Phase 2 Clinical Study of ART-123 for the Prevention of Cancer Treatment Related Symptoms in Patients With Postoperative Stage II / III Colon Cancer: a Multicenter Randomized Placebo-controlled Double-blind Study to Investigate the Efficacy and Safety of ART-123
Phase: PHASE2
Conditions: Postoperative Stage II/III Colon Cancer
Sponsor: Asahi Kasei Therapeutics Corporation

 
 
 
 
A Randomized, Double-Blind, Placebo-Controlled, 
Multi-center, Parallel-group, Phase 2 Study to 
Assess the Preventive Effect of ART-123 on 
Oxaliplatin-Induced Peripheral Neuropathy 
 
 
Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Asahi Kasei Pharma Corporation 
 
 
 
 
Protocol No. ART-123 (CIPN)–201 Ver.3 
Release date: April 22, 2016 
 

 
 
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This Protocol Contains Confidential Information 
The information contained in this protocol is confidential and is intended only for the study center 
directors, investigators, subinvestigators, clinical research coordinators, investigational product 
controllers, medical experts, medical advisors, assignment managers, and institutional review boards 
participating in the study. This protocol must be handled carefully because it may not be disclosed to 
any third party without the prior written approval of Asahi Kasei Pharma Corporation except when used 
to obtain informed consent from a subject. The written approval of Asahi Kasei Pharma Corporation is 
required to externally publish any or all of the study results at a conference, in a journal, or via any other 
medium. 
----------------------------------------------------------------------------------------------------------------- 
 
Version 3, release date: April 22, 2016 
 
 
 
 
 

 
i 
 
Protocol Synopsis 
 
Study title 
A randomized, double-blind, placebo-controlled, multi-center, parallel-group, 
Phase 2 study to assess the preventive effect of ART-123 on oxaliplatin-induced 
peripheral neuropathy 
Protocol number 
ART-123 (CIPN) - 201 
Study objectives 
To assess, under placebo-controlled conditions, the efficacy and safety of 
ART-123 for preventing the onset of oxaliplatin-induced peripheral neuropathy 
in postoperative adjuvant chemotherapy that includes oxaliplatin in patients with 
pStage II or III colon cancer after radical resection (R0 surgery) 
Clinical phase 
Phase 2 
Study design 
Multi-center, randomized, double-blind, placebo-controlled, parallel-group 
comparative study 
Study methodology 
This study consists of a screening period, a treatment period, and a follow-up 
period and is of a placebo-controlled, double-blind, intergroup comparative 
design. After eligibility confirmation in the screening period, subjects will 
undergo 12 courses of postoperative adjuvant chemotherapy (mFOLFOX6) that 
includes oxaliplatin in the treatment period. From Days 1 to 3 in each course, 
subjects will receive ART-123 380 U/kg or placebo once daily by intravenous 
infusion over 30 minutes and undergo tests and observation (Figure 1). Subjects 
will be allocated to ART-123 groups: one to receive three doses and the other to 
receive one dose in each course of postoperative adjuvant chemotherapy (Figure 
2). In the follow-up period, subjects will undergo the end-of-study tests and 
observations. 
See Appendix Table 1, Summary of study schedule, for details about the tests 
and observations. 
 
Figure 1 Study design 

 
ii 
 
 
Figure 2 Investigational product dosing schedule during Days 1 to 3 of 
each course 
 
Study population 
Patients with pStage II or III colon cancer after radical resection (R0 surgery) 
Inclusion criteria 
Patients who meet all of the following criteria are eligible: 
[1] Age 20 years or older but not older than 79 years at the time of informed 
consent 
[2] Male or female 
[3] Inpatient or outpatient 
[4] Patients with histologically diagnosed colon cancer (or rectosigmoid 
cancer) at pStage II, IIIa, or IIIb based on “Japanese Classification of 
Colorectal Carcinoma (Eighth Edition)” 
[5] Deemed to have undergone curative A (Cur A) surgery 
[6] ECOG performance status of 0 or 1 on the day of registration 
[7] The most recent laboratory findings from 7 days to 1 day before 
registration meet all of the following criteria: 
• White blood cell count 
>3,500/mm3 and <100,000/mm3 
• Neutrophil count  
>1,500/mm3 
• Platelet count 
 
>100,000/mm3 
• Haemoglobin 
 
>9.0 g/dL 
• Total bilirubin  
 
<2.0 mg/dL 
• Serum creatinine  
not more than the upper limit of the 
normal range and not more than 2 mg/dL 
• AST (GOT) and ALT (GPT) not more than 2.5-fold the upper limit of 
the normal range and not more than 100 IU/L 
[8] Scheduled as of the time of registration to undergo 12 courses of 
postoperative adjuvant chemotherapy with mFOLFOX6 

 
iii 
 
[9] Able to sufficiently understand the clinical study and give informed 
consent 
Exclusion criteria 
The presence of any of the following at the time of registration will exclude the 
patient from this study: 
[1] History of hypersensitivity to any of the ingredients in thrombomodulin 
alfa (recombinant) 
[2] Peripheral neuropathy or central nervous system (CNS) damage 
[3] Mental disorder of a severity that would affect the efficacy and safety 
evaluations in this study 
[4] Any treatment history of systemic chemotherapy (including any drug in 
the clinical trial stage) or radiotherapy intended to provide an anti-tumor 
effect 
[5] Active double cancer*1 
*1 Synchronous double cancer or metachronous double cancer with disease-free 
period of no more than 5 years; does not include lesions equivalent to 
carcinoma in situ or intramucosal carcinoma deemed to have resolved with 
local treatment 
[6] Yet to recover from an operation or a complication such as a 
postoperative infection 
[7] Serious intestinal obstruction, diarrhoea, or pyrexia 
[8] History of cerebrovascular disorder (e.g., cerebral haemorrhage, cerebral 
infarction) within 52 weeks (364 days) before informed consent 
[9] Intracranial haemorrhage, pulmonary haemorrhage, or gastrointestinal 
haemorrhage (persistent haematemesis/blood in stool or gastrointestinal 
ulcer-induced haemorrhage) 
[10] Unconfirmed completion of a haemostasis procedure after central 
nervous system surgery or after trauma 
[11] Receiving transfusion, a blood derivative, G-CSF, or another 
hematopoietic factor within 7 days before the laboratory tests performed 
to assess registration eligibility 
[12] Hepatitis B infection and a positive test result for HBs antigen. Patients 
negative for HBs antigen but positive for HBc or HBs antibody must 
undergo an HBV-DNA test. A result at or above the normal range will 
disqualify the patient from enrollment. Test data obtained within 6 
months before registration may be used. 
[13] A positive test result for HIV antigen or antibody 
[14] Establishment of an artificial anus (even if temporary) in colorectal 
cancer surgery 
[15] Administration of another investigational product within 16 weeks (112 
days) before informed consent or undergoing observation that is still 
ongoing a day before informed consent 

 
iv 
 
[16] Pregnancy or possible pregnancy; wish to become pregnant during the 
study period; breastfeeding 
[17] Having participated in this study in the past 
[18] Prior treatment history with thrombomodulin alfa (recombinant) 
[19] Is otherwise found unsuited for the study by the investigator or 
subinvestigator 
Investigational 
products 
Investigational medicinal product  
 Investigational product code: ART-123 
 Nonproprietary name: Thrombomodulin alfa (recombinant) (JAN) 
 A freeze-dried formulation containing 12,800 U thrombomodulin alfa 
(recombinant) per vial 
 
Control drug (placebo) 
 Investigational product code: ART-123 (placebo) 
 A freeze-dried formulation free of thrombomodulin alfa (recombinant) 
that is indistinguishable in appearance from ART-123 (the investigational 
medicinal product) 
Dose and mode of 
administration and 
number of doses of 
the investigational 
product 
Dose and mode of administration 
Administer the investigational product (ART-123 380 U/kg or placebo) once 
daily by intravenous infusion over approximately 30 minutes from Days 1 to 3 
of each course of postoperative adjuvant chemotherapy (mFOLFOX6). 
[1] ART-123 3-dose group 
On Day 1, initiate ART-123 administration from 2 hours to 30 minutes 
before oxaliplatin administration and complete administration before the 
start of oxaliplatin administration. On Days 2 and 3, administer ART-123 
at about the same time as on Day 1 whenever possible. 
[2] ART-123 1-dose group 
On Day 1, initiate ART-123 administration from 2 hours to 30 minutes 
before oxaliplatin administration and complete administration before the 
start of oxaliplatin administration. On Days 2 and 3, administer the 
placebo at about the same time as on Day 1 whenever possible. 
[3] Placebo group 
On Day 1, initiate placebo administration from 2 hours to 30 minutes 
before oxaliplatin administration and complete administration before the 
start of oxaliplatin administration. On Days 2 and 3, administer the 
placebo at about the same time as on Day 1 whenever possible. 
 
Criteria for suspension/resumption of the investigational product 
Suspend use of the investigational product when the administration of 
oxaliplatin, as a part of the postoperative adjuvant chemotherapy, is suspended. 
Resume investigational product administration concurrently with the resumption 

 
v 
 
of oxaliplatin administration. 
 
Number of doses 
36 (three/course × 12 courses) 
Dose and mode of 
administration of 
standard 
concomitant 
medications 
Administer mFOLFOX6 as postoperative adjuvant chemotherapy. 
See Section 8.3 for the specific doses, administration procedures, and dosing 
schedule. 
Treatments 
prohibited during 
the study 
Prohibited concomitant medications 
 The administration of the following medications is prohibited from 
informed consent until study completion. 
(1) Other investigational products 
(2) Thrombomodulin alfa (recombinant) 
(3) Antineoplastic agents other than those specified for use in the 
postoperative adjuvant chemotherapy in this study 
 The administration of the following medications is prohibited from the 
start of administration of the investigational product until study 
completion. 
(1) Thrombolytic drugs (e.g., t-PA preparations, urokinase) 
 
Restricted concomitant medications 
Over-the-counter medications and ready-made transfusion preparations are not 
considered restricted concomitant medications. 
 The administration of the following medications is prohibited from 
informed consent until study completion except in association with use 
while peripheral motor neuropathy or peripheral sensory neuropathy is 
found by the investigator or subinvestigator to be Grade 2 or greater 
based on National Cancer Institute-Common Terminology Criteria for 
Adverse Events version 4.0 (NCI-CTCAE). 
(1) Calcium gluconate, magnesium sulfate 
(2) Glutathione 
(3) L-glutamine 
(4) Vitamin B6, B12, and E preparations 
(5) Goshajinkigan, shakuyaku-kanzoto 
(6) Narcotics and similar drugs (including the opioid receptor agonist 
codeine phosphate) 
(7) Oral and injected adrenocorticosteroids (except when used to treat 
nausea/vomiting associated with the administration of an 
antineoplastic agent or to treat an allergy) 
(8) Pregabalin, gabapentin 

 
vi 
 
(9) Nonsteroidal anti-inflammatory drugs (NSAIDs, except when used 
for a purpose other than chemotherapy-induced peripheral neuropathy 
[CIPN] treatment) 
(10) Tricyclic antidepressants 
(11) Serotonin/noradrenaline reuptake inhibitors 
 Initiating the administration of or increasing the dose of any of the 
following medications is prohibited from informed consent until study 
completion. Subjects may continue to use the medications that they had 
been using before informed consent provided that no dose changes are 
made. (Dose reductions are allowed.) 
(1) Isoniazid, ethambutol, metronidazole, medications for the treatment 
of HIV infection, HMG-CoA reductase inhibitors, tacrolimus, 
colchicine, and interferon preparations 
 
Prohibited therapies 
 The following treatments are prohibited from informed consent until 
study completion. 
(1) Radiotherapy 
(2) Operations and other surgical procedures that could affect efficacy 
evaluation 
Endpoints 
Efficacy 
[1] NCI-CTCAE peripheral motor neuropathy, peripheral sensory 
neuropathy (CIPN only) 
[2] DEB-NTC 
[3] FACT/GOG-NTX-12 
[4] FACT-G 
[5] Numerical rating scale (NRS) (pain) 
[6] Discontinuation, suspension, and dose reduction of oxaliplatin due to 
CIPN 
The efficacy endpoints will not be classified as primary or secondary because 
this is an exploratory study of ART-123 in prevention of the onset of 
oxaliplatin-induced peripheral neuropathy. 
 
Safety 
[1] Vital signs (body temperature, blood pressure systolic/diastolic, pulse 
rate) 
[2] Laboratory tests (routine blood tests, clinical chemistry tests, urine 
analysis, coagulation tests) 
[3] Immunogenicity (anti-drug antibodies, neutralising antibodies) 
[4] Adverse events other than CIPN 
 

 
vii 
 
Pharmacokinetics 
Blood concentration of thrombomodulin alfa (recombinant) 
Treatment and 
observation periods 
Screening period: up to 14 days 
Treatment period: 24 weeks (up to 36 weeks) 
Follow-up period: 4 weeks (up to 6 weeks) 
Target sample size 
75 subjects (25 per group) 
Study period 
July 2016 to January 2018 
Primary analysis 
methods 
[1] Analysis set 
The primary efficacy analysis set is the full analysis set (FAS). 
[2] Handling of primary efficacy data 
• Handling of missing data on whether an assessment is NCI-CTCAE 
Grade 1 or greater 
Consider subjects for whom these data are missing to have had an 
NCI-CTCAE Grade 1 or greater event. Perform sensitivity analysis 
that includes analysis with a missing NCI-CTCAE grade for all such 
subjects. 
• Handling of NCI-CTCAE evaluation data in the second and 
subsequent courses 
Evaluate the Day 1 (baseline) NCI-CTCAE grades as those from 
the immediately preceding course. Evaluate the Days 2, 3, 15, and 29 
NCI-CTCAE grades as those observed within the course. 
• Handling of missing efficacy endpoint data (continuous variables) 
Do not impute missing continuous efficacy endpoint data. Perform 
sensitivity analyses with imputation using the 
last-observation-carried-forward (LOCF) approach. 
[3] General matters pertaining to efficacy analysis 
This study is conducted to assess and characterize the clinical effect of 
ART-123 for preventing the onset of oxaliplatin-induced peripheral 
neuropathy and to explore appropriate efficacy indices. Thus, efficacy 
analyses will be performed primarily with descriptive statistics obtained 
by summarizing and graphing data from each evaluation time point. 
The incidences of NCI-CTCAE Grade 1 or greater events will be 
evaluated with statistical tests and 95% confidence intervals as necessary 
in addition to descriptive statistics to allow intergroup comparison. The 
incidences of NCI-CTCAE Grade 1 or greater events with 
discontinuations and dropouts factored in will also be estimated. 
The significance level is set at 5% (two-sided), with a two-sided 
confidence interval and a confidence coefficient of 95%. Given the 
exploratory nature of the study, multiplicity will not be adjusted for. 

 
ix 
 
NRS (pain) 
 
● 
 
 
 
 
● 
◯ 
◯ 
● 
 
 
 
 
● 
◯ 
◯ 
● 
 
 
 
 
● 
● 
● 
● 
 
Safety 
Laboratory tests 
●c) 
 
 
 
 
 
 
 
 
●k) 
 
 
 
 
 
 
 
●k) 
 
 
 
 
 
● 
● 
● 
 
Vital signs 
● 
 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
● 
● 
● 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
● 
 
Immunogenicity 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
Pharmacokinetics 
 
● 
 
●f) 
●f) 
●f) 
 
 
 
 
 
 
△f) 
△f) 
 
 
 
 
 
 
△f) 
△f) 
 
 
 
 
 
Time points are expressed as “Day (D),” and numbers of days are expressed as “day (d).” 
●: required 
◯: to be performed only in the event of postponement of the administration of all drugs for postoperative adjuvant chemotherapy 
△: if no blood samples are available from course 1, perform once in one of the courses from 2 to 12 
a) Not required in courses in which oxaliplatin is suspended 
b) To be performed before investigational product administration if efficacy and safety evaluations take place on the same day as investigational product administration 
c) To be performed between Day −7 and Day −1 (1 day before registration); hepatitis B test data obtained within 6 months before the day of registration may also be used 
d) To be performed only in course 2; may be determined on the day before Day 1 
e) To be performed only in courses 5 and 9 
f) Collect blood samples immediately after and from 30 to 120 minutes after completion of investigational product administration 
g) If the evaluation at treatment period discontinuation takes place on or after Day 43 of the last course of postoperative adjuvant chemotherapy, or if the subsequent 
tests/observations for the study are not possible, perform the end-of-study evaluations instead of the treatment-period discontinuation evaluations. If the course 12 
postoperative adjuvant chemotherapy has not commenced within 34 weeks (Day 239 from the day of registration), discontinue the subject from the study, perform the 
treatment-period discontinuation evaluations, and then perform the end-of-study evaluations on Day 43 of the last course of postoperative adjuvant chemotherapy. 
h) If any postoperative adjuvant chemotherapy for the subsequent course has not commenced by Day 43 of a course, discontinue the subject from the study and perform the 
end-of-study evaluations. 
i) If the subject is discontinued from the study in the follow-up period, perform the end-of-study evaluations 
j) Determine the status of fluorouracil continuous intravenous infusion use 
k) May be determined on the day before Day 1 
 
 

 
 
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Table of Contents 
1. Background Information and History of Development .......................................................... 1 
1.1 Background Information ....................................................................................................................... 1 
1.1.1 Epidemiology and Treatment of Colorectal Cancer ....................................................................... 1 
1.1.2 Overview of Chemotherapy-induced Peripheral Neuropathy ........................................................ 1 
1.1.3 Oxaliplatin-induced Peripheral Neuropathy .................................................................................. 1 
1.1.4 Status of CIPN Prevention and Treatment ..................................................................................... 1 
1.2 History of Development and Characteristics of ART-123 .................................................................... 2 
1.2.1 Pharmacological Characteristics of ART-123 ............................................................................... 2 
1.2.2 Characteristics of ART-123 (nonclinical) ...................................................................................... 2 
2. Study Objectives .................................................................................................................... 3 
3. Study Population .................................................................................................................... 4 
3.1 Inclusion Criteria ................................................................................................................................... 4 
3.2 Exclusion Criteria ................................................................................................................................. 4 
3.3 Rationale for Inclusion and Exclusion Criteria ..................................................................................... 5 
3.3.1 Rationale for Inclusion Criteria...................................................................................................... 5 
3.3.2 Rationale for Exclusion Criteria .................................................................................................... 6 
4. Subject Informed Consent ...................................................................................................... 7 
4.1 Authoring of the Informed Consent Form ............................................................................................. 7 
4.2 When and How to Obtain Informed Consent ........................................................................................ 8 
4.3 Informing Other Hospitals When Informed Consent Is Obtained ......................................................... 8 
4.4 Information to Consider When Obtaining Informed Consent ............................................................... 8 
4.5 Amending the Informed Consent Form ................................................................................................ 9 
5. Study Design and Schedule .................................................................................................. 10 
5.1 Study Design ....................................................................................................................................... 10 
5.2 Rationale for Study Design ................................................................................................................. 11 
5.2.1 Endpoints and Rationale .............................................................................................................. 11 
5.2.2 Control Drug and Rationale ......................................................................................................... 11 
5.3 Study Methods .................................................................................................................................... 11 
5.4 Study Period ........................................................................................................................................ 12 
6. Investigational Products ....................................................................................................... 13 
6.1 Names and Descriptions of Investigational Products .......................................................................... 13 
6.2 Investigational Product Dosage Form and Strength ............................................................................ 13 
6.3 Investigational Product Packaging and Labeling ................................................................................ 14 
6.4 Shelf Life of Investigational Products ................................................................................................. 15 
6.5 Investigational Product Assignment.................................................................................................... 15 
6.6 Retention of Key Codes and Emergency Keys ................................................................................... 15 
6.7 Unblinding of Emergency Keys During Study ................................................................................... 15 
6.8 Confirmation of Indistinguishability ................................................................................................... 16 
6.9 Dispensing of Investigational Product ................................................................................................ 16 
6.10 Storage and Control of Investigational Product ................................................................................ 16 
6.11 Collection of Investigational Products .............................................................................................. 16 
7. From Subject Selection to Start of Treatment ...................................................................... 18 
7.1 Subject Registration Flowchart ........................................................................................................... 18 
7.2 Enrolling Subjects in the Study ........................................................................................................... 19 
7.2.1 Information to Enter in IWRS ...................................................................................................... 19 
7.2.2 Creation of Screening Log ........................................................................................................... 19 
7.2.3 Assigning Subjects to Treatment Groups ..................................................................................... 19 
8. Subject Treatment ................................................................................................................ 20 
8.1 Investigational Product Dosage and Administration ........................................................................... 20 
8.1.1 Dosage and Administration .......................................................................................................... 20 
8.1.2 Number of Doses ......................................................................................................................... 20 

 
 
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8.1.3 Instructions for Prescribing the Investigational Product .............................................................. 20 
8.1.4 Criteria for Suspension/Resumption and Criteria for Discontinuation of the Investigational 
Product ........................................................................................................................................ 21 
8.2 Rationale for Dosage and Administration and Number of Doses of the Investigational Product ....... 21 
8.2.1 Dosage and Administration .......................................................................................................... 21 
8.2.2 Number of Doses ......................................................................................................................... 21 
8.3 Dosage and Administration of Standard Concomitant Drugs ............................................................. 21 
8.3.1 Doses, Administration Procedures, and Dosing Schedule ........................................................... 21 
8.3.2 Changing the Dosage and Schedule of Postoperative Adjuvant Chemotherapy .......................... 22 
8.3.2.1 Criteria for Changing Postoperative Adjuvant Chemotherapy .............................................. 23 
8.4 Prohibited Treatments and Interventions During the Study ................................................................ 24 
8.4.1 Prohibited Concomitant Drugs..................................................................................................... 24 
8.4.2 Restricted Concomitant Drugs ..................................................................................................... 24 
8.4.3 Prohibited Concomitant Therapies ............................................................................................... 25 
9. Investigations/Observations and Evaluations ....................................................................... 26 
9.1 Investigation/Observation and Evaluation Schedule ........................................................................... 26 
9.2 Investigations/Observations and Evaluations to be Conducted at Each Time Point ........................... 29 
9.2.1 Screening Period (Day −14 to Day −1) ........................................................................................ 29 
9.2.2 Treatment Period*1 ....................................................................................................................... 29 
9.2.2.1 Day 1 of Course 1 .................................................................................................................. 29 
9.2.2.2 Days 2 and 3 of Course 1 ....................................................................................................... 29 
9.2.2.3 Day 8 of Course 1*1 ................................................................................................................ 30 
9.2.2.4 Day 15 (permitted window, +7 days)*1 and Day 29 (permitted window, +7 days)*1 of 
Course 1 ................................................................................................................................ 30 
9.2.2.5 Day 1 of Courses 2 to 12 ........................................................................................................ 30 
9.2.2.6 Days 2 and 3 of Courses 2 to 12 ............................................................................................ 31 
9.2.2.7 Day 8 of Courses 2 to 12*1 ..................................................................................................... 31 
9.2.2.8 Day 15 (permitted window, +7 days)*1 and Day 29 (permitted window, +7 days)*1 of 
Courses 2 to 11 ..................................................................................................................... 31 
9.2.2.9 Day 15 of Course 12 (permitted window, +7 days) ............................................................... 32 
9.2.3 At Discontinuation in the Treatment Period*1 .............................................................................. 32 
9.2.4 Follow-up Period*1 ....................................................................................................................... 32 
9.2.4.1 At Study Completion (Day 43 of the last course [permitted window, +14 days]) ................. 33 
9.2.5 At Unscheduled CIPN Evaluations (if a restricted concomitant medication is prescribed by the 
investigator for the prevention or treatment of CIPN at any time other than the above-mentioned 
evaluations)*1 .............................................................................................................................. 33 
9.3 Subject Demographic Information Survey .......................................................................................... 33 
9.4 Survey of Investigational Product Administration Status and Postoperative Adjuvant Chemotherapy 
Administration Status ........................................................................................................................ 34 
9.5 Survey of Concomitant Medications/Therapies .................................................................................. 34 
9.5.1 Concomitant Medications ............................................................................................................ 34 
9.5.1.1 Concomitant Medications that are Neither Prohibited nor Restricted ................................... 34 
9.5.1.2 Prohibited and Restricted Concomitant Medications ............................................................. 34 
9.5.2 Concomitant Therapies ................................................................................................................ 35 
9.6 Investigations/Observations Pertaining to Efficacy and Evaluation Methods .................................... 35 
9.6.1 Efficacy Endpoints ....................................................................................................................... 35 
9.6.2 Considerations for Efficacy Evaluations ...................................................................................... 35 
9.6.3 Evaluation Methods ..................................................................................................................... 35 
9.6.3.1 NCI-CTCAE Peripheral Motor Neuropathy, Peripheral Sensory Neuropathy (CIPN only) . 35 
9.6.3.2 DEB-NTC .............................................................................................................................. 36 
9.6.3.3 FACT/GOG-NTX-12 ............................................................................................................. 37 
9.6.3.4 FACT-G ................................................................................................................................. 37 
9.6.3.5 NRS (pain) ............................................................................................................................. 38 
9.7 Investigations/Observations Pertaining to Safety and Evaluation Methods ........................................ 38 
9.7.1 Vital Signs .................................................................................................................................... 38 

 
 
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9.7.2 Laboratory Tests .......................................................................................................................... 39 
9.7.3 Immunogenicity (anti-drug antibodies, neutralising antibodies) ................................................. 39 
9.7.4 Adverse Events ............................................................................................................................ 40 
9.7.4.1 Definition of Adverse Events ................................................................................................. 40 
9.7.4.2 Identification of Adverse Events ............................................................................................ 40 
9.7.4.3 Adverse Event Reporting Period ............................................................................................ 40 
9.7.4.4 Assessing Adverse Events ..................................................................................................... 41 
9.7.4.5 Follow-up for Adverse Events ............................................................................................... 42 
9.8 Other Investigations/Observations and Evaluation Methods .............................................................. 42 
9.8.1 Pharmacokinetics (blood concentration of recombinant thrombomodulin alfa) .......................... 42 
9.8.2 Urine Pregnancy Testing .............................................................................................................. 42 
9.8.3 Pathology of CIPN and Exploratory Assessments of Efficacy and Safety of the Investigational 
Product ........................................................................................................................................ 43 
10. Ensuring Subject Safety ..................................................................................................... 44 
10.1 Basic Information .............................................................................................................................. 44 
10.2 Particularly Notable Information ...................................................................................................... 44 
10.2.1 Precautions Related to Bleeding ................................................................................................ 44 
10.2.2 Interventions for Overdoses ....................................................................................................... 44 
10.2.3 Monitoring for Hypersensitivity ................................................................................................ 44 
10.3 Actions to Take for Serious Adverse Events .................................................................................... 45 
10.3.1 Procedures for Investigator or Subinvestigator .......................................................................... 45 
10.3.2 Sponsor Procedures .................................................................................................................... 46 
10.3.3 Emergency Protocol Deviations/Modifications and Emergency Key Unblinding..................... 46 
10.4 Actions to Take for Identified Pregnancies ....................................................................................... 46 
11. Completion and Discontinuation of Treatment and Observations ..................................... 47 
11.1 Days of Completion and Discontinuation of Individual Subjects ..................................................... 47 
11.2 Discontinuation Criteria for Individual Subjects............................................................................... 47 
11.2.1 Study Discontinuation Criteria................................................................................................... 47 
11.3 Rationale for Discontinuation Criteria .............................................................................................. 48 
11.4 Discontinuation Procedures .............................................................................................................. 48 
11.4.1 Procedures for Study Discontinuation from Informed Consent to Before Registration ............ 48 
11.4.2 Procedures for Post-registration Discontinuations ..................................................................... 48 
11.5 Procedures for Post-discontinuation Follow-up ................................................................................ 49 
12. Statistical Analysis ............................................................................................................. 50 
12.1 Selection of Sample Size ................................................................................................................... 50 
12.2 Statistical Analysis Plan .................................................................................................................... 50 
12.3 Analysis Populations ......................................................................................................................... 50 
12.3.1 Analysis Populations for Assessing Efficacy ............................................................................. 50 
12.3.2 Analysis Population for Assessing Safety.................................................................................. 50 
12.3.3 Analysis Populations for Assessing Pharmacokinetics .............................................................. 50 
12.4 Handling of Data ............................................................................................................................... 50 
12.5 Analysis of Demographic Variables and Other Baseline Characteristics ......................................... 51 
12.6 Analysis of Efficacy .......................................................................................................................... 51 
12.6.1 Overall Information ................................................................................................................... 51 
12.6.2 Efficacy Endpoints ..................................................................................................................... 51 
12.6.2.1 NCI-CTCAE ........................................................................................................................ 51 
12.6.2.2 DEB-NTC ............................................................................................................................ 52 
12.6.2.3 FACT/GOG-NTX-12 ........................................................................................................... 52 
12.6.2.4 FACT-G ............................................................................................................................... 52 
12.6.2.5 NRS (pain) ........................................................................................................................... 53 
12.6.2.6 Discontinuation, Suspension, and Dose Reduction of Oxaliplatin due to CIPN.................. 53 
12.6.2.7 Other Analyses ..................................................................................................................... 53 
12.7 Safety Analysis ................................................................................................................................. 53 
12.7.1 Analysis of Adverse Events ....................................................................................................... 53 

 
 
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12.7.2 Analyses of Laboratory Findings ............................................................................................... 53 
12.7.3 Analyses of Vital Signs .............................................................................................................. 54 
12.7.4 Analysis of Immunogenicity (anti-drug antibodies, neutralising antibodies) ............................ 54 
12.8 Pharmacokinetic Analysis ................................................................................................................. 54 
12.9 Timing of Analyses ........................................................................................................................... 54 
12.10 Reporting of Changes to the Analytical Plan .................................................................................. 54 
13. Protocol Compliance, Deviations/Modifications, and Amendment ................................... 55 
13.1 Protocol Compliance ......................................................................................................................... 55 
13.2 Protocol Deviations and Modifications ............................................................................................. 55 
13.3 Protocol Amendment ........................................................................................................................ 55 
14. Study Completion or Termination ...................................................................................... 56 
14.1 Study Completion ............................................................................................................................. 56 
14.2 Unblinding Following Study Completion ......................................................................................... 56 
14.3 Termination or Suspension of the Study as a Whole or Partially ...................................................... 56 
14.4 Termination at a Study Site ............................................................................................................... 56 
15. Case Report Forms ............................................................................................................. 57 
15.1 Completion and Reporting of Case Report Forms ............................................................................ 57 
15.2 Revising or Adding to a Case Report Form ...................................................................................... 57 
16. Direct Access to Source and Other Documents ................................................................. 58 
16.1 Definition of Source Documents ....................................................................................................... 58 
16.2 Direct Access .................................................................................................................................... 58 
17. Study Quality Control and Quality Assurance ................................................................... 59 
17.1 Sponsor (and contract research organizations) .................................................................................. 59 
17.2 Study Sites......................................................................................................................................... 59 
18. Retention of Records .......................................................................................................... 60 
18.1 Retention of Records at the Study Sites ............................................................................................ 60 
18.2 Retention of Records by Sponsor ...................................................................................................... 60 
18.3 Retention of Records at Other Institutions ........................................................................................ 60 
19. Compliance with Ethical Principles and Laws ................................................................... 61 
20. Monetary and Other Payments and Compensation and Insurance for Injuries .................. 62 
20.1 Monetary Payments ........................................................................................................................... 62 
20.2 Compensation and Insurance for Injuries .......................................................................................... 62 
21. Decisions Regarding Publication ....................................................................................... 63 
22. Study Administrative Structure .......................................................................................... 64 
23. References .......................................................................................................................... 65 
Appendix 1 Study administrative structure 
Appendix 2 Investigational product handling procedures 
Appendix 3 NCI-CTCAE ver.4.0 
Appendix 4 DEB-NTC 
Appendix 5 Japanese version of the FACT/GOG-NTX-12 (Version 4) 
Appendix 6 Japanese version of the FACT-G (Version 4) 
 

 
 
1
1. Background Information and History of Development 
1.1  Background Information 
1.1.1  Epidemiology and Treatment of Colorectal Cancer 
An estimated 136,000 people in Japan were diagnosed with colon cancer in 2015, and the number of 
afflicted people is growing (2015 estimate of National Cancer Center Japan). Treatment options such as 
endoscopic treatment, surgery, chemotherapy, and radiotherapy are selected according to how advanced 
the disease is1). Rapid advances in antineoplastic agents have made chemotherapy an option comparable 
in benefit to surgery and radiotherapy. Chemotherapy, however, must sometimes be modified or 
discontinued because of the adverse reactions it causes2). 
 
1.1.2  Overview of Chemotherapy-induced Peripheral Neuropathy 
Chemotherapy-induced peripheral neuropathy (CIPN) is one adverse reaction that can affect whether 
chemotherapy can be continued. Symptoms of CIPN include numbness, abnormal sensations, and 
hypoaesthesia of the extremities caused by sensory nerve damage and muscular atrophy and muscular 
weakness caused by motor nerve damage3). CIPN varies in incidence from drug to drug, occurring most 
frequently in association with the antineoplastic agent oxaliplatin, which is a platinum compound, 
followed by the taxane drug paclitaxel4). 
 
1.1.3  Oxaliplatin-induced Peripheral Neuropathy 
Oxaliplatin-induced peripheral neuropathy takes the forms of acute peripheral neuropathy, which 
appears just after to several days after oxaliplatin administration, and chronic peripheral neuropathy, 
which appears later over the course of oxaliplatin treatment. Temporary numbness and abnormal 
sensations in the limbs and mouth, one manifestation of acute peripheral neuropathy, affect almost 
everyone (85% to 95%) treated with oxaliplatin. Manifestations of chronic peripheral neuropathy 
include persistent numbness and abnormal sensations of the limbs, fine-motor impairments such as 
difficulty buttoning clothing, and movement disorders such as difficulty walking. The risk of these 
conditions increases as the cumulative dose of oxaliplatin increases. These conditions, moreover, 
substantially reduce patient quality of life (QOL). The modification and discontinuation of 
chemotherapy caused by chronic peripheral neuropathy is particularly clinically significant3)5)6). 
Although the specific mechanism of the onset of oxaliplatin-induced peripheral neuropathy remains 
uncharacterized, chronic peripheral neuropathy is attributed to axonal degeneration resulting from nerve 
cell body damage. Because damaged nerves require a long time for repair, symptoms may persist for 
several months or years after the end of oxaliplatin treatment7). Preventing the onset of 
oxaliplatin-induced peripheral neuropathy is therefore important. 
 
1.1.4  Status of CIPN Prevention and Treatment 
No drug indicated for preventing the onset of or treating CIPN is available in Japan or elsewhere8). 
In Japan, CIPN is empirically treated with products including calcium-magnesium formulations, 
carbamazepine, gabapentin, pregabalin, and Chinese herbal medications (goshajinkigan), although 

 
 
2
sufficient evidence supporting their use is lacking, and efficacy has not been demonstrated4)9). 
Oxaliplatin dose reduction or suspension is therefore performed as symptomatic treatment for CIPN7). 
The American Society of Clinical Oncology published a guideline on the prevention and 
management of CIPN8) in 2014. The guideline recommends only duloxetine for treating CIPN and has 
no recommended pharmacotherapies for preventing onset. 
 
1.2  History of Development and Characteristics of ART-123 
1.2.1  Pharmacological Characteristics of ART-123 
Thrombomodulin (TM) is a glycoprotein present on vascular endothelial cells. This physiologic 
coagulation factor facilitates the regulation of blood coagulation in the body. ART-123 (non-proprietary 
name: thrombomodulin alfa (recombinant)) is soluble human TM, expressed in animal cells, that 
consists of only the extracellular domain of poorly soluble natural TM, the extracellular domain 
containing the active site. ART-123 has a coagulation-regulating effect comparable to natural TM. A 
drug product containing ART-123 as the active ingredient (proprietary name: Recomodulin® Inj. 
12800) was approved in Japan in 2008 for the indication of disseminated intravascular coagulation 
syndrome. ART-123 appears to have anti-inflammatory actions and protects against vascular endothelial 
damage10). 
 
1.2.2  Characteristics of ART-123 (nonclinical) 
One mechanism for the onset of neuropathy is thought to be prolongation of the inflammatory 
response11). The supposed anti-inflammatory action of ART-123 was investigated in a rat model of 
CIPN induced with oxaliplatin. Intraperitoneal administration of 0.3 mg/kg (1,900 U/kg) to 10 mg/kg 
(65,000 U/kg) of ART-123 given for 7 days suppressed escape behavior in response to mechanical 
hyperalgesia in a dose-dependent manner12). ART-123 did not suppress the growth-inhibiting effect of 
oxaliplatin on cancer cells in a cultured human cancer cell line13). These findings suggest that ART-123 
may prevent the onset of oxaliplatin-induced peripheral neuropathy without affecting the anti-tumor 
activity of oxaliplatin. 
 

 
 
3
2. Study Objectives 
To assess, under placebo-controlled conditions, the efficacy and safety of ART-123 for preventing 
the onset of oxaliplatin-induced peripheral neuropathy in postoperative adjuvant chemotherapy that 
includes oxaliplatin in patients with pStage II or III colon cancer after radical resection (R0 surgery) 

4
3. Study Population
Patients with pStage II or III colon cancer after radical resection (R0 surgery) 
3.1  Inclusion Criteria 
Patients who meet all of the following criteria are eligible: 
[1] Age 20 years or older but not older than 79 years at the time of informed consent
[2] Male or female
[3] Inpatient or outpatient
[4] Patients with histologically diagnosed colon cancer (or rectosigmoid cancer) at pStage II, IIIa, or
IIIb based on “Japanese Classification of Colorectal Carcinoma (Eighth Edition)”14)
[5] Deemed to have undergone curative A (Cur A) surgery
[6] ECOG performance status of 0 or 1 on the day of registration
[7] The most recent laboratory findings from 7 days to 1 day before registration meet all of the
following criteria:
• White blood cell count
>3,500/mm3 and <100,000/mm3
• Neutrophil count
>1,500/mm3
• Platelet count
>100,000/mm3
• Haemoglobin
>9.0 g/dL
• Total bilirubin
<2.0 mg/dL
• Serum creatinine
not more than the upper limit of the normal range and not more
than 2 mg/dL
• AST (GOT) and ALT (GPT)  not more than 2.5-fold the upper limit of the normal range and not
more than 100 IU/L
[8] Scheduled as of the time of registration to undergo 12 courses of postoperative adjuvant
chemotherapy with mFOLFOX6
[9] Able to sufficiently understand the clinical study and give informed consent
3.2  Exclusion Criteria 
The presence of any of the following at the time of registration will exclude the patient from this 
study: 
[1] History of hypersensitivity to any of the ingredients in thrombomodulin alfa (recombinant)
[2] Peripheral neuropathy or central nervous system (CNS) damage
[3] Mental disorder of a severity that would affect the efficacy and safety evaluations in this study
[4] Any treatment history of systemic chemotherapy (including any drug in the clinical trial stage) or
radiotherapy intended to provide an anti-tumor effect
[5] Active double cancer*1
*1 Synchronous double cancer or metachronous double cancer with disease-free period of no more than 5
years; does not include lesions equivalent to carcinoma in situ or intramucosal carcinoma deemed to have
resolved with local treatment 
[6] Yet to recover from an operation or a complication such as a postoperative infection
[7] Serious intestinal obstruction, diarrhoea, or pyrexia

5
[8] History of cerebrovascular disorder (e.g., cerebral haemorrhage, cerebral infarction) within 52
weeks (364 days) before informed consent
[9] Intracranial haemorrhage, pulmonary haemorrhage, or gastrointestinal haemorrhage (persistent
haematemesis/blood in stool or gastrointestinal ulcer-induced haemorrhage)
[10] Unconfirmed completion of a haemostasis procedure after CNS surgery or after trauma
[11] Receiving transfusion, a blood derivative, G-CSF, or another hematopoietic factor within 7 days
before the laboratory tests performed to assess registration eligibility
[12] Hepatitis B infection and a positive test result for HBs antigen. Patients negative for HBs antigen
but positive for HBc or HBs antibody must undergo an HBV-DNA test. A result at or above the
normal range will disqualify the patient from enrollment. Test data obtained within 6 months before
registration may be used.
[13] A positive test result for HIV antigen or antibody
[14] Establishment of an artificial anus (even if temporary) in colorectal cancer surgery
[15] Administration of another investigational product within 16 weeks (112 days) before informed
consent or undergoing observation that is still ongoing a day before informed consent
[16] Pregnancy or possible pregnancy; wish to become pregnant during the study period; breastfeeding
[17] Having participated in this study in the past
[18] Prior treatment history with thrombomodulin alfa (recombinant)
[19] Is otherwise found unsuited for the study by the investigator or subinvestigator
3.3  Rationale for Inclusion and Exclusion Criteria 
3.3.1  Rationale for Inclusion Criteria 
[1] Subjects must be at least 20 years old to be sufficiently competent to give consent. An upper age
limit of 79 years was set out of concern for subject safety.
[2] The sex of the subjects is not limited because sex is not thought to affect the evaluation of efficacy
or safety in the study.
[3] The hospitalization status of the subjects is not limited because this is not thought to affect the
evaluation of efficacy or safety in the study.
[4] and [5] The study will be in patients with colorectal cancer following radical resection, who have a
better prognosis than patients with unresectable, advanced, or recurrent colorectal cancer. The study
will be in patients with pStage II or III colon cancer following resection because the Guidelines for
the Treatment of Colorectal Cancer1), in the section on chemotherapy eligibility, requires Stage II
colorectal cancer with a high risk of recurrence or Stage III colorectal cancer for postoperative
adjuvant chemotherapy, and patients with Stage II and III colon cancer are indicated for
postoperative adjuvant chemotherapy in the package insert of oxaliplatin.
[6] This criterion was established to select relatively healthy subjects.
[7] This criterion was established out of concern for subject safety.
[8] The efficacy of Recomodulin will be investigated on CIPN induced by oxaliplatin, which frequently
causes this condition. The oxaliplatin-containing postoperative adjuvant chemotherapy regimens
recommended in the Guidelines for the Treatment of Colorectal Cancer are FOLFOX and CapeOX.
FOLFOX compliance is readily determinable because the regimen is administered under the control

  
 
6
of healthcare professionals, which makes the regimen ideal for this first study to evaluate the 
efficacy of Recomodulin in CIPN. The standard FOLFOX regimen mFOLFOX6 was selected. The 
standard mFOLFOX6 treatment duration of 6 months (12 courses) was selected to allow evaluation 
of the efficacy of Recomodulin in oxaliplatin-induced chronic neuropathy. 
[9] This criterion was established to ensure that the study is ethically consistent. 
 
3.3.2  Rationale for Exclusion Criteria 
[1] This criterion was established out of concern for subject safety. 
[2] to [4] These criteria were established because of the possible impact these conditions could have on 
the efficacy and safety evaluations in the study. 
[5] This criterion was established because of the potential impact on the evaluation of safety. 
[6] and [7] These criteria were established out of concern for subject safety and in reference to the 
general indications for postoperative adjuvant chemotherapy in the Guidelines for the Treatment of 
Colorectal Cancer. 
[8] to [10] As these conditions are listed in the Careful Administration and Contraindications sections 
of the Recomodulin package insert, these criteria were established out of concern for subject safety. 
[11] This criterion was established out of concern for subject safety to prevent the registration of patients 
satisfying the inclusion criteria because of transfusion or the like. 
[12] This criterion was established out of concern for subject safety because HBV reactivation during or 
after postoperative adjuvant chemotherapy could lead to hepatitis B onset15). 
[13] to [16] These criteria were established out of concern for subject safety. 
[17] and [18] These criteria were established because of the possible impact these conditions could have 
on the efficacy and safety evaluations in the study. 
[19] This criterion was included to allow exclusion when the evaluation of efficacy and safety in the 
study could be impacted by another reason and when the investigator or subinvestigator determines 
that subject safety cannot be guaranteed. 

7
4. Subject Informed Consent
4.1  Authoring of the Informed Consent Form
Based on the reference informed consent form provided by the sponsor, the investigator will author 
an informed consent form and submit the document to the sponsor. The informed consent form will 
contain the statements for patients presented below. The investigator will consult with the sponsor to 
review the completed informed consent form and then obtain the approval of an institutional review 
board selected by the director of the study site. 
Information for patients 
[1] That the study involves research.
[2] Purpose of the study.
[3] The name, title, and contact information of the investigator or subinvestigator.
[4] Study methodology.
[5] The expected clinical benefits and risks or inconveniences.
[6] The alternative treatments that may be available for the disease and their important potential risks
and benefits.
[7] The scheduled duration of study participation by the subjects.
[8] That participation in the study is voluntary and that the subject may refuse to participate or stop
participating in the study at any time. Also that the subject would not be treated disadvantageously
for refusing to participate or withdrawing consent and would not lose benefits to which the subject
would be otherwise entitled for not participating.
[9] That the monitor(s), the auditor(s), the institutional review board, and the regulatory authority(ies)
will be granted direct access to the subject’s treatment-related source documents, without violating
the confidentiality of the subject, and that, by signing the written informed consent form, the subject
is authorizing such access.
[10] The privacy of the subject would be maintained if the study results are published.
[11] The person(s) in the study site to contact for obtaining further information regarding the study and
the rights of subjects, and whom to consult or contact in the event of a study-related injury.
[12] Compensation and treatment to which the subject is entitled if the subject is injured in relation to the
study.
[13] The number of subjects scheduled to participate in the study.
[14] That the subject will be promptly informed if information becomes available that may be relevant to
the subject’s willingness to continue participating in the study.
[15] The foreseeable circumstances and/or reasons under which the subject’s participation in the study
may be terminated.
[16] The expenses, if any, required of the subject.
[17] The monetary and other payments, if any, to the subject for participating in the study.
[18] Rules with which the subject is expected to comply.
[19] That any doctor treating the subject will be notified about the participation of the subject in the
study.
[20] The type of institutional review board, that the institutional review board will conduct reviews to
determine whether the study should be conducted or continued based on its scientific and ethical

8
merits, and that the opinions of the institutional review board will be relayed to the director of the 
study site. 
[21] The name and address of the person installing the institutional review board and how to obtain
information about this person.
[22] That any remaining samples might be used for future research for drug development.
[23] That data may be used not only for approval review of the drug product but also for cross-sectional
studies by the regulatory authorities as well as guideline preparation.
[24] That data may be used secondarily.
[25] That data obtained before the subject gives informed consent could be used.
4.2  When and How to Obtain Informed Consent 
The investigator or subinvestigator will use the informed consent form to fully inform each patient 
about the study and his or her rights before the subject begins the study and then obtain voluntary 
consent from the patient along with the date of consent by having the patient personally sign the 
informed consent form. 
The investigator or subinvestigator will sign or seal the informed consent form and enter the date on 
which the subject was informed. If a clinical research coordinator provides a supplementary explanation, 
that clinical research coordinator will also sign or seal the informed consent form and enter the date of 
the explanation. The investigator or subinvestigator will give the written information for patients and a 
copy of the informed consent form to the subject. Study-specific tests and treatment changes not 
performed in routine care and treatment will not be conducted before informed consent is obtained. 
4.3  Informing Other Hospitals When Informed Consent Is Obtained 
The investigator or subinvestigator will determine if the subject is being treated at another hospital or 
department. If this is the case, the investigator or subinvestigator will, with the consent of the subject, 
notify the responsible doctor. 
4.4  Information to Consider When Obtaining Informed Consent 
The following should be kept in mind when obtaining informed consent: 
[1] The investigator or subinvestigator will discuss the study using plain language understandable to the
patients.
[2] The investigator or subinvestigator must not force the subjects to participate or continue
participating in the study or exert inappropriate influence on their decisions to do so.
[3] After discussing the study, the investigator or subinvestigator will grant the patient an opportunity
to ask questions, will address the questions to the patient’s satisfaction, and grant adequate time for
the patient to decide whether to participate in the study.
[4] The investigator or subinvestigator will specify the visit days for the patients and discuss and obtain
permission for the tests and observations.
[5] When informing the subjects, the investigator or subinvestigator must not force the subjects to
waive their rights, use language that could be construed as doing so, absolve the investigator, study
site or sponsor of their legal obligations, or use language that could be construed as doing so.

9
[6] Informed consent by a proxy is not allowed in the study.
[7] Patients requiring a witness are not allowed as study subjects.
4.5  Amending the Informed Consent Form 
[1] The sponsor will promptly inform the director of the study site and the investigator in writing on
obtaining any information that could affect the willingness of the subjects to continue participating
in the study.
[2] The investigator or subinvestigator will promptly orally convey this information to the subjects and
determine their willingness to continue in the study.
[3] If determining an amendment to be necessary, the investigator will promptly amend the informed
consent form based on the information and submit the amended document to the sponsor. The
investigator will consult with the sponsor to review the document and then obtain the approval of
the institutional review board of the study.
[4] The investigator or subinvestigator will again inform the subjects currently participating in the study
using the amended informed consent form and obtain written consent to continue in the study
according to Section 4.2 .

10
5. Study Design and Schedule
5.1  Study Design
Category
Description
Location of
detailed 
description 
Study design 
Multi-center, randomized, double-blind, placebo-controlled, 
parallel-group comparative study 
- 
Clinical phase 
Phase 2 
- 
Group composition 
ART-123 3-dose group, ART-123 1-dose group, placebo 
group 
Section 8 
Dose and mode of 
administration 
Administer the investigational product (ART-123 380 U/kg 
or placebo) once daily by intravenous infusion over 
approximately 30 minutes from Days 1 to 3 of each course 
of postoperative adjuvant chemotherapy (mFOLFOX6). 
Section 8 
Target sample size 
75 registered subjects (25 per group) 
Section 12 
Investigational product 
assignment 
The investigational product assignment manager will prepare 
key codes and assign drug numbers to the investigational 
products based on these. 
Section 6 
Assigning subjects to 
treatment groups 
A subject registration center will randomly assign the 
subjects. 
Section 7 
Efficacy endpoints 
[1]
NCI-CTCAE version 4.0 (NCI-CTCAE) peripheral
motor neuropathy, peripheral sensory neuropathy
(CIPN only)
[2]
DEB-NTC
[3]
FACT/GOG-NTX-12
[4]
FACT-G
[5]
NRS (pain)
[6]
Discontinuation, suspension, and dose reduction of
oxaliplatin due to CIPN
Sections 9 
and 12 
Safety endpoints 
[1]
Vital signs (body temperature, blood pressure
systolic/diastolic, pulse rate)
[2]
Laboratory tests (routine blood tests, clinical chemistry
tests, urine analysis, coagulation tests)
[3]
Immunogenicity (anti-drug antibodies, neutralizing
antibodies)
[4]
Adverse events other than CIPN
Sections 9 
and 12 
Others 
Pharmacokinetics (blood concentration of thrombomodulin 
alfa (recombinant)) 
Sections 9 
and 12 
Study period 
July 2016 to January 2018 
Section 5 
Interim analysis 
Will not be performed. 
-

11 
5.2  Rationale for Study Design 
5.2.1  Endpoints and Rationale 
[1] NCI-CTCAE is widely used throughout the world to evaluate adverse reactions to antineoplastic
agents. The NCI-CTCAE events related to peripheral neuropathy are peripheral motor neuropathy
and peripheral sensory neuropathy, which are included as endpoints in this study.
[2] DEB-NTC, in addition to NCI-CTCAE, is used for evaluating peripheral neuropathy in Japanese
clinical studies of oxaliplatin. Characteristically, DEB-NTC assigns grades according to the
duration of the symptoms. DEB-NTC is therefore suited to obtaining information on the duration of
CIPN in the study, which is why it was included as an endpoint.
[3] and [4] The FACT subscale FACT/GOG-NTX-12, which is specialized for evaluating
oxaliplatin-induced peripheral neuropathy, was selected as a patient reported outcome for assessing
peripheral neuropathy severity. Because the significance of CIPN prevention and treatment lies in
preventing reductions in patient QOL in addition to facilitating chemotherapy, FACT-G was
selected to allow the evaluation of patient-reported QOL.
[5] NRS was selected for evaluating pain, which is highly relevant to patient QOL.
[6] Oxaliplatin compliance was selected as an endpoint because allowing adequate chemotherapy to be
initiated and continued for the underlying disease is one reason for this Recomodulin development
program.
5.2.2  Control Drug and Rationale 
No drug for preventing the onset of CIPN is available. A placebo-controlled design was therefore 
determined to be appropriate for investigating the absolute effects of the investigational medicinal 
product on the prevention of CIPN onset. 
5.3  Study Methods 
As shown in Figure 5.3-1, the study consists of a screening period, treatment period, and follow-up 
period. 
Screening period (up to 14 days)
This period for registering subjects lasts for up to 14 days, spanning from the day of informed 
consent to the day before the first day of investigational product administration. 
Treatment period [24 weeks (up to 36 weeks)]
This period spans the 24-week period over which 12 courses of biweekly postoperative adjuvant 
chemotherapy are administered. The treatment period extends from the first day of investigational 
product administration to Day 15 of the last course or the day of the treatment-period 
discontinuation evaluations. 
Follow-up period [4 weeks (up to 6 weeks)]
This period lasts from the day after Day 15 of the last course or the day of the treatment-period 
discontinuation evaluations to the study completion. 

12
Figure 5.3-1 Screening, treatment, and follow-up periods of the study 
5.4  Study Period 
July 2016 to January 2018 

  
 
13
6. Investigational Products 
6.1  Names and Descriptions of Investigational Products 
[1] Investigational medicinal product 
• Investigational product code: ART-123 
• Nonproprietary name: Thrombomodulin alfa (recombinant) (JAN) 
• Description: Recomodulin is a glycoprotein consisting of 498 amino acid residues 
(C2230H3357N633O718S50, molecular weight: 52,124.58) produced by Chinese hamster ovary cells 
designed to express cDNA that encodes amino acid residues 1 to 498 of human thrombomodulin 
(total molecular weight: approximately 64,000). 
• Storage conditions: Store at room temperature and away from light 
• Location of manufacture: 
. 
[2] Control drug (placebo) 
• Investigational product code: ART-123 (placebo) 
• Storage conditions: Store at room temperature and away from light 
• Location of manufacture: 
 
 
6.2  Investigational Product Dosage Form and Strength 
[1] Investigational medicinal product 
• Injection 
• A freeze-dried formulation containing 12,800 U thrombomodulin alfa (recombinant) per vial 
• Contains 40 mg L-arginine hydrochloride and a pH adjuster as excipients 
[2] Control drug 
• Injection 
• A freeze-dried formulation free of thrombomodulin alfa (recombinant) that is indistinguishable 
in appearance from ART-123 (the investigational medicinal product) 
• Contains 29 mg L-arginine hydrochloride, 800.1 mg Polysorbate, 1.5 mg sodium chloride, and a 
pH adjuster as excipients 
 

14
6.3  Investigational Product Packaging and Labeling 
[1] Vial
Vial label
Day 2 and 3 labels are similarly formatted 
[2] Inner box
Each Day 1, 2, or 3 inner box contains 18 vials of ART-123 or ART-123 placebo.
Label (top)
Day 2 and 3 labels are similarly formatted 
Labels (one on front and one on side of box) 
ART-123 for investigational use (18 vials per box) 
Day 1 
Subject code: 
Asahi Kasei Pharma Corporation 
Day 2 and 3 labels are similarly formatted 

  
 
16
[2] The subject registration center will process the emergency key unblinding request and ask the 
sponsor for permission to unblind the emergency key. 
[3] The sponsor will determine the need to unblind the emergency key and approve the unblinding 
request of the subject registration center. 
[4] After confirming that the sponsor has approved the unblinding request, the subject registration 
center will issue a passcode for unblinding the emergency key and notify the person who requested 
unblinding. 
[5] The person who requested unblinding will input the passcode from the subject registration center in 
the emergency key unblinding result screen of the IWRS, submitting this to the subject registration 
center. 
[6] The subject registration center will check the passcode entered and display the result of emergency 
key unblinding on the emergency key unblinding result screen of the IWRS. 
[7] The subject registration center will inform the sponsor that the emergency key has been unblinded. 
[8] The sponsor will inform the medical expert of the result of emergency key unblinding. 
[9] The investigator or subinvestigator will promptly complete the electronic case report form of the 
subject in question and submit the document to the sponsor. 
 
6.8  Confirmation of Indistinguishability 
At the time of investigational product assignment and after the study completion, the investigational 
product assignment manager will check some of the investigational products assigned to confirm 
indistinguishability. 
 
6.9  Dispensing of Investigational Product 
The sponsor will confirm that the contract has been executed and then dispense the investigational 
product to the investigational product controller designated by the study site director. 
 
6.10  Storage and Control of Investigational Product 
After receiving the investigational products from the sponsor, the investigational product controller 
will store and control the investigational products according to Appendix 2 of the investigational 
product handling procedures provided by the sponsor. 
 
6.11  Collection of Investigational Products 
 The study site investigational product controller will determine investigational product usage and 
document the amount remaining at the time of investigational product replacement or when 
investigational product administration is discontinued or completed at the study site for the subject 
in question. All unused investigational product will be returned to the sponsor. At this time, all outer 
boxes in use (including those that have been opened but not used) will be sealed after the sponsor 
determines the quantity. 

  
 
17
 The investigational product controller will not discard the unused investigational product, inner 
boxes (empty and in use), or outer boxes (empty and in use), retaining these items until they are 
collected by the sponsor. 
 

  
 
19
7.2  Enrolling Subjects in the Study 
7.2.1  Information to Enter in IWRS 
The investigator or subinvestigator or a clinical research coordinator will enter the following 
information via the IWRS, based on the source documents, after informed consent for study 
participation is given and before registration. 
[1] Study center and name of investigator or subinvestigator 
[2] Subject identification code 
[3] Date of informed consent 
[4] Confirmation of eligibility in terms of inclusion and exclusion criteria 
[5] Background information 
Subject background information to determine: Date of birth, age, sex (male, female), race, previous 
subject identification code (if subject is rescreened) 
 
7.2.2  Creation of Screening Log 
The investigator or subinvestigator will create and retain a screening log with the following 
information for each patient giving informed consent: 
• Subject identification code 
• Subject name 
• Chart number 
• Sex 
• Date when patient is informed 
• Date of informed consent 
• Eligibility for registration and date of registration 
• Drug number 
 
7.2.3  Assigning Subjects to Treatment Groups 
Subjects will be assigned to treatment groups after IWRS entry. 
The subject registration center will confirm subject eligibility and then assign each subject to the 
ART-123 3-dose group, ART-123 1-dose group, or placebo group. Block randomization with the study 
sites as a stratification factor will be used to achieve an ART-123 3-dose group, ART-123 1-dose group, 
and placebo group assignment ratio of 1:1:1. 
 

 
 
20
8. Subject Treatment 
8.1  Investigational Product Dosage and Administration 
8.1.1  Dosage and Administration 
Administer the investigational product (ART-123 380 U/kg or placebo) once daily by intravenous 
infusion over approximately 30 minutes from Days 1 to 3 of each course of postoperative adjuvant 
chemotherapy (mFOLFOX6). 
[1] ART-123 3-dose group 
On Day 1, initiate ART-123 administration from 2 hours to 30 minutes before oxaliplatin 
administration and complete administration before the start of oxaliplatin administration. On Days 2 
and 3, administer ART-123 at about the same time as on Day 1 whenever possible. 
[2] ART-123 1-dose group 
On Day 1, initiate ART-123 administration from 2 hours to 30 minutes before oxaliplatin 
administration and complete administration before the start of oxaliplatin administration. On Days 2 
and 3, administer the placebo at about the same time as on Day 1 whenever possible. 
[3] Placebo group 
On Day 1, initiate placebo administration from 2 hours to 30 minutes before oxaliplatin 
administration and complete administration before the start of oxaliplatin administration. On Days 2 
and 3, administer the placebo at about the same time as on Day 1 whenever possible. 
 
8.1.2  Number of Doses 
36 (three/course × 12 courses) 
If the course 12 postoperative adjuvant chemotherapy has not commenced within 34 weeks (Day 239 
from the day of registration), discontinue the subject from the study, perform the treatment-period 
discontinuation evaluations, and then perform the end-of-study evaluations on Day 43 of the last course 
of postoperative adjuvant chemotherapy. 
 
8.1.3  Instructions for Prescribing the Investigational Product 
• Dissolve the contents of one vial (12,800 U) in 2 mL Japanese Pharmacopoeia physiological 
saline or Japanese Pharmacopoeia glucose injection (5%). Collect the required amount of this 
solution based on the weight of the subject and dilute with 100 mL of the same diluent to 
prepare enough infusion for 1 day. Prepare according to the separately provided investigational 
product handling procedures (Appendix 2) because the number of vials needed and required 
volume of the dissolved solution depend on the dose and the weight of the subject. 
• Determine the investigational product dose by weighing the subject before investigational 
product administration on Day 1 or on the day before Day 1 of each course. Give the same 
investigational product dose on Days 1 to 3 of each course. 
• If administering an injection concurrently with the investigational product and the injection 
cannot be combined with other products, follow the procedures that the sponsor will provide to 
the study site. 
 

 
 
21
8.1.4  Criteria for Suspension/Resumption and Criteria for Discontinuation of the Investigational 
Product 
• Suspend use of the investigational product when the administration of oxaliplatin is suspended. 
Resume investigational product administration concurrently with the resumption of oxaliplatin 
administration. 
• Discontinue use of the investigational product if the administration of oxaliplatin is 
discontinued. 
 
8.2  Rationale for Dosage and Administration and Number of Doses of the Investigational Product 
8.2.1  Dosage and Administration 
A dosage of 380 U/kg once daily, which is already approved and supported by safety data, was 
selected as the dose for this study. As stated in Section 1.2.2 , moreover, the suppression of hyperalgesia 
by ART-123 in a rat model of oxaliplatin-induced peripheral neuropathy was correlated with the dose, 
with greater activity occurring at higher doses, and it is preferable to administer the doses frequently. To 
make treatment clinically feasible, a 3-dose group that will receive treatment on three consecutive days 
in each course was established. To make treatment convenient for patients, a 1-dose group was 
established because administering a single dose in each course is optimal. 
 
8.2.2  Number of Doses 
Thirty-six doses (three per course) were selected because the Guidelines for the Treatment of 
Colorectal Cancer recommend 12 courses of mFOLFOX6, and the investigational product will be 
administered to match the number of courses of oxaliplatin. 
 
8.3  Dosage and Administration of Standard Concomitant Drugs 
8.3.1  Doses, Administration Procedures, and Dosing Schedule 
Administer mFOLFOX6 as postoperative adjuvant chemotherapy according to the following 
administration procedures, doses, and dosing schedule: 
 
One course: Repeat every 2 weeks (14 days) 
• Oxaliplatin 85 mg/m2 
On Day 1 of the course, intravenously infuse over 2 hours*1 
• Levofolinate 200 mg/m2 
On Day 1 of the course, intravenously infuse over 2 hours*1 concurrently with oxaliplatin 
• Fluorouracil 400 mg/m2 
On Day 1 of the course, give as an intravenous bolus after the completion of oxaliplatin 
administration 
• Fluorouracil 2,400 mg/m2 
On Day 1 of the course, continuously intravenously infuse over 46 hours after the intravenous 
bolus of fluorouracil 
*1 The duration of infusion may be extended to address allergies. 

 
 
22
 
Table 8.3-1 Dosing schedule for investigational product and postoperative adjuvant 
chemotherapy 
 
Day 1 
Day 2 
Day 3 
Investigational product 
 
 
 
Oxaliplatin infusion 
 
 
 
Levofolinate infusion 
 
 
 
Fluorouracil bolus 
 
 
 
Continuous fluorouracil 
infusion 
  
 
 
One course: Repeat every 2 weeks (14 days) 
On Day 1, initiate investigational product administration from 2 hours to 30 minutes before oxaliplatin 
administration and complete administration before the start of postoperative adjuvant chemotherapy. On 
Days 2 and 3, administer the investigational product at about the same time as on Day 1 whenever possible. 
 
8.3.2  Changing the Dosage and Schedule of Postoperative Adjuvant Chemotherapy 
This document uses the following terms in relation to changing the dosage and schedule of 
postoperative adjuvant chemotherapy: 
 
Table 8.3-2 Terms related to changing the dosage and schedule of postoperative adjuvant 
chemotherapy 
 
mFOLFOX6 
All drugs 
Some drugs 
Postpone 
Refers to not starting administration 
of all drugs in the next mFOLFOX6 
course on the Day 15 evaluation 
day. 
- 
Suspend 
- 
Refers to not administering some 
drugs in a course. 
Reduce (the dose) 
- 
Refers to reducing the dose of some 
drugs in a course below the 
specified dose. 
Discontinue 
(discontinue 
treatment) 
Refers to stopping, without resumption, some or all of the mFOLFOX6 
drugs beginning in a given course. 
 
46 h 
2 h 
2 h 
 
 
30 min 
 
30 min 
 
30 min 

 
 
23
8.3.2.1  Criteria for Changing Postoperative Adjuvant Chemotherapy 
[1] Criteria for postponing all postoperative adjuvant chemotherapy drugs 
Referring to the criteria in Table 8.3-3 before administration on the day of postoperative adjuvant 
chemotherapy administration in course 2 and beyond, the investigator or subinvestigator will 
postpone the administration of all postoperative adjuvant chemotherapy drugs until the subject’s 
condition satisfies the criteria. The administration of all drugs may be postponed if any of the 
criteria for suspending oxaliplatin in Table 8.3-5 are satisfied on the day scheduled for oxaliplatin 
administration. If no postoperative adjuvant chemotherapy for the subsequent course is begun 
within 43 days of the start of the most recent postoperative adjuvant chemotherapy (Day 1), the 
subject will be discontinued from the study and undergo the end-of-study evaluations. 
 
Table 8.3-3 Criteria for postponing all postoperative adjuvant chemotherapy drugs 
Type 
Initiation criteria 
Neutrophil count 
≥1,500/mm3 
Platelet count 
≥75,000/mm3 
 
[2] Criteria for reducing the dose of oxaliplatin and fluorouracil in association with adverse events 
If a subject experiences an adverse event, the investigator or subinvestigator will reduce the dose 
of oxaliplatin and fluorouracil in reference to the following criteria: 
 
Table 8.3-4 Criteria for reducing the dose of oxaliplatin and fluorouracil in association with 
adverse events 
Type 
Greatest severity 
Next dose 
Neutrophil count 
<500/mm3 
Reduce oxaliplatin dose to 75 mg/m2 
Reduce fluorouracil dose by 20% 
Platelet count 
<50,000/mm3 
Gastrointestinal tract adverse 
events (occurring despite 
prophylactic treatment) 
≥Grade 3 a) 
a) NCI-CTCAE 
 
[3] Criteria for suspending or reducing the dose of oxaliplatin in association with peripheral neuropathy 
The investigator or subinvestigator will determine the dose of oxaliplatin according to the criteria 
in Table 8.3-5 on Day 1 of each course. 
• If reducing the oxaliplatin dose, do not increase the dose even if the CTCAE grade improves. 
• After suspending oxaliplatin, resume treatment at the dose of 75 mg/m2. 
The investigator or subinvestigator need not comply with these criteria when determining that 
other criteria are necessary to ensure subject safety. 
 
Table 8.3-5 Criteria for suspending or reducing the dose of oxaliplatin in association with 
peripheral neuropathy 

 
 
24
Greatest NCI-CTCAE*1 grade after 
previous oxaliplatin dose 
Day 1 
NCI-CTCAE 
grade 
(day of 
evaluation) 
Action to take for oxaliplatin 
≤Grade 1 
≤Grade 1 
Do not reduce dose or suspend. 
≥Grade 2 
≤Grade 1 
Do not reduce dose or suspend. 
(The dose may be reduced to 75 mg/m2.) 
Any 
Grade 2 
Reduce the dose to 75 mg/m2. 
(Treatment may be suspended.) 
Any 
≥Grade 3 
Treatment may be suspended. 
*1 Assess the NCI-CTCAE grade of the more severe of peripheral motor neuropathy or peripheral sensory 
neuropathy. 
8.4  Prohibited Treatments and Interventions During the Study 
8.4.1  Prohibited Concomitant Drugs 
 The administration of the following medications is prohibited from informed consent until study 
completion. 
(1) Other investigational products 
(2) Thrombomodulin alfa (recombinant) 
(3) Antineoplastic agents other than those specified for use in the postoperative adjuvant 
chemotherapy in this study 
Rationale 
• (1) Out of concern for subject safety. 
• (2) This is the active ingredient of the investigational medicinal product and would not allow 
proper evaluation of efficacy and safety. 
• (3) The use of these drugs could induce drug-induced peripheral neuropathy, which would 
prevent proper evaluation of efficacy. Adding other antineoplastic agents, moreover, would 
affect the safety evaluation of Recomodulin. 
 The administration of the following medications is prohibited from the start of administration of the 
investigational product until study completion. 
(1) Thrombolytic drugs (e.g., t-PA preparations, urokinase) 
Rationale 
• (1) Out of concern for subject safety because the pharmacological action of the investigational 
medicinal product could increase the risk of bleeding. 
 
8.4.2  Restricted Concomitant Drugs 
Over-the-counter medications and ready-made transfusion preparations are not considered restricted 
concomitant medications. 
 The administration of the following medications is prohibited from informed consent until study 
completion except in association with use while peripheral motor neuropathy or peripheral sensory 

 
 
25
neuropathy is found by the investigator or subinvestigator to be Grade 2 or greater based on 
NCI-CTCAE. 
(1) Calcium gluconate, magnesium sulfate 
(2) Glutathione 
(3) L-glutamine 
(4) Vitamin B6, B12, and E preparations 
(5) Goshajinkigan, shakuyaku-kanzoto 
(6) Narcotics and similar drugs (including the opioid receptor agonist codeine phosphate) 
(7) Oral and injected adrenocorticosteroids (except when used to treat nausea/vomiting associated 
with the administration of an antineoplastic agent or to treat an allergy) 
(8) Pregabalin, gabapentin 
(9) Nonsteroidal anti-inflammatory drugs (NSAIDs, except when used for a purpose other than 
CIPN treatment) 
(10) Tricyclic antidepressants 
(11) Serotonin/noradrenaline reuptake inhibitors 
Rationale 
• For ethical reasons, prohibitions of these medications are lifted because NCI-CTCAE Grade 2 or 
greater peripheral motor neuropathy or peripheral sensory neuropathy is of a severity requiring 
consideration of oxaliplatin dose reduction/suspension. 
• (1) to (5) These drugs are reported to be effective in the prevention or treatment of CIPN, 
meaning that their use would prevent proper evaluation of efficacy. 
• (6) to (11) These drugs may be effective in the treatment of CIPN, meaning that their use would 
prevent proper evaluation of efficacy. 
 
 Initiating the administration of or increasing the dose of any of the following medications is 
prohibited from informed consent until study completion. Subjects may continue to use the 
medications that they had been using before informed consent provided that no dose changes are 
made. (Dose reductions are allowed.) 
(1) Isoniazid, ethambutol, metronidazole, medications for the treatment of HIV infection, 
HMG-CoA reductase inhibitors, tacrolimus, colchicine, and interferon preparations 
Rationale 
• (1) These drugs could induce drug-induced peripheral neuropathy. Initiation or dose escalation 
during the study could affect efficacy evaluation. 
 
8.4.3  Prohibited Concomitant Therapies 
 The following treatments are prohibited from informed consent until study completion. 
(1) Radiotherapy 
(2) Operations and other surgical procedures that could affect efficacy evaluation 
Rationale 
• (1) Because of the potential impact on the evaluation of safety. 
• (2) Because of the impact on properly evaluating subject efficacy. 

 
 
26
 
9. Investigations/Observations and Evaluations 
The investigator or subinvestigator will perform the investigations/observations and evaluations 
specified in this section. The investigator or subinvestigator or a clinical research coordinator will 
complete electronic case report forms (eCRFs) based on the source documents. 
 
9.1  Investigation/Observation and Evaluation Schedule 
The time points for investigations/observations are shown in Table 9.1-1, Summary of study schedule. 
Hereafter, time points are indicated with the first day of postoperative adjuvant chemotherapy in each 
course counted as Day 1 (D1). 

 
 
28
Safety 
Laboratory tests 
●c) 
 
 
 
 
 
 
 
 
●k) 
 
 
 
 
 
 
 
●k) 
 
 
 
 
 
● 
● 
● 
 
Vital signs 
● 
 
 
 
 
 
 
 
 
● 
 
 
 
 
 
 
 
● 
 
 
 
 
 
● 
● 
● 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
● 
 
Immunogenicity 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
● 
 
Pharmacokinetics 
 
● 
 
●f) 
●f) 
●f) 
 
 
 
 
 
 
△f) 
△f) 
 
 
 
 
 
 
△f) 
△f) 
 
 
 
 
 
Time points are expressed as “Day (D),” and numbers of days are expressed as “day (d).” 
●: required 
◯: to be performed only in the event of postponement of the administration of all drugs for postoperative adjuvant chemotherapy 
△: if no blood samples are available from course 1, perform once in one of the courses from 2 to 12 
a) Not required in courses in which oxaliplatin is suspended 
b) To be performed before investigational product administration if the evaluation takes place on the same day as investigational product administration 
c) To be performed between Day −7 and Day −1 (1 day before registration); hepatitis B test data obtained within 6 months before the day of registration may also be used 
d) To be performed only in course 2; may be determined on the day before Day 1 
e) To be performed only in courses 5 and 9 
f) Collect blood samples immediately after and from 30 to 120 minutes after completion of investigational product administration 
g) If the evaluation at treatment period discontinuation takes place on or after Day 43 of the last course of postoperative adjuvant chemotherapy, or if the tests/observations 
for the subsequent clinical study are not possible, perform the end-of-study evaluations instead of the treatment-period discontinuation evaluations. If the course 12 
postoperative adjuvant chemotherapy has not commenced within 34 weeks (Day 239 from the day of registration), discontinue the subject from the study, perform the 
treatment-period discontinuation evaluations, and then perform the end-of-study evaluations on Day 43 of the last course of postoperative adjuvant chemotherapy. 
h) If any postoperative adjuvant chemotherapy for the subsequent course has not commenced by Day 43 of a course, discontinue the subject from the study and perform the 
end-of-study evaluations. 
i) If the subject is discontinued from the study in the follow-up period, perform the end-of-study evaluations. 
j) Determine the status of fluorouracil continuous intravenous infusion use. 
k) May be determined on the day before Day 1 
 

 
 
29
9.2  Investigations/Observations and Evaluations to be Conducted at Each Time Point 
9.2.1  Screening Period (Day −14 to Day −1) 
• Informed consent 
• Subject demographic information survey 
• Initiation of a survey on concomitant medications/therapies 
• Initiation of a survey on adverse events 
• Pregnancy test (only subjects for whom the test is required) 
• Vital sign measurement 
• Laboratory tests (blood/urine)*1 
*1 To be performed between Day −7 and Day −1 (1 day before registration) 
 
9.2.2  Treatment Period*1 
*1 If any postoperative adjuvant chemotherapy for the subsequent course has not commenced by Day 43 of a 
course, discontinue the subject from the study and perform the study completion evaluations. 
9.2.2.1  Day 1 of Course 1 
 Before investigational product administration 
• Subject demographic information survey 
• Laboratory test results verification 
• Patient registration 
• Concomitant medications/therapies survey 
• Adverse events survey 
• Efficacy endpoints survey 
- NCI-CTCAE: As of the time of evaluation 
- DEB-NTC 
- FACT/GOG-NTX-12 
- FACT-G 
- NRS (pain) 
• Blood sampling for pharmacokinetic analysis 
• Blood sampling for immunogenicity test 
• Weighing of subject to determine investigational product dose*1 
 Investigational product administration and administration status survey 
 After investigational product administration 
• Postoperative adjuvant chemotherapy administration and administration status survey 
• Blood sampling for pharmacokinetic analysis 
• Adverse events survey 
*1 Subjects may be weighed on the previous day 
 
9.2.2.2  Days 2 and 3 of Course 1 
 Before investigational product administration 
• Concomitant medications/therapies survey 
• Adverse events survey 

 
 
30
• Efficacy endpoint survey 
- NCI-CTCAE: The worst condition noted between the preceding evaluation (excluding any 
unscheduled evaluation) and the day of evaluation 
 Investigational product administration and administration status survey 
 Fluorouracil continuous intravenous infusion status survey 
 After investigational product administration 
• Blood sampling for pharmacokinetic analysis 
• Adverse events survey 
 
9.2.2.3  Day 8 of Course 1*1 
• Efficacy endpoint survey 
- FACT/GOG-NTX-12 
- NRS (pain) 
*1 No office visit required. The survey may be performed when the subject is at home or elsewhere. 
 
9.2.2.4  Day 15 (permitted window, +7 days)*1 and Day 29 (permitted window, +7 days)*1 of 
Course 1 
• Concomitant medications/therapies survey 
• Adverse events survey 
• Investigational product administration status survey 
• Postoperative adjuvant chemotherapy administration status survey 
• Efficacy endpoint survey 
- NCI-CTCAE 
i) The worst condition noted between the preceding evaluation (excluding any unscheduled 
evaluation) and the day of evaluation 
ii) Condition at the time of evaluation 
- DEB-NTC 
- FACT/GOG-NTX-12 
- NRS (pain) 
*1 To be performed only in the event of postponement of the administration of all drugs for postoperative 
adjuvant chemotherapy 
 
9.2.2.5  Day 1 of Courses 2 to 12 
 Before investigational product administration 
• Concomitant medications/therapies survey 
• Adverse events survey 
• Efficacy endpoints survey 
- NCI-CTCAE 
i) The worst condition noted between the preceding evaluation (excluding any unscheduled 
evaluation) and the day of evaluation 
ii) Condition at the time of evaluation 
- DEB-NTC 

 
 
31
- FACT/GOG-NTX-12 
- FACT-G*1 
- NRS (pain) 
• Pregnancy test (only subjects for whom the test is required)*2 
• Vital sign measurement 
• Laboratory tests (blood/urine)*3 
• Weighing of subject to determine investigational product dose*3 
 Investigational product administration and administration status survey 
 After investigational product administration 
• Postoperative adjuvant chemotherapy administration and administration status survey 
• Adverse events survey 
*1 To be performed only in Courses 5 and 9 
*2 To be performed only in Course 2; may be determined on the day before Day 1 
*3 May be determined on the day before Day 1 
 
9.2.2.6  Days 2 and 3 of Courses 2 to 12 
 Before investigational product administration 
• Concomitant medications/therapies survey 
• Adverse events survey 
• Efficacy endpoint survey 
- NCI-CTCAE: The worst condition noted between the preceding evaluation (excluding any 
unscheduled evaluation) and the day of evaluation 
 Investigational product administration and administration status survey 
 Fluorouracil continuous intravenous infusion status survey 
 After investigational product administration 
• Blood sampling for pharmacokinetic analysis*1 
• Adverse events survey 
*1 To be performed once in any of Courses 2 to 12 if blood is not sampled in Course 1 
 
9.2.2.7  Day 8 of Courses 2 to 12*1 
• Efficacy endpoint survey 
- FACT/GOG-NTX-12 
- NRS (pain) 
*1 No office visit required. The survey may be performed when the subject is at home or elsewhere. 
 
9.2.2.8  Day 15 (permitted window, +7 days)*1 and Day 29 (permitted window, +7 days)*1 of 
Courses 2 to 11 
• Concomitant medications/therapies survey 
• Investigational product administration status survey 
• Postoperative adjuvant chemotherapy administration status survey 
• Adverse events survey 
• Efficacy endpoints survey 

 
 
32
- NCI-CTCAE 
i) The worst condition noted between the preceding evaluation (excluding any unscheduled 
evaluation) and the day of evaluation 
ii) Condition at the time of evaluation 
- DEB-NTC 
- FACT/GOG-NTX-12 
- NRS (pain) 
*1 To be performed only in the event of postponement of the administration of all drugs for postoperative 
adjuvant chemotherapy 
 
9.2.2.9  Day 15 of Course 12 (permitted window, +7 days) 
• Concomitant medications/therapies survey 
• Adverse events survey 
• Efficacy endpoints survey 
- NCI-CTCAE: The worst condition noted between the preceding evaluation (excluding any 
unscheduled evaluation) and the day of evaluation 
- DEB-NTC 
- FACT/GOG-NTX-12 
- FACT-G 
- NRS (pain) 
• Vital sign measurement 
• Laboratory tests (blood/urine) 
 
9.2.3  At Discontinuation in the Treatment Period*1 
• Concomitant medications/therapies survey 
• Adverse events survey 
• Efficacy endpoints survey 
- NCI-CTCAE: The worst condition noted between the preceding evaluation (excluding any 
unscheduled evaluation) and the day of evaluation 
- DEB-NTC 
- FACT/GOG-NTX-12 
- FACT-G 
- NRS (pain) 
• Vital sign measurement 
• Laboratory tests (blood/urine) 
*1 If the evaluation at treatment period discontinuation takes place on or after Day 43 of the last course of 
postoperative adjuvant chemotherapy, or if the tests/observations for the subsequent clinical study are not 
possible, perform the end-of-study evaluations instead of the treatment-period discontinuation evaluations. 
 
9.2.4  Follow-up Period*1 
*1 If the subject is discontinued from the study in the follow-up period, perform the end-of-study evaluations. 

 
 
33
9.2.4.1  At Study Completion (Day 43 of the last course [permitted window, +14 days]) 
• Concomitant medications/therapies survey 
• Adverse events survey 
• Efficacy endpoints survey 
- NCI-CTCAE: The worst condition noted between the preceding evaluation (excluding any 
unscheduled evaluation) and the day of evaluation 
- DEB-NTC 
- FACT/GOG-NTX-12 
- FACT-G 
- NRS (pain) 
• Pregnancy test (only subjects for whom the test is required) 
• Vital sign measurement 
• Laboratory tests (blood/urine) 
• Blood sampling for immunogenicity 
 
9.2.5  At Unscheduled CIPN Evaluations (if a restricted concomitant medication is prescribed by 
the investigator or subinvestigator for the prevention or treatment of CIPN at any time other 
than the above-mentioned evaluations)*1 
• Efficacy endpoint survey 
- NCI-CTCAE: The worst condition noted between the preceding evaluation and the day of 
evaluation 
*1 An office visit is required. 
 
9.3  Subject Demographic Information Survey 
The investigator or subinvestigator will determine the following information and enter it in the eCRF. 
 Initially assigned drug number 
 Day of registration 
 Body height and weight (date of measurement and values), smoking status, drinking status and 
alcohol consumption 
 ECOG performance status 
 Details of colon cancer (site [cecum/ascending colon/transverse colon/descending colon/sigmoid 
colon/rectosigmoid], disease stage [I/II/IIIa/IIIb/IV], date of resection) 
 Comorbidities: disease(s) present at informed consent 
 History: history of peripheral neuropathy (disease name, time of disease), history of CNS 
neuropathy (disease name, time of disease), history of diabetes mellitus (disease name, time of 
disease), history of alcohol abuse (time of disease) 
 Details of menopause*1 (premenopausal or <2 years since menopause/≥2 years since menopause) 
*1 Female subjects only 
 

 
 
34
9.4  Survey of Investigational Product Administration Status and Postoperative Adjuvant 
Chemotherapy Administration Status 
The investigator or subinvestigator will determine the following information about the investigational 
product and postoperative adjuvant chemotherapy from after subject registration to study completion 
(Day 43 of the last course). 
[1] Investigational product 
• Whether administered, the drug number of the drug actually administered, time and date of the 
first dose, time and date of the last dose, status of administration (entire amount/other) 
[2] Postoperative adjuvant chemotherapy 
• Oxaliplatin: 
Whether administered (if not administered, the reason [CIPN/adverse event/other]); any 
reduction from the planned dose of 85 mg/m2 (if dose reduction took place, the reason 
[CIPN/adverse event/other]); time and date of the first dose; time and date of the last dose; the 
actual dose 
• Levofolinate:  
Whether administered (if not administered, the reason [change in fluorouracil dose/adverse 
event/other]); any reduction from the planned dose of 200 mg/m2 (if dose reduction took place, 
the reason [change in fluorouracil dose/adverse event/other]); first day of administration  
• Fluorouracil intravenous bolus: 
Whether administered (if not administered, the reason [CIPN/adverse event/other]); any 
reduction from the planned dose of 400 mg/m2 (if dose reduction took place, the reason 
[CIPN/adverse event/other]); first day of administration  
• Fluorouracil continuous intravenous infusion: 
Whether administered (if not administered, the reason [CIPN/adverse event/other]); any 
reduction from the planned dose of 2,400 mg/m2 (if dose reduction took place, the reason 
[CIPN/adverse event/other]); first day of administration; last day of administration (if the 
treatment ended before Day 3, the reason [CIPN/adverse event/other]) 
 
9.5  Survey of Concomitant Medications/Therapies 
9.5.1  Concomitant Medications 
The investigator or subinvestigator will determine the following information about the concomitant 
medications used from after informed consent to study completion (the day of the Day 43 evaluations in 
the last course). 
 
9.5.1.1  Concomitant Medications that are Neither Prohibited nor Restricted 
• Name of drug, first day of administration, last day of administration 
 
9.5.1.2  Prohibited and Restricted Concomitant Medications 
The information listed below will be determined for any prescription drug used that corresponds to 
the definition of a prohibited or restricted medication, even if the route of administration and the reason 
for its use are in compliance. Over-the-counter medications and ready-made transfusion preparations are 

 
 
35
considered concomitant medications described in “9.5.1.1 Concomitant medications that are neither 
prohibited nor restricted.” 
• Name of drug, route of administration, first day of administration, last day of administration, 
dose, reason for administration (CIPN/adverse event/other) 
 
9.5.2  Concomitant Therapies 
The investigator or subinvestigator will determine the following information about all therapies 
performed concomitantly from after informed consent to study completion. 
• Name of therapy, first day of treatment, last day of treatment 
 
9.6  Investigations/Observations Pertaining to Efficacy and Evaluation Methods 
9.6.1  Efficacy Endpoints 
 Endpoints to be evaluated by the investigator or subinvestigator 
• NCI-CTCAE peripheral motor neuropathy, peripheral sensory neuropathy (CIPN only) 
• DEB-NTC 
 Endpoints to be evaluated by the subject 
• FACT/GOG-NTX-12 
• FACT-G 
• NRS (pain) 
 Other 
• Discontinuation, suspension, and dose reduction of oxaliplatin due to CIPN 
 
The efficacy endpoints will not be classified as primary or secondary because this is an exploratory 
study of ART-123 for preventing the onset of oxaliplatin-induced peripheral neuropathy. 
 
9.6.2  Considerations for Efficacy Evaluations 
Evaluations performed on a day when the investigational product is administered will be performed 
before administration. 
 
9.6.3  Evaluation Methods 
9.6.3.1  NCI-CTCAE Peripheral Motor Neuropathy, Peripheral Sensory Neuropathy (CIPN only) 
The investigator or subinvestigator will evaluate neuropathy as follows: 
 Assessment time points 
• Days 1, 2, 3, 15*1, and 29*1 of courses 1 to 11 
• Days 1, 2, 3, and 15 of course 12 
• At Study completion 
• At Discontinuation in the Treatment Period 
• At unscheduled CIPN evaluations 
*1 To be performed only in the event of postponement of the administration of all drugs for postoperative 
adjuvant chemotherapy 

 
 
36
 Information to be determined and evaluated 
• Date and time point of evaluation (before investigational product administration/after 
investigational product administration/not applicable) 
• Evaluate the grade on a 6-step scale (none, Grade 1 to 5) for each of the evaluation 
classifications (peripheral motor neuropathy, peripheral sensory neuropathy) based on the 
NCI-CTCAE grade classification system provided in Appendix 3 
• Assess the condition at the time of evaluation on Day 1 of course 1 
• On Days 15 and 29 of courses 1 to 11 and Day 1 of courses 2 to 12, assess the worst condition 
noted between the preceding evaluation (excluding any unscheduled evaluation) and the day of 
evaluation and the condition at the time of evaluation 
• On days of evaluation other than Day 1 and Days 15 and 29 of courses 1 through 11, assess the 
worst condition noted between the preceding evaluation (excluding any unscheduled evaluation) 
and the day of evaluation. At unscheduled CIPN evaluations, assess the worst condition noted 
between the preceding evaluation and the day of evaluation 
 
9.6.3.2  DEB-NTC 
The investigator or subinvestigator will evaluate neuropathy as follows: 
 Assessment time points 
• Days 1, 15*1, and 29*1 of courses 1 to 11 
• Days 1 and 15 of course 12 
• At Study completion 
• At Discontinuation in the Treatment Period 
 Information to be determined and evaluated 
• Date and time point of evaluation (before investigational product administration/after 
investigational product administration/not applicable) 
• Evaluate each of the following symptoms based on the DEB-NTC grade classification system 
provided in Appendix 4 
- Peripheral sensory abnormalities or discomfort when touching things (Grade 0 to 2) (If Grade 
1 or greater, the site of symptom: hand/foot/lip, tongue and surroundings, 
face/pharyngolarynx/other) 
- Painless peripheral sensory abnormalities or discomfort under normal conditions (Grade 0 to 
2) (If Grade 1 or greater, the site of symptom: hand/foot/lip, tongue and surroundings, 
face/pharyngolarynx/other) 
- Painful peripheral sensory abnormalities or discomfort under normal conditions (Grade 0 to 
2) (If Grade 1 or greater, the site of symptom: hand/foot/lip, tongue and surroundings, 
face/pharyngolarynx/other) 
- Functional disorders (Grade 0, 3) 
*1 To be performed only in the event of postponement of the administration of all drugs for postoperative 
adjuvant chemotherapy 
 

 
 
37
9.6.3.3  FACT/GOG-NTX-12 
A clinical research coordinator will have subjects complete the Japanese version of the 
FACT/GOG-NTX-12 (Version 4, Appendix 5) questionnaire. The clinical research coordinator will 
collect questionnaires from subjects and enter the date and results of evaluation in the eCRF. 
 Assessment time points 
• Days 1, 8, 15*1, and 29*1 of courses 1 to 11 
• Days 1, 8, and 15 of course 12 
• At Study completion 
• At Discontinuation in the Treatment Period 
 Information to be determined 
• Date and time point of evaluation (before investigational product administration/after 
investigational product administration/not applicable) 
 Considerations for evaluations 
• If the day of an evaluation falls on the day of an office visit, inform the subject to complete the 
questionnaire before the efficacy evaluation by the investigator or subinvestigator. 
• To allow the evaluation of physician-evaluated severity of peripheral neuropathy independently 
from subject evaluations, the investigator or subinvestigator and clinical research coordinator 
present during the physician evaluation of peripheral neuropathy will not review evaluations 
entered by the subjects. 
• A clinical research coordinator not present during the physician evaluation of peripheral 
neuropathy will collect the questionnaires from the subjects and enter them in the eCRFs without 
informing the investigator or subinvestigator and clinical research coordinator present during the 
physician evaluation of peripheral neuropathy. 
*1 To be performed only in the event of postponement of the administration of all drugs for postoperative 
adjuvant chemotherapy 
 
 
9.6.3.4  FACT-G 
The investigator or subinvestigator will have subjects complete the Japanese version of the FACT-G 
(Version 4, Appendix 6) questionnaire. The clinical research coordinator will collect questionnaires 
from subjects and enter the date and results of evaluation in the eCRF. 
 Assessment time points 
• Day 1 of courses 1, 5, and 9 
• Day 15 of course 12 
• At Study completion 
• At Discontinuation in the Treatment Period 
 Information to be determined 
• Date and time point of evaluation (before investigational product administration/after 
investigational product administration/not applicable) 
 

 
 
38
9.6.3.5  NRS (pain) 
The investigator or subinvestigator will have subjects evaluate the severity of pain at the site subject 
to evaluation based on the NRS. The clinical research coordinator will collect the evaluation forms from 
subjects and enter the date and results of evaluation in the eCRF. 
 Assessment time points 
• Days 1, 8, 15*1, and 29*1 of courses 1 to 11 
• Days 1, 8, and 15 of course 12 
• At Study completion 
• At Discontinuation in the Treatment Period 
•  
 Sites subject to evaluation 
• Hands 
• Feet 
 Date and time point of evaluation (before investigational product administration/after 
investigational product administration/not applicable) 
*1 To be performed only in the event of postponement of the administration of all drugs for postoperative 
adjuvant chemotherapy 
 
0: no pain at all; 10: the most severe pain imaginable 
 
 
9.7  Investigations/Observations Pertaining to Safety and Evaluation Methods 
9.7.1  Vital Signs 
The investigator or subinvestigator will measure body temperature, blood pressure, and pulse rate. 
Vital signs will be measured with the subjects at rest. 
 Measurement time points 
• Screening period 
• Day 1 of courses 2 to 12 
• Day 15 of course 12 
• At Study completion 
• At Discontinuation in the Treatment Period 
•  
 Parameters 
• Axillary temperature 
• Sitting systolic/diastolic blood pressure 
• Sitting pulse rate 
 Information to be determined 

 
 
39
• Date and time point of measurement (before investigational product administration/after 
investigational product administration/not applicable) 
• Results 
 
9.7.2  Laboratory Tests 
The investigator or subinvestigator will collect samples from subjects at the following measurement 
time points and have the samples analyzed at the study site. 
 Measurement time points 
• Screening period*1 
• Day 1 of courses 2 to 12*2 
• Day 15 of course 12 
• At Study completion 
• At Discontinuation in the Treatment Period 
 
 Laboratory test parameters 
• Routine blood tests: Red blood cell count, haemoglobin, haematocrit, white blood cell count, 
white blood cell differential (neut, lympho, mono, eosino, baso), platelet count 
• Clinical chemistry tests: AST (GOT), ALT (GPT), ALP, LDH, total bilirubin, total protein, 
albumin, BUN, creatinine, glucose, uric acid, electrolytes (Na, K, Cl) 
• Urine analysis: Protein (qualitative), glucose (qualitative), occult blood (qualitative) 
• Immunological assays*3: HBs antigen, HBc antibody, HBs antibody, HBV-DNA*4 
• Coagulation tests: PT-INR, activated partial thromboplastin time, fibrinogen 
 
 Information to be determined 
• Dates of blood/urine sampling, time points of blood/urine sampling (before investigational 
product administration/after investigational product administration/not applicable) 
• Results (routine blood tests, clinical chemistry tests, urine analysis, coagulations tests) 
*1 To be performed between Day −7 and Day −1 (one day before registration) 
*2 May be determined on the day before Day 1 
*3 To be performed only in the screening period to determine eligibility. Test data obtained within 6 months 
before registration may be used. 
*4 In cases where the test result is positive for HBc antibody or HBs antibody 
 
9.7.3  Immunogenicity (anti-drug antibodies, neutralising antibodies) 
The investigator or subinvestigator will collect samples from the subjects at the time points listed 
below, separate the serum, and temporarily store the serum before submitting the samples to the 
immunogenicity assay laboratory. Samples will be collected, processed, stored, and shipped as directed 
in written procedures to be submitted by the sponsor to each study site. The immunogenicity assay 
laboratory will conduct assays of anti-drug antibodies and neutralising antibodies and submit the results 
to the sponsor after unblinding. As the sponsor will be electronically notified of the results, the data 
need not be input into the eCRFs. Only the dates and time points of blood sampling should be entered. 
 Measurement time points 

 
 
40
• Before investigational product administration on Day 1 of course 1 
• At study completion 
 Blood sample volume: 6 mL 
 Information to be determined 
• Date and time point of blood sampling (before investigational product administration/after 
investigational product administration/not applicable) 
 
9.7.4  Adverse Events 
9.7.4.1  Definition of Adverse Events 
An adverse event is defined as any untoward or unintended disease or sign (including abnormal 
laboratory findings and vital signs) that occurs after informed consent. Any adverse event occurring 
after investigational product administration is considered a treatment-emergent adverse event (TEAE). 
When a diagnosis can appropriately be assigned for an adverse event, that diagnosis rather than the 
symptom or sign will be the adverse event name. Abnormal laboratory findings and vital signs are 
constituted when: 
[1] An abnormal laboratory finding or vital sign satisfies the definition of a serious adverse event. 
[2] An abnormal laboratory finding or vital sign results in the suspension or discontinuation of the 
investigational product. 
[3] An abnormal laboratory finding or vital sign results in the use of a drug or intervention for 
treatment. 
[4] The physician determines that an abnormal laboratory finding or vital sign is of a medically 
significant severity (e.g., is an abnormality consistent with [2] or [3] above but there was no 
opportunity for intervention). 
 
CIPN will not be considered an adverse event in this study. 
 
9.7.4.2  Identification of Adverse Events 
The investigator or subinvestigator will identify adverse events spontaneously reported by the 
subjects and through interview and tests on each observation day. 
Information to be determined:  
Name of adverse event, date of occurrence, status of investigational product administration 
(discontinuation/suspension/no change [including completion]), date of outcome, outcome, 
seriousness classification, rationale for seriousness, severity, causal relationship to the 
investigational product, whether the subject was discontinued from the study 
 
9.7.4.3  Adverse Event Reporting Period 
Adverse events occurring from after informed consent to study completion (Day 43 of the last 
course) will be reported. 
 

 
 
41
9.7.4.4  Assessing Adverse Events 
9.7.4.4.1  Seriousness Classifications 
The investigator or subinvestigator will classify each adverse event as a serious adverse event or 
non-serious adverse event according to the criteria given below. For serious adverse events, the reason 
will be selected from items 1 to 6 below. 
 Serious adverse events: 
 1: Results in death (death) 
 2: Life threatening (possibility of death) 
 3: Requires hospitalization or prolongation of hospitalization for treatment (hospitalization or 
prolongation of hospitalization) 
 4: Persistent or significant disability or incapacity (disability) 
 5: Is a congenital anomaly (congenital anomaly) 
 6: Other medically significant condition (possibility of disability, seriousness consistent with 1 to 4 
above) 
 Non-serious adverse events: 
 This refers to all adverse events that are not serious adverse events. 
 
9.7.4.4.2  Severity 
The investigator or subinvestigator will assess the severity of each adverse event as Grade 1 to 5 
based on NCI-CTCAE. The severity of adverse events not corresponding to the events in the glossary 
will be assessed according to the following criteria: 
 
Table 9.7-1 Adverse event severity assessment criteria 
Grade 1 
Mild 
Asymptomatic or mildly symptomatic 
Clinical findings or laboratory test findings only 
Treatment not indicated 
Grade 2 
Moderate 
Minimal/local/non-invasive treatment indicated 
Limiting age-appropriate instrumental activities of daily livinga) 
Grade 3 
Severe or medically significant but not immediately life-threatening 
Hospitalization or prolongation of hospitalization indicated 
Disability/disabling 
Limiting self-care activities of daily livingb) 
Grade 4 
Life-threatening consequences 
Urgent intervention indicated 
Grade 5 
Death related to an adverse event 
a) Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b) Self-care activities of daily living refer to bathing, dressing and undressing, eating, using the toilet, taking 
medications, and being not bedridden. 

 
 
42
Source: JCOG Japanese translation of the NCI Common Terminology Criteria for Adverse Events Version 
4.0. 
 
9.7.4.4.3  Causal Relationships to Investigational Product 
The investigator or subinvestigator will assess adverse event causality according to the criteria below. 
Events classified as item 1 will be handled as adverse reactions. 
1. Related 
When there is a reasonable possibility that the investigational product caused the adverse 
event. The causality will be assessed as “related” when a reasonable possibility that the 
investigational product caused the adverse event is not evaluable. 
2. Not related 
When there is no reasonable possibility that the investigational product caused the adverse 
event. 
 
9.7.4.5  Follow-up for Adverse Events 
All adverse events will be followed until resolution or return to baseline level or until the 
symptoms/test values are found to have stabilized and are no longer clinically significant. Data obtained 
during the period specified in Section 9.7.4.3 . will be entered in the eCRFs. 
 
9.8  Other Investigations/Observations and Evaluation Methods 
9.8.1  Pharmacokinetics (blood concentration of thrombomodulin alfa (recombinant)) 
The investigator or subinvestigator will collect samples from the subjects at the time points listed 
below, separate the plasma, and temporarily store the plasma before submitting the samples to the 
plasma concentration laboratory. Samples will be collected, processed, stored, and shipped as directed 
in written procedures to be submitted by the sponsor to each study site. The plasma concentration 
laboratory will determine plasma drug concentrations and submit the results to the sponsor after 
unblinding. As the sponsor will be electronically notified of the results, the data need not be input into 
the eCRFs. Only the times and dates of blood sampling should be entered. 
 Assessment time points 
• Day 1 of course 1: Before investigational product administration and just after and 30 to 120 
minutes after completion of investigational product administration 
• Days 2 and 3 of course 1*1: Just after and 30 to 120 minutes after completion of investigational 
product administration 
*1 To be performed once in any of courses 2 to 12 if blood is not sampled in course 1 
 Blood sample volume: 3 mL 
 Information to be determined 
• Time and date of blood sampling 
 
9.8.2  Urine Pregnancy Testing 
The investigator or subinvestigator will collect urine samples from subjects at the time points listed 
below and test for pregnancy in reference to human chorionic gonadotropin test (urine) findings. Only 

 
 
43
female subjects will undergo pregnancy testing. Testing is not required for women who have been 
postmenopausal for at least 2 years at informed consent. Male subjects will be interviewed at these 
testing times to determine if their partner is pregnant. Data will be entered in the eCRF only if the 
subject is female. 
 Measurement time points: Screening period, Day 1 of course 2*1, study completion 
 Information to be determined: Date of urine sampling, pregnancy status 
*2 May be determined on the day before Day 1 
 
9.8.3  Pathology of CIPN and Exploratory Assessments of Efficacy and Safety of the 
Investigational Product 
Collected serum and plasma samples that remain after immunogenicity and pharmacokinetic 
evaluations will be stored for up to 5 years after study completion in the immunogenicity assay 
laboratory and plasma concentration laboratory according to separately established sample handling 
procedures and may be used during this period to elucidate the mechanism of CIPN onset or the 
mechanism of action of Recomodulin or for research to develop drugs to prevent or treat CIPN. No 
genetic information will be handled. Any such investigations will be initiated in accordance with 
procedures established by the sponsor. 
 

 
 
44
10. Ensuring Subject Safety 
10.1  Basic Information 
The investigator or subinvestigator will determine patient eligibility by conducting observations and 
examinations at the time of screening and will not enroll a patient in the study when safety cannot be 
ensured. 
The investigator or subinvestigator will investigate the health of the subjects on each observation day 
during the study and ensure that emergency contact is possible. If a subject-reported or other adverse 
event occurs, the investigator or subinvestigator will promptly take appropriate actions as necessary for 
ensuring subject safety. 
The sponsor will appropriately collect and relay any safety information relevant to the study. 
The investigator or subinvestigator will endeavor to identify adverse reactions early by closely 
monitoring subject symptoms. 
10.2  Particularly Notable Information 
10.2.1  Precautions Related to Bleeding 
Because Recomodulin has anticoagulant activity and could potentially cause or exacerbate bleeding 
symptoms, the drug must be administered with bleeding symptoms sufficiently managed. If a 
bleeding-related serious adverse event occurs, Recomodulin administration will be discontinued as 
necessary, and appropriate intervention, such as transfusion, will be provided as necessary. 
 
10.2.2  Interventions for Overdoses 
There is no drug that is known to neutralise the anticoagulant activity of Recomodulin. In the event of 
an accidental overdose, discontinue administration of Recomodulin and give intravenous fluids, a 
transfusion, or other intervention to reduce plasma levels as necessary while closely monitoring for 
worsening of bleeding tendencies and changes in coagulation activity and the like. 
 
10.2.3  Monitoring for Hypersensitivity 
Recomodulin is a protein product and could therefore cause shock, anaphylactoid symptoms, and 
similar conditions. The investigator or subinvestigator should therefore closely observe the subject 
during Recomodulin administration. If anaphylaxis is suspected based on skin symptoms such as 
urticaria, gastrointestinal symptoms, respiratory symptoms such as dyspnea, or disturbance of 
consciousness and the like, immediately discontinue Recomodulin administration and provide 
intervention according to “The manual for handling disorders due to adverse drug reactions-focus on the 
anaphylaxis” (March 2008, Ministry of Health, Labour and Welfare)16) (Figure 10.2-1). 
 

 
 
45
 
Figure 10.2-1 Procedures for treating anaphylaxis16) 
 
10.3  Actions to Take for Serious Adverse Events 
10.3.1  Procedures for Investigator or Subinvestigator 
When a serious adverse event occurs, the investigator or subinvestigator will promptly notify the 
sponsor and study site director orally or by telephone, fax, or a similar means regardless of the causal 
relationship to the investigational product. The sponsor will be notified no later than 24 hours after a 
serious adverse event is identified. 
The investigator will complete a written report about each serious adverse event (using the specified 
form of the study site or sponsor) for submission to the sponsor and study site director. With the first 
reporting day as Day 0, the investigator will submit the written report to the sponsor by Day 4 if the 
event is a death or life threatening or by Day 7 if the event is another serious adverse event. 
The investigator or subinvestigator will comply with any instructions of the study site director based 
on the findings of the institutional review board about whether the study should continue and the 
instructions of the sponsor about amending the protocol or taking other appropriate actions. 
 
Skin and gastrointestinal symptoms 
• Generalised erythema, urticaria 
• Nausea, vomiting, abdominal pain 
Respiratory symptoms 
• Wheezing, hoarse voice 
Cardiovascular symptoms 
• Palpitations, cold sweat 
• 
Decreased 
blood 
pressure, 
disturbance of consciousness 
Oral or intravenously infused H1 
receptor antagonist 
★ 1 
1  Intramuscular injection of adrenaline 0 3-0 5 mL (children: 0 01 mg/kg, maximum of 0 3 mg) 
2  Oxygen (mask, 6-8 L/minute) 
3  Steroid infusion 
 Hydrocortisone 100-200 mg (children: 5 mg/kg) or 
 methylprednisolone 40 mg (children: 1 mg/kg) in 6-8 hour intervals 
4  H1 receptor antagonist infusion 
5  Nebulizer (β2 stimulant) 
6  Endotracheal intubation or tracheostomy for respiratory failure 
★ In addition to 1 
1  Rapidly infused intravenous fluids (infusion with 5-10 mL/kg of saline over the first 5 
minutes)  
 Subsequently switch to Ringer’s solution  Maintain systolic blood pressure at 90 mmHg  
2  Intramuscular injection of adrenaline 0 3-0 5 mg in 5- to 30-minute intervals or gradual 
intravenous injection of 0 1 mg/mL over at least 5 minutes 
Note: When the patient is on an oral β blocker, intravenously inject 1-5 mg of glucagon (20-30 μg/kg, over at 
least 5 minutes) instead of adrenaline. Then change to an intravenous infusion at 5-15 μg/minute. 
○ If anaphylaxis is suspected, immediately take the ABCDE approach and administer treatment according to the 
following procedures: 
A: airway, B: breathing, C: circulation, D: disability, E: exposure 

 
 
46
10.3.2  Sponsor Procedures 
On receiving a written report of a serious adverse event from the investigator, the sponsor will 
consult with the medical expert as necessary to deliberate whether the study should be continued or 
suspended and the need to change the protocol or amend the reference informed consent form. 
After this deliberation, the sponsor will notify the regulatory authorities, study site directors, and 
investigators by the specified deadlines as necessary. 
 
10.3.3  Emergency Protocol Deviations/Modifications and Emergency Key Unblinding 
The investigator or subinvestigator may deviate from or modify the protocol without the prior 
agreement of the sponsor and prior approval of the institutional review board in a medically 
unavoidable situation such as to avoid exposing a subject to acute risk (Section 13.2 ). The investigator 
or subinvestigator may request unblinding of the emergency key when finding this to be necessary to 
ensure subject safety (Section 6.7 ). 
 
10.4  Actions to Take for Identified Pregnancies 
The investigator or subinvestigator will discontinue any subject found to be pregnant from the 
investigational product (Section 11). 
Pregnancies will not be considered adverse events (unless the investigational product is suspected of 
having inhibited the effect of a contraceptive drug). The investigator or subinvestigator will conduct 
follow-up for all pregnancy outcomes (spontaneous abortion, induced abortion, normal delivery, 
delivery with congenital anomaly) and notify the sponsor. Pregnancies in the partners of male subjects 
will be similarly handled. 
Deliveries, induced abortions, and spontaneous abortions associated with a congenital anomaly and 
induced abortions and spontaneous abortions because of a maternal abnormality in a female subject will 
be treated as serious adverse events. 
 

 
 
47
11. Completion and Discontinuation of Treatment and Observations 
11.1  Days of Completion and Discontinuation of Individual Subjects 
When a subject completes the study, promptly enter the day of completion (i.e., the day when the 
final tests and observations specified in the protocol are performed) in the eCRF. 
When a subject is discontinued from the study, promptly enter the day of discontinuation (i.e., the 
day when the final tests and observations specified in the protocol are performed) and the reason for 
discontinuation (select the primary and other reasons from the choices in Section 11.2.1 ) in the eCRF. 
Determine whether oxaliplatin was discontinued and, if so, promptly enter the reason for 
discontinuation (CIPN/adverse event/other) in the eCRF. 
 
11.2  Discontinuation Criteria for Individual Subjects 
11.2.1  Study Discontinuation Criteria 
The investigator or subinvestigator will discontinue from the study subjects satisfying any of the 
following discontinuation criteria: 
[1] Adverse event 
This refers to when a subject is discontinued for an adverse event. This includes cases when a 
subject is discontinued by request because of an adverse event and when a subject dies because of 
an adverse event and cannot continue in the study. 
[2] Allowable range for the postoperative adjuvant chemotherapy schedule exceeded 
This refers to when a subsequent course of postoperative adjuvant chemotherapy is not started 
within 43 days of the start of the most recent postoperative adjuvant chemotherapy (Day 1). 
[3] Extension of study period 
This refers to when the 12th course of postoperative adjuvant chemotherapy has not started as of 
Week 34 (239 days after the day of registration). 
[4] Lack of efficacy 
This refers to discontinuations because study procedures are not effective in the targeted disease 
(CIPN onset). This includes cases when the targeted disease progresses because of lack of efficacy. 
[5] Subject lost to follow-up 
This refers to when subsequent tests and observations (including follow-up by telephone) are not 
possible because the subject is unable to visit. 
[6] Discontinued by investigator or subinvestigator 
This refers to when the physician finds a subject unsuited to study continuation for a reason in 
another category. 
[7] Major protocol deviation 
This refers to when the subject is discontinued on the identification of a major protocol deviation 
(GCP violation, inclusion/exclusion criteria violation, drug number violation, multiple 
registrations). 
[8] Subject ineligible at screening 
This refers to discontinuations, taking place before assignment, according to the 
inclusion/exclusion criteria. 

 
 
48
[9] Identification of pregnancy 
This refers to when the subject is found to be pregnant during the treatment period. 
[10] By subject request 
This refers to when a subject is discontinued by request. 
[11] Per decision by sponsor 
This refers to when a subject is discontinued after the sponsor submits a notification such as to 
completely or partially terminate or suspend the study or terminate the study at a study site. 
Termination of the study at a study site includes cases in which an investigator transfer or study site 
closure complicates study continuation by a subject in the opinion of the sponsor. 
 
11.3  Rationale for Discontinuation Criteria 
These criteria were established to respect the wishes of the subjects, ensure safety, avoid influencing 
evaluations, and honor subject circumstances. 
 
11.4  Discontinuation Procedures 
11.4.1  Procedures for Study Discontinuation from Informed Consent to Before Registration 
The investigator or subinvestigator will perform discontinuations according to the following 
procedures if a subject must be discontinued from the study from the time of informed consent to before 
registration. 
[1] Promptly inform the affected subject of discontinuation and state in the medical records that the 
subject was discontinued on determining that any of the discontinuation criteria in Section 11.2.1  
are applicable (criteria 1 and 6 to 11). 
[2] Promptly notify the sponsor of the discontinuation. The investigator or subinvestigator will 
promptly enter the information in Section 7.2.1  and the reason for discontinuation in the IWRS 
and then send the data to the subject registration center. All complications and adverse events up to 
the time of discontinuation will be recorded in the eCRF. 
 
11.4.2  Procedures for Post-registration Discontinuations 
After deciding to discontinue a subject who has been registered from the study, the investigator or 
subinvestigator will: 
[1] Promptly inform the affected subject and, if the subject is receiving the investigational product, 
promptly discontinue treatment on determining that any of the above discontinuation criteria in 
Section 11.2.1  are applicable. 
[2] Promptly administer the appropriate treatment to the affected subject when a subject is discontinued 
for an adverse event, worsening of symptoms, or other incident. 
[3] Promptly perform the observations and tests/evaluations scheduled for treatment-period 
discontinuations if the subject is discontinued during the treatment period. Assess the reason for 
discontinuation as in Section 11.2 . 
• If the evaluation at treatment period discontinuation takes place on or after Day 43 of the last 
course of postoperative adjuvant chemotherapy, or if the subsequent tests/observations for the 

 
 
49
study are not possible, perform the study completion evaluations instead of the treatment-period 
discontinuation evaluations. 
• If the evaluation at treatment-period discontinuation takes place on or before Day 42 of the last 
course of postoperative adjuvant chemotherapy, have the subject re-visit on Day 43 of the last 
course of postoperative adjuvant chemotherapy and perform the end-of-study evaluations. 
[4] Promptly perform the observations and tests/evaluations scheduled for end of study if the subject is 
discontinued during the follow-up period. Assess the reason for discontinuation as in Section 11.2. 
[5] If a subject is discontinued for not visiting, inquire about the reason and condition after last visit by 
telephone, written correspondence, or another means whenever possible. 
[6] Promptly notify the sponsor of the study discontinuation. 
 
11.5  Procedures for Post-discontinuation Follow-up 
All unresolved (including improved) adverse events will be followed as described in Section 9.7.4.5 . 

 
 
50
12. Statistical Analysis 
12.1  Selection of Sample Size 
A precision-based sample size was selected for this exploratory study. 
To allow the estimation of the incidence of CIPN in each of the ART-123 1-dose, ART-123 3-dose, 
and placebo groups at a precision of ±20%, a target sample size of 25 per group for a total of 75 was 
selected. 
 
12.2  Statistical Analysis Plan 
Key elements of the statistical analysis plan are presented here. The detailed aspects of statistical 
analysis will be stated in a statistical analysis plan to be finalized before unblinding. 
 
12.3  Analysis Populations 
12.3.1  Analysis Populations for Assessing Efficacy 
The two analysis populations for assessing efficacy are defined as the full analysis set (FAS) and the 
per-protocol set (PPS). Decisions on whether subjects will be included in the analysis populations and 
the following details will comply with subject handling criteria to be established later. 
 Full analysis set (FAS) 
This population consists of all subjects assigned to the investigational product except: 
• Subjects with a GCP violation 
• Subjects who do not receive oxaliplatin 
• Subjects who do not receive the investigational product 
• Subjects with no available efficacy data following investigational product administration 
 Per-protocol set (PPS) 
The PPS consists of all full analysis set subjects except: 
• Subjects with an inclusion/exclusion criterion violation 
• Subjects with another major protocol deviation 
 
12.3.2  Analysis Population for Assessing Safety 
This population consists of all subjects assigned to the investigational product except: 
• Subjects who do not receive the investigational product 
 
12.3.3  Analysis Populations for Assessing Pharmacokinetics 
This population consists of all subjects assigned to the investigational product except: 
• Subjects with a GCP violation 
• Subjects who do not receive the investigational product 
 
12.4  Handling of Data 
Major rules for handling efficacy data are discussed below. Details about the following and other 
data-handling rules will comply with data-handling criteria to be established later. 

 
 
51
• Handling of missing data on whether an assessment is NCI-CTCAE Grade 1 or greater 
Consider subjects for whom these data are missing to have had an NCI-CTCAE Grade 1 or 
greater event. Perform sensitivity analysis that includes analysis with a missing NCI-CTCAE 
grade for all such subjects. 
• Handling of NCI-CTCAE evaluation data in the second and subsequent courses 
Evaluate the Day 1 (before infusion of investigational product or mFOLFOX6) NCI-CTCAE 
grades as those from the immediately preceding course. Evaluate the Days 2, 3, 15, and 29 
NCI-CTCAE grades as those observed within the course. 
• Handling of missing efficacy endpoint data (continuous variables) 
Do not impute missing continuous efficacy endpoint data. Perform sensitivity analyses with 
imputation using the last-observation-carried-forward (LOCF) approach. 
 
12.5  Analysis of Demographic Variables and Other Baseline Characteristics 
Summary statistics will be calculated and categorical tabulations will be performed for demographic 
variables and other baseline characteristics in the FAS on a by-group basis. 
 
12.6  Analysis of Efficacy 
12.6.1  Overall Information 
This study is conducted to assess and characterize the clinical effect of ART-123 in preventing the 
onset of oxaliplatin-induced peripheral neuropathy and to explore appropriate efficacy endpoints. Thus, 
efficacy analyses will be performed primarily with descriptive statistics obtained by summarizing and 
graphing data from each evaluation time point. 
The incidences of NCI-CTCAE Grade 1 or greater events will be evaluated with statistical tests and 
95% confidence intervals as necessary in addition to descriptive statistics to allow intergroup 
comparison. The incidences of NCI-CTCAE Grade 1 or greater events with discontinuations and 
dropouts factored in will also be estimated. 
The FAS will be used as the primary analysis population for evaluating efficacy. Similar analyses 
will be conducted as necessary with the PPS as a secondary analysis population to confirm the stability 
of the analysis results. 
 
The significance level is set at 5% (two-sided), with a two-sided confidence interval and a confidence 
coefficient of 95%. Given the exploratory nature of the study, multiplicity will not be adjusted for. 
 
12.6.2  Efficacy Endpoints 
12.6.2.1  NCI-CTCAE 
For subjects found to have had one or more NCI-CTCAE Grade 1 or greater events during the study 
period, the incidence of NCI-CTCAE Grade 1 or greater events will be calculated by evaluation 
category, by course, and by treatment group. To provide reference data, differences will be calculated 
between the ART-123 1-dose and placebo groups and between the ART-123 3-dose and placebo groups. 
Moreover, survival analysis will be conducted with the occurrence of an NCI-CTCAE Grade 1 or 

 
 
52
greater event during the study period considered to be an event, and Kaplan-Meier curves will be 
plotted with the incidence of events on the vertical axis and items (1) and (2) below on the horizontal 
axis. 
(1) Observation period 
(2) Cumulative oxaliplatin dose 
The occurrence of NCI-CTCAE Grade 2 and greater events will be analyzed similarly to 
NCI-CTCAE Grade 1 and greater events. 
The number of subjects with events in each NCI-CTCAE grade will be tabulated by evaluation 
category, evaluation time point, and treatment group. As necessary, shift tables showing Day 1 of 
course 1 (baseline) and certain evaluation time points will be created for each treatment group. 
 Evaluation categories 
• Peripheral motor neuropathy 
• Peripheral sensory neuropathy 
 
12.6.2.2  DEB-NTC 
The number of subjects with events in each grade will be tabulated for the symptoms and sites shown 
below on the basis of the evaluation time point and treatment group. As necessary, shift tables showing 
Day 1 of course 1 (baseline) and certain evaluation time points will be created for each treatment group. 
 Symptoms 
• Peripheral sensory abnormalities or discomfort when touching things 
• Painless peripheral sensory abnormalities or discomfort under normal conditions 
• Painful peripheral sensory abnormalities or discomfort under normal conditions 
• Functional disorders 
 Sites 
• Hands, feet, lips/tongue and surroundings, face, pharyngolarynx, other 
 
12.6.2.3  FACT/GOG-NTX-12 
Summary statistics will be calculated for FACT/GOG-NTX-12 scores and changes from Day 1 of 
course 1 (baseline) by evaluation time point and treatment group, and figures showing changes over 
time in individuals will be plotted. 
 
12.6.2.4  FACT-G 
Summary statistics will be calculated for FACT-G scores and changes from Day 1 of course 1 
(baseline) by evaluation time point and treatment group. Scores calculated in each of the following 
evaluation categories will be similarly evaluated. 
 Evaluation categories 
Physical, social/family, emotional, and functional well-being 
 

 
 
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12.6.2.5  NRS (pain) 
For each of the sites listed below, summary statistics will be calculated for NRS scores and changes 
from Day 1 of course 1 (baseline) by evaluation time point and treatment group. 
 Sites 
Hands, feet 
 
12.6.2.6  Discontinuation, Suspension, and Dose Reduction of Oxaliplatin due to CIPN 
For each treatment group, Kaplan-Meier curves with the observation period and cumulative 
oxaliplatin dose on the horizontal axis and event incidence on the vertical axis will be plotted, with 
items [1] and [2] as events. 
[1] Discontinuation of oxaliplatin due to CIPN 
[2] Discontinuation, suspension, and dose reduction of oxaliplatin due to CIPN 
Discontinuations of oxaliplatin other than [1] and [2] is used as censored. 
The numbers of subjects who undergo discontinuation, suspension, or dose reduction of oxaliplatin 
due to CIPN will also be tabulated. 
 
12.6.2.7  Other Analyses 
The analyses listed below will be conducted as necessary. The details about statistical analyses will 
be presented in the statistical analysis plan. 
• Analysis adjusted for baseline values and other covariates 
• Analysis that factors in the effects of how dropouts or missing data are handled 
• Subgroup analyses 
• Analysis of the correlation between NCI-CTCAE grades and other efficacy endpoints 
• Analysis of postoperative adjuvant chemotherapy administration status 
 
12.7  Safety Analysis 
12.7.1  Analysis of Adverse Events 
TEAEs evaluated in the study will conform to the definition in Section 9.7.4.1 . All TEAEs identified 
from the first day of investigational product administration to study completion (Day 43 of the last 
course) will be included in the tabulations. The numbers of subjects with a TEAE in each treatment 
group will be tabulated by adverse event name, organ class, severity (per NCI-CTCAE grading), 
seriousness classification, causality, and the timing of onset. Differences from the placebo group in 
TEAE incidences will be calculated along with two-sided 95% confidence intervals of these differences. 
 
12.7.2  Analyses of Laboratory Findings 
Summary statistics will be calculated according to the evaluation time point and treatment group for 
each laboratory parameter. Variance in each laboratory parameter will be investigated in each treatment 
group. 
 

 
 
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12.7.3  Analyses of Vital Signs 
Each vital sign parameter will be analyzed as in Section 12.7.2 . 
 
12.7.4  Analysis of Immunogenicity (anti-drug antibodies, neutralising antibodies) 
These data will be categorically tabulated by evaluation time point and treatment group. 
 
12.8  Pharmacokinetic Analysis 
Lists and graphs of plasma drug concentrations following investigational product administration will 
be created for each subject. 
 
12.9  Timing of Analyses 
The analyses will be performed after unblinding. 
 
12.10  Reporting of Changes to the Analytical Plan 
Any analyses not described in the protocol or statistical analysis plan that are additionally conducted 
after unblinding will be reported independently of the analyses conducted according to the protocol or 
statistical analysis plan. 

 
 
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13. Protocol Compliance, Deviations/Modifications, and Amendment 
13.1  Protocol Compliance 
The investigators and sponsor will conduct the study in compliance with this protocol, to which both 
parties have agreed. The investigators and sponsor will sign or seal and date an agreement to be decided 
on elsewhere. 
 
13.2  Protocol Deviations and Modifications 
The investigator or subinvestigator will not deviate from or modify the protocol without prior 
agreement with the sponsor documented in writing and written approval based on prior review by the 
institutional review board. This is not applicable to protocol deviations for a medically necessary reason, 
such as to avoid exposing a subject to acute risk, and to clerical modifications. 
If deviating from the protocol for a medically necessary reason such as to avoid exposing a subject to 
acute risk, the investigator will enter the reason and other pertinent information in the “Report of 
protocol deviation to avoid acute risk,” promptly submitting this document to the study site director and 
sponsor. The investigator or subinvestigator will document all protocol deviations, regardless of the 
reason. 
 
13.3  Protocol Amendment 
The sponsor may amend the protocol as necessary, for example, if obtaining information pertinent to 
the proper execution of the study, to address a medically unavoidable event, or to correct the protocol as 
instructed by the study site director based on the findings of the institutional review board. 
If the protocol must be amended, the investigators and sponsor will discuss the revisions and sign or 
seal and date an agreement to be decided on elsewhere. The sponsor or investigators will promptly 
submit the amended protocol to the study site director. The approval of the institutional review board 
will be obtained if necessary. 
 

 
 
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14. Study Completion or Termination 
14.1  Study Completion 
The sponsor will promptly notify all study sites of the conclusion of registration on confirming that 
the number of subjects registered has reached the number of subjects targeted in the protocol and 
deciding that no new patients will be registered. 
The investigator will inform the study site director of the completion of the study and submit a 
summary of the study results in writing after the treatment, examinations, observations, and tests 
specified in the protocol have concluded for the last patient at that study site. 
 
14.2  Unblinding Following Study Completion 
After study completion, the data will be unblinded according to the following procedures: 
[1] The sponsor will decide how to handle all subjects registered in the study. 
[2] The investigational product assignment manager will confirm that the investigational products are 
indistinguishable after study completion. 
[3] After [1] and [2], the investigational product assignment manager will retrieve the copy of key 
codes and emergency keys retained by the sponsor and check if they have been opened. 
[4] The investigational product assignment manager will seal the documents at data lock. 
[5] The investigational product assignment manager will conduct unblinding. 
 
14.3  Termination or Suspension of the Study as a Whole or Partially 
The sponsor will resolve to terminate or suspend the study as a whole or partially if determining that 
the study should not continue due to a serious adverse reaction or similar incident. 
Subsequently, the sponsor will promptly submit a written report about study termination and the 
reason for termination to the investigators and subinvestigators, study site directors, and 
Pharmaceuticals and Medical Devices Agency (Ministry of Health, Labour and Welfare). 
The investigator or subinvestigator will promptly submit written notification to the subjects, and the 
study site director will promptly submit written notification to the institutional review board. 
 
14.4  Termination at a Study Site 
The sponsor may terminate the study at any study site where any of the situations listed below occurs. 
The sponsor will promptly submit written notification of the reason for termination to the study site 
director. The study site director will submit written notification to the investigator and the institutional 
review board. On receiving this notification, the investigator will follow the specified procedures for 
that study site. 
Conditions for terminating the study at a study site 
[1] When a study site commits a violation of the Japanese GCP Ministerial Ordinance, the protocol, or 
the study contract that interferes with the proper execution of the study, the study contract with that 
study site will be rendered null and void and the study will be terminated. This is not applicable 
when the violation is committed for a medically necessary reason such as to avoid exposing a 
subject to acute risk. 

 
 
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[2] When a study site no longer satisfies the conditions required for properly conducting the study. 
• There are no patients that satisfy the eligibility criteria. 
• Reassignment of the investigator or a similar circumstance is found to make the proper conduct 
of the study infeasible. 
15. Case Report Forms 
In the study, an electronic data capture (EDC) system will be used to electronically record the subject 
data in the eCRFs based on the source documents. The sponsor will provide the system to the study sites. 
Before using the EDC system, the investigator, subinvestigator, or clinical research coordinator must 
undergo training and be issued an account. After an account is issued, the user will log in with his or her 
account and enter data. 
The investigator, subinvestigator, or clinical research coordinator will enter patient registration 
information (e.g., inclusion/exclusion criteria eligibility) in the IWRS and transfer the data to the EDC 
system. 
Anti-drug antibody, neutralising antibody, and pharmacokinetic measurements will not be entered in 
the system. Anti-drug antibody, neutralising antibody, and pharmacokinetic measurements will be 
electronically submitted to the sponsor by contract laboratories after unblinding. 
 
15.1  Completion and Reporting of Case Report Forms 
The investigator or subinvestigator or a clinical research coordinator will make entries in the eCRFs. 
[1] Clinical research coordinators are allowed to enter only information contained in the source 
documents. 
[2] Data are to be entered when required in the EDC system according to the sponsor-provided “Data 
Entry Handbook.” 
[3] EDC system entry based on the source documents will be promptly completed for each subject who 
has given informed consent after the subject completes the follow-up period. EDC system entry will 
be promptly completed for any subject discontinued from the study. 
[4] The investigator will inspect all entries to confirm that no problems are present before electronically 
signing the eCRF. The system will be configured so that the investigators and subinvestigators 
cannot review FACT/GOG-NTX-12 entries, and the investigators will not electronically sign these 
entries. 
[5] After the sponsor locks the database, the investigator will accept electronically viewable electronic 
reports from the sponsor as the case report forms to be stored at the study site. 
 
15.2  Revising or Adding to a Case Report Form 
The investigator or subinvestigator or a clinical research coordinator will revise entries in or add 
entries to eCRFs. The records of changes made (date, description, and reason of change) will be stored 
as an audit trail in the EDC system. 
The investigator will inspect all revisions made after the investigator has signed the document to 
confirm that no problems are present before electronically re-signing the eCRF. 
 

 
 
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16. Direct Access to Source and Other Documents 
16.1  Definition of Source Documents 
Source documents are all medical records, laboratory test reports, informed consent forms, 
administration records, investigational product control records, and other documents on which the 
eCRFs are based. 
 
16.2  Direct Access 
The investigators and study sites will make available the source documents and all other study-related 
records to study-related monitoring, auditing, and institutional review board and regulatory authority 
inspections. 
 

 
 
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17. Study Quality Control and Quality Assurance 
17.1  Sponsor (and contract research organizations) 
The sponsor will conduct quality control and quality assurance according to the “Rules and 
procedures for conducting clinical studies of pharmaceuticals” (as agreed to by the sponsor and the 
contract research organization). The sponsor will maintain systems for quality control and quality 
assurance based on the procedures. 
 
17.2  Study Sites 
Study quality control and quality assurance will be conducted according to procedures for 
study-related duties specified by the study site directors. 
 

 
 
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18. Retention of Records 
18.1  Retention of Records at the Study Sites 
[1] The storage manager designated by the study site director will retain all documents and records 
specified under GCP in the location specified by the study site until the latter of: 
• The day of approval of the drug product of the study. 
• The day 3 years after the termination or completion of the study. 
[2] The approval of the sponsor will be obtained before the documents are destroyed following the 
retention period. 
[3] Appropriate measures will be taken if the location of document retention is moved because of 
facility relocation or for another reason so that the documents are not lost or destroyed during the 
retention period. If necessary, records of relocation will be created under the supervision of the 
study site director or storage manager. 
[4] The sponsor will notify the study site when the retention period is over. 
 
18.2  Retention of Records by Sponsor 
The GCP management officer designated by the sponsor will retain all documents and records 
specified under GCP until the latest of: 
• The day 5 years after the day of approval of the drug product of the study. 
• The day 3 years after the termination or completion of the study. 
• The final day of the reexamination period. 
 
18.3  Retention of Records at Other Institutions 
The contract research organization, site management organization, testing facility, and subject 
registration center will retain the contract and all documents for retention specified in the contract until 
the latter of: 
• The day of approval of the drug product of the study. 
• The day 3 years after the termination or completion of the study. 
 

 
 
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19. Compliance with Ethical Principles and Laws 
The study will be conducted in compliance with the Declaration of Helsinki: Ethical Principles for 
Medical Research Involving Human Subjects, the Ministerial Ordinance on Good Clinical Practice for 
Drugs, and all other related laws and rules. 
 

 
 
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20. Monetary and Other Payments and Compensation and Insurance for Injuries 
20.1  Monetary Payments 
The sponsor will cover the expenses associated with testing and diagnostic imaging performed during 
the investigational product treatment period and the expenses associated with dispensing and injecting 
drug products with an indication similar to the investigational product according to the national 
expenditure system for special healthcare not covered by insurance. 
The sponsor will comply with any system put in place by the institutional review board or other body 
of the study sites for paying an allowance to the subjects to alleviate subject inconvenience and 
disadvantage. The sponsor will decide on payments and other terms in consultation with the study sites. 
 
20.2  Compensation and Insurance for Injuries 
The sponsor will purchase a clinical study insurance plan and take other necessary measures to fulfill 
its obligations to compensate and pay damages for subject injuries. 
The investigator or subinvestigator will appropriately treat any subject who develops a study-related 
disability, disease, or other injury as a result of participating in the study. 
[1] The investigator or subinvestigator will prepare a written request for injury compensation (the form 
of which will be provided by a monitor when the injury occurs) and submit this document to the 
sponsor. 
[2] The sponsor will pay the medical expenses incurred by the subject for treatment as well as a 
medical allowance and monetary compensation according to the compensation plan. The sponsor 
will in general not provide compensation if the injury is a result of the investigational product not 
providing the expected effect or other benefits. 
[3] Compensation for injury will not be paid or the amount paid will be reduced if: 
• The injury is the result of an intentional act or gross negligence on the part of the subject. 
• The injury is the result of the investigator or subinvestigator substantially deviating from the 
protocol or another intentional act or gross negligence on the part of the study site. 
• The injury is the result of an illegal act or nonperformance by a third party. 
• The injury is coincidental (e.g., struck by a speeding car while going to the hospital, food 
poisoning). 
• The injury is caused by postoperative adjuvant chemotherapy. 

 
 
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21. Decisions Regarding Publication 
The results of all joint research conducted according to this protocol are the property of the sponsor. 
If an individual study site wishes to publish the results for its subjects, it must do so after the results of 
the joint research are published and with the acknowledgment of the sponsor. The privacy of the 
subjects will be protected when the results are published. 
 

64 
22. Study Administrative Structure
The study administrative structure is presented in Appendix 1.

 
65 
 
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Colorectal Cancer. Tokyo: Kanehara & Co., Ltd.; 2014. 
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anticancer drugs!? The role of TRPA1 in acute peripheral neuropathy characteristic of oxaliplatin. 
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4) Oishi R, Egashira N. Peripheral neuropathy caused by anticancer drugs. Fukuoka Acta Med 2013; 
104 (5): 171-80. 
5) Gamelin E, Gamelin L, Bossi L, Quasthoff S. Clinical aspects and molecular basis of oxaliplatin 
neurotoxicity: current management and development of preventive measures. Semin Oncol 2002; 29 
(5 Suppl 15) : 21-33.  
6) Miltenburg NC, Boogerd W. Chemotherapy-induced neuropathy: A comprehensive survey. Cancer 
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7) Arakawa K, Torigoe K, Kuzumaki N, Suzuki T, Narita M. Characteristics of and mechanism of 
peripheral neuropathy caused by anticancer drugs. Jpn J Pharm Palliat Care Sci 2011; 4: 1-13. 
8) Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, et al. Prevention 
and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: 
American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2014; 32  (18) : 
1941-67. 
9) Egashira N, Kawashiri T, Oishi R. Current state of pharmacotherapy for peripheral neuropathy 
caused by anticancer drugs. Folia Pharmacologica Japonica 2010; 136: 275-9. 
10) Ito T, Kakihana Y, Maruyama I. Thrombomodulin as an intravascular safeguard against 
inflammatory and thrombotic diseases. Expert Opin Ther Targets 2015; 20 (2) :1-8. 
11) Mantyh PW. Cancer pain and its impact on diagnosis, survival and quality of life. Nature Rev 
Neurosci 2006; 7 (10) : 797-809. 
12) 
 
 
 
13) 
 
 
14) Japanese Society for Cancer of the Colon and Rectum. Japanese Classification of Colorectal 
Carcinoma, eighth edition. Tokyo: Kanehara & Co., Ltd.; 2013. 
15) Drafting Committee for Hepatitis Management Guidelines and the Japan Society of Hepatology. JSH 
Guidelines for the Management of Hepatitis B Virus Infection. Version 2.1. by Japan Society of 
Hepatology. 2015. 
16) Ministry of Health, Labour and Welfare. The manual for handling disorders due to adverse drug 
reactions-focus on the anaphylaxis. March 2008. Available from 
URL:http://www.info.pmda.go.jp/juutoku/file/jfm0803003.pdf