irrespective of the time of administration. 
Figure 8.6.1-2 
Dose and Administration Method for Early Transition Subjects 
100 mg 
bida) 
100 mg 
bid 
150 mg 
bid 
100 mg 
bid 
100 mg 
bid 
100 mg 
bid 
150 mg 
bid 
Platelet < 50000/μL 
 and study drug is well 
tolerated 
Platelet < 50000/μL 
 and study drug is well 
tolerated 
150 mg 
bid 
100 mg 
bid 
Administration of the 
study drug will be started 
initiated with the last 
dose and administration 
in Period II. 
No study 
drug 
No study 
drug 
150 mg 
bid 
100 mg 
bida) 
100 mg 
bid 
150 mg 
bid 
100 mg 
bid 
100 mg 
bid 
100 mg 
bid 
150 mg 
bid 
Platelet < 50000/μL 
 and study drug is well 
tolerated 
Platelet < 50000/μL 
 and study drug is well 
tolerated 
150 mg 
bid 
100 mg 
bid 
The study drug is 
initiated with the last 
dose and administration 
in Period II. 
No study 
drug 
No study 
drug 
150 mg 
bid 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 46 - 
8.6.2 Dose adjustment 
8.6.2.1 Dose escalation for subjects not responding 
1) 
Period I 
If the platelet count at Week 4 or after is below 50000/μL and the study drug has been well 
tolerated, the dose of study drug should be increased from 100 mg bid to 150 mg bid at 
the discretion of the investigator. Subjects whose dose is escalated should continue to be 
monitored carefully for adverse events. 
2) 
Period II 
(1) Subjects who completed Period I: 
If the platelet count after the study drug for Period II is initiated remains below 
50000/μL and the study drug has been well tolerated, the dose of study drug should be 
increased from 100 mg bid to 150 mg bid at the discretion of the investigator. Subjects 
whose dose is escalated should continue to be monitored carefully for adverse events. 
(2) Early transition subjects: 
If the platelet count at ET Week 4 or after is below 50000/μL and the study drug has 
been well tolerated, the dose of study drug should be increased from 100 mg bid to 150 
mg bid at the discretion of the investigator. Subjects whose dose is escalated should 
continue to be monitored carefully for adverse events. 
3) 
Period III 
If the platelet count is below 50000/μL and the study drug has been well tolerated, the dose 
of study drug should be increased from 100 mg bid to 150 mg bid at the discretion of the 
investigator. Subjects whose dose is escalated should continue to be monitored carefully 
for adverse events. 
8.6.2.2 Dose adjustment due to adverse events 
The dose of the study drug will be adjusted according to the applicable appendices if the 
following adverse events or abnormal results of laboratory tests, abnormal findings, and 
abnormal symptoms associated with adverse events are observed. 
 
Increases in ALT, AST, or bilirubin (see Appendix 3) 
 
Neutrophil count decreased (see Appendix 4) 
 
Onset of diarrhea (see Appendix 5) 
 
Increase in blood pressure (see Appendix 6) 
Additionally, if any other severe or serious adverse events with a potential relationship to the 
study drug are observed, the dose of the study drug should be adjusted at the discretion of the 
investigator. 
If adverse events or abnormal results of laboratory tests, abnormal findings, and abnormal 
symptoms associated with adverse events which result in dose reduction of study drug recover, 
the dose of study drug can be re-escalated by 1 dose level in accordance with Table 8.6.2.2-1 
based on the investigator’s decision. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 47 - 
If adverse events or abnormal results of laboratory tests, abnormal findings, and abnormal 
symptoms associated with adverse events which leads to interruption of study drug recover, the 
study drug is restarted at 1 lower dose level than that before the interruption. After restarting 
the study drug, the dose of study drug can be re-escalated by 1 dose level in accordance with 
Table 8.6.2.2-1 based on the investigator’s decision. The study drug will be restarted at 100 mg 
qd when the dose regimen before interruption is 100 mg qd. For “2) Recurrence of neutrophil 
count of < 1000/μL” in “Appendix 4 Management of Neutrophil Count Decreased” or “3) 
Recurrence of Grade 3 or 4 diarrhea” in “Appendix 5 Management of Diarrhea,” study drug is 
restarted at 2 lower dose level after the adverse event or laboratory test abnormality, abnormal 
finding, or symptom associated with the adverse event is recovered. However, the study drug 
will be restarted at 100 mg qd when the dose before interruption is 100 mg qd or 150 mg qd. 
The study drug will be administered in the morning when it is administered once daily. 
Table 8.6.2.2-1 
Dose Adjustment 
Dose reduction 
Dose before 
dose 
increase/ 
reduction 
Dose escalation 
Dose level 
−4 
Dose level 
−3 
Dose level 
−2 
Dose level 
−1 
Dose 
level 
+1 
Dose 
level 
+2 
Dose 
level 
+3 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
 
8.6.2.3 Dose adjustment due to excessive elevation of platelet count 
1) 
Period I 
If excessive platelet count increase is observed, the investigator should respond in 
accordance with Table 8.6.2.3-1. The doses/regimens of allowed ITP therapies 
(corticosteroids, azathioprine, or danazol) should not be changed. If platelet count is above 
250000/μL even after the dose of the study drug is adjusted, the dose of allowed ITP 
therapy is reduced according to “8.7.7 Allowed ITP therapies”. 
Table 8.6.2.3-1 
Actions Taken with the Study Drug for Excessive Elevation of 
Platelet Count in Period I 
 
Actions 
1) Platelet counts > 250000/μL 
 
Reduce the dose of the study drug by 1 dose level until the 
platelet count falls to ≤ 250000/μL. 
 
Monitor platelet count until platelet count falls to 
< 200000/μL (the frequency of additional measurements 
will be determined by the investigator). 
 
If the excessive elevation of platelet count is improved, the 
dose of study drug can be re-escalated by 1 dose level based 
on the investigator’s decision. 
2) Platelet counts > 150000/μL and 
≤ 250000/μL 
 
Continue the study drug at full dose. 
 
Monitor the platelet count until stable to assure it does not 
exceed 250000/μL (the frequency of additional 
measurements will be determined by the investigator). 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 48 - 
 
2) 
Periods II and III 
If excessive platelet count increase is observed, the investigator should respond in 
accordance with “8.7.7 Allowed ITP therapies.” If platelet count is above 250000/μL even 
after the dose of allowed ITP therapy is adjusted, reduce the dose of the study drug by 1 
dose level until the platelet count falls to ≤ 250000/μL (see Table 8.6.2.2-1) and measure 
the platelet count until it falls to < 200000/μL (the frequency of additional measurements 
will be determined by the investigator). If the excessive elevation of platelet count is 
improved, the dose of study drug can be re-escalated by 1 dose level based on the 
investigator’s decision. 
8.6.3 Rationale for dose 
In an overseas Phase II clinical study (D4300-022 study) in which R788 was administered in 
18 patients with ITP in a dose ascending manner from a starting dose of 75, 100, 125, or 150 
mg bid with monitoring of safety and efficacy, increase of platelet count was mainly observed 
at 100, 125, or 150 mg bid. 
In the overseas Phase III clinical studies in 150 patients with persistent or chronic ITP (C788-
047 and C788-048 studies), R788 or placebo was administered for 24 weeks at a starting dose 
of 100 mg bid, which was allowed to increase to 150 mg bid when platelet count was 
< 50000/μL at Week 4 or later. The integrated analysis of the 2 studies showed that the primary 
endpoint, or the “achievement rate of platelet count of ≥ 50000/μL at 4 or more of the 6 visits 
between Weeks 14 and 24 (stable platelet response)” was 17.8% (18/101) in the R788 group 
and 2.0% (1/49) in the placebo group, indicating a significantly higher achievement in the R788 
group (P = 0.0003, Fisher's exact test). In the overseas Phase III clinical studies (C788-047 and 
C788-048 studies), serious bleeding-related adverse events occurred in 5.0% (5/101) of the 
R788 group and 10.2% (5/49) of the placebo group and moderate to severe bleeding-related 
adverse events occurred in 9.9% (10/101) and 16.3% (8/49), respectively. These results indicate 
that R788 given at 100 to 150 mg bid provided ITP patients with an effect to increase platelet 
count and concomitantly reduce bleeding symptoms. 
Phase I clinical studies in Japanese and White healthy adults (D4300-007 and D4300-032 
studies) have been conducted so far. The single oral administration of 150 mg of R788 followed 
by the repeated oral administration with qd for 7 days showed no major differences in the 
pharmacokinetics of the active substance, R406, between Japanese and White subjects, 
suggesting similar pharmacokinetics between Japanese and White subjects. 
Given the similar pharmacokinetics of R406 between Japanese and non-Japanese subjects and 
similar exposure-response relationship of R788 between Japanese and non-Japanese subjects 
based on the lack of report of ethnic difference in the onset of SYK inhibited by R406, the 
starting dose of R788 was set at 100 mg bid and an increase in dose to 150 mg bid was allowed 
when a platelet count of < 50000/μL was observed and R788 was well tolerated at Week 4 or 
later after the start of treatment, as in the overseas Phase III clinical studies (C788-047 and 
C788-048 studies) in which the efficacy of R788 was verified. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
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8.7 Concomitant Medications 
Drugs for various symptoms with ITP and drugs used at the start of the screening period for 
complications should not change the doses/regimens as much as possible until the end of the 
follow-up period or market authorization. It is acceptable to change the doses/regimens of 
concomitant medications for safety, such as the occurrence of adverse events. 
8.7.1 Prohibited concomitant medications 
The concomitant use of the medications listed in Table 8.7.1-1 is prohibited from 2 weeks before 
Day 1 to the end of the follow-up period or market authorization. 
Table 8.7.1-1 
Prohibited Concomitant Medications 
Classification 
Principal drugs 
1) Strong CYP3A4 inhibitors 
Itraconazole, indinavir sulfate ethanol adduct, clarithromycin, 
cobicistat, diltiazem hydrochloride, nelfinavir mesilate, 
voriconazole, ritonavir containing preparation 
2) Study drugs other than R788 
Any study drugs other than R788 
 
8.7.2 Rationale for prohibited concomitant medications 
1) 
This criterion was set considering the possible drug interaction with R788 because the 
concurrent administration with a strong CYP3A4 inhibitor increases the exposure to R406 
by about 2.0-fold, which may affect the safety of subjects. 
2) 
This criterion was set to assure subject safety because the safety of study drugs under 
development has not been established and their interactions with R788 are unknown. 
8.7.3 Prohibited ITP concomitant medications 
The concomitant use of the medications listed in Table 8.7.3-1 is prohibited from the period 
specified in “8.7.9 Washout” before Day 1 to the end of the follow-up period or market 
authorization. 
Table 8.7.3-1 
Prohibited ITP concomitant medications 
Classification 
Principal drugs 
ITP medications other than the allowed ITP 
therapies or ITP medications specified as 
rescue therapies 
Cyclosporine, mycophenolate mofetil, eltrombopag olamine, 
romiplostim, rituximab or other anti CD20 monoclonal 
antibodies, alkylating agents 
 
8.7.4 Rationale for prohibited ITP concomitant medications 
These criteria were set to exclude the matters that might affect the efficacy evaluation of R788. 
8.7.5 Restricted concomitant medications 
Medications listed in Table 8.7.5-1 should be administered with attention to subject safety from 
2 weeks before Day 1 to the end of the follow-up period or market authorization. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
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Table 8.7.5-1 
Restricted concomitant medications 
Classification 
Principal drugs 
Precautions for co-administration 
1) 
Moderate 
CYP3A4 
inhibitors 
Atazanavir sulfate, aprepitant, 
amiodarone hydrochloride, istradefylline, 
imatinib mesylate, erythromycin, 
crizotinib, cyclosporine, ciprofloxacin 
hydrochloride, cimetidine, tofisopam, 
fluconazole, fluvoxamine maleate, 
verapamil hydrochloride, fosamprenavir 
calcium hydrate, fosfluconazole, 
miconazole 
Concomitant use with a moderate 
CYP3A4 inhibitor increases the exposure 
to R406 by approximately 1.4-fold, 
which may affect the safety of subjects. 
The investigator will decide whether or 
not to use it concomitantly, taking into 
account the necessity of treatment. 
2) 
CYP3A4 
inducers 
Etravirine, efavirenz, enzalutamide, 
carbamazepine, St. John’s wort, 
nevirapine, barbiturates, phenytoin, 
bosentan hydrate, mitotane, modafinil, 
rifabutin, rifampicin, rufinamide 
Concomitant use with a CYP3A4 inducer 
reduces the exposure to R406 by 
approximately 0.25-fold, which may be 
below the therapeutic range of R406. The 
investigator will decide whether or not to 
use it concomitantly, taking into account 
the necessity of treatment. 
3) 
P-gp substrates 
Digoxin 
Concomitant use with R788 increases the 
exposure to digoxin by approximately 
1.4-fold, which may affect the safety of 
subjects. Since the dose reduction of 
digoxin may be required in subjects who 
need to take digoxin or who are taking 
digoxin, the investigator should carefully 
monitor adverse events. 
4) 
HMG-CoA 
reductase 
inhibitors 
Simvastatin, rosuvastatin, atorvastatin, 
pitavastatin 
Concomitant use with R788 increases the 
exposure to HMG-CoA reductase 
inhibitors by approximately 1.6 to 2.0-
folds, which may affect the safety of 
subjects. Since the dose reduction of 
HMG-CoA reductase inhibitors may be 
required in subjects taking HMG-CoA 
reductase inhibitors, the investigator 
should carefully monitor adverse events 
such as lipid reactions or myositis. 
 
8.7.6 Rationale for restricted concomitant medications 
1) to 4) 
These restricted medications were selected, considering the possible interactions 
with R788. 
8.7.7 Allowed ITP therapies 
1) 
Screening period and Period I 
Subjects are allowed to use only one of the specific therapies for ITP: corticosteroids 
(equivalent to 10 mg/day prednisolone or less), azathioprine, or danazol, throughout the 
screening period and Period I. Dosage of these allowed ITP therapies should not be 
changed from at least 2 weeks before Day 1 to any of the following visit. Tapering of the 
allowed ITP therapies will not be permitted, even if platelet count exceeds 50000/μL. New 
treatments allowed for ITP should not be added from at least 2 weeks before Day 1. 
 
Withdrawal Visit ( subjects who withdraw from Period I and do not transition to 
Period II) 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 51 - 
 
ET Day 1 (subjects who withdraw from Period I and transition to Period II) 
 
Week 24 (except for the above) 
If platelet count is above 250000/μL even after the dose of study drug is adjusted in 
accordance with “8.6.2.3 Dose adjustment due to excessive elevation of platelet count,” 
reduce the dose of allowed ITP therapy until the platelet count falls to ≤ 250000/μL and 
measure the platelet count until it falls to < 200000/μL (the frequency of additional 
measurements will be determined by the investigator). 
2) 
Period II 
The same drug as in Period I can be used as ITP therapy in Period II with the same 
doses/regimens as in Period I. Consideration can be given to tapering the dose of allowed 
ITP therapy in subjects whose platelet count is stable at ≥ 50000/μL during Period II 
(including the start of Period II) at the discretion of the investigator. New treatments for 
ITP should not be added. If excessive platelet count increase is observed during Period II 
(including the start of Period II), the investigator should respond in accordance with Table 
8.7.7-1. 
3) 
Non-dosing period 
The same drug as in Period II can be used as ITP therapy in Non-dosing period with the 
same doses/regimens as used at the end of Period II. Doses/regimens of these allowed ITP 
therapies should not be changed until any of the following visit. New treatments for ITP 
should not be added. If excessive platelet count increase is observed during Non-dosing 
period, the investigator should respond in accordance with Table 8.7.7-1. 
 
Period III Day 1 (subjects who transition to Period III) 
 
Withdrawal Visit (subjects who withdraw from the Non-dosing period) 
4) 
Period III 
The same drug as in Non-dosing period can be used as ITP therapy in Period III with the 
same doses/regimens as used at the end of Non-dosing period. Consideration can be given 
to tapering the dose of allowed ITP therapy in subjects whose platelet count is stable at 
≥ 50000/μL during Period III (including the start of Period III) at the discretion of the 
investigator. New treatments for ITP should not be added. If excessive platelet count 
increase is observed during Period III (including the start of Period III), the investigator 
should respond in accordance with Table 8.7.7-1. 
5) 
Follow-up period 
Doses/regimens of the allowed ITP therapy at the completion of Period II or at the 
Withdrawal Visit should not be changed during the follow-up period. New treatments for 
ITP should not be added. However, if excessive platelet count increase is observed, the 
investigator should respond in accordance with Table 8.7.7-1. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 52 - 
Table 8.7.7-1 
Actions Taken for Allowed ITP Therapy for Excessive Elevation of 
Platelet Count 
 
Action 
1) 
Platelet counts > 250000/μL 
 
Reduce the dose of the allowed ITP therapy. 
 
Monitor platelet count until platelet count falls to 
< 200000/μL (the frequency of additional measurements will 
be determined by the investigator). 
 
If the excessive elevation of platelet count is improved, the 
dose of allowed ITP therapies can be re escalated based on 
the investigator’s decision. 
2) 
Platelet counts > 150000/μL and 
≤ 250000/μL 
 
Leave the dose of the allowed ITP therapy unchanged. 
 
Monitor the platelet count until stable to assure it does not 
exceed 
250000/μL 
(the 
frequency 
of 
additional 
measurements will be determined by the investigator). 
 
8.7.8 Rescue therapy 
Rescue therapy may be used at the discretion of the investigator from the start of the study drug 
in Period I to the end of the follow-up period or market authorization for subjects who meet any 
one or both of the following conditions. 
 
Platelet count < 50000/μL and at immediate risk of bleeding or with clinically 
significant bleeding or wet purpura. 
 
Platelet count < 50000/μL and requires urgent or emergent surgery. 
The drugs listed in Table 8.7.8-1 can be used for rescue therapy. The investigator should 
determine the dose and administration of rescue therapy with reference to Table 8.7.8-1. 
Table 8.7.8-1 
Rescue Therapy 
Drug 
Doses/regimens 
Platelet transfusion 
10 to 20 units/dose 
Intravenous immunoglobulin 
400 mg/kg/day for 5 consecutive days 
Intravenous 
methylprednisolone 
1 g/day for 3 consecutive days 
Oral dexamethasone 
Up to 40 mg/day for 1 to 2 days 
Oral prednisolone 
Up to 1 mg/kg/day for 1 to 3 days 
 
8.7.9 Washout 
Prior to start of the study drug administration in Period I, the use of all ITP medications except 
the allowed ITP therapies are prohibited during the specific period as shown in Table 8.7.9-1. 
Table 8.7.9-1 
Washout Period 
Drug 
Prohibited period prior to 
study drug administration 
Cyclosporine or mycophenolate mofetil 
2 weeks 
Eltrombopag olamine 
2 weeks 
Romiplostim 
3 weeks 
Alkylating agents 
8 weeks 
Rituximab or other anti-CD20 monoclonal antibody 
24 weeks 
 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 53 - 
8.8 Randomization and Blinding 
8.8.1 Allocation of study drugs 
The responsible person for study drug allocation prepares the randomization code list for Period 
I, with the ratio of R788 to placebo being 2:1. 
8.8.2 Preparation of emergency key code 
The person responsible for study drug allocation will prepare an emergency key code so that 
the study drug can be identified immediately in an emergency. 
8.8.3 Storage of the study drug assignment table and emergency key code 
The person responsible for study drug assignment will seal the study drug assignment table and 
emergency key code and retain them until unblinding according to the written procedure 
specified elsewhere. 
8.8.4 Registration 
8.8.4.1  First registration 
The investigator will confirm the eligibility of each subject who provides informed consent at 
the time of collection, fill in the first registration form, and promptly perform the procedure to 
enroll him/her. 
The Subject Registry Center will notify the investigator of whether to accept the first 
registration or not. The completed first registration form and first registration confirmation form 
from the Subject Registry Center will be stored at the study institution. 
8.8.4.2  Second registration 
The investigator will confirm the eligibility of each subject at Screening A, fill in the second 
registration form, and promptly perform the procedure to enroll him/her. 
The Subject Registry Center will notify the investigator of whether to accept the second 
registration or not. The completed second registration form and second registration 
confirmation form obtained from the Subject Registry Center will be stored at the study 
institution. In addition, the investigator will inform the Subject Registry Center of the reason 
subjects who were considered eligible at the first registration were not considered eligible at 
the second registration. 
8.8.4.3  Third registration 
The investigator will make the last confirmation of eligibility of each subject on Day 1, fill in 
the third registration form, and promptly perform the procedure to register the subject. 
The Subject Registry Center will notify the investigator of whether to accept the third 
registration or not. The completed third registration form and third registration confirmation 
form obtained from the Subject Registry Center will be stored at the study institution. In 
addition, the investigator will inform the Subject Registry Center of the reason subjects who 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 54 - 
were considered eligible at the second registration were not considered eligible at the third 
registration. 
8.8.4.4 Randomization 
The Subject Registry Center will randomly assign each subject considered eligible at the third 
registration to either of the treatment groups based on the study drug assignment table according 
to the dynamic allocation method using platelet count (</≥ 15000/μL) as a stratification factor, 
and inform the investigator of the number of the study drug to be administered to the subject 
using the drug number confirmation form. The drug number confirmation form obtained from 
the Subject Registry Center will be retained at the study institution. 
8.8.4.5 Enrollment for transition to Period II 
The investigator will fill in the Period II transition enrollment form for each subject who 
completes Period I at Week 24 and promptly perform the procedure to enroll the subject. The 
completed Period II transition enrollment form and Period II transition enrollment confirmation 
form obtained from the Subject Registry Center will be stored at the study institution. 
In addition, the investigator will examine each subject who withdraws from Period I due to “2) 
Lack of efficacy (inadequate response)” in “5.3.1 Withdrawal criteria (withdrawal in individual 
subjects)” for the eligibility for the transition to Period II (see “8.3.1 Transition criteria to Period 
II for subjects who withdraw from ”) on ET Day 1 and then fill in the Period II transition 
enrollment form to promptly enroll the subject. The Subject Registry Center will notify the 
investigator of whether to accept the subject for the Period II transition enrollment. The 
completed Period II transition enrollment form and Period II transition enrollment confirmation 
form obtained from the Subject Registry Center will be stored at the study site. 
8.8.5 Emergency key code breaking 
When it is necessary to immediately know the identity of the study drug in an emergency, the 
emergency key code of the drug number in question will be opened in accordance with the 
following unblinding procedure. 
1) 
In an emergency, the investigator should promptly provide appropriate treatment to the 
subject, check the subject's health status, and report it to the sponsor. The investigator 
should request the sponsor to break the emergency key code when it is considered 
necessary to secure the subject’s safety. 
2) 
The sponsor will open the emergency key code of the drug number in question according 
to the procedure specified elsewhere and report the result to the investigator when the 
sponsor is requested to open it by the investigator or when the sponsor decides it necessary 
to open it. 
3) 
The investigator will prepare the CRF and “Record of earlier than scheduled unblinding 
of study drug assignment code” for the subject with the drug number and submit them to 
the sponsor. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
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8.8.6 Unblinding 
The person responsible for study drug assignment will unblind the study drug assignment table 
after confirming that the blindness of the study was maintained until the data on all enrolled 
subjects in Period I were fixed. 
8.9 Number of Subjects 
8.9.1 Number of subjects 
Twenty-four subjects (16 in the Period I R788 group and 8 in the Period I placebo group) 
8.9.2 Rationale for the number of subjects 
It is expected that only a limited number of patients will be included in the study because ITP 
is rare and because patients with ITP are included in the study when they poorly responded to 
at least 1 of the standard therapies for ITP or when at least 1 of the standard therapies were not 
tolerated. Therefore, the number of subjects was set at 24 (16 in the Period I R788 group and 8 
in the Period I placebo group), considering availability of subjects. 
Achievement rate of stable platelet response, which is the primary endpoint of this study, was 
0.0% (0/25) and 4.2% (1/24) in the placebo groups and 17.6% (9/51) and 18.0% (9/50) in the 
R788 group in the overseas Phase III clinical studies (C788-047 and C788-048 studies), 
respectively. In the target sample size of 24 patients (16 in the Period I R788 group and 8 in the 
Period I placebo group), assuming that the primary endpoint is 17.8% in the R788 group and 
2.0% in the placebo group, the likelihood that the point estimate would be exceed in the R788 
group compared with the placebo group is calculated as 89% by performing 100000 simulations 
of the Simon selection design. 
9. Guidance to and Management of Subjects 
The investigator will fully explain the significance and objectives of this study to subjects and 
give guidance to subjects and manage them particularly for the following points. 
1) 
Subjects should immediately inform the investigator and follow his/her instructions when 
they experience increased bowel movements, diarrhea, or other physical abnormalities. 
2) 
Subjects should properly take the study drug according to the instructions from the 
investigator and should not discontinue the study drug or change its dose on their own 
judgment. 
3) 
Morning and evening doses will be given at an interval of at least 8 hours and at 
approximately the same time of the day irrespective of diet. 
4) 
Subjects should visit the study institution after taking the morning dose of the study drug. 
Subjects should try to visit the study institution at the same time of the day during the 
study period. However, at Week 2 and 6, subjects should visit the study institution in the 
morning without taking the morning dose and take it at the study institution. At Week 4 
and Weeks 8 to 24, subjects should take the morning dose of the study drug 1 to 4 hours 
before the blood sampling and visit the study institution in the morning. 
5) 
Subjects should take the morning dose of the study drug when the dose regimen is changed 
to once daily because of dose reduction. 


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6) 
Subjects should not talk with other subjects about the intake of the study drug (eg, taste 
and color). 
7) 
Subjects should bring all the study drugs given, including empty bottles, at each study visit. 
Subjects should report the reason to the investigator, clinical research coordinator, or study 
drug administrator when they fail to bring all of the study drugs given. Subjects should 
bring the bottle(s) to the next visit and should not take the study drug from the bottle(s) 
when they failed to bring it. 
8) 
Subjects should quickly inform the investigator, clinical research coordinator of any loss 
of study drug bottles and receive the shortage from the investigator. 
9) 
Subjects should accurately complete the dosing diary every day by themselves. Subject 
should bring the dosing diary with them at each visit. Subjects should bring the dosing 
diary at the next visit if they leave the dose diary at home. 
10) Subjects should take all the prescribed drugs other than the study drug, including the 
allowed ITP drug, as directed. 
11) Subjects should not take the study drug with grapefruit or food and beverages containing 
grapefruit. 
12) Subjects should visit the study institution as scheduled. Subjects should inform the study 
institution if they cannot visit the institution as scheduled. 
13) Subjects should report the drugs they are currently taking to the investigator before 
participating in the study. Subjects should consult the investigator when they are 
prescribed new drugs by other departments or medical institutions or when they use OTC 
drugs. Subjects should immediately inform the investigator when they use such drugs 
without consulting the investigator. 
14) Subjects should inform the investigator in advance when they visit other departments or 
medical institutions, and report their participation in the clinical study to the physicians in 
other departments or medical institutions. Subjects should report their participation in this 
clinical study to physicians in other departments or medical institutions when they visit 
them in an emergency. They should immediately report their visit to other medical 
institutions and drugs prescribed to the investigator. 
15) Subjects should report any physical abnormality they experience after completing the 
study to the investigator. 
16) Female subjects of childbearing potential must avoid sexual intercourse or use appropriate 
contraception from the time of informed consent to 30 days after the last dose of the study 
drug. Subjects should immediately inform the investigator if they suspect that they have 
become pregnant from informed consent to 30 days after the last dose of the study drug. 
17) Subjects should use appropriate, highly effective contraception methods, such as the 
combination of the barrier method (condom or diaphragm) and another method (eg, 
spermicides, oral contraceptives, or intrauterine devices) or sterilization of the subject or 
his/her partner. 
18) Subjects should not disclose any information related to this study, such as materials used 
for the study, adverse events that occurred during the study period, tests/examinations 
performed, and personal impression about the study drug on the Internet (eg, Facebook, 
Twitter, and blogs) or on media (eg, newspapers, magazines, or advertisements). 


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10. Study Assessments and Procedures 
The investigator will perform investigations, observations, tests/examinations, and evaluations 
according to the study schedule and investigation/observation/test/examination procedures. 
10.1 Demographics 
The following information should be investigated as subject's background and should be 
recorded in CRF. 
1) 
Date of informed consent 
2) 
Month and year of birth, sex, race 
3) 
The disease affecting at the time of obtaining consent form, or medical history of 
autoimmune diseases including autoimmune hemolytic anemia, together with the disease 
name(s) 
4) 
Information regarding the inclusion and exclusion criteria 
5) 
Onset date of ITP 
6) 
Prior medication for ITP, treatment period, and reason for discontinuation 
7) 
Received splenectomy or not. If yes, time of splenectomy 
8) 
Any treatment for ITP and treatment period (excluding splenectomy) 
9) 
Need of pregnancy test 
10.2 Administration State 
The investigator or a clinical research coordinator will check the compliance of administration 
(amount of dose, drug number, starting day of dosing, completion day of dosing, and number 
of tablets administered) and record these information in the CRF. When the investigators change 
the amount of dose, the reason for the change and the compliance of administration after the 
change (amount of dose after the change, drug number, starting day of dosing, completion day 
of dosing, and number of tablets administered) will be checked and recorded on the CRF. 
10.2.1 Dosing diary 
The investigator or clinical research coordinator will instruct subjects on how to complete the 
dosing diary. Subjects will record the study drug taken and time it was taken in the dosing diary 
every day. The time that the study drug was taken will be recorded in the dosing diary only 
during Period I but not during Periods II and III. 
10.3 Concomitant Medications 
10.3.1 Concomitant medications 
For all drugs (including over-the-counter drugs) used during the study period from the time of 
obtaining informed consent to the tests at the end of the follow-up period, the status of use 
(name of the drug, route of administration, duration of administration, and reason for use) will 
be recorded on the CRF. The equivalent information on the drugs used in Period III (including 
over-the-counter drugs) will not be recorded in the CRF. 


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10.3.2 ITP treatment 
For all the ITP drugs (including prohibited concomitant ITP drugs, allowed ITP drugs, and 
rescue therapy) used during the study period from the time of obtaining informed consent to the 
tests at the end of the follow-up period or market authorization, the status of use (name of the 
drug, route of administration, dosage, duration of administration, and reason for use) will be 
recorded on the CRF. 
10.4 Efficacy Endpoints 
10.4.1 SF 36 
Health related QOL will be assessed by subjects themselves using SF-36 v2 Japanese version. 
SF-36 assessment is performed before any other procedures and evaluations. Assessment date 
and results will be recorded in the CRF. 
10.5 Laboratory Tests 
10.5.1 Hematology 
The following laboratory tests will be measured in the laboratory in each study institution. The 
standard range of each parameter, blood sample collection date and time, and test results will 
be recorded on the CRF. As a general rule, the laboratory parameters should be measured by 
the same devices for the same subject throughout the study period. 
Platelet count, red blood cell count, white blood cell count, hemoglobin, hematocrit, differential 
white blood count (neutrophils, eosinophils, basophils, lymphocytes, and monocytes), 
neutrophil count, eosinophil count, basophil count, lymphocyte count, monocyte count, 
reticulocyte ratio, MCHC, MCH, and MCV 
10.5.2 Serum chemistry 
The following laboratory test parameters will be measured in the designated central laboratory. 
The presence or absence of sample collection will be recorded on the CRF. When additional 
laboratory tests are performed at the laboratory in the study institution, the standard range, blood 
sample collection date and time, and tests results will be recorded on the CRF. 
Sodium, potassium, chlorine, calcium, phosphorus, BUN, creatinine*, A/G ratio, blood glucose, 
total protein, albumin, ALT, AST, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), 
γ-glutamyltransferase (γ-GTP), total bilirubin, direct bilirubin, and indirect bilirubin 
*The eGFR will be calculated using the following formula. Age at the date of informed consent should be used for calculation. 
For male, eGFR (mL/min/1.73 m2) = 194 × serum creatinine-1.094 × Age-0.287 
For female, eGFR (mL/min/1.73 m2) = 194 × serum creatinine-1.094 × Age-0.287 × 0.739 
10.5.3 Urinalysis 
The following laboratory test parameters will be measured in the designated central laboratory. 
The presence or absence of sample collection will be recorded on the CRF. 
Glucose, ketone bodies, occult blood, proteins, nitrites, bilirubin, specific gravity, pH, 
urobilinogen, and white blood cells 


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10.5.4 D-dimer 
A D-dimer assay will be performed at the designated central laboratory for subjects with a 
history of venous thromboembolism > 6 months before Screening A. D-dimer assay should be 
performed only after resolution of the venous thromboembolism and after all anticoagulants 
have been discontinued for at least 30 days. The presence or absence of sample collection will 
be recorded on the CRF. 
10.5.5 PT-INR/APTT 
PT-INR/APTT will be measured at the designated central laboratory. The presence or absence 
of sample collection will be recorded on the CRF. 
10.6 Immunoglobulin Test 
Serum immunoglobulin levels (immunoglobulins M, G, and A) will be measured in the 
designated central laboratory. The presence or absence of sample collection will be recorded on 
the CRF. 
10.7 Immunological Test 
The following immunology test items will be measured in the designated central laboratory. 
The presence or absence of sample collection will be recorded on the CRF. 
HIV antigen, HIV antibody, HBs antigen, HBs antibody, HBV DNA assay, HBc antibody, HCV 
RNA assay 
10.8 Eastern Cooperative Oncology Group (ECOG) Performance Status 
The investigator will evaluate the condition of subjects using the ECOG Performance Status 
Japanese translation (see Appendix 1). Assessment date and results will be recorded in the CRF. 
10.9 Vital Signs 
Systolic and diastolic blood pressure, pulse rate, and body temperature (axillary) are measured 
after the subject rests (approximately for 3 minutes) in the sitting position. The measurement 
date, time, and results of systolic and diastolic blood pressure will be recorded on the CRF. The 
measurement date and results of pulse rate and body temperature (axillary) will be recorded on 
the CRF. If the initial blood pressure on each specified visit is > 130 mmHg systolic or 
> 80 mmHg diastolic, the blood pressure should be taken 2 additional times at least 5 minutes 
apart, and date, time and results for all 3 measurements will be recorded on the CRF. When the 
systolic and diastolic blood pressure is measured 3 times, the mean value of the 3 measurements 
will be used to make a decision for “5.2 Exclusion Criteria,” “8.3.1 Transition criteria to Period 
II for subjects who withdraw from ,” and “8.6.2.2 Dose adjustment due to adverse events.” As 
a general rule, the laboratory parameters should be measured by the same devices for the same 
subject throughout the study period. 
10.10 Height and Weight 
Height and weight will be measured. The measurement date and results will be recorded on the 
CRF. 


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10.11 12-lead ECG 
Twelve-lead ECG will be measured after subject rests (approximately for 5 minutes) in the 
supine position, and the measurement date and investigator's assessment will be recorded on 
the CRF. As a general rule, the 12-lead ECG should be measured by the same devices for the 
same subject throughout the study period. In principle, the 12-lead ECG is taken before the vital 
signs, laboratory tests, immunoglobulin test, immunological test, pregnancy test (women of 
childbearing potential only), and pharmacokinetics. 
10.12 Pregnancy Test 
Pregnancy test (serum human chorionic gonadotropin [HCG]) will be performed in women of 
childbearing potential (women who have not had their uteri or bilateral ovaries removed and 
had their last menstrual within 1 year) in the designated central laboratory. The presence or 
absence of sampling and pregnancy will be recorded in the CRF. 
10.13 ITP Bleeding Score 
The investigator will evaluate the bleeding score of subjects using the ITP Bleeding Scale (see 
Appendix 2). In principle, the same investigator should evaluate the same subjects. Assessment 
date and results will be recorded in the CRF. 
10.14 Pharmacokinetics 
The plasma concentration of R406 (active substance) will be measured. Plasma R406 
concentrations will be measured by the liquid chromatography-tandem mass spectrometer (LC-
MS/MS) method in the designated pharmacokinetic measurement laboratory (the detailed 
procedure of pharmacokinetic measurement is specified in the separate pharmacokinetic 
protocol). The date and time of the administration of the study drug from 2 days before to the 
day of blood sampling for the pharmacokinetic examination and the date and time of blood 
sampling on the day of the pharmacokinetic examination will be recorded in the CRF. 
10.15 Adverse Events 
An adverse event is defined as any untoward or unintended sign, symptom, aggravation of a 
complication, or disease that occurs in a subject, irrespective of the causal relationship with the 
study drug. The worsening of an efficacy variable is not considered to be an adverse event. 
10.15.1 Collection of adverse events 
The following information on each adverse event will be recorded in the CRF: name of the 
adverse event, date of onset, date of resolution (when the outcome is recovered/resolved, 
recovered/resolved with sequelae, or death), severity, dose at onset, seriousness assessment, 
action taken on the study drug, other actions taken, outcome, and causal relationship with the 
study drug. For adverse events that occur from the collection of informed consent to before the 
start of study treatment, the name of the adverse event and seriousness assessment will be 
recorded in the CRF. 
10.15.1.1 Adverse event collection period 
AEs will be collected from the collection of informed consent to the end of the follow-up period 


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or market authorization. 
10.15.1.2 Inquiry about adverse events 
The investigator should give sufficient consideration not to affect the voluntary reporting by 
subjects when conducting interviews with subjects. Specifically, the investigator should ask a 
general question, such as “Has anything happened since the last visit?” 
10.15.1.3 Considerations for recording adverse events 
1) 
When a diagnosis is determined from the signs and/or symptoms, the diagnosis will be 
recorded as an adverse event. Abnormal laboratory test values, abnormal findings, and 
symptoms associated with the adverse event will not be considered as an adverse event. 
2) 
When a diagnosis is not determined from signs and/or symptoms, abnormal laboratory test 
values, abnormal findings, and symptoms will be handled as adverse events. 
3) 
Abnormal laboratory test values and abnormal findings will be handled as an adverse event 
when they are clinically relevant variations or changes, as judged by the investigator. A 
clinically relevant variation or change is defined as a variation or change that requires 
medical intervention or treatment or is out of the normal physiological variation for the 
subject, as judged by the investigator. 
4) 
Abnormal laboratory test values or abnormal findings observed at the start of the screening 
period should not be handled as an adverse event. 
5) 
Diseases, symptoms, and findings present before the informed consent should not be 
handled as an adverse event. 
6) 
Any worsening of a complication, existing symptom, or finding should be handled as an 
adverse event. Worsening of a complication, existing symptom, or finding is defined as an 
increase in the frequency or severity of a seasonal or intermittent symptom or finding when 
the investigator considers that the relevant disease, symptom, or finding before study 
participation has worsened more than expected. 
7) 
Any adverse event that occurs from the collection of informed consent to before the start 
of the study treatment and worsens after the start of the study treatment is considered as a 
new adverse event. 
8) 
Any surgery or procedure scheduled before the collection of informed consent is not 
handled as an adverse event. 
9) 
Elective surgeries or procedures that have no impact on disease (eg, dental implant surgery, 
cosmetic surgery, or suture removal after skin suture at the subject's request) are not 
handled as an adverse event. However, any clinically relevant finding or symptom caused 
by such a surgery/procedure should be handled as an adverse event. 
10) Events considered as a worsening within the range expected for the target disease are not 
handled as an adverse event. 
10.15.2 Onset date of adverse events 
 
Date when the subject or investigator noticed the sign or symptom 
 
Date when the subject or investigator noticed the aggravation of the complication, existing 


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symptom, or finding 
 
Date of diagnosis confirmed even if the time of onset can be estimated for asymptomatic 
diseases 
 
For abnormal laboratory test values and abnormal findings, the date of examination from 
which a clinically relevant variation or change is obtained, as judged by the investigator 
10.15.3 Severity of adverse events 
The severity of adverse events will be evaluated with a 3-rank scale according to Table 10.15.3-
1. The most severe rank will be recorded for adverse events that vary in severity. 
Table 10.15.3-1 
Severity of Adverse Events 
Severity 
Decision criteria 
Mild 
Events that do not interfere with activities of daily living,a) or slightly interfere with them but 
do not require particular treatment, or require simple treatment 
Moderate 
Events that interfere with activities of daily livinga) and require treatment 
Severe 
Events that make activities of daily livinga) almost impossible or requiring systemic treatment 
a) For example, sleeping, moving, working, going out, eating, exercise, and bathing 
 
10.15.4 Serious adverse events 
Any adverse event that meets any of the following criteria will be handled as a serious adverse 
event for all adverse events, including those that occur from the collection of informed consent 
to before the start of the study treatment. If any serious adverse event occurs, its symptom or 
laboratory test parameter and the reason for judging it as serious will be recorded in the CRF. 
1) 
Death 
2) 
Life Threatening 
3) 
Initial or Prolonged Hospitalization 
4) 
Persistent or Significant Disability/Incapacity 
5) 
Congenital Anomaly or Birth Defect 
6) 
Other Medically Important Event 
Other Medically Important Event is defined as cases that do not immediately threaten life or 
lead to hospitalization, but may expose patients to danger, or cases associated with medical 
events that require treatment or procedure to prevent the outcomes listed in the above 1) to 5). 
10.15.5 Adverse events of special interest 
The following adverse events are considered as an adverse event of special interest (regardless 
of seriousness). The details of adverse events of special interest are specified in the Statistical 
Analysis Plan. 
1) 
Bleeding-related adverse events 
2) 
Gastrointestinal disorders 
3) 
Infection 
4) 
Hypertension 


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5) 
Neutropenia 
6) 
Hepatic dysfunction 
7) 
Thrombosis, embolism, and thromboembolism 
10.15.6 Actions taken with the study drug 
Actions taken with the study drug are defined in Table 10.15.6-1. 
Table 10.15.6-1 
Actions Taken with the Study Drug 
Action 
Definition 
Drug withdrawn 
Discontinuation of the study treatment due to the adverse event in question, including the 
discontinuation requested by the subject 
Drug interrupted 
Interruption of the study drug due to the adverse event in question, including the 
interruption requested by the subject 
Dose Reduced 
Dose reduction of the study drug due to the adverse event in question, including the dose 
reduction requested by the subject 
Inability to increase the dose of the study drug due to the adverse event in question in 
subjects who meet the dose increase criteria 
Dose not 
changed 
Study treatment continued without taking any action to the study drug 
Unknown 
Actions taken to the study drug cannot be determined 
Not applicable 
The administration of the study drug is completed or discontinued before the onset of the 
adverse event in question 
 
10.15.7 Outcome of the adverse event 
The outcome of adverse events will be assessed according to Table 10.15.7-1. 
Table 10.15.7-1 
Outcome of the Adverse Event 
Outcome 
Decision criteria 
Recovered/Resolved 
Resolution of or recovery from symptoms, normalization of test values, or recovery 
to the baseline level 
Recovering/Resolving 
Reduction or improving tendency of the severity of symptoms or abnormal values 
Not Recovered/Not 
Resolved 
Almost no change or exacerbation in symptoms or abnormal values 
Recovered/Resolved 
with Sequelae 
Dysfunction derived from symptoms or abnormal values and interfering with 
activities of daily living 
Fatal 
Death related to symptoms/abnormal values 
*This outcome should not be chosen for death not related to symptoms or abnormal values. 
Unknown 
Inability to follow the outcome despite every possible effort to follow symptoms and 
abnormal values 
 
10.15.8 Causal relationship between adverse events and the study drug 
The causal relationship of adverse events with the study drug will be assessed on a 2-point scale 
according to Table 10.15.8-1, considering the condition of subjects, complications, medical 
history, concomitant drugs, and temporal relationship with the onset. Of adverse events that 
develop after the start of the study treatment, those evaluated as “Yes” for the causal relationship 
with the study drug are considered to be an adverse drug reaction. 
For adverse events secondary to another adverse event, the causal relationship with the study 
drug should be evaluated for each adverse event independently. 


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Table 10.15.8-1 
Causal Relationship between Adverse Events and the Study Drug 
Relationship 
to study 
treatment 
Decision criteria 
Related 
An adverse event is considered to have a causal relationship with the study drug because, for 
example, the onset of the adverse event can be easily explained from the condition of the 
subject, complications, medical history, concomitant drugs, or temporal relationship with the 
onset of the adverse event. 
Not related 
An adverse event does not meet the above decision criteria for the causal relationship with the 
study drug because it meets any of the following criteria. 
 
The adverse event is clearly attributable to a factor other than the study drug. 
 
There is no temporal correlation between the onset/resolution of the adverse event and 
administration of the study drug and there is a long interval between them. 
 
The occurrence of the adverse event is considered incidental (eg, the same event has been 
frequently observed since before the study and the adverse event that occurred during the 
study is considered to be one of them). 
 
There are possible factors other than the study drug, such as the medical history/condition 
of the subject or other concomitant drugs/measures, treatment, and meals. 
 
10.15.9 Follow-up 
Among serious adverse events that occur from the collection of the informed consent to before 
the start of the study treatment and adverse events that occur after the start of the study treatment, 
those for which symptoms are not resolved or improved to the level before onset by the end of 
the follow-up period as judged by the investigator will be followed. Follow-up will be 
terminated in either of the following cases. 
1) 
The event is improved or resolved, as judged by the investigator. 
2) 
The event no longer requires additional follow-up, as judged by the investigator. 
10.16 Evaluation of Diarrhea 
When diarrhea occurs as an adverse event, the grade of diarrhea according to Common 
Terminology Criteria for Adverse Events (CTCAE) Ver. 5.0 (see Appendix 5), duration of onset 
by grade, and actions taken with the study drug will be recorded in the CRF to confirm the 
appropriateness of dose adjustment of the study drug. 
11. Schedule of Study Assessments and Procedures 
The investigator and clinical research coordinator will perform the specified study assessments 
and procedures according to the study schedule and “10 Study Assessments and Procedures.” 
11.1 Collection of Informed Consent 
 
Written informed consent 
 
Inclusion/exclusion criteria 
 
First registration 


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11.2 Screening Period 
11.2.1 Visit 1 (Screening A) 
 
Demographics 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
12-lead ECGa) 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, urinalysis, D-dimer assay,b) PT-
INR/APTT) 
 
Immunoglobulin test 
 
Immunological test 
 
Pregnancy test (women of childbearing potential only) 
 
Inclusion/exclusion criteria 
 
Second registration 
a) In principle, the 12-lead ECG is taken before vital signs, laboratory tests, immunoglobulin test, immunological test, and 
pregnancy test (women of childbearing potential only). 
b)  D-dimer assay is performed if the patient has a history of venous thromboembolism more than 6 months prior to Screening 
A. 
11.2.2 Visit 2 (Screening B) 
 
Demographics 
 
Adverse events/concomitant medications 
 
Vital signs 
 
Laboratory test (Hematology) 
11.3 Period I 
11.3.1 Visit 3 (Day 1) 
 
QOL evaluation (SF-36)a) 
 
Demographics 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Height and weight 


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 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, urinalysis, and PT-INR/APTT) 
 
Immunoglobulin test 
 
Inclusion/exclusion criteria 
 
Third registration 
 
Study drug dispensed (Period I) 
 
Administration of study drug 
a) The QOL evaluation (SF-36) is performed before other procedures and evaluations. 
11.3.2 Visit 4 (Week 2) 
In principle, subjects should visit the study institution in the morning without taking the 
morning dose of the study drug. 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
Vital signs 
 
Laboratory tests (hematology and serum chemistry) 
 
Pharmacokinetics (before study drug administration) 
 
Study drug dispensed (Period I)a) 
 
Administration of study drug 
 
Pharmacokinetics (1 to 4 hours after study drug administration) 
a) The need of dispensing the study drug is decided, considering the number of tablets to be taken before the next visit. 
11.3.3 Visit 5 (Week 4) 
In principle, subjects should take the morning dose of the study drug 1 to 4 hours before blood 
sampling and then visit the study institution in the morning. 
 
QOL evaluation (SF-36)a) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Pharmacokinetics (1 to 4 hours after study drug administration) 


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 
Study drug dispensed (Period I)b) 
a) The QOL evaluation (SF-36) is performed before other procedures and evaluations. 
b) The need of dispensing the study drug is decided, considering the number of tablets to be taken before the next visit. 
11.3.4 Visit 6 (Week 6) 
In principle, subjects should visit the study institution in the morning without taking the 
morning dose of the study drug. 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
Vital signs 
 
Laboratory tests (hematology and serum chemistry) 
 
Pharmacokinetics (before study drug administration) 
 
Study drug dispensed (Period I)a) 
 
Administration of study drug 
 
Pharmacokinetics (1 to 4 hours after study drug administration) 
a) The need of dispensing the study drug is decided, considering the number of tablets to be taken before the next visit. 
11.3.5 Visit 7 (Week 8) 
In principle, subjects should take the morning dose of the study drug 1 to 4 hours before blood 
sampling and then visit the study institution in the morning. 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Pharmacokinetics (1 to 4 hours after study drug administration) 
 
Study drug dispensed (Period I)a) 
a) The need of dispensing the study drug is decided, considering the number of tablets to be taken before the next visit. 
11.3.6 Visit 8 (Week 10) 
In principle, subjects should take the morning dose of the study drug 1 to 4 hours before blood 
sampling and then visit the study institution in the morning. 
 
Study drug compliance 
 
ITP Bleeding Score 


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 
Adverse events/concomitant medications 
 
Vital signs 
 
Laboratory tests (hematology and serum chemistry) 
 
Pharmacokinetics (1 to 4 hours after study drug administration) 
 
Study drug dispensed (Period I)a) 
a) The need of dispensing the study drug is decided, considering the number of tablets to be taken before the next visit. 
11.3.7 Visit 9 (Week 12) 
In principle, subjects should take the morning dose of the study drug 1 to 4 hours before blood 
sampling and then visit the study institution in the morning. 
 
QOL evaluation (SF-36)a) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Pregnancy test (women of childbearing potential only) 
 
Pharmacokinetics (1 to 4 hours after study drug administration) 
 
Study drug dispensed (Period I)b) 
a) The QOL evaluation (SF-36) is performed before other procedures and evaluations. 
b) The need of dispensing the study drug is decided, considering the number of tablets to be taken before the next visit. 
11.3.8 Visit 10 (Week 14) 
In principle, subjects should take the morning dose of the study drug 1 to 4 hours before blood 
sampling and then visit the study institution in the morning. 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
Vital signs 
 
Laboratory tests (hematology and serum chemistry) 
 
Pharmacokinetics (1 to 4 hours after study drug administration) 
 
Study drug dispensed (Period I)a) 
a) The need of dispensing the study drug is decided, considering the number of tablets to be taken before the next visit. 


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11.3.9 Visit 11 (Week 16) 
In principle, subjects should take the morning dose of the study drug 1 to 4 hours before blood 
sampling and then visit the study institution in the morning. 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Pharmacokinetics (1 to 4 hours after study drug administration) 
 
Study drug dispensed (Period I)a) 
a) The need of dispensing the study drug is decided, considering the number of tablets to be taken before the next visit. 
11.3.10 Visit 12 (Week 18) 
In principle, subjects should take the morning dose of the study drug 1 to 4 hours before blood 
sampling and then visit the study institution in the morning. 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
Vital signs 
 
Laboratory tests (hematology and serum chemistry) 
 
Pharmacokinetics (1 to 4 hours after study drug administration) 
 
Study drug dispensed (Period I)a) 
a) The need of dispensing the study drug is decided, considering the number of tablets to be taken before the next visit. 
11.3.11 Visit 13 (Week 20) 
In principle, subjects should take the morning dose of the study drug 1 to 4 hours before blood 
sampling and then visit the study institution in the morning. 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 


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 
Pharmacokinetics (1 to 4 hours after study drug administration) 
 
Study drug dispensed (Period I)a) 
a) The need of dispensing the study drug is decided, considering the number of tablets to be taken before the next visit. 
11.3.12 Visit 14 (Week 22) 
In principle, subjects should take the morning dose of the study drug 1 to 4 hours before blood 
sampling and then visit the study institution in the morning. 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
Vital signs 
 
Laboratory tests (hematology and serum chemistry) 
 
Pharmacokinetics (1 to 4 hours after study drug administration) 
 
Study drug dispensed (Period I)a) 
a) The need of dispensing the study drug is decided, considering the number of tablets to be taken before the next visit. 
11.3.13 Visit 15 (Week 24) 
In principle, subjects should take the morning dose of the study drug 1 to 4 hours before blood 
sampling and then visit the study institution in the morning. 
 
QOL evaluation (SF-36)a) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
12-lead ECGb) 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Immunoglobulin test 
 
Pregnancy test (women of childbearing potential only) 
 
Pharmacokinetics (1 to 4 hours after study drug administration) 
 
Enrollment for Transition to Period II 
 
Study drug dispensed (Period II) 
a) The QOL evaluation (SF-36) is performed before other procedures and evaluations. 
b) In principle, the 12-lead ECG is taken before the vital signs, laboratory tests, immunoglobulin test, pregnancy test (women 
of childbearing potential only), and pharmacokinetics. 


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11.4 Period II (Subjects Who Completed Period I) 
11.4.1 Visit 16 (Week 28) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Study drug dispensed (Period II) 
11.4.2 Visit 17 (Week 32) and Visit 18 (Week 36) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Vital signs 
 
Laboratory tests (hematology and serum chemistry) 
 
Study drug dispensed (Period II) 
11.4.3 Visit 19 (Week 40) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Pregnancy test (women of childbearing potential only) 
 
Study drug dispensed (Period II) 
11.4.4 Visit 20 (Week 44) and Visit 21 (Week 48) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 


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 
Vital signs 
 
Laboratory tests (hematology and serum chemistry) 
 
Study drug dispensed (Period II) 
11.4.5 Visit 22 (Week 52) 
 
QOL evaluation (SF-36)a) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
12-lead ECGb) 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Immunoglobulin test 
 
Pregnancy test (women of childbearing potential only) 
 
Written informed consent (only for subjects who want to participate in the Non-dosing 
period and Period III) 
a) The QOL evaluation (SF-36) is performed before other procedures and evaluations. 
b) In principle, the 12-lead ECG is taken before vital signs, laboratory tests, immunoglobulin test, and pregnancy test (women 
of childbearing potential only). 
11.5 Period II (Early Transition Subjects) 
11.5.1 ET Visit 1 (ET Day 1) 
If the subject withdraws from Period I and transition to Period II, in principle, the study 
procedures on ET Day 1 will be performed on the same day as the last visit in Period I. When 
the study procedures on ET Day 1 are performed on the same day as the last visit for Period I, 
the procedures overlapping on ET Day 1 with the last visit of Period I may be omitted when the 
procedures on ET Day 1 are performed. If the procedures on ET Day 1 cannot be performed on 
the same day as the last visit of Period I, all procedures on ET Day 1 must be performed within 
1 week from the last visit of Period I. All procedures on ET Day 1 should be performed on the 
same day. 
 
QOL evaluation (SF-36)a) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
12-lead ECGb) 


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 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Immunoglobulin test 
 
Pregnancy test (women of childbearing potential only) 
 
Inclusion/exclusion criteria 
 
Enrollment for Transition to Period II 
 
Study drug dispensed (Period II) 
a) The QOL evaluation (SF-36) is performed prior to other procedures and assessments on ET Day 1. 
b) In principle, the 12-lead ECG is taken before vital signs, laboratory tests, immunoglobulin test, and pregnancy test (women 
of childbearing potential only). 
11.5.2 ET Visit 2 (ET Week 4) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Study drug dispensed (Period II) 
11.5.3 ET Visit 3 (ET Week 8) and ET Visit 4 (ET Week 12) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Vital signs 
 
Laboratory tests (hematology and serum chemistry) 
 
Study drug dispensed (Period II) 
11.5.4 ET Visit 5 (ET Week 16) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Vital signs 


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 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Pregnancy test (women of childbearing potential only) 
 
Study drug dispensed (Period II) 
11.5.5 ET Visit 6 (ET Week 20) and ET Visit 7 (ET Week 24) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
Vital signs 
 
Laboratory tests (hematology and serum chemistry) 
 
Study drug dispensed (Period II) 
11.5.6 ET Visit 8 (ET Week 28) 
 
QOL evaluation (SF-36)a) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
12-lead ECGb) 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Immunoglobulin test 
 
Pregnancy test (women of childbearing potential only) 
 
Written informed consent (only for subjects who want to participate in the Non-dosing 
period and Period III) 
a) The QOL evaluation (SF-36) is performed before other procedures and evaluations. 
b) In principle, the 12-lead ECG is taken before vital signs, laboratory tests, immunoglobulin test, and pregnancy test (women 
of childbearing potential only). 
11.6 Non-dosing Period 
11.6.1 ND Visit 1 (ND Week 2) 
The study procedures for ND Week 2 are not performed for subjects who skip the Non-dosing 
period and transition to Period III, or transition from the Non-dosing period to Period III before 
performing the study procedures for ND Week 2. 
 
QOL evaluation (SF-36)a) 


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 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
12-lead ECGb) 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Immunoglobulin test 
 
Pregnancy test (women of childbearing potential only) 
a) The QOL evaluation (SF-36) is performed before other procedures and evaluations. 
b) In principle, the 12-lead ECG is taken before vital signs, laboratory tests, immunoglobulin test, and pregnancy test (women 
of childbearing potential only). 
11.7 Period III 
11.7.1 Period III Visit 1 (Period III Day 1) 
The study procedures for Period III Day 1 are not performed for subjects who skip the Non-
dosing period and transition to Period III. The study procedures for Period III Day 1 will be 
immediately performed irrespective of the allowance of visit for subjects who transition from 
the Non-dosing period to Period III before completing the Non-dosing period. When the study 
procedures on Period III Day 1 are performed on the same day as hose for ND Week 2, the 
procedures overlapping on Period III Day 1 with ND Week 2 may be omitted when the 
procedures on Period III Day 1 are performed. 
 
QOL evaluation (SF-36)a) 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
12-lead ECGb) 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Immunoglobulin test 
 
Pregnancy test (women of childbearing potential only) 
 
Study drug dispensed (Period III) 
a) The QOL evaluation (SF-36) is performed before other procedures and evaluations. 
b) In principle, the 12-lead ECG is taken before vital signs, laboratory tests, immunoglobulin test, and pregnancy test (women 
of childbearing potential only). 
11.7.2 Period III Visit 2 (Period III Visit 2) 
After Period III Week 8, subjects will visit the study institution every 8 weeks to undergo the 


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same study procedures as those at Period III Week 8. 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events and use of ITP concomitant medications 
 
ECOG Performance Status 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Pregnancy test (women of childbearing potential only) 
 
Study drug dispensed (Period III) 
11.8 At Withdrawal 
11.8.1 Withdrawal Visit 
Subjects will undergo the Withdrawal Visit when they withdraw from Period I and do not 
transition to Period II, when they withdraw from Period II, or when they withdraw from Period 
III. Early transition subjects will not undergo the Withdrawal Visit. When the tests/examinations 
and evaluations on ET Day 1 do not meet “8.3.1 Transition criteria to Period II for subjects who 
withdraw from ,” the tests/examinations and evaluations on ET Day 1 will be considered as 
those for Withdrawal Visit. Subjects who withdraw from the Non-dosing period will not 
undergo the Withdrawal Visit. 
 
QOL evaluation (SF-36)a) 
 
Study drug compliance 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
12-lead ECGb) 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Immunoglobulin testc) 
 
Pregnancy test (women of childbearing potential only) 
 
Pharmacokineticsd) 
a) The QOL evaluation should be performed only for subjects who withdraw from Period I and do not transition to Period II 
or subjects who withdraw from Period II. If the QOL evaluation is performed, it should be performed before the other 
tests/examinations and evaluations. 
b)  The 12-lead ECG should be performed only for subjects who withdraw from Period I and do not transition to Period II or 
subjects who withdraw from Period II. In principle, the 12-lead ECG is taken before vital signs, laboratory tests, 
immunoglobulin test, immunological test, pregnancy test (women of childbearing potential only), and pharmacokinetics. 
c) The Immunoglobulin test should be performed only for subjects who withdraw from Period I and do not transition to Period 
II or subjects who withdraw from Period II. 
d) Pharmacokinetics should be examined only for subjects who withdraw from Period I and do not transition to Period II. The 


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time of the last study drug administration before blood sampling to the date of blood sampling are not specified. 
11.9 Follow-up Period 
11.9.1 Test at the end of the follow-up period 
Subjects will undergo the test at the end of the follow-up period when they withdraw from 
Period I and do not transition to Period II, when they withdraw from Period II, when they 
complete Period II and do not want to participate in the Non-dosing period and Period III, when 
they withdraw from the Non-dosing period before ND Week 2, or when they withdraw from 
Period III. The tests at the end of the follow-up period are not performed for subjects who 
withdraw from the Non-dosing period at ND Week 2 or later. 
 
QOL evaluation (SF-36)a) 
 
ITP Bleeding Score 
 
Adverse events/concomitant medications 
 
ECOG Performance Status 
 
12-lead ECGb) 
 
Vital signs 
 
Laboratory tests (hematology, serum chemistry, and urinalysis) 
 
Immunoglobulin testc) 
 
Pregnancy test (women of childbearing potential only) 
a) Subjects should undergo the QOL evaluation only at the end of the follow-up period when they withdraw from Period I and 
do not transition to Period II, when they withdraw from Period II, or when they complete Period II and do not want to 
participate in the Non-dosing period and Period III. If the QOL evaluation is performed, it should be performed before the 
other tests/examinations and evaluations. 
b)  Subjects should undergo the 12-lead ECG only at the end of the follow-up period when they withdraw from Period I and 
do not transition to Period II, when they withdraw from Period II, or when they complete Period II and do not want to 
participate in the Non-dosing period and Period III. If the 12-lead ECG is taken, it should be taken, in principle, before the 
vital signs, laboratory tests, immunoglobulin test, and pregnancy test (women of childbearing potential only). 
c) Subjects should undergo the immunoglobulin test only at the end of the follow-up period when they withdraw from Period 
I and do not transition to Period II, when they withdraw from Period II, or when they complete Period II and do not want 
to participate in the Non-dosing period. 
12. Security of Study 
12.1 Management of Adverse Events 
When an adverse event occurs during the study period, the investigator will provide appropriate 
treatment to ensure the safety of the subject. The investigator will follow the adverse event 
according to “10.15.9 Follow-up” if it meets the criteria specified in the section. 
12.2 Management of Serious Adverse Events 
12.2.1 Measures to be taken against serious adverse events 
When any serious adverse event specified in “10.15.4 Serious adverse events” occurs, the 
investigator will provide appropriate emergency measures to improve the health of the subject. 


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12.2.2 Handling of serious adverse events 
The investigator will notify the person in charge of monitoring within 24 hours after he/she 
learns of the occurrence of the serious adverse event, and will submit the designated document 
within 3 days. 
The principal investigator will promptly report the serious adverse event to the head of the study 
institution according to the applicable procedure of the study institution. 
12.3 Management of Pregnant Women 
When any female subject is found or suspected to be pregnant during the period from the start 
of the study drug administration to 30 days after the end of the study drug administration, the 
investigator should promptly discontinue the study treatment for the subject. Additionally, when 
the investigator becomes aware of any information suggesting pregnancy, he/she will promptly 
report it to the sponsor. Furthermore, the investigator will follow the course of pregnancy until 
delivery and the offspring up to about 1.5 years after birth and notify the sponsor of the 
information obtained. However, the follow-up is not necessary for subjects who are found to 
belong to the placebo group and do not transition to Period II. 
12.4 Management of Abnormal Liver Function Test Values 
The investigator will submit the designated form provided by the sponsor to the sponsor within 
5 days after learning that all the following criteria are met at the same time. When the 
investigator determines the event as serious adverse event, the investigator will take actions 
according to “12.2 Management of Serious Adverse Events” and does not need to submit the 
specified form to the sponsor. 
1) 
Increase in AST or ALT to ≥ 3 × ULN 
2) 
Increase in total bilirubin to ≥ 2 × ULN 
12.5 Collection and Provision of Safety Information 
12.5.1 Collection of new safety information 
The sponsor will continuously collect and evaluate information that may adversely affect the 
safety of subjects, affect the conduct of the study, or change the approval of the IRB for 
continuation of the study. 
12.5.2 Provision of new safety information 
The sponsor will promptly notify in writing all the principal investigators, heads of the study 
institutions, and IRBs (via the head of each study institution) involved in the study of any new 
information on the safety of the study drug that has to be reported to the investigators. The 
sponsor may notify the IRBs at the same time only for the notifications related to Article 20, 
Paragraphs 2 and 3 of GCP if the sponsor, IRBs, and heads of the study institutions have agreed 
to it. 
When the investigator thinks that the information may affect the willingness of subjects to 
continue the study, the investigator will immediately inform subjects of the information and 
confirm their intention to continue the study. At the same time, the investigator will record in 


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writing (in the medical records) that the information was provided to subjects, and that their 
intention to continue the study was confirmed. If the principal investigator obtains information 
indicating the need to revise the informed consent form, the principal investigator will promptly 
revise it based on the information and obtain prior approval from the IRB. The investigator will 
explain the study to the subjects participating in the study again using the revised informed 
consent form and obtain the written informed consent to continue participation in the study 
from the subjects. In principle, no new subjects will be enrolled in the study until the revision 
of the informed consent form is approved. However, new subjects may be enrolled if the 
sponsor and the principal investigator decide that it is not necessary to change, discontinue, or 
suspend the study. In that case, the original informed consent form will be used and new safety 
information that may affect subjects’ willingness to continue the study will be provided and that 
fact will be recorded. The consent to participate in the study will be obtained again using the 
revised informed consent form approved by the IRB. 
13. Discontinuation/suspension of Study 
13.1 Discontinuation/suspension of Part of the Study or the Entire 
Study 
If an event that meets any of the discontinuation criteria occurs during the study period, the 
sponsor or the principal investigator will determine the handling of the event in consideration 
of discontinuation/suspension of part of the study or the entire study. 
13.2 Discontinuation Criteria (Discontinuation/suspension of Part of 
the Study or the Entire Study) 
1) 
The continuation of the study is considered difficult based on new safety information 
(including the onset of a serious adverse event). 
2) 
The sponsor, study institution, or the principal investigator commits a serious violation of 
GCP, protocol, or contract, which interferes with the appropriate continuation of the study. 
3) 
The continuation of the study is considered difficult due to the change in the study system 
(eg, transfer of the principal investigator) 
4) 
The continuation of the study is considered inappropriate based on the new information 
obtained or change in the study environment during the study. 
13.3 Procedure for Discontinuation/suspension 
The following procedure should be taken to discontinue or suspend the study. 
1) 
When the sponsor discontinues or suspends part of the study or the entire study, the sponsor 
will promptly notify the head of each study institution of the fact and detailed reason in 
writing. 
2) 
When the principal investigator discontinues or suspends the study, the principal 
investigator will promptly report the fact and reason to the head of the study institution in 
writing. 
3) 
When the head of each study institution receives the notification of the 
discontinuation/suspension of part of the study or the entire study from the sponsor, the 


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head of each study institution will immediately notify the principal investigator and IRB 
of the fact in writing and then report the reason for discontinuation/suspension in writing. 
When the head of the study institution receives the notification from the principal 
investigator, the head of the study institution will immediately notify the sponsor and IRB 
of the fact in writing and then report the reason for discontinuation/suspension in writing. 
When the principal investigator receives the notification of the discontinuation/suspension of 
the study, the principal investigator will promptly inform the subjects with the study drug 
administration of the fact and take appropriate follow-up measures. 
14. Statistical Analysis 
Data analysis will be performed by the associate statistician as directed by the statistical analysis 
manager. The main analysis methods are as specified below. The detailed analyses methods will 
be specified in the statistical analysis plan to be prepared separately before the data from Period 
I are locked. Any necessary analysis other than the pre-specified analyses will be performed 
using an appropriate method at the discretion of the statistical analysis manager. SAS 9.4 or 
later will be used as the analysis software. 
Inclusion/exclusion of subjects in analysis sets and handling of data will be determined before 
data lock in Period I. 
Statistical tests will be performed using a two-sided significance level of 5%. Summary 
statistics will include the number of subjects, mean, standard deviation, minimum, median, 
maximum, and quartile. Unless otherwise specified, data will be tabulated for each analysis 
group, each period, and each time point. 
The time points of analysis are shown in this chapter. The time window of each time point will 
be specified separately. 
14.1 Analysis Sets 
Analysis will be performed based on the assigned treatment when the full analysis set (FAS) is 
used as the analysis set. Analysis will be performed based on the actual treatment when the 
safety set (SS) and pharmacokinetic analysis set (PKS) are used as an analysis set. 
 
FAS: Subject population which excludes subjects who deviated GCP, who did not receive 
any study drug, who discontinued prior to Period I, who was ineligible to the major 
inclusion/exclusion criteria, and who could not obtain any of the primary endpoint data. 
 
SS: Subject population which excludes subjects who deviated GCP, who did not receive 
any study drug, and who discontinued prior to Period I. 
 
PKS: Set of subjects excluding subjects who have no plasma drug concentration data at all 
from subjects in the SS 
14.2 Analysis Group 
1) 
Evaluation in Period I 
 
R788 group: Subjects who receive R788 in Period I 
 
Placebo group: Subjects who receive placebo in Period I 


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2) 
Evaluation of long-term treatment of R788 
 
R788 group: Subjects who complete the treatment with R788 in Period I and then 
transition to Period II (subjects who receive the long-term continuous treatment 
with R788) 
3) 
Evaluation in Period II 
 
R788 group in Period I: Early transition subjects after completing the treatment 
with R788 in Period I 
 
Placebo group in Period I: Subjects who transition to Period II after the treatment 
with placebo in Period I 
4) 
Evaluation in the Non-dosing period 
 
R788 group: Subjects who transition to the Non-dosing period 
5) 
Evaluation in Period III 
 
R788 group: Subjects who receive R788 in Period III 
6) 
Evaluation in the R788 treatment period 
 
R788 group: Subjects of R788 group in Period I and subjects who transition to 
Period II/III 
14.3 Disposition of Subjects 
The number and percentage of subjects will be presented for the inclusion or exclusion of 
subjects in/from the analysis sets in Period I and the presence or absence of withdrawal in each 
period. The difference between groups in Period I will be evaluated using Fisher's exact test. 
14.4 Demographic and Other Baseline Characteristics 
For the major demographic characteristics of Period I, summary statistics or number and 
percentage of subjects will be presented both overall and by treatment groups, depending on 
data characteristics. 
14.5 Efficacy 
FAS will be used as the efficacy analysis set. 
14.5.1 Primary endpoint 
The primary efficacy endpoint in this study is the achievement rate of stable platelet response. 
The primary endpoint will be analyzed using data from Period I. 
Achievement rate of stable platelet response: Subjects who achieve a platelet count of 
≥ 50000/μL at 4 or more of the 6 visits from Weeks 14 to 24 are considered to be a responder 
and the percentage of responders will be evaluated. 
The following procedures should be taken to evaluate the achievement rate of stable platelet 
response. 
 
Subject who withdrawn from the study due to “adverse event” or “lack of efficacy” or 


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subject receiving rescue therapy from Week 10 to Week 24 will be considered non-
responders. 
 
For missing data in subjects other than those listed above, data will be imputed using last 
observation carried forward (LOCF) method until Week 24 and the achievement rate of 
stable platelet response will be analyzed based on imputed data. 
14.5.1.1 Analysis method for primary endpoint 
The achievement rate of stable platelet response with two-sided 95% exact confidence interval 
(Clopper-Pearson) will be presented. The difference in the achievement rate between the groups 
with two-sided 95% exact confidence interval will be calculated. The superiority of the R788 
group to the placebo group will be evaluated using the Fisher's exact test. The significance level 
is two-sided 5%. 
14.5.1.2 Sensitivity analysis of primary endpoint 
The robustness of the primary endpoint will be evaluated by a sensitivity analysis using multiple 
imputation as shown below. 
First, non-monotone missing data will be imputed using MI procedure with MCMC options. 
This imputation is based on platelet count from Week 2 to 24 as covariate. Then, monotone 
missing data will be imputed based on the chained equation method. This imputation will be 
performed by MI procedure with MONOTONE REG options. The imputed data sets will be 
analyzed for stable platelet response using a logistic regression model by treatment, and the 
results will be summarized using PROC MIANALYZE. 
14.5.2 Secondary efficacy endpoints 
14.5.2.1 Evaluation in Period I 
The following analyses will be performed for the R788 and placebo treatment groups in Period 
I. Baseline is defined as Day 1 in Period I. 
1) 
Achievement rate of platelet count 
The achievement rate with two-sided 95% exact confidence interval (Clopper-Pearson) 
will be presented for the following endpoints. The difference in the achievement rate 
between the groups and its two-sided 95% exact confidence interval will be presented. 
Any subject not evaluated as a responder will be regarded as a non-responder. 
 
Achievement rate of a platelet count of at least 50000/μL at Weeks 12 and 24 
 
Achievement rate of a platelet count increase at least 20000/μL above baseline and 
≥ 30000/μL at Week 12 and 24 (for subjects with baseline platelet count 
< 15000/μL) 
 
Achievement rate of overall response (subjects who achieve a platelet count of 
≥ 50000/μL at least 1 of the 6 visits from Weeks 2 to 12 are defined as a responder 
and the percentage of responders will be evaluated) 
2) 
Number of times of achieving platelet count 
Frequency distributions will be presented for the following endpoints. 


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 
Number of times a platelet count ≥ 50000/μL in the 6 visits between Week 2 to 
Week 12 
 
Number of times a platelet count of ≥ 50000/μL in the 12 visits from Weeks 2 to 
24 
3) 
Duration of stable platelet response 
Summary statistics will be presented for the duration of the stable platelet response since 
the first achievement of a platelet count of ≥ 50000/μL after administration of the study 
drug. 
4) 
Summary statistics will be presented for the measured value of platelet count and change 
from the baseline. 
5) 
Frequency distributions of platelet count will be presented. 
6) 
The time course of platelet count in individual subjects will be presented. 
7) 
The summary statistics of the QOL evaluation (SF-36) will be presented. 
14.5.2.2 Evaluation of long-term treatment of R788 
The data from subjects who receive the long-term continuous treatment with R788 in Periods I 
and II will be analyzed as follows. Baseline is measurements at Day 1 in Period I. 
1) 
Achievement rate of platelet count 
The achievement rate with two-sided 95% exact confidence interval (Clopper-Pearson) 
will be presented for the following endpoints. Any subject not evaluated as a responder 
will be regarded as a non-responder. 
 
Achievement rate of platelet count of ≥ 50000/μL at Weeks 12, 24, 36, 48, and 52 
 
Achievement rate of a platelet count increase at least 20000/μL above baseline and 
≥ 30000/μL at Weeks 12, 24, 36, 48, and 52 (for subjects with a baseline platelet 
count of < 15000/μL) 
2) 
Duration of stable platelet response 
Summary statistics will be presented for the duration of the stable platelet response since 
the first achievement of a platelet count of ≥ 50000/μL after administration of the study 
drug. 
3) 
Summary statistics will be presented for the measured value of platelet count and change 
from the baseline. 
4) 
Frequency distributions of platelet count will be presented. 
5) 
The time course of platelet count in individual subjects will be presented. 
6) 
The summary statistics of the QOL evaluation (SF-36) will be presented. 
14.5.2.3 Evaluation in Period II 
The data in Periods I and II from subjects who receive placebo in Period I and transition to 
Period II will be analyzed as described in 1). The data in Period II from early transition subjects 
after completing the treatment with R788 in Period I and those who receive placebo in Period I 


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and transition to Period II will be analyzed by groups, as specified in 2) to 7). The periods from 
Weeks 24 to 52 and from ET Day 1 to ET Week 28 will be hereinafter expressed as Day 1 to 
Week 28 of Period II and Day 1 of Period II will be considered as the baseline of Period II. 
1) 
Achievement rate of maintenance of platelet count in Periods I and II 
Considering the subjects who achieve a platelet count of ≥ 50000/μL within 12 weeks after 
the start of study treatment in Periods I and II and maintain it for 12 weeks as a responder, 
the achievement rate with two-sided 95% exact confidence interval (Clopper-Pearson) will 
be presented. The difference in the achievement rate between Periods I and II and its two-
sided 95% exact confidence interval will be presented. McNemar test will be used to 
evaluate the difference in the achievement rate between Periods I and II. 
2) 
Achievement rate of platelet count 
The achievement rate with two-sided 95% exact confidence interval (Clopper-Pearson) 
will be presented for the following endpoints. Any subject not evaluated as a responder 
will be regarded as a non-responder. 
 
Achievement rate of platelet count of ≥ 50000/μL at Weeks 12, 24, and 28 in Period 
II 
 
Achievement rate of a platelet count increase at least 20000/μL above baseline and 
≥ 30000/μL at Weeks 12, 24, and 28 in Period II (for subjects with a baseline 
platelet count of < 15000/μL) 
3) 
Duration of stable platelet response 
Summary statistics will be presented for the duration of stable platelet response from the 
first achievement of a platelet count of ≥ 50000/μL after administration of the study drug 
in Period II. 
4) 
Summary statistics will be presented for the measured value of platelet count and change 
from the baseline. 
5) 
Frequency distributions of platelet count will be presented. 
6) 
The time course of platelet count in individual subjects will be presented. 
7) 
The summary statistics of the QOL evaluation (SF-36) will be presented. 
14.5.2.4 Evaluation in the Non-dosing period 
Data during the Non-dosing period from subjects who transition to the Non-dosing period are 
included. Week 52 and ET Week 28 are considered as Day 1 of the Non-dosing period, which 
is regarded as the baseline. 
1) 
Summary statistics will be presented for the measured value of platelet count and change 
from the baseline. 
2) 
Frequency distributions of platelet count will be presented. 
3) 
The time course of platelet count in individual subjects will be presented. 
14.5.2.5 Evaluation in Period III 
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Period III will be regarded as the baseline. 
1) 
Summary statistics will be presented for the measured value of platelet count and change 
from the baseline. 
2) 
Frequency distributions of platelet count will be presented. 
3) 
The time course of platelet count in individual subjects will be presented. 
14.6 Safety 
SS will be used as the safety analysis set. Safety will be analyzed by the analysis groups and 
Day 1 of each period will be considered as the baseline. Day 1 of Period I will be considered as 
the baseline for the evaluation of the long-term administration of R788. In addition, the analysis 
for the Non-dosing period and Period III will be performed only for “14.6.1 Adverse events and 
adverse drug reactions” and “14.6.2 ITP Bleeding Score”, and the analysis for R788 treatment 
period will be performed only for “14.6.1 Adverse events and adverse drug reactions.” 
14.6.1 Adverse events and adverse drug reactions 
The data on adverse events and adverse drug reactions will be analyzed as follows. Adverse 
events and adverse drug reactions that occur after the dosing of R788 will be analyzed in the 
evaluation of the R788 treatment period. 
1) 
Incidence rate of adverse events and adverse drug reactions 
The number of events, number of subjects with events, and incidence rate with two-sided 
95% exact confidence interval (Clopper-Pearson) will be presented for adverse events and 
adverse drug reactions. The difference in incidence rate between the groups and its two-
sided 95% exact confidence interval will be presented. 
2) 
Incidence of adverse events and adverse drug reactions (major events) 
The number of events, number of subjects with events, and incidence rate will be presented 
for the overall adverse events and adverse drug reactions, events leading to death, serious 
events excluding death, events leading to discontinuation, events leading to interruption, 
events leading to dose reduction, and events of special interest. 
3) 
Adverse events and adverse drug reactions 
The number of events, number of subjects with events, and incidence rate will be presented 
for the overall adverse events and adverse drug reactions, primary System organ classes 
(SOCs) and Preferred terms (PTs). The same analysis will be performed for adverse events 
and adverse drug reactions of special interest. 
4) 
Severity of adverse events and adverse drug reactions 
The number of events by severity will be presented for the overall adverse events and 
adverse drug reactions, primary SOCs and PTs. The same analysis will be performed for 
adverse events and adverse drug reactions of special interest. 


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14.6.2 ITP Bleeding Score 
1) 
Summary statistics will be presented for the mean and total scores of the anatomical sites 
(9 sites except Skin [Hx] and Oral [Hx]) and distribution of the maximum score will be 
presented. 
14.6.3 ECOG performance status 
1) 
The frequency distribution of scores will be presented. 
14.6.4 Vital signs 
1) 
For vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, and body 
temperature), the summary statistics of measured values and changes from the baseline 
will be presented. Scatter plot of measured values before and after administration will be 
presented. 
2) 
The maximum systolic blood pressure after the dosing of the study treatment in each period 
will be categorized into < 140 mmHg, ≥ 140 mmHg to < 160 mmHg, ≥ 160 mmHg to 
< 180 mmHg, and ≥ 180 mmHg and frequency distribution will be shown. 
3) 
The maximum diastolic blood pressure after the dosing of the study treatment in each 
period will be categorized into < 90 mmHg, ≥ 90 mmHg to < 100 mmHg, ≥ 100 mmHg to 
< 110 mmHg, and ≥ 110 mmHg, and frequency distribution will be shown. 
4) 
For systolic and diastolic blood pressure, frequency distribution of the number of times of 
systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg after the 
dosing of the study treatment in each period will be shown. The number of times of systolic 
blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg will also be 
presented in the same manner. 
14.6.5 Laboratory and immunoglobulin tests 
1) 
Summary statistics will be presented for quantitative values and changes from the baseline. 
Scatter plot of measured values before and after administration will be presented. 
2) 
The number and percentage of subjects will be presented for qualitative parameters. 
3) 
Shift tables before and after administration will be presented. 
4) 
The maximum ALT or AST value after the start of the study treatment in each period will 
be categorized into ≤ 3 × ULN, ≥ 3 × ULN to < 5 × ULN, ≥ 5 × ULN to < 10 × ULN, and 
≥ 10 × ULN, and frequency distribution will be presented. 
14.7 Pharmacokinetics 
PKS will be used as the pharmacokinetic analysis set. 
14.7.1 Plasma drug concentration 
1) 
Summary statistics of the plasma concentrations of R406 (active metabolite) will be 
presented. 


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14.8 Timing of Analysis 
The statistical analysis will be performed with the data in Period I when the data in Period I are 
locked. The data until the date of data cutoff will be analyzed after all subjects complete Period 
II. 
15. Agreement on and Amendment to the Protocol 
15.1 Agreement on the Protocol 
The principal investigator must write his or her name and seal or sign, and date the protocol or 
an alternative document in order to prove that the principal investigator has agreed to the 
contents of the protocol and agreed to comply with the protocol. 
15.2 Amendment to the Protocol 
The sponsor must revise the protocol, where necessary, when the sponsor becomes aware of 
important information to ensure the quality, efficacy, and safety of the study drug or to conduct 
the study proper manner. When the protocol is revised and even when the protocol is revised 
by the order of the head of the study institutions based on the opinion from the IRB, the sponsor 
must obtain agreement with the principal investigator. 
The investigator should not implement any deviation from or change to the protocol without 
prior documented agreement between the principal investigator and the sponsor, and prior 
review and documented approval from the IRB of an amendment, except where necessary for 
medical emergency such as to eliminate an immediate hazard(s) to subjects, or when the change 
involves only administrative aspects of the study. 
15.3 Protocol Deviations 
If a deviation from or change to the protocol is implemented to eliminate an immediate 
hazard(s) to subjects or for other medical emergency prior to obtaining approval, the principal 
investigator must, as soon as possible, submit the deviation or change with its reason(s) and, if 
appropriate, the proposed protocol amendment to the sponsor, the head of the study institution, 
and to the IRB via the head of the study institution for approval. The principal investigator also 
should obtain approval from the head of the study institution, as well as a documented 
agreement with the sponsor via the head of the study institution. In addition, the investigator 
should document all deviations from the protocol. 
16. Direct access to Source Documents 
16.1 Source Documents 
A “source documents” is defined as a document, data, and record to create a document such as 
a CRF. Specifically, that is a necessary record to allow reconstruction of the course of events 
and evaluation of the study, including the informed consent form, medical records, 
test/examination data, and a history of the study drug administration. The study institution 
should consult with the sponsor to identify source documents. 


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16.2 Direct Access 
The head of the study institution and the principal investigator should accept monitoring and 
audit by the sponsor, and investigations by the IRB and regulatory authorities of Japan and other 
countries, and make available for direct access the source documents. 
The sponsor should confirm that each subject has consented in written to allow the direct access 
to his or her source clinical records at the time of such monitoring, audit, or investigations by 
the IRB and regulatory authorities of Japan and other countries. 
16.3 Consistency of a Case Report From with the Source Documents 
The sponsor should check the CRF from created by principal investigator against the study-
related documents such as source documents and confirm that both are accurate. 
The CRF should be consistent with the source documents. If any discrepancy is found, the 
principal investigator should create a document to explain the reason(s) and submit to the 
sponsor. The study institution should retain a copy of the document. 
17. Quality Control and Assurance for the Study 
The sponsor will implement quality control and assurance for the study in accordance with the 
standard operating procedures. The sponsor's auditor should assess whether or not this study is 
being conducted in compliance with the GCP, the protocol and the operating procedures 
independently, separating from the routine monitoring and quality control functions in the study. 
18. Ethics 
18.1 Compliance with GCP 
This study will be conducted in accordance with Article 14 (3) and Article 80 (2) of the Act on 
Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical 
Devices and any other relevant standards for clinical studies of drug, which have been specified 
by the Minister of Health, Labour and Welfare, “Ministerial Ordinance on Good Clinical 
Practice for Drugs” that was established as the standards stipulated by the ministerial ordinance, 
and the protocol consistent with the ethical principles that have their origin in the latest 
Declaration of Helsinki. 
18.2 Subject Confidentiality Considerations 
The head of the study institution should take necessary measures to ensure the subject's 
confidentiality. The confidentiality of records related to subjects (e.g., CRFs) must be protected 
using subject identification codes, and the subject's right should be fully taken into account. 
The monitor, the auditor, the IRB, and regulatory authorities must maintain subject information 
as confidential when they access the source documents. 
18.3 Compensation to Subjects 
1) 
In the event of study-related health damages in a subject, the study institution must provide 
treatment and take any other necessary procedures. 


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2) 
Regarding the study-related health damages, if the subject claims compensation or 
indemnification to the study institution or there is such a possibility, the study institution 
must immediately notify the sponsor and strive to resolve the problem together. 
3) 
The sponsor must compensate the study-related health damages in accordance with the 
compensation regulations set by the sponsor. 
4) 
In the event of study-related health damages for which indemnity liability arises later, the 
compensation should be made at the liable person's own risk and expense. 
5) 
The sponsor must purchase insurance for compensation or indemnification described 
above. 
19. Data Handling and Records Retention 
19.1 Case Report from Creation and Submission 
In this study, clinical study data including investigations, observations, tests and evaluations 
will be electronically collected and recorded, creating the subject's CRFs. The investigator 
should create the CRF for each subject who provided informed consent, and the principal 
investigator will confirm the all record. Data on platelet count, rescue therapy, compliance with 
the study drug, vital signs (systolic and diastolic blood pressure), diarrhea and neutrophil count 
should be recorded in the CRFs generally within 3 days (excluding Saturday, Sunday, and 
holidays) after the data become available. For subjects who do not enter the Period I, 
demographics (excluding those related to the inclusion/exclusion criteria), tests/examinations 
and evaluations performed during the screening period, adverse events, and study 
discontinuation will be collected and recorded. For the creation method of CRF, the separate 
documented procedure is to be followed. 
19.2 External Data 
If the results measured at external laboratories are obtained as electronic data, the data should 
be obtained directly from external laboratories. For the method and timing of the data creation, 
the written procedure established at the external laboratory should to be followed. 
19.3 Records Retention 
19.3.1 Study institution 
The head of the study institution must retain all documents and records associated with this 
study until the sponsor notifies the study institution that such documents and records are no 
longer needed. The head of the study institution or the records retention manager must take 
measures to avoid any loss or destroying these records during retention and to provide them 
upon request. 
The principal investigator must retain all documents associated with the conduct of the study 
in accordance with the instructions from the head of the study institution. 
19.3.2 Institutional Review Board 
The founder of the IRB must retain all documents and records associated with this study until 
the sponsor notifies the founder that such documents and records are no longer needed. These 


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records should be readily available to be provided upon request from the regulatory authorities. 
19.3.3 Sponsor notifications 
The sponsor will notify the head of the study institution as well as the founder of the IRB via 
the head of the study institution when the retained documents and records associated with the 
study by the head of the study institution and the founder of the IRB are no longer needed. 
20. Payment 
Regarding payments to subjects, the study institution and the sponsor will have a prior 
discussion and obtain approval from the IRB. When approval is obtained, payments should be 
based on the documents relating to payment to subjects. 
21. Publication Policy 
Unpublished data in this protocol is proprietary information of the sponsor and must not be 
disclosed to third parties without prior documented agreement with the sponsor. External 
disclosure of whole or part of the results from this study in the academic conference or journals 
requires prior approval from the sponsor. 
22. Study Organization 
This study will be planned and conducted by the organization described in a separate addendum. 
Revisions of the addendum should be managed separately from this protocol. 
23. Protocol Revision History 
Prepared on August 28, 2019. 
Version: 1.0 


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24. References
1)
Japan Intractable Diseases Information Center Certification Criteria for Idiopathic
Thrombocytopenic Purpura (homepage on the Internet). (cited on April 19, 2018)
Available from http://www.nanbyou.or.jp/upload_files/File/063-201704-kijyun.pdf
2)
Fujimura K. Idiopathic Thrombocytopenic Purpura. The Journal of the Japanese Society
of Internal Medicine. 2009;98(7):1619-26
3)
Kuwana M. Idiopathic Thrombocytopenic Purpura. Japanese Journal of Thrombosis
and Hemostasis. 2008;19(2):199-201
4)
Ministry of Health, Labour and Welfare, Report on Public Health Administration and
Services (as of the end of 2017)
5)
Fujimura K, Miyagawa Y, and Kurata Y, et al. Reference Guide for the Management of
Adult Idiopathic Thrombocytopenic Purpura (ITP) 2012 Version. The Japanese Journal
of Clinical Hematology. 53(4):433-42
6)
Tomiyama Y. Current topics in primary immune thrombocytopenia. The Japanese
Journal of Clinical Hematology. 2017;58(5):537-41
7)
Annual Report of Research Study Team for Intractable Disease (Blood Coagulation
Abnormalities), the Ministry of Health, Labour, and Welfare. 2017 General Assigned
Study Report
8)
Depre F, Aboud N, Ringel F, et al. Thrombopoietin Receptor Agonists Are Often
Ineffective in Immune Thrombocytopenia and/or Cause Adverse Reactions: Results
from One Hand. Transfus Med Hemother 2016;43:375-9
9)
Carpenedo M, Cantoni S, Coccini V, et al. Response loss and development of
neutralizing antibodies during long-term treatment with romiplostim in patients with
immune thrombocytopenia: a case series. European Journal of Haematology.
2016;97(1):101-3
10) Miyakawa Y, Katsutani S, Yano T, et al. Efficacy and safety of rituximab in Japanese
patients with relapsed chronic immune thrombocytopenia refractory to conventional
therapy. Int J Hematol 2015;102(6):654-61
11) Tomiyama Y. Rituximab Therapy for Autoimmune Thrombocytopenic Purpura.
Hematology. 2012;65(6):832-7
12) Bussel J, Arnold D, Grossbard E, et al. Fostamatinib for the Treatment of Adult
Persistent and Chronic Immune Thrombocytopenia: Results of Two Phase 3,
Randomized, Placebo-Controlled Trials. Am J Hematol. 2018;93:921-30


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Appendix 1 
Eastern 
Cooperative 
Oncology 
Group 
(ECOG) 
Performance Status (PS)  
Score 
Definition 
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 housework, 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. 
Source: 
Common Toxicity Criteria, Version 2.0 Publish Date April 30, 1999 
National Cancer Institute（https://ctep.cancer.gov/） 


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Appendix 2 
Immune Thrombocytopenic Purpura Bleeding Scale 
Site 
Bleeding score 
0 
1 
2 
Skin (Physical Examination 
[PE]) 
None 
1–5 bruises and/or 
scattered petechiae 
> 5 bruises with size 
> 2 cm and/or diffuse 
petechiae 
Oral (PE) 
None 
1 blood blister or 
> 5 petechiae or gum 
bleeding that clears 
easily with rinsing 
Multiple blood blisters 
and/or gum bleeding 
Skin (Hx) 
None 
1–5 bruises and/or 
scattered petechiae 
> 5 bruises with size 
> 2 cm and/or diffuse 
petechiae 
Oral (Hx) 
None 
1 blood blister or 
> 5 petechiae and/or 
gum bleeding < 5 min 
Multiple blood blisters 
and/or gum bleeding 
> 5 min 
Epistasis 
None 
Blood when blowing 
nose and/or epistaxis 
< 5 min (per episode) 
Bleeding > 5 min (per 
episode) 
Gastrointestinal (GI) 
None 
Occult blood 
Gross blood 
Urinary (U) 
None 
Microscopic 
(+ve dipstick) 
Macroscopic 
Gynecological (GYN) 
None (normal period) 
Spotting not at time of 
normal period 
Bleeding > spotting 
not at time of period 
or very heavy period 
Pulmonary 
None 
N/A 
Yes 
Intracranial haemorrhage 
None 
N/A 
Yes 
Subconjunctival haemorrhage 
None 
Yes 
N/A 
Source: 
Page LK, Psaila B, Provan D, et al. The immune thrombocytopenic purpura (ITP) bleeding score: assessment of bleeding in 
patients with ITP. British journal of haematology. 2007;138(2):245-8. 
 


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Appendix 3 
Management of Increases in AST, ALT, or Bilirubin 
Liver enzyme abnormities or associated symptoms should be managed by adjusting the dose of 
the study drug or performing additional tests/examinations according to the following 
instructions. Additional tests/examinations may be performed at the study institution. The 
investigator should inform the sponsor of the onset of liver function test abnormality specified 
in “12.4 Management of Abnormal Liver Function Test Values” by the due date specified in 
“12.4 Management of Abnormal Liver Function Test Values.” 
R788 is an inhibitor of UGT1A1, the enzyme responsible for the glucuronidation of bilirubin; 
occasionally an isolated increase in total and unconjugated (indirect) bilirubin may be observed. 
Study drug should not be interrupted for an isolated increase in total and unconjugated (indirect) 
bilirubin. 
 
1) 
In the case that subjects meet a), b) and c) 
a) 
ALT or AST ≥ 3 × ULN 
b) 
Total bilirubin > 2 × ULN 
c) 
ALP < 2 × ULN 
(1) Interrupt the study drug and consider withdrawing the subject from the study due to 
suspected drug-induced liver injury. 
(2) The investigator will follow the subject until liver function test results and clinical 
symptoms and findings return to normal or the level of Day 1, or as long as medically 
indicated. 
(3) The investigator will investigate the etiology of the event and perform diagnostic 
examinations. 
 
2) 
In the case that subjects meet a) or b) and have nausea, vomiting, abdominal pain 
a) 
ALT or AST ≥ 3 × ULN 
b) 
Total bilirubin > 2 × ULN 
(1) Study drug administration should be interrupted. 
(2) Liver function tests, including bilirubin and alkaline phosphatase should be repeated 
until ALT/AST or total bilirubin returns to < 1.5 × ULN (the frequency of repeat tests is 
decided by the investigator). 
(3) When the ALT/AST or total bilirubin returns to < 1.5 × ULN, the study drug may be 
restarted at 1 lower dose level. 
(4) The recurrence of the condition of 2) should be managed in the same manner. 
 


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3) 
In the case that subject meet a) or b) and subject is asymptomatic 
a) 
ALT or AST ≥ 3 × ULN 
b) 
Total bilirubin > 2 × ULN 
(1) Repeat liver function tests immediately, including ALP. 
(2) If repeat testing shows an increase in ALT/AST or total bilirubin and the ALT/AST value 
exceeds 5 × ULN, immediately interrupt study drug administration. 
(3) Liver function tests including ALP will be repeated until ALT, AST, or total bilirubin 
returns to < 1.5 × ULN (the frequency of repeat tests is decided by the investigator). 
(4) When the ALT/AST or total bilirubin returns to < 1.5 × ULN, the study drug may be 
restarted at 1 lower dose level. 
(5) The recurrence of the condition of 3) should be managed in the same manner. 
 
Dose Adjustment 
Dose reduction 
Dose before 
dose 
increase/ 
reduction 
Dose escalation 
Dose level 
−4 
Dose level 
−3 
Dose level 
−2 
Dose level 
−1 
Dose 
level 
+1 
Dose 
level 
+2 
Dose 
level 
+3 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
 
References: 
FDA. Guidance for Industry: Drug-induced liver injury: premarketing clinical evaluation. In: 
FDA,CDER,CBER.http://www.fda.gov/downloads/drugs/guidancecomplianceregulatory 
information/guidances/ucm174090.pdf: issued July 2009. 
 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 96 - 
Appendix 4 
Management of Neutrophil Count Decreased 
Neutrophil count decreased should be managed by adjusting the dose of the study drug or 
performing additional tests/examinations according to the following instructions. 
 
1) 
Neutrophil count decreased to < 1000/μL 
(1) Repeat neutrophil count measurement immediately. 
(2) If repeat testing confirms that neutrophil count is < 1000/μL, immediately interrupt 
study drug administration and repeat the measurement of neutrophil count (the 
frequency of additional measurements will be determined by the investigator). 
(3) When neutrophil count recovers to > 1500/μL, restart study drug at 1 lower dose level. 
 
2) 
Recurrence of neutrophil count of < 1000/μL 
(1) Repeat neutrophil count measurement immediately. 
(2) If repeat testing confirms that neutrophil count is < 1000/μL, immediately interrupt 
study drug administration and repeat the measurement of neutrophil count (the 
frequency of additional measurements will be determined by the investigator). 
(3) When neutrophil count recovered to > 1500/μL, restart study drug at 2 lower dose level 
from the dose level at which the “1) Neutrophil count decreased to < 1000/μL” occurred. 
 
Dose Adjustment 
Dose reduction 
Dose before 
dose 
increase/ 
reduction 
Dose escalation 
Dose level 
−4 
Dose level 
−3 
Dose level 
−2 
Dose level 
−1 
Dose 
level 
+1 
Dose 
level 
+2 
Dose 
level 
+3 
Interruption 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruption 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruption 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruption 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 97 - 
Appendix 5 
Management of Diarrhea 
Subjects should be made aware that they may experience diarrhea and instructed to contact the 
clinical site if they experience diarrhea. If diarrhea is observed, the investigator decide grade of 
diarrhea according to CTCAE v 5.0 (see the table below) and adjust the dose of study drug or 
perform additional tests in accordance with the following instructions. 
 
Grade of Diarrhea (CTCAE v 5.0) 
Grade 
Decision criteria 
Grade 1 
 
Increase of < 4 stools per day over baseline 
 
Mild increase in ostomy output compared to baseline 
Grade 2 
 
Increase of 4 to 6 stools per day over baseline 
 
Moderate increase in ostomy output compared to baseline 
 
Limiting instrumental activities of daily living 
Grade 3 
 
Increase of ≥ 7 stools per day over baseline 
 
Hospitalization indicated 
 
Severe increase in ostomy output compared to baseline 
 
Limiting self care activities of daily living 
Grade 4 
 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
 
Death 
Source: 
Quoted from Common Terminology Criteria for Adverse Events v 5.0  
National Cancer Institute（https://ctep.cancer.gov/） 
 
1) 
Grade 1 or 2 diarrhea 
(1) Study drug may be continued. Diarrhea should be managed until resolution of symptom 
in reference to the following items. 
 
Discontinue all laxatives. 
 
Subjects should be instructed to drink 8 to 10 glasses of water or clear fluids per 
day. 
 
Subjects should be encouraged to make dietary changes including elimination of 
dairy products and eating smaller but more frequent meals. 
 
Consider stool sample for microbiologic evaluation and antibiotics if subject is 
neutropenic. 
 
Grade 1, consider initiating treatment with loperamide according to the regimen 
below. Grade 2, initiate treatment with loperamide according to the regimen below. 
a) 
Up to 2 mg loperamide initial dose. 
b) 
If loose stool persists, the dose of loperamide will be adjusted and 
administration will be continued. 
(2) Subjects with persistent diarrhea (> 48 hours) should be monitored carefully for 
dehydration and electrolyte imbalance. 
(3) Manage the recurrence of 1) in the same manner. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 98 - 
2) 
Grade 3 or 4 diarrhea 
(1) Study drug administration should be interrupted. Diarrhea should be managed until 
resolution of symptoms in reference to the following items. 
 
Initiate aggressive fluid replacement to treat potential dehydration. 
 
Consider stool sample for microbiologic evaluation and antibiotics if subject is 
neutropenic. 
 
Begin treatment with loperamide and continue treatment until the diarrhea has been 
resolved. 
a) 
Up to 2 mg loperamide initial dose. 
b) 
If loose stool persists, the dose of loperamide will be adjusted and 
administration will be continued. 
(2) When diarrhea improves to ≤ Grade 1, restart study drug at 1 lower dose level. 
 
3) 
Recurrence of Grade 3 or 4 diarrhea 
(1) Study drug administration should be interrupted. Diarrhea should be managed until 
resolution of symptoms in reference to the following items. 
 
Initiate aggressive fluid replacement to treat potential dehydration. 
 
Consider stool sample for microbiologic evaluation and antibiotics if subject is 
neutropenic. 
 
Begin treatment with loperamide and continue treatment until the diarrhea has been 
resolved. 
a) 
Up to 2 mg loperamide initial dose. 
b) 
If loose stool persists, the dose of loperamide will be adjusted and 
administration will be continued. 
(2) When diarrhea improves to ≤ Grade 1, restart study drug at 2 lower dose level from that 
at the onset of “2) Grade 3 or 4 diarrhea.” 
 
Dose Adjustment 
Dose reduction 
Dose before 
dose 
increase/ 
reduction 
Dose escalation 
Dose level 
−4 
Dose level 
−3 
Dose level 
−2 
Dose level 
−1 
Dose 
level 
+1 
Dose 
level 
+2 
Dose 
level 
+3 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
References: 
Yang JC, Reguart N, Barinoff J, et al. Diarrhea associated with afatinib: an oral ErbB family blocker. Expert review of 
anticancer therapy. 2013;13(6):729-36. 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 99 - 
Appendix 6 
Management of Increased Blood Pressure 
Increases in blood pressure have proven to be amenable to treatment, generally without a 
requirement for study drug interruption. Subjects with elevated blood pressure should receive 
prompt treatment. Blood pressure for all subjects should be kept systolic blood pressure 
< 140 mmHg and diastolic blood pressure < 90 mmHg; for subjects with increased 
cardiovascular risk, diabetes or renal insufficiency consideration should be given to maintaining 
systolic blood pressure < 130 mmHg and diastolic blood pressure < 80 mmHg. 
In previous overseas clinical studies evaluating R788, the following antihypertensive agents 
have been proven effective in managing blood pressure: 
 
Calcium channel blockers 
 
Angiotensin converting enzyme inhibitors 
 
Angiotensin receptor blockers 
 
β blockers 
If antihypertensive therapy does not control systolic blood pressure < 140 mmHg and diastolic 
blood pressure < 90 mmHg, the investigator adjust the dose of study drug or perform additional 
tests in accordance with the following instructions. 
 
1) 
Immediately interrupt the study drug when the subject meets either or both of the following 
criteria. 
 
The subject becomes symptomatic due to blood pressure elevation. 
 
The blood pressure cannot be brought under control despite best efforts at blood 
pressure management. 
 
2) 
If systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg at any 
time after the start of study treatment: 
(1) Study drug administration should be interrupted. 
(2) Initiate antihypertensive medication or increase the dose of the existing antihypertensive 
drug, if any. 
(3) Instruct the subject to visit the study institution within 1 week to measure blood pressure. 
(4) Increase the dose of the antihypertensive drug until systolic blood pressure is controlled 
at < 140 mmHg and diastolic blood pressure at < 90 mmHg. 
(5) Restart study drug at 1 lower dose level when systolic blood pressure < 140 mmHg and 
diastolic blood pressure < 90 mmHg. 
(6) If systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg again 
despite antihypertensive treatment, interrupt study drug. 
 


CONFIDENTIAL 
Protocol No.: R788-1301 
Version: 1.0 
 
- 100 - 
3) 
If systolic blood pressure ≥ 160 mmHg and < 180 mmHg or diastolic blood pressure 
≥ 100 mmHg and < 110 mmHg at any visit after the start of the study treatment: 
(1) Continue study drug at assigned dose level. 
(2) Initiate antihypertensive medication or increase the dose of the existing antihypertensive 
drug, if any. 
(3) Instruct the subject to visit the study institution within 2 weeks to measure blood 
pressure. If the result of measurement still shows systolic blood pressure ≥ 160 mmHg 
and < 180 mmHg or diastolic blood pressure ≥ 100 mmHg and ≥ 110 mmHg despite 
aggressive antihypertensive treatment, interrupt study drug. 
(4) Increase the dose of the antihypertensive drug until systolic blood pressure is controlled 
at < 140 mmHg and diastolic blood pressure at < 90 mmHg. 
(5) Restart study drug at 1 lower dose level when systolic blood pressure is controlled at 
< 140 mmHg and diastolic blood pressure at < 90 mmHg. 
 
4) 
If systolic blood pressure ≥ 140 mmHg but less than 160 mmHg or diastolic blood pressure 
≥ 90 mmHg but less than 100 mmHg at any visit after the start of study treatment: 
(1) Continue study drug at assigned dose level. 
(2) Instruct the subject to visit the study institution within 2 weeks to measure blood 
pressure. 
(3) If systolic blood pressure remains above ≥ 140 mmHg or diastolic blood pressure 
remains ≥ 90 mmHg after 2 weeks, initiate or increase antihypertensive therapy. 
(4) Instruct the subject to visit the study institution once every 2 weeks to measure blood 
concentration until systolic blood pressure is controlled at < 140 mmHg and diastolic 
blood pressure at < 90 mmHg. 
(5) If systolic blood pressure remains ≥ 140 mmHg or diastolic blood pressure remains 
≥ 90 mmHg for more than 8 weeks, despite appropriate antihypertensive therapy, reduce 
dose of study drug at 1 lower dose level. 
 
Dose Adjustment 
Dose reduction 
Dose before 
dose 
increase/ 
reduction 
Dose escalation 
Dose level 
−4 
Dose level 
−3 
Dose level 
−2 
Dose level 
−1 
Dose 
level 
+1 
Dose 
level 
+2 
Dose 
level 
+3 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
— 
— 
— 
— 
Interruptio
n 
100 mg 
qd 
150 mg 
qd 
100 mg 
bid 
150 mg 
bid 
References: 
Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance, and management of blood pressure in patients 
receiving vascular endothelial growth factor signaling pathway inhibitors. Journal of the National Cancer Institute. 
2010;102(9):596-604.

SAP_001.pdf: 
CONFIDENTIAL 
Kissei Pharmaceutical Co., Ltd. 
Statistical Analysis Plan 
Protocol No.: R788-1301 
Version: 3.0 
1 
Statistical Analysis Plan 
Study title: 
Phase 3 Clinical Study of R788 in Patients with 
Chronic Idiopathic Thrombocytopenic Purpura 
Protocol number: 
R788-1301 
Version: 
3.0 
Date of preparation/revision: 
June 24, 2022 
Sponsor: 
Kissei Pharmaceutical Co., Ltd. 
Request for confidentiality 
This confidential document is the property of the sponsor. The unpublished 
information contained in this document may not be disclosed without written consent 
of the sponsor. 
This is the translated version of the Statistical Analysis Plan written in Japanese. 
NCT number: 
NCT04132050


CONFIDENTIAL 
Kissei Pharmaceutical Co., Ltd. 
 
Statistical Analysis Plan 
Protocol No.: R788-1301 
 
Version: 3.0 
2 
Table of Contents 
1. Objectives ............................................................................................................... 3 
2. Analysis Sets .......................................................................................................... 3 
3. Analysis Group ....................................................................................................... 3 
4. General Principles of Statistical Analysis ................................................................ 5 
5. Data Handling ......................................................................................................... 6 
6. Statistical/Analytical Issues ................................................................................... 12 
7. Definition of Derived Data ..................................................................................... 13 
8. Disposition of Subjects ......................................................................................... 15 
9. Demographics and Other Baseline Characteristics .............................................. 16 
10. Treatment compliance ........................................................................................ 17 
11. Efficacy ............................................................................................................... 19 
12. Safety ................................................................................................................. 25 
13. Pharmacokinetics ............................................................................................... 30 
14. Software Used for Analysis ................................................................................. 32 
15. Tables, Figures and Listing Shells ...................................................................... 32 
16. Changes from the Protocol ................................................................................. 32 
17. Revision History of the Statistical Analysis Plan ................................................. 35 
18. References ......................................................................................................... 35 
 


CONFIDENTIAL 
Kissei Pharmaceutical Co., Ltd. 
 
Statistical Analysis Plan 
Protocol No.: R788-1301 
 
Version: 3.0 
3 
1. Objectives 
The purpose of this statistical analysis plan is to provide details of the analyses described in 
“14. Statistical Analysis” of the protocol (Version: 1.0). 
2. Analysis Sets 
When the full analysis set (FAS) is used for analysis, the analysis will be performed based on 
the treatment groups to which the subjects have been assigned. When the safety set (SS) or 
pharmacokinetic analysis set (PKS) is used for analysis, the analysis will be performed based 
on the actual treatment received by the subjects. 
1) 
FAS 
Subject population which excludes subjects who deviated GCP, who did not receive any 
study drug, who discontinued prior to Period I, who was ineligible to the major 
inclusion/exclusion criteria, and who could not obtain any of the primary endpoint data. 
2) 
SS 
Subject population which excludes subjects who deviated GCP, who did not receive any 
study drug, and who discontinued prior to Period I. 
3) 
PKS 
Set of subjects excluding subjects who have no plasma drug concentration data at all from 
subjects in the SS 
The correspondence between analysis variables and analysis sets is shown in Table 2-1. 
 
Table 2-1 
Analysis Variables and Analysis Sets 
Variables evaluated 
Variables analyzed 
Analysis set 
Demographics and other baseline 
characteristics 
Subject demographics 
SS 
Other 
SS 
Treatment compliance 
All variables 
SS 
Efficacy 
All variables 
FAS 
Safety 
All variables 
SS 
Pharmacokinetics 
All variables 
PKS 
3. Analysis Group 
Unless otherwise specified, the analysis will be performed on the following subjects and data. 
For FAS analysis, “treated subjects” will be handled as “randomized subjects.” 
1) 
Evaluation in Period I 
 R788 group: Period I data of subjects who received R788 in Period I 
 Placebo group: Period I data of subjects who received placebo in Period I 
2) 
Evaluation during long-term treatment of R788 
 R788 group: The analysis will be performed on the following subjects and data: 
 
Period I data of subjects who received R788 in Period I 
 
Period II data of subjects who received R788 in Period I, completed treatment with 
R788 in Period I and transitioned to Period II (subjects on long-term treatment of 
R788) 


CONFIDENTIAL 
Kissei Pharmaceutical Co., Ltd. 
 
Statistical Analysis Plan 
Protocol No.: R788-1301 
 
Version: 3.0 
4 
3) 
Evaluation in Period II 
 R788-R788 group: Period II data of subjects who received R788 in Period I and early 
transitioned to Period II after discontinuing Period I 
 P-R788 group: Period II data of subjects who received placebo in Period I and 
transitioned to Period II 
4) 
Evaluation in non-dosing period 
 R788 group: Non-dosing period data of subjects who transitioned to the non-dosing 
period (subjects who transitioned from Period II to Period III without non-dosing period 
are excluded). 
5) 
Evaluation in Period III 
 R788 group: Period III data of subjects who transitioned to Period III 
6) 
Evaluation in R788 treatment period 
 R788 group: The analysis will be performed on the following subjects and data: 
 
Data from Period I, Period II, and Period III of subjects who received R788 in 
Period I 
 
Data from Period II and Period III of subjects who received placebo in Period I and 
transitioned to Period II 
7) 
Evaluation in the entire study period 
 R788-R788 group: Data from Period I, Period II, non-dosing period, and Period III of 
subjects who received R788 in Period I 
 P-R788 group: Data from Period I, Period II, non-dosing period, and Period III of 
subjects who received placebo in Period I 
 


CONFIDENTIAL 
Kissei Pharmaceutical Co., Ltd. 
 
Statistical Analysis Plan 
Protocol No.: R788-1301 
 
Version: 3.0 
5 
Randomized 
group 
Period I 
Period II 
 
Randomized 
group 
Period I 
Period II 
 
Randomized 
group 
Period I 
Period II 
 R788 
R788 
Completed 
Period I 
Transitioned to 
Period II 
 
R788 
Completed 
Period I 
Transitioned to 
Period II 
 
R788 
Completed 
Period I 
Transitioned to 
Period II 
  
 
 
 
 
 
 Placebo 
Discontinued 
Period I 
Early 
transitioned 
 
Discontinued 
Period I 
Early 
transitioned 
 
Discontinued 
Period I 
Early 
transitioned 
  
 
 
 
 
 
 R788-R788 
Placebo 
Completed 
Period I 
 
Transitioned to 
Period II 
 
Placebo 
Completed 
Period I 
Transitioned to 
Period II 
 
Placebo 
Completed 
Period I 
Transitioned to 
Period II 
  
 
 
 
 
 
 P-R788 
Discontinued 
Period I 
Early 
transitioned 
 
Discontinued 
Period I 
Early 
transitioned 
 
Discontinued 
Period I 
Early 
transitioned 
  
 
 
 
 
 
  
Evaluation in Period I 
 
Evaluation during long-term treatment of 
R788 
 
Evaluation in Period II 
  
 
Randomized 
group 
Re-consent 
Non-dosing 
period 
Period III 
 Randomized 
group 
Re-consent 
Non-dosing 
period 
Period III 
R788 
Consented 
Transitioned to 
non-dosing 
period 
Transitioned to 
Period III 
 R788 
Consented 
Transitioned to 
non-dosing period 
Transitioned to 
Period III 
Skip 
 
Skip 
Placebo 
Consented 
Transitioned to 
non-dosing 
period 
Transitioned to 
Period III 
 Placebo 
Consented 
Transitioned to 
non-dosing period 
Transitioned to 
Period III 
Skip 
 
Skip 
Evaluation in non-dosing period 
 
Evaluation in Period III 
 
Randomized 
group 
Period I 
Period II 
Non-dosing 
period 
Period III 
R788 
Completed 
Period I 
Completed Period II Not required 
Transitioned to 
Period III 
Discontinued Period 
II 
 
 
Discontinued 
Period I 
Completed after 
early transition 
Not required 
Transitioned to 
Period III 
Discontinued after 
early transition 
 
 
 
Placebo 
Completed 
Period I 
Completed Period II Not required 
Transitioned to 
Period III 
Discontinued Period 
II 
 
 
Discontinued 
Period I 
Completed after 
early transition 
Not required 
Transitioned to 
Period III 
Discontinued after 
early transition 
 
 
 
Evaluation in R788 treatment period 
Figure 3-1 
Analyzed subjects and data for each evaluation 
4. General Principles of Statistical Analysis 
 Statistical tests will be performed using a two-sided significance level of 5%. 
 Summary statistics will include the number of subjects, mean, standard deviation, minimum, 
median, maximum, and quartiles. 
 Unless otherwise specified, data will be summarized for each analysis group, each period, 
and each analysis visit. 
 For confidence intervals (CIs) of proportions, Clopper-Pearson exact two-sided 95% CIs 
will be presented for each group, and Chan-Zhang exact two-sided 95% CIs will be presented 
for between-group differences. 


CONFIDENTIAL 
Kissei Pharmaceutical Co., Ltd. 
 
Statistical Analysis Plan 
Protocol No.: R788-1301 
 
Version: 3.0 
6 
5. Data Handling 
5.1 Number of Digits to be Reported for Calculated Values 
1) 
P values and statistics 
Values will be rounded down to the third decimal place. Exceptionally, P values less than 
0.001 will be reported as “P < 0.001” or “< 0.001.” 
2) 
Mean, standard deviation, geometric mean, adjusted mean, estimate of difference, and 
confidence interval 
Values will be rounded off to one digit after the last place of the significant digits of the 
data. 
3) 
Minimum, median, maximum, and quartiles 
Values will be presented by the significant digits of the data. 
4) 
Proportion, estimate and CI of incidence, and geometric coefficient of variation (CV) 
Values will be rounded off to the first decimal place. 
5.2 Reporting of Prior ITP Medications, Concomitant Medications, 
and Rescue Medications 
Prior ITP medications, concomitant medications, and rescue medications will be coded using 
the World Health Organization Drug Dictionary (WHO-DD) Global and reported with the 
following categories and Standardized Medication Names. 
 Prior ITP medication categories: Corticosteroids, Rituximab, Thrombopoietin Receptor 
Agonists, Intravenous Immunoglobulins, Immunosuppressants, and Other 
 Concomitant medication categories: ATC Level 3 Class Code 
 Rescue medication categories: Platelet Transfusion, Intravenous Immunoglobulins, 
Intravenous Methylprednisolone, Oral Dexamethasone, Oral Prednisolone, and Other. 
5.3 Reporting of Complications, Adverse Events, and Adverse Drug 
Reactions 
Primary System Organ Classes (SOCs) and Preferred Terms (PTs) will be reported according 
to Medical Dictionary for Regulatory Activities (MedDRA). 
For adverse events (AEs) of interest, event categories will be presented instead of primary SOCs. 
Subcategories will be set and reported for gastrointestinal complaints among AEs of interest. 
Category-based data summarization will also include subcategory-based summarization. 
AEs for which more than one action was taken with the study drug will be reported with the 
highest level of action taken (discontinuation > dose reduction > interruption). 
The definition of AEs of interest is shown in Table 5.3-1. 
 


CONFIDENTIAL 
Kissei Pharmaceutical Co., Ltd. 
 
Statistical Analysis Plan 
Protocol No.: R788-1301 
 
Version: 3.0 
7 
Table 5.3-1 
Adverse Events of Interest 
AEs of interest (category) 
Applicable PT (PT code) 
Bleeding events 
Conjunctival haemorrhage (10010719), Epistaxis (10015090), 
Haemorrhage subcutaneous (10018999), Menorrhagia (10027313), Mouth 
haemorrhage (10028024), Purpura (10037549), Contusion (10050584), 
Procedural haemorrhage (10071229) 
Gastrointestinal complaints 
AEs that fall under the following subcategories: 
 Nausea 
Nausea (10028813) 
 Vomiting 
Vomiting (10047700) 
 Non-infectious diarrhea SMQ 
Diarrhoea (10012735) 
 Abdominal pain 
Abdominal discomfort (10000059), Abdominal pain (10000081), 
Abdominal pain upper (10000087) 
Infection 
Cellulitis (10007882), Cystitis (10011781), Diarrhoea infectious 
(10012742), Diverticulitis (10013538), Gastroenteritis (10017888), 
Gingivitis (10018292), Herpes zoster (10019974), Nasopharyngitis 
(10028810), Otitis media (10033078), Paronychia (10034016), 
Periodontitis (10034539), Pulpitis dental (10037464), Urinary tract 
infection (10046571), Viral infection (10047461), Tinea infection 
(10060889), COVID-19 (10084268) 
Hypertension SMQ 
Blood pressure increased (10005750), Hypertension (10020772) 
Neutropenia 
Neutropenia (10029354), Neutrophil count decreased (10029366) 
Drug related hepatic disorders 
SMQ 
Alanine aminotransferase increased (10001551), Aspartate 
aminotransferase increased (10003481), Autoimmune hepatitis (10003827), 
Blood bilirubin increased (10005364), Hepatic cyst (10019646), Hepatic 
function abnormal (10019670), Hepatic steatosis (10019708), Liver 
function test abnormal (10024690), Hepatic enzyme increased (10060795), 
Liver function test increased (10077692) 
Thrombosis, embolism, and 
thromboembolism 
Not applicable 
5.4 Handling of Drug Concentration Data 
Measurements below the limit of quantification (LOQ) for the plasma R406 concentration will 
be handled as 0 (LOQ: 2.5 ng/mL). Plasma R406 concentration data collected during 
interruption of R788 will be excluded from the analysis. When calculating the geometric mean 
and geometric CV, if the measured value before logarithmic transformation is 0, it will be 
handled as missing. 
5.5 Handling of Laboratory and Immunoglobulin Test Data 
Values below the LOQ in laboratory and immunoglobulin tests will be handled as the LOQ. 
5.5.1 Handling of platelet count data 
Any platelet count data obtained within 4 weeks (28 days) after the use of a rescue medication 
will be handled as missing in the efficacy evaluation. 
In the analysis of the primary endpoint, missing data will be imputed except for data from 
subjects who discontinued due to an AE or lack of efficacy or those who used a rescue 
medication between Week 10 and Week 24. For details, see “11.1.1 Analysis methods for the 
primary endpoint.” 
5.6 Handling of Quality of Life Assessment (SF-36) Data 
The following scores calculated based on the Japanese Version of MOS 36-Item Short-Form 


CONFIDENTIAL 
Kissei Pharmaceutical Co., Ltd. 
 
Statistical Analysis Plan 
Protocol No.: R788-1301 
 
Version: 3.0 
8 
Health Survey Version 2 (SF-36v2) Scoring Program1) will be included in the evaluation. 
 Norm-based scoring (NBS) 
 Bodily pain 
 General health 
 Mental health 
 Physical functioning 
 Role emotional 
 Role physical 
 Social functioning 
 Vitality 
 Three component summary scores 
 Mental component summary 
 Physical component summary 
 Role/social component summary 
5.7 Handling of ITP Bleeding Score 
The following variables calculated from 9 anatomical sites (Skin [PE], Oral [PE], Epistasis, 
Gastrointestinal, Urinary, Gynecological, Pulmonary, Intracranial haemorrhage, and 
Subconjunctival haemorrhage) will be included in the evaluation: 
 Average score 
Defined as the mean of 9 sites at each time point. Handled as missing if there is a missing 
score for any of the sites. 
 Total score 
Defined as the sum of 9 sites at each time point. Handled as missing if there is a missing 
score for any of the sites. 
 Maximum score 
Defined as the maximum of 9 sites at each time point. Handled as missing if there is a 
missing score for any of the sites. 
 Post-dose mean of average scores 
Defined as the mean of average scores after study drug administration in each period. 
5.8 Handling of Blood Pressure Data 
At analysis visits where blood pressure is measured multiple times, the mean blood pressure 
value will be used for evaluation. 
5.9 Analysis Visits 
Unless otherwise specified, each analysis variable will be evaluated at the following time points. 
 Data obtained outside the time window of analysis visits and data from unscheduled visits 


CONFIDENTIAL 
Kissei Pharmaceutical Co., Ltd. 
 
Statistical Analysis Plan 
Protocol No.: R788-1301 
 
Version: 3.0 
9 
will be excluded from summarization at each time point. 
 For analyses of each treatment period, test data obtained outside the range of “the day of the 
last dose plus the specified number of days” will be excluded from the analysis. The specified 
number of days is 3 days for Period I and 7 days for Periods II and III. 
 The last observed visit (LOV) other than the non-dosing period is defined as the last 
scheduled visit or the discontinuation visit, whichever is later, performed within the range of 
“the day of the last dose plus the specified number of days” for each period. The specified 
number of days is 3 days for Period I and 7 days for Periods II and III. 
 The LOV in the non-dosing period is defined as the data for the latest test among all tests 
performed up to the last day of the non-dosing period. 
 For all variables, Day 1 of Period I will be used as a baseline and only changes at time points 
after Day 1 of each period will be evaluated. 
 In the non-dosing period, change from the start of the non-dosing period will be evaluated 
in addition to the change from Period I Day 1. Time points after Day 1 of the non-dosing 
period will be evaluated. 
 
1) 
Evaluation in Period I 
 
Table 5.9-1 
Analysis Visits in Period I 
Variables evaluated 
Analysis visit 
Platelets 
Screening A, B, Day 1, Week 2 to 24 (every 2 weeks) 
Treatment dose 
Day 1, Week 2 to 24 (every 2 weeks) 
QOL assessment (SF-36) 
Day 1, Week 4, 12, 24 
ITP Bleeding Score 
Screening A, Day 1, Week 2 to 24 (every 2 weeks), LOV 
ECOG Performance Status 
Screening A, Day 1, Week 4 to 24 (every 4 weeks), LOV 
Hematology (excluding platelets) 
Screening A, B, Day 1, Week 2 to 24 (every 2 weeks), LOV 
Serum chemistry 
Screening A, Day 1, Week 2 to 24 (every 2 weeks), LOV 
Urinalysis 
Screening A, Day 1, Week 4 to 24 (every 4 weeks), LOV 
Immunoglobulin test 
Screening A, Day 1, Week 24, LOV 
Vital signs 
Screening A, B, Day 1, Week 2 to 24 (every 2 weeks), LOV 
Plasma drug concentration 
Pre-study drug administration: Week 2, 6; Post-study drug 
administration: Week 2 to 24 (every 2 weeks) 
 
Table 5.9-2 
Time Windows for Each Analysis Visit in Period I 
Analysis visit 
Target study daya) 
Lower limit 
Upper limit 
Screening A 
−28 
−31 
−25 
Screening B 
−14 
−17 
−11 
Day 1 
1 
1 
1 
Week 2 to 24 
7 × x + 1b) 
Target study day −3 
Target study day +3 
a) The first day of study drug administration in Period I is defined as Day 1, and the day before the first day of study drug 
administration as Day −1. 
b) x: Number of weeks 
 
2) 
Evaluation during long-term treatment of R788 
 


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Table 5.9-3 
Analysis visits during long-term treatment of R788 
Variables evaluated 
Analysis visit 
Platelets 
Screening A, B, Day 1, Week 2 to 24 (every 2 weeks), Week 28 to 52 (every 
4 weeks) 
Treatment dose 
Day 1, Week 2 to 24 (every 2 weeks), Week 28 to 52 (every 4 weeks) 
QOL assessment (SF-36) 
Day 1, Week 4, 12, 24, 52 
ITP Bleeding Score 
Screening A, Day 1, Week 2 to 24 (every 2 weeks), Week 28 to 52 (every 4 
weeks), LOV 
ECOG Performance Status 
Screening A, Day 1, Week 4 to 52 (every 4 weeks), LOV 
Hematology (excluding platelets) 
Screening A, B, Day 1, Week 2 to 24 (every 2 weeks), Week 28 to 52 (every 
4 weeks), LOV 
Serum chemistry 
Screening A, Day 1, Week 2 to 24 (every 2 weeks), Week 28 to 52 (every 4 
weeks), LOV 
Urinalysis 
Screening A, Day 1, Week 4 to 24 (every 4 weeks), Week 28 to 52 (every 12 
weeks), LOV 
Immunoglobulin test 
Screening A, Day 1, Week 24, Week 52, LOV 
Vital signs 
Screening A, B, Day 1, Week 2 to 24 (every 2 weeks), Week 28 to 52 (every 
4 weeks), LOV 
 
Table 5.9-4 
Time Windows for Each Analysis Visit during Long-term 
Treatment of R788 
Analysis visit 
Target study daya) 
Lower limit 
Upper limit 
Screening A 
−28 
−31 
−25 
Screening B 
−14 
−17 
−11 
Day 1 
1 
1 
1 
Week 2 to 24 
7 × x + 1b) 
Target study day −3 
Target study day +3 
Week 28 to 52 
7 × x + 1b) 
Target study day −7 
Target study day +7 
a) The first day of study drug administration in Period I is defined as Day 1, and the day before the first day of study drug 
administration as Day −1. 
b) x: Number of weeks 
 
3) 
Evaluation in Period II 
The following data will be used as Week 24 to 52 data: 
 Data from Week 24 to 52 of subjects who received placebo in Period I, completed Period I, 
and transitioned to Period II. 
 Data from early transition Day 1 to early transition Week 28 of subjects who discontinued 
Period I and early transitioned to Period II. 
 
Table 5.9-5 
Analysis Visits in Period II 
Variables evaluated 
Analysis visit 
Platelets 
Week 24 to 52 (every 4 weeks) 
Treatment dose 
Week 24 to 52 (every 4 weeks) 
QOL assessment (SF-36) 
Week 24, Week 52 
ITP Bleeding Score 
Week 24 to 52 (every 4 weeks), LOV 
ECOG Performance Status 
Week 24 to 52 (every 4 weeks), LOV 
Hematology (excluding platelets) 
Week 24 to 52 (every 4 weeks), LOV 
Serum chemistry 
Week 24 to 52 (every 4 weeks), LOV 
Urinalysis 
Week 24, Week 28 to 52 (every 12 weeks), LOV 
Immunoglobulin test 
Week 24, Week 52, LOV 
Vital signs 
Week 24 to 52 (every 4 weeks), LOV 
 


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Table 5.9-6 
Time Windows for Each Analysis Visit in Period II (for those who 
completed Period I) 
Analysis visit 
Target study daya) 
Lower limit 
Upper limit 
Week 24 to 52 (every 4 weeks) 
7 × x + 1b) 
Target study day −7 
Target study day +7 
a) The first day of study drug administration in Period I is defined as Day 1, and the day before the first day of study drug 
administration as Day −1. 
b) x: Number of weeks 
 
Table 5.9-7 
Time Windows for Each Analysis Visit in Period II (for those who 
early transitioned) 
Analysis visit 
Target study daya) 
Lower limit 
Upper limit 
Week 24 
1 
−1 
1 
Week 28 to 52 (every 4 weeks) 
7 × (x−24) + 1b) 
Target study day −7 
Target study day +7 
a) The first day of study drug administration in Period II is defined as Day 1 and the day before the first day of study drug 
administration as Day −1. 
b) x: Number of weeks 
 
4) 
Evaluation in non-dosing period 
Day 1 of the non-dosing period is defined as Week 52 of Period II for subjects who completed 
Period I, and as early transition Week 28 for subjects who early transitioned to Period II. Day 1 
of Period III is defined as Week 4 of the non-dosing period. 
 
Table 5.9-8 
Analysis Visits in Non-Dosing Period 
Variables evaluated 
Analysis visit 
Platelets 
Day 1, Week 2, Week 4, LOV 
ITP Bleeding Score 
Day 1, Week 2, Week 4, LOV 
QOL assessment (SF-36) 
Day 1, Week 2, Week 4, LOV 
ITP Bleeding Score 
Day 1, Week 2, Week 4, LOV 
ECOG Performance Status 
Day 1, Week 2, Week 4, LOV 
Hematology (excluding 
platelets) 
Day 1, Week 2, Week 4, LOV 
Serum chemistry 
Day 1, Week 2, Week 4, LOV 
Urinalysis 
Day 1, Week 2, Week 4, LOV 
Immunoglobulin test 
Day 1, Week 2, Week 4, LOV 
Vital signs 
Day 1, Week 2, Week 4, LOV 
 
Table 5.9-9 
Time Windows for Each Analysis Visit in Non-Dosing Period 
Analysis visit 
Target study daya) 
Lower limit 
Upper limit 
Day 1 
1 
1 
1 
Week 2, Week 4 
7 × x + 1b) 
Target study day −3 
Target study day +3 
a) Day 1 is defined as the day of Week 52 visit for subjects who completed Period I and the day of Week 28 visit for those who 
early transitioned to Period II. 
b) x: Number of weeks 
 
5) 
Evaluation in Period III 
Day 1 is the first visit in Period III. 
 


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Table 5.9-10 
Analysis Visits in Period III 
Variables evaluated 
Analysis visit 
Platelets 
Day 1, Week 8 (every 8 weeks thereafter) 
Treatment dose 
Week 8 (every 8 weeks thereafter) 
ITP Bleeding Score 
Day 1, Week 8 (every 8 weeks thereafter) 
ECOG Performance Status 
Day 1, Week 8 (every 8 weeks thereafter) 
Hematology (excluding 
platelets) 
Day 1, Week 8 (every 8 weeks thereafter) 
Serum chemistry 
Day 1, Week 8 (every 8 weeks thereafter) 
Urinalysis 
Day 1, Week 8 (every 8 weeks thereafter) 
Vital signs 
Day 1, Week 8 (every 8 weeks thereafter) 
 
Table 5.9-11 
Time Windows for Each Analysis Visit in Period III 
Analysis visit 
Target study daya) 
Lower limit 
Upper limit 
Day 1 
1 
1 
1 
Week 8 (every 8 weeks thereafter) 
7 × x + 1b) 
Target study day −14 
Target study day +14 
a) The first visit in Period III is defined as Day 1, and the day before the first visit as Day −1. 
b) x: Number of weeks 
 
6) 
Evaluation in R788 treatment period 
Day 1 of the R788 treatment period is defined as the first day of study drug administration in 
Period I for subjects who received R788 in Period I, and as the first day of study drug 
administration in Period II for those who received placebo in Period I and transitioned to Period 
II. No analysis visit-specific analysis will be performed for evaluation in the R788 treatment 
period. 
7) 
Evaluation in the entire study period 
Day 1 is defined as the first day of study drug administration in Period I. No analysis visit-
specific analysis will be performed for evaluation in the entire study period. 
6. Statistical/Analytical Issues 
6.1 Adjustments for Covariates 
Analyses adjusted for covariates will not be performed. 
6.2 Handling of Dropouts and Missing Data 
When data to be used for analysis are missing, they will be handled as missing, and no statistical 
imputation will be performed, excluding the variables listed in “5 Data Handling” and below. 
Last observation carried forward (LOCF) imputation will be applied to the primary endpoint. 
For details, see “11.1 Primary Endpoint.” 
6.3 Interim Analyses and Data Monitoring 
6.3.1 Timing of analysis 
1) 
First data cutoff 
After all subjects have completed Period I, the following data collected by the first data cut-off 
date will be analyzed for Period I, long-term treatment of R788, R788 treatment period, and the 


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entire study period. 
 Period I data of all subjects 
 Period II data of subjects who completed Period II 
 Follow-up data of subjects who completed the follow-up period 
2) 
Second data cutoff 
After all subjects have completed the non-dosing period, all data collected by the second data 
cut-off date will be analyzed for Period I, long-term treatment of R788, Period II, non-dosing 
period, Period III, R788 treatment period, and the entire study period. 
6.4 Multicenter Studies 
No site-specific analysis will be performed because the per site sample size is not large enough. 
6.5 Multiple Comparison/Multiplicity 
6.5.1 Multiplicity for multiple analyses and multiple analysis visits 
The primary endpoint is defined as stable platelet response based on platelet counts from Week 
14 to Week 24 in Period I, and other variables, and time points will be used for reference only. 
Therefore, multiplicity adjustment for multiple analysis visits will not be performed. 
6.5.2 Multiplicity among multiple evaluations 
Stable platelet response is set as the primary endpoint and other variables will be used for 
reference only. Therefore, multiplicity adjustment among multiple variables will not be 
performed. 
6.5.3 Multiplicity for multiple analysis sets 
Not applicable because only the FAS, SS, and PKS will be used for the analysis of efficacy, 
safety, and pharmacokinetics, respectively. 
6.6 Use of an “Efficacy Subset” of Subjects 
Not applicable because only the FAS will be used for efficacy analysis. 
6.7 Active-Control Studies Intended to Show Non-inferiority 
Not applicable. 
6.8 Subgroup Analyses 
Efficacy will be analyzed for each line of therapy and by stable platelet response. For details, 
see “11.3 Subgroup Analysis of Efficacy.” No subgroup analysis of safety will be performed. 
7. Definition of Derived Data 
Each variable will be calculated based on the following definitions. 
 The following drugs are considered as prior ITP medications: 


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 Drugs collected as prior ITP medications 
 Drugs collected as permitted concomitant ITP medications that were used prior to study 
drug administration 
 Number of unique prior ITP medications (categories) 
Defined as the number of categories of prior ITP medications used. For example, if 3 
corticosteroids and rituximab are used, the number of prior ITP medications (categories) will 
be 2. 
 Number of unique prior ITP medications (drugs) 
Defined as the number of prior ITP medications used. For example, if eltrombopag olamine 
and romiplostim are used, the number of prior ITP medications will be 2. 
 Line of therapy 
Prior ITP medications will be classified into the following line of therapy categories. The 
line of therapy will be the number obtained by adding 1 to the number of categories 
(excluding “Other”). For category “Other,” the number of generic names of the relevant 
medications will be added to the line number. If splenectomy was performed, add 1 to the 
line number. However, if prior ITP medications only include steroid (“Corticosteroids” or 
“Danazol”) and/or “Intravenous Immunoglobulins” and splenectomy has not been 
performed, the line of therapy will be 2 instead of 3. 
 Line of therapy categories: Thrombopoietin Receptor Agonists, Corticosteroids, 
Intravenous 
Immunoglobulins, 
Rituximab, 
Immunosuppressant, 
Danazol, 
Chemotherapy, Other. 
 Duration of exposure 
 Period I: Day of last administration in Period I − Day of first administration in Period I 
+ 1 
 Long-term treatment of R788 
 
For subjects who discontinued Period I: Day of last administration in Period I − 
Day of first administration in Period I + 1 
 
For subjects who completed Period I and transitioned to Period II: Day of last 
administration in Period II − Day of first administration in Period I + 1 
 Period II: Day of last administration in Period II − Day of first administration in Period 
II + 1 
 Non-dosing period: End day of the non-dosing period − Start day of the non-dosing 
period + 1 
 Period III: Day of last administration in Period III − Day of first administration in Period 
III + 1 
 R788 treatment period: Day of last administration of R788 − Day of first administration 
of R788 + 1 − (End day of the non-dosing period − Start day of the non-dosing period) 
 Elapsed time after administration = Time of blood sampling − Time of study drug 
administration 
 Treatment compliance = Total number of administered tablets / Number of prescribed tablets 
× 100 


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 Number of prescribed tablets 
Defined as the sum of the products of the number of tablets prescribed per day and the 
duration of treatment. However, if dose interruption due to an AE or any other reasons occurs 
during a period other than the non-dosing period, the dose prescribed immediately before 
the dose interruption will be applied. 
 Treatment dose at each analysis visit 
Defined as the dose at the time of measurement of platelet count. For Day 1 of Period I, 
Week 24 of Period II, and Day 1 of Period III, the initial doses for each period will be used. 
If the study drug is interrupted on the relevant day, the dose will be categorized as 
interruption. Analysis visits after treatment discontinuation will be excluded from the 
analysis. 
 Average daily dose 
Defined as the weighted average of treatment dose, with the duration of exposure at each 
dose as the weighting factor. Dose interruption will be handled as 0 mg dose. 
 Duration of platelet response = End day of response − Start day of response + 1 
The start day of response is defined as the first day after the start of study treatment in each 
period on which a platelet count of ≥ 50000/μL for at least 28 consecutive days without the 
use of rescue medications was achieved. The end day of response is defined as the day of 
use of a rescue medication or the first day of the period in which the platelet count fell below 
50000/μL for at least 28 consecutive days, whichever is earlier. For subjects who discontinue 
or complete each period with the platelet count maintained at ≥ 50000/μL, the last 
measurement day in each period is defined as the end day of response. The calculation of the 
duration of platelet response includes analysis visits outside the acceptable time window and 
unscheduled visits. 
 Sustained stable platelet response 
Subjects who achieve a platelet count of ≥ 50000/μL within 12 weeks after the start of study 
treatment and maintain it for the subsequent 12 weeks will be considered as responders. 
Maintenance of the platelet count for the subsequent 12 weeks is defined as platelet response 
for at least 12 weeks (85 days). All subjects not assessed as responders due to discontinuation 
or missing data will be considered as non-responders. 
8. Disposition of Subjects 
8.1 Analysis Sets 
Applicable period: Period I 
For all randomized subjects, the number and percentage of subjects included in or excluded 
from the analysis sets listed in Table 8.1-1 will be presented. Differences between groups will 
be analyzed using Fisher’s exact test. 
 
Table 8.1-1 
Category 
Analysis set 
Category 
FAS 
Included, Excluded 
SS 
Included, Excluded 
PKS 
Included, Excluded 


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8.2 Discontinuation and Reasons for Discontinuation 
Applicable period: Period I, long-term treatment of R788, Period II, Period III, and R788 
treatment period 
The number and percentage of subjects who discontinued the study will be presented. In Period 
I, differences between groups will be analyzed using Fisher’s exact test. Subjects who are 
ongoing in the applicable period at the time of data cut-off will be categorized as “Ongoing.” 
Reasons for discontinuation will be classified into the following categories, and the number and 
percentage of subjects will be presented. 
Evaluation during long-term treatment of R788 includes whether there were discontinuations 
after transition to Period II and their reasons. For evaluation in Period II, the number of subjects 
who completed Period I or early transitioned to Period II will also be presented. 
 Adverse events: Withdrawal due to Withdrawal Criteria (withdrawal in individual subjects) 
1) “Adverse Events” 
 Lack of efficacy: Withdrawal due to Withdrawal Criteria (withdrawal in individual subjects) 
2) “Lack of Efficacy (inadequate response)” 
 Withdrawal by subject: Withdrawal due to Withdrawal Criteria (withdrawal in individual 
subjects) 3) “Subject’s voluntary request for withdrawal from the study” 
 Significant deviation: Withdrawal due to Withdrawal Criteria (withdrawal in individual 
subjects) 4) “Significant deviation from the protocol during the study period” 
 Other: When the reason for discontinuation does not correspond to “adverse event,” “lack of 
efficacy,” “withdrawal by subject” or “significant deviation” in this category. 
9. Demographics and Other Baseline Characteristics 
9.1 Subject Demographics 
Applicable period: Period I, R788 treatment period 
The variables to be analyzed are listed below. The pooled analysis of R788 and placebo groups 
will be performed only for Period I. For both Period I and the R788 treatment period, data from 
Day 1 of Period I will be used for analysis. 
 Nominal scale variables 
 Sex: Male, female 
 Splenectomy: Yes, no 
 Prior ITP medications: Corticosteroids, rituximab, thrombopoietin receptor agonists, 
intravenous immunoglobulins, immunosuppressants, other 
 Ordinal scale variables 
 Age: < 65 years, ≥ 65 years 
 Time since ITP diagnosis: < 3 years, ≥ 3 years 
 Time since splenectomy: < 6 months, ≥ 6 months 


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 Number of unique prior ITP medications (categories): 1, 2, 3, ≥ 4 
 Number of unique prior ITP medications (drugs): 1, 2, 3, 4, 5, ≥ 6 
 Line of therapy: 2, ≥ 3 
 Platelet count: < 15000, 15000 ≤ < 30000, 30000 ≤ < 35000, ≥ 35000/μL 
 Continuous variables: Age, height, weight, body mass index (BMI), time since ITP diagnosis 
(years), time since splenectomy (months), number of unique prior ITP medications 
(categories), number of unique prior ITP medications (drugs), line of therapy, platelet count 
The numbers and percentages of subjects will be presented for nominal and ordinal scale 
variables, and summary statistics for continuous variables. 
Subjects who have not undergone splenectomy will be excluded from the evaluation of time 
since splenectomy. 
9.2 Complications and Medical History 
Applicable period: Period I 
The numbers and percentages of subjects will be presented for the entire population and by 
primary SOC and PT. 
9.3 Prior ITP medications 
Applicable period: Period I 
For medications used for the treatment of ITP before study drug administration, the numbers 
and percentages of subjects who used such drugs will be presented. 
9.4 Concomitant Medications Used for Complications 
Applicable period: Period I, long-term treatment of R788, Period II, and non-dosing period 
For medications used to treat complications after study drug administration, the numbers and 
percentages of subjects who used such drugs will be presented. 
10. Treatment compliance 
10.1 Duration of Exposure 
Applicable period: Period I, long-term treatment of R788, Period II, non-dosing period, Period 
III, and R788 treatment period 
Summary statistics will be presented. For the non-dosing period, the duration of dose 
interruption will be presented. 
10.2 Distribution of Duration of Exposure 
Applicable period: Period I, long-term treatment of R788, Period II, non-dosing period, Period 
III, and R788 treatment period 
The variables to be analyzed are as follows: 
 Duration of treatment (Period I): <4, 4≤ <8, 8≤ <12, ≥12 weeks 
 Duration of treatment (long-term treatment of R788): <4, 4≤ <8, 8≤ <12, 12≤ <24, ≥24 weeks 


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 Duration of treatment (Period II): <4, 4≤ <8, 8≤ <12, 12≤ <24, ≥24 weeks 
 Duration of dose interruption (non-dosing period): <4, ≥4 weeks 
 Duration of treatment (Period III): <24, 24≤ <48, 48≤ <72, ≥72 weeks 
 Duration of treatment (R788 treatment period): <4, 4≤ <8, 8≤ <12, 12≤ <24, 24≤ <52, ≥52 
weeks 
The numbers and percentages of subjects will be presented. The duration of dose interruption 
will be presented for the non-dosing period. 
10.3 Treatment Compliance 
Applicable period: Period I, long-term treatment of R788, Period II, Period III 
Summary statistics will be presented. The evaluation in Period III will be conducted at study 
completion only. 
10.4 Daily Dose 
Applicable period: Period I, long-term treatment of R788, Period II, Period III 
 Dose: 100, 150, 200, and 300 mg/day, withdrawal 
The numbers and percentages of subjects treated with each dose level will be presented. 
10.5 Average Daily Dose 
Applicable period: Period I, long-term treatment of R788, Period II, Period III, and R788 
treatment period 
Summary statistics will be presented. 
10.6 ITP Concomitant Medications 
Applicable period: Period I, long-term treatment of R788, Period II, non-dosing period, Period 
III, and R788 treatment period 
For medications used to treat ITP after study drug administration (excluding rescue 
medications), the numbers and percentages of subjects who used such drugs will be presented. 
10.7 Rescue Medications 
Evaluation will be made for all rescue medications and for each indication (increased platelet, 
other). 
10.7.1 Use of rescue medications 
Applicable period: Period I, long-term treatment of R788, Period II, non-dosing period, Period 
III, and R788 treatment period 
For rescue medications used after study drug administration, the numbers and percentages of 
subjects who used such medications will be presented. 
10.7.2 Frequency of rescue medication use 
Applicable period: Period I, long-term treatment of R788, Period II 


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The number and percentage of subjects by the frequency of rescue medication use will be 
presented. The type of rescue medications will not be considered. 
10.7.3 Use of rescue medications (in each period) 
Applicable period: Period I, long-term treatment of R788, Period II 
The numbers and percentages of subjects who used rescue medications after study drug 
administration will be presented every 2 weeks for Period I and every 4 weeks for Period II. 
Subjects who used rescue medications across two or more periods will be considered to have 
used those medications throughout all applicable periods. 
11. Efficacy 
11.1 Primary Endpoint 
Applicable period: Period I 
The primary efficacy endpoint in this study is the achievement rate of stable platelet response. 
The analysis of the primary endpoint will be based on data from Period I. 
Stable platelet response: Subjects who achieve a platelet count of ≥ 50000/μL at 4 or more of 
the 6 visits from Weeks 14 to 24 will be considered as responders, and the percentage of 
responders will be evaluated. 
Whether a subject has achieved stable platelet response will be evaluated according to the 
following rules: 
 Subjects who discontinued due to an AE or lack of efficacy and those who used rescue 
medications between Week 10 and Week 24 will be considered as non-responders. 
 Missing data in subjects other than those listed above will be imputed by LOCF until 
Week 24, and whether stable platelet response has been achieved will be determined 
based on the imputed data. 
11.1.1 Analysis methods for the primary endpoint 
The number and percentage of subjects achieving stable platelet response and their two-sided 
95% CIs will be presented. The difference in the achievement rate between groups and its two-
sided 95% CI will be calculated. The superiority of the R788 group to the placebo group will 
be evaluated using Fisher’s exact test. 
11.2 Secondary Endpoints 
11.2.1 Evaluation in Period I 
Applicable period: Period I 
11.2.1.1 Achievement rates for platelet count-related endpoints 
The variables to be analyzed are as follows: 
 Achievement rate of a platelet count of ≥ 50000/μL at Weeks 12 and 24 
 Achievement rate of a platelet count of ≥ 30000/μL and change from the baseline in platelet 
count of ≥ 20000/μL at Weeks 12 and 24 (for subjects with a baseline platelet count of < 
15000/μL) 


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 Achievement rate of overall response (subjects who achieve a platelet count of ≥ 50000/μL 
at 1 or more of the 6 visits from Weeks 2 to 12 will be considered as responders, and the 
percentage of responders will be evaluated) 
The number and percentage of responders and their two-sided 95% CIs will be presented. The 
difference in the achievement rate between groups and its two-sided 95% CI will be presented. 
All subjects who are not assessed as responders due to discontinuation or missing data will be 
considered as non-responders. 
11.2.1.2 Number of scheduled visits with platelet ≥ 50000/μL 
The variables to be analyzed are as follows: 
 Number of visits with a platelet count of ≥ 50000/μL among 6 visits from Week 2 to Week 12 
 Number of visits with a platelet count of ≥ 50000/μL among 12 visits from Week 2 to Week 
24 
The numbers and percentages of subjects will be presented. 
11.2.1.3 Duration of platelet response 
Summary statistics will be presented. 
11.2.1.4 Summary statistics of platelet count 
The variables to be analyzed are as follows: 
 Platelet count 
 Change from baseline in platelet count 
Summary statistics will be presented. Additionally, medians and quartiles will be presented 
graphically. 
11.2.1.5 Distribution of platelet count 
The variables to be analyzed are as follows: 
 Platelet count: < 15000, 15000 ≤ < 30000, 30000 ≤ < 50000, ≥ 50000/μL 
 Change from baseline in platelet count: < 20000, ≥ 20000/μL 
The numbers and percentages of subjects will be presented. 
11.2.1.6 Individual plots of platelet count 
Individual plots and a swimmer plot will be presented for the change in platelet count in each 
subject. The swimmer plot will show the duration of exposure, as well as the number of days 
until the following events: 
 Maintenance start: The start day of platelet response 
 Maintenance end: The end day of platelet response 
 Continued response: The end day of the evaluation period when the platelet response is 
ongoing at the end of the evaluation period. 


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11.2.1.7 Summary statistics of quality of life assessment (SF-36) 
Summary statistics will be presented. 
11.2.2 Evaluation during long-term treatment of R788 
Applicable period: Long-term treatment of R788 
11.2.2.1 Achievement rates for platelet count-related endpoints 
The variables to be analyzed are as follows: 
 Achievement rate of a platelet count of ≥ 50000/μL at Weeks 12, 24, 36, 48, and 52 
 Achievement rate of a platelet count of ≥ 30000/μL and change from the baseline in platelet 
count of ≥ 20000/μL at Weeks 12, 24, 36, 48, and 52 (for subjects with a baseline platelet 
count of < 15000/μL) 
Achievement rates and their two-sided 95% CIs will be presented. All subjects who are not 
assessed as responders due to discontinuation or missing data will be considered as 
non-responders. 
11.2.2.2 Duration of platelet response 
Summary statistics will be presented. 
11.2.2.3 Summary statistics of platelet count 
The variables to be analyzed are as follows: 
 Platelet count 
 Change from baseline in platelet count 
Summary statistics will be presented. Additionally, medians and quartiles will be presented 
graphically. 
11.2.2.4 Distribution of platelet count 
The variables to be analyzed are as follows: 
 Platelet count: < 15000, 15000 ≤ < 30000, 30000 ≤ < 50000, ≥ 50000/μL 
 Change from baseline in platelet count: < 20000, ≥ 20000/μL 
The numbers and percentages of subjects will be presented. 
11.2.2.5 Individual plots of platelet count 
Individual plots and a swimmer plot will be presented for the change in platelet count in each 
subject. The dates to be displayed in the figures are as described in “11.2.1.6 Individual plots 
of platelet count.” 
11.2.2.6 Summary statistics of quality of life assessment (SF-36) 
Summary statistics will be presented. 


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11.2.3 Evaluation in Period II 
Applicable period: Period II 
11.2.3.1 Achievement rate of platelet response in Periods I and II (sustained 
stable platelet response) 
This analysis includes data from Periods I and II of subjects who received placebo in Period I 
and transitioned to Period II. 
The achievement rate of sustained stable platelet response in each period and their two-sided 
95% CIs will be presented. The difference in the achievement rate between Periods I and II and 
its two-sided 95% CI will be presented. A CI (normal approximation) based on the standard 
error of the difference in the rate will be calculated. McNemar test will be used to analyze the 
difference in the achievement rate between Periods I and II. 
11.2.3.2 Achievement rates for platelet count-related endpoints 
The variables to be analyzed are as follows: 
 Achievement rate of a platelet count of ≥ 50000/μL at Weeks 36, 48, and 52 
 Achievement rate of a platelet count of ≥ 30000/μL and change from the baseline in platelet 
count of ≥ 20000/μL at Weeks 36, 48, and 52 (for subjects with a baseline platelet count of 
< 15000/μL) 
Achievement rates and their two-sided 95% CIs will be presented. The difference in the 
achievement rate between groups and its two-sided 95% CI will be presented. All subjects not 
assessed as responders due to discontinuation or missing data will be considered as 
non-responders. 
11.2.3.3 Duration of platelet response 
Summary statistics will be presented. 
11.2.3.4 Summary statistics of platelet count 
The variables to be analyzed are as follows: 
 Platelet count 
 Change from baseline in platelet count 
Summary statistics will be presented. Additionally, medians and quartiles will be presented 
graphically. 
11.2.3.5 Distribution of platelet count 
The variables to be analyzed are as follows: 
 Platelet count: < 15000, 15000 ≤ < 30000, 30000 ≤ < 50000, ≥ 50000/μL 
 Change from baseline in platelet count: < 20000, ≥ 20000/μL 
The numbers and percentages of subjects will be presented. 


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Statistical Analysis Plan 
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11.2.3.6 Individual plots of platelet count 
Individual plots and a swimmer plot will be presented for the change in platelet count in each 
subject. The dates to be displayed in the figures are as described in “11.2.1.6 Individual plots 
of platelet count.” 
11.2.3.7 Summary statistics of quality of life assessment (SF-36) 
Summary statistics will be presented. 
11.2.4 Evaluation in the non-dosing period 
Applicable period: Non-dosing period 
11.2.4.1 Summary statistics of platelet count 
The variables to be analyzed are as follows: 
 Platelet count 
 Change from baseline in platelet count 
 Change in platelet count from the start of the non-dosing period 
Summary statistics will be presented. 
11.2.4.2 Distribution of platelet count 
The variables to be analyzed are as follows: 
 Platelet count: < 15000, 15000 ≤ < 30000, 30000 ≤ < 50000, ≥ 50000/μL 
 Change from baseline in platelet count: < 20000, ≥ 20000/μL 
The numbers and percentages of subjects will be presented. 
11.2.4.3 Individual plots of platelet count 
Individual plots will be presented for the change in platelet count in each subject. 
The number of days will be shown on the horizontal axis. The platelet count in unscheduled 
measurements and after the use of rescue medication will also be displayed. 
11.2.4.4 Decrease in platelet count after dose interruption 
The variables to be analyzed are as follows: 
 
Platelet count of <10000/μL with a decrease from baseline of ≥10000/μL 
The number and percentage of subjects who met the conditions of the analysis variables during 
the non-dosing period will be presented. 
11.2.4.5 Summary statistics of quality of life assessment (SF-36) 
Summary statistics will be presented. 


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Statistical Analysis Plan 
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11.2.5 Evaluation in Period III 
Applicable period: Period III 
11.2.5.1 Summary statistics of platelet count 
The variables to be analyzed are as follows: 
 Platelet count 
 Change from baseline in platelet count 
Summary statistics will be presented. 
11.2.5.2 Distribution of platelet count 
The variables to be analyzed are as follows: 
 Platelet count: < 15000, 15000 ≤ < 30000, 30000 ≤ < 50000, ≥ 50000/μL 
 Change from baseline in platelet count: < 20000, ≥ 20000/μL 
The numbers and percentages of subjects will be presented. 
11.2.5.3 Individual plots of platelet count 
Individual plots will be presented for the change in platelet count in each subject. 
11.2.6 Evaluation in R788 treatment period 
Applicable period: R788 treatment period 
11.2.6.1 Platelet response rate 
The variables to be analyzed are as follows: 
 Platelet count: ≥ 50000/μL 
The number and percentage of subjects achieving a platelet count of ≥ 50000/μL at least one 
analysis visit between the day of first administration of R788 and Week 52 of Period II will be 
presented. 
11.2.6.2 Duration of platelet response 
Summary statistics will be presented. The non-dosing period will be included in the evaluation 
of the duration of platelet response. This assessment will be performed for the R788 group, 
R788-R788 group, and P-R788 group. 
11.2.6.3 Individual plots of platelet count 
A swimmer plot will be presented for the platelet count. Items to be presented graphically are 
as shown in “11.2.1.6 Individual plots of platelet count.” The non-dosing period will be 
included in the duration of exposure. This assessment will be performed for the R788-R788 
group and P-R788 group. 


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Statistical Analysis Plan 
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11.2.7 Evaluation in the entire study period 
Applicable period: Entire study period excluding follow-up 
11.2.7.1 Individual plots of platelet count 
Individual plots will be presented for the change in platelet count in each subject. The horizontal 
axis represents the number of days from the first day of study drug administration in Period I. 
The plot will include all platelet count measurements obtained between the start of the screening 
period and the end or discontinuation of the study, including unscheduled measurements and 
measurements affected by rescue medications. In addition, the dose of R788, times of use of 
rescue medications, and types and doses of permitted concomitant ITP medications will be 
presented. 
11.3 Subgroup Analysis of Efficacy 
1) 
The analyses described in “11.2.6.1 Platelet response rate” will be performed for each line 
of therapy (2nd line, 3rd line or later). 
2) 
At the first data cut-off, the analyses described in “11.2.2.1 Achievement rates for platelet 
count-related endpoints” will be performed, excluding subjects who are still in Period II. 
3) 
Summary statistic of platelet count in “11.2.1.4 Summary statistics of platelet count” will 
be presented for responders and non-responders in stable platelet response. Additionally, 
medians and quartiles will be presented graphically for responders and non-responders in 
the R788 group, and for the placebo group. 
4) 
For the data in Period I, the median platelet count after the administration of the 
investigational product will be calculated for each subject, and the summary statistics will 
be presented for the R788 group, for responders and non-responders in stable platelet 
response in the R788 group, and for the placebo group. 
12. Safety 
12.1 Adverse Events and Adverse Drug Reactions 
Applicable period: Period I, long-term treatment of R788, Period II, non-dosing period, Period 
III, and R788 treatment period 
The following analyses will be performed. For evaluation in the R788 treatment period, AEs 
and adverse drug reactions (ADRs) that occurred after administration of R788 will be included 
in the analysis. 
12.1.1 Incidence rates of adverse events and adverse drug reactions 
The number of events, number of subjects with events, and incidence rates of events with two-
sided 95% CIs will be presented. For Period I, the difference in incidence rates between groups 
and their two-sided 95% CIs will be presented. 
12.1.2 Incidence of adverse events and adverse drug reactions (summary) 
The variables to be analyzed are as follows: 
 AEs and ADRs 


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 AEs and ADRs leading to death 
 Serious AEs and ADRs excluding deaths 
 AEs and ADRs leading to study drug withdrawal 
 AEs and ADRs leading to dose reduction 
 AEs and ADRs leading to dose interruption 
 AEs and ADRs of interest 
The number of events, number of subjects with events, and incidence rates of events will be 
presented. 
12.1.3 Occurrence of adverse events and adverse drug reactions 
The variables to be analyzed are as follows: 
 AEs and ADRs 
 AEs and ADRs leading to study drug withdrawal 
 AEs and ADRs leading to dose reduction 
 AEs and ADRs leading to dose interruption 
 Serious AEs and ADRs 
 AEs and ADRs of interest 
 AEs and ADRs of interest leading to study drug withdrawal 
 AEs and ADRs of interest leading to dose reduction 
 AEs and ADRs of interest leading to dose interruption 
 Serious AEs and ADRs of interest 
The number of events, number of subjects with events, and incidence rates of events will be 
presented overall and by primary SOC and PT. For AEs and ADRs of interest, event categories 
will be presented instead of primary SOCs. 
12.1.4 Severity of adverse events and adverse drug reactions 
The variables to be analyzed are as follows: 
 AEs and ADRs 
 AEs and ADRs of interest 
The number of events by severity will be presented overall and by primary SOC and PT. 
The number of subjects with events and incidence rates by severity will be presented overall 
and by primary SOC and PT. For multiple events of the same category occurring in a single 
subject, only the event with the highest severity will be considered in the calculation of the 
number of subjects with events and incidence rates. 
For AEs and ADRs of interest, event categories will be presented instead of primary SOCs. 


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Statistical Analysis Plan 
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12.1.5 Early occurrence of adverse events and adverse drug reactions 
Applicable period: Period I, R788 treatment period 
The variables to be analyzed are as follows: 
 AEs and ADRs occurring up to Week 4 (Day 29) 
 AEs and ADRs of interest occurring up to Week 4 (Day 29) 
 AEs and ADRs occurring up to Week 12 (Day 85) 
 AEs and ADRs of interest occurring up to Week 12 (Day 85) 
The number of events, number of subjects with events, and incidence rates of events will be 
presented overall and by primary SOC and PT. 
For AEs and ADRs of interest, event categories will be presented instead of primary SOCs. 
12.1.6 Timing of occurrence of adverse events and adverse drug reactions 
Applicable period: R788 treatment period 
The variables to be analyzed are as follows: 
 AEs and ADRs 
 AEs and ADRs of interest 
The categories of timing of onset are shown as follows. 
 ≤12, 12< ≤24, 24< ≤36, 36< ≤48, 48< ≤72, 72< weeks, follow-up period 
For each category of timing of onset, the number of events, number of subjects with events, and 
incidence rates of events will be presented overall and by primary SOC and PT. The 
denominator for the calculation of incidence of the events occurring in the follow-up period 
will be the subjects who received R788, excluding the ongoing subjects.  
For AEs and ADRs of interest, the event categories will be presented instead of primary SOCs. 
If the same event occurred multiple times, analysis will also be conducted to include only the 
events of initial onset. In such cases, the first occurrence of the event within each category of 
timing of onset will be analyzed overall and by primary SOC and category of AEs of interest 
as well. 
12.1.7 Occurrence of adverse events and adverse drug reactions by dose at 
onset 
Applicable period: R788 treatment period 
The variables to be analyzed are as follows: 
 AEs and ADRs 
 AEs and ADRs of interest 
For each dose at onset, the number of events, number of subjects with events, and incidence 
rates of events will be presented overall and by primary SOC and PT. Events occurring during 
drug interruption will be excluded from the analysis. The denominator for the incidence will be 
the subjects who received the applicable dose at least once. For AEs and ADRs of interest, event 
categories will be presented instead of primary SOCs. 


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12.2 ITP Bleeding Score 
Applicable period: Period I, long-term treatment of R788, Period II, non-dosing period, and 
Period III 
The variables to be analyzed are as follows: 
 Average score 
 Total score 
 Maximum score 
 Post-dose mean of average scores (Period I, Period II) 
Summary statistics will be presented for the average score, total score, and post-dose mean of 
average scores. For maximum score, the numbers and percentages of subjects will be presented. 
12.3 ECOG Performance Status 
Applicable period: Period I, long-term treatment of R788, Period II, non-dosing period, Period 
III 
The numbers and percentages of subjects with each score will be presented. 
12.4 Laboratory and Immunoglobulin Tests 
Applicable period: Period I, long-term treatment of R788, Period II 
The variables to be analyzed are listed below. 
 Laboratory tests (quantitative variables) 
Hematology: Platelets, red blood cells, white blood cells, hemoglobin, hematocrit, 
neutrophils, eosinophils, basophils, lymphocytes, monocytes, reticulocyte ratio, MCHC, 
MCH, MCV 
Serum chemistry: Sodium, potassium, chloride, calcium, phosphorus, BUN, creatinine, A/G 
ratio, blood glucose, total protein, albumin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma 
glutamyl transferase (gamma-GTP), total bilirubin, direct bilirubin, indirect bilirubin 
Urinalysis: Specific gravity, pH 
 Laboratory tests (qualitative variables) 
Urinalysis: Glucose, ketone bodies, occult blood, protein, nitrite, bilirubin, urobilinogen, 
white blood cells 
 Immunoglobulin test 
Immunoglobulin M (IgM), immunoglobulin G (IgG), immunoglobulin A (IgA) 
12.4.1 Summary statistics of laboratory tests (quantitative variables) and 
immunoglobulin tests 
Applicable period: 
Laboratory tests (quantitative variables); Period I, long-term treatment of R788, Period II, non-
dosing period, Period III 
Immunoglobulin test; Period I, long-term treatment of R788, Period II, non-dosing period 
The variables to be analyzed are as follows: 


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Statistical Analysis Plan 
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 Laboratory tests (quantitative variables) and immunoglobulin tests 
 Changes from baseline in laboratory tests (quantitative variables) and immunoglobulin tests 
Summary statistics will be presented. 
12.4.2 Scatter 
plots 
of 
laboratory 
tests 
(quantitative 
variables) 
and 
immunoglobulin tests 
Scatter plots of quantitative variables before and after treatment will be presented. 
Applicable analysis visits: Baseline, LOV 
12.4.3 Distribution of laboratory tests (qualitative variables) 
Applicable period:Period I, long-term treatment of R788, Period II, non-dosing period, Period 
III 
The numbers and percentages of subjects will be presented. 
12.4.4 Shift tables of laboratory and immunoglobulin tests 
For measurements obtained before and after administration, the number and percentages of 
subjects with low, normal, or high values will be presented. 
Applicable analysis visit: Baseline, LOV 
12.4.5 Distribution of post-baseline extrema of laboratory tests 
The variables to be analyzed are as follows: ULN stands for the upper limit of normal. 
 ALT (post-baseline maximum): > 3 × ULN, > 5 × ULN, > 10 × ULN 
 AST (post-baseline maximum): > 3 × ULN, > 5 × ULN, > 10 × ULN 
 ALP (post-baseline maximum): > 1.5 × ULN 
 Total bilirubin (post-baseline maximum): > 2 × ULN 
 Neutrophils (post-baseline minimum): < 500, 500 ≤ < 1000, 1000 ≤ < 1500, ≥ 1500/μL 
The numbers and percentages of subjects will be presented. 
12.5 Vital Signs 
Applicable period: Period I, long-term treatment of R788, Period II 
The variables to be analyzed are as follows: 
 Systolic blood pressure, diastolic blood pressure, pulse rate, body temperature 
12.5.1 Vital signs 
Applicable period:Period I, long-term treatment of R788, Period II, non-dosing period, Period 
III 
The variables to be analyzed are as follows: 
 Measured value 
 Change from baseline in measured values 


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Statistical Analysis Plan 
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Summary statistics will be presented. 
12.5.2 Scatter plots of vital signs 
Scatter plots of measured values before and after treatment will be presented. 
Applicable analysis visits: Baseline, LOV 
12.5.3 Distribution of blood pressure 
The variables to be analyzed are as follows: 
 Systolic blood pressure (post-baseline maximum): < 120, 120 ≤ < 140, 140 ≤ < 160, 160 ≤ < 
180, ≥ 180 mmHg 
 Diastolic blood pressure (post-baseline maximum): < 80, 80 ≤ < 90, 90 ≤ < 100, 100 ≤ < 110, 
≥ 110 mmHg 
The numbers and percentages of subjects will be presented. 
12.5.4 Distribution of post-baseline extrema of blood pressure 
The variables to be analyzed are as follows: 
 Systolic and diastolic blood pressure: Systolic blood pressure ≥ 140 mmHg or diastolic blood 
pressure ≥ 90 mmHg 
 Systolic and diastolic blood pressure: Systolic blood pressure ≥ 160 mmHg or diastolic blood 
pressure ≥ 100 mmHg 
The number and percentage of subjects will be presented for the number of post-baseline 
scheduled visits with blood pressure values within the above ranges. 
12.6 Listing of Safety Data 
The lists of the following events will be prepared. If no applicable event is observed, the 
corresponding table will not be prepared. 
 Deaths 
 Serious AEs excluding deaths 
 AEs leading to study drug withdrawal 
 AEs leading to dose reduction 
 AEs leading to dose interruption 
 AEs of interest 
 Abnormal laboratory values for each subject 
13. Pharmacokinetics 
Applicable period: Period I 
13.1 Plasma drug concentration 
This analysis will include subjects who received R788 in Period I. 


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Statistical Analysis Plan 
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Plasma concentration: Plasma R406 concentration 
13.1.1 Plasma Concentration 
Summary statistics, geometric means, and geometric CVs of plasma R406 concentration will 
be presented for each of the following groups based on the R788 dose immediately before 
pharmacokinetic sampling. At evaluation time point 1, the analysis will be performed separately 
before and after study drug administration on pharmacokinetic sampling days. At evaluation 
time point 2, the analysis will be performed on pooled data from before and after study drug 
administration on pharmacokinetic sampling days. In addition, for post-dose plasma 
concentration data at evaluation time point 1, measured values and their geometric means will 
be presented graphically. 
R788 dose groups: Twice daily (BID), 100 mg BID, 150 mg BID 
 
Table 13.1.1-1 
Evaluation time point 1 
Applicable weeks 
Applicable time 
point 
Time window 
(time elapsed since study drug 
administration immediately before 
pharmacokinetic sampling) 
Weeks 2 and 6 
Pre-dose 
— 
Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 
Post-dose 
— 
 
≤ 4 hr post-dose 
≤ 4 hr 
 
> 4 hr post-dose 
> 4 hr 
 
Table 13.1.1-2 
Evaluation time point 2 
Applicable weeks 
Applicable time 
point 
Time window 
(time elapsed since study drug 
administration immediately before 
pharmacokinetic sampling) 
Weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 
0 hr post-dose 
0 ≤ < 0.5 hr 
 
1 hr post-dose 
0.5 ≤ < 1.5 hr 
 
2 hr post-dose 
1.5 ≤ < 3 hr 
 
4 hr post-dose 
3 ≤ < 5 hr 
 
6 hr post-dose 
5 ≤ and < 7 hr 
 
8 hr post-dose 
7 ≤ and < 10 hr 
 
12 hr post-dose 
10 ≤ < 14 hr 
 
14 hr post-dose 
≥ 14 hr 
13.1.2 Individual plots of plasma concentrations 
The time course of plasma concentration and R788 dose will be presented for each subject. 
Plasma concentrations measured during R788 interruption will also be plotted. 
13.1.3 Scatter plots of plasma concentrations 
Scatter plots of plasma concentrations and time after R788 administration immediately before 
pharmacokinetic sampling will be presented for each of the following groups based on the R788 
dose immediately before pharmacokinetic sampling. 
R788 dose groups: 100 mg BID, 150 mg BID 


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14. Software Used for Analysis 
Analyses will be performed using SAS System Release 9.4 for Windows (SAS Institute Inc.). 
Other statistical software will also be used as appropriate. 
15. Tables, Figures and Listing Shells 
The tables, figures and listing (TFL) shells will be provided separately. 
16. Changes from the Protocol 
16.1 Changes in Statistical Analysis Plan Version 1.0 
1) 
In “3 Analysis Group,” the “period I data of subjects who discontinued R788 treatment in 
Period I” were added to the evaluation during long-term treatment of R788. 
Reason: The purpose of this analysis was to evaluate the efficacy and safety of R788 from 
the start to the end of treatment with the product. Therefore, it was considered appropriate 
to include subjects who discontinued Period I in the analysis. 
2) 
In “3 Analysis Group,” evaluation in the entire study period was added. 
Reason: To evaluate platelet response throughout the entire period after study entry. 
3) 
In “5.9 Analysis Visits,” the baseline for change calculation was defined as Day 1 of Period 
I for all periods. 
Reason: In the protocol, the baseline was defined as Day 1 of each period. However, it was 
considered appropriate to use the value not affected by study drug administration as the 
baseline value. 
4) 
In “6.3.1 Timing of analysis,” the scope of data to be cutoff was changed, and variables to 
be analyzed were clarified. 
Reason: To include Period II data in the first data cutoff and the non-dosing period data in 
the second data cutoff. In addition, variables to be analyzed at the time of cutoff were 
clarified. 
5) 
Evaluation of line of therapy-related variables was added to “9.1 Subject Demographics,” 
and evaluation of achievement rate of platelet-related endpoints was added to “11.2.6.1 
Platelet response rate” and “11.3 Subgroup Analysis of Efficacy.” 
Reason: To evaluate the effect of line of therapy on efficacy, as evaluated in the paper of 
foreign studies. 
6) 
In “7 Definition of Derived Data,” the definition of the start day of platelet response was 
changed to “the first day after the start of study treatment in each period on which a platelet 
count of ≥ 50000/μL for at least 28 consecutive days without the use of rescue medications 
was achieved.” 
Reason: To evaluate stable maintenance of platelet count. 
7) 
In “11.1 Primary Endpoint,” sensitivity analysis of the primary endpoint planned in the 
protocol was deleted. 
Reason: A blind review confirmed that no subject would need imputation of missing 


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platelet count data for the evaluation of stable platelet response. It was thus decided not to 
perform sensitivity analysis because no imputation would be performed. 
8) 
In 12.4.5 Distribution of post-baseline extrema of laboratory tests, the analysis categories 
were changed for ALT and AST. In addition, evaluations of ALP, total bilirubin, and 
neutrophils were added. 
Reason: The above evaluations were added for comparison with safety evaluations in 
foreign studies. 
9) 
In “12.5.3 Distribution of blood pressure,” the analysis categories were changed for 
systolic and diastolic blood pressure. 
Reason: The above changes were made to allow for comparison with safety evaluations in 
foreign studies. 
16.2 Changes in Statistical Analysis Plan Version 2.0 
1) 
In “8.2 Discontinuation and Reasons for Discontinuation,” the “Ongoing” category was 
added. 
Reason: To clarify the number of ongoing subjects at the time of data cutoff. 
2) 
In “11.2.7.1 Individual plots of platelet count,” the statement was changed to include 
permitted concomitant ITP medications used outside the treatment period in the figure. 
Reason: To allow permitted concomitant ITP medications discontinued during the 
screening period to appear on the figure. 
3) 
In “11.3 Subgroup Analysis of Efficacy,” the analysis of “11.2.2.1 Achievement rates for 
platelet count-related endpoints” excluding ongoing subjects was added. 
Reason: To perform the analysis after excluding subjects who are still on long-term 
treatment at the time of data cutoff. 
4) 
In “13.1.1 Plasma Concentration,” the statement on evaluation time point 2 was changed 
to include pre-dose data obtained on pharmacokinetic sampling days in the analysis. 
Reason: To align the analysis with “13.1.3 Scatter plots of plasma concentrations.” 
16.3 Changes in Statistical Analysis Plan Version 3.0 
1) 
In “5.3 Reporting of Complications, Adverse Events, and Adverse Drug Reactions,” PTs 
applicable to AEs of interest were changed. 
Reason: To add applicable events at the time of the second data cutoff. 
2) 
In “5.5.1 Handling of platelet count data,” platelets to be regarded as missing after the use 
of rescue medication were corrected. 
Reason: Corrected to clarify the scope of assessment on platelet count after the use of 
rescue medication. 
3) 
In “5.9 Analysis Visits,” LOV in the non-dosing period and change from the start of the 
non-dosing period were added. 
Reason: Since the non-dosing period only includes a small number of scheduled evaluation 


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time points and includes many unscheduled measurements, evaluation at LOV that 
includes unscheduled measurements was added to enable a more appropriate evaluation. 
In addition, change from the start of the non-dosing period was added to assess the change 
in platelet count after dose interruption. 
4) 
In “6.3.1 Timing of analysis,” descriptions regarding the details of analysis conducted at 
the second data cutoff were corrected. Also, in “10.3 Treatment Compliance,” description 
regarding implementation at study completion only was added. 
Reason: Corrected the descriptions to clarify the details of analysis at the second data 
cutoff. Since the number of tablets administered in Period III cannot be finalized at cutoff, 
the evaluation of treatment compliance rate was set to be performed at study completion 
only. 
5) 
In “10.2 Distribution of Duration of Exposure,” evaluation of the duration of dose 
interruption in the non-dosing period was added. 
Reason: Added to evaluate the early termination of the non-dosing period. 
6) 
In “11.2.4.1 Summary statistics of platelet count,” evaluation on the change from the start 
of the non-dosing period was added. 
Reason: Added to evaluate the change in platelet count after transitioning to the non-dosing 
period. 
7) 
In “11.2.4.3 Individual plots of platelet count,” unscheduled measurements and 
measurements after the use of rescue medication were included in evaluation. 
Reason: Since the non-dosing period only includes a small number of scheduled evaluation 
time points and includes many unscheduled measurements, evaluation at LOV that 
includes unscheduled measurements was added to enable a more appropriate evaluation. 
In addition, measurements after the use of rescue medication were presented graphically 
as there is a limited number of measurements on platelet count during the non-dosing 
period. 
8) 
In “11.2.4.4 Decrease in platelet count after dose interruption,” evaluation of the decrease 
in platelet count during the non-dosing period was added. 
Reason: Added to evaluate the impact of dose interruption on platelet count. 
9) 
In “11.2.6.2 Duration of platelet response,” evaluation of the duration of maintenance in 
R788 treatment period was added. In “11.2.6.3 Individual plots of platelet count,” a 
swimmer plot in R788 treatment period was added. 
Reason: Added for evaluation including the platelet response from Period III onwards. 
10) In “6.8 Subgroup Analyses” and “11.3 Subgroup Analysis of Efficacy,” evaluation of 
platelet count for responders and non-responders in stable platelet response was added. 
Reason: Evaluation methods in the research papers on overseas studies and integrated 
analysis were added for the detailed evaluation of differences in platelet response between 
responders and non-responders for stable platelet response. 
11) In “12.1.6 Timing of occurrence of adverse events and adverse drug reactions,” categories 
of the timing of onset were corrected. In addition, evaluation on the initial onset of AEs 
and ADRs in the multiple occurrences of the same event was added. 


CONFIDENTIAL 
Kissei Pharmaceutical Co., Ltd. 
 
Statistical Analysis Plan 
Protocol No.: R788-1301 
 
Version: 3.0 
35 
Reason: Period III was previously classified in an independent category; however, it was 
decided that categorized by the number of days from the day of first administration of 
R788, combined with the events that occurred in other periods. Also, this was added to 
evaluate the duration to the initial onset of AEs and ADRs. 
12) In “12.1.7 Occurrence of adverse events and adverse drug reactions by dose at onset,” 
evaluation of the AEs and ADRs by dose at onset was added. 
Reason: Added to evaluate the impact of the dose on the onset of AEs and ADRs. 
13) Evaluation of the non-dosing period was added to “11.2.4.5 Summary statistics of quality 
of life assessment (SF-36)”and immunoglobulin tests in “12.4.1 Summary statistics of 
laboratory tests (quantitative variables) and immunoglobulin tests.” In addition, applicable 
evaluation time points were added in “5.9 Analysis Visits.” 
Reason: Added as a certain number of evaluable subjects is expected even in the non-
dosing period. 
14) Evaluation of the non-dosing period and Period III was added to the “12.3 ECOG 
Performance Status,” laboratory tests in “12.4.1 Summary statistics of laboratory tests 
(quantitative variables) and immunoglobulin tests,” “12.4.3 Distribution of laboratory tests 
(qualitative variables),” and “12.5.1 Vital signs.” In addition, applicable evaluation time 
points were added in “5.9 Analysis Visits.” 
Reason: Added as a certain number of evaluable subjects is expected even in the non-
dosing period and Period III. 
17. Revision History of the Statistical Analysis Plan 
Version 
Date of preparation/revision: 
Author 
Description 
1.0 
December 2, 2021 
 
Preparation of the first version 
2.0 
December 16, 2021 
 
Preparation of the 2nd version 
3.0 
June 24, 2022 
 
Preparation of the 3rd version 
18. References 
1) Qualitest Co., Ltd. “Japanese Version of SF-36v2® Scoring Program [Web version]” 
https://www.qualitest.jp/manual/scrong-prog.html, (cited on May 27, 2021).