An Open-label, Phase 2 Study to Assess the Efficacy and Safety of Nemolizumab in Subjects With Systemic Sclerosis
Phase: PHASE2
Conditions: Systemic Sclerosis
Sponsor: Maruho Co., Ltd.



List of Definitions of Abbreviations and Technical Terms 
 
Acronym/Abbreviation/ 
Technical term 
Full text/Definition 
ACR-CRISS 
American College of Rheumatology Combined Response Index in 
diffuse cutaneous Systemic Sclerosis 
ADL 
Activities of daily living 
AE 
Adverse events 
AIDS 
Acquired immunodeficiency syndrome 
ALB 
Albumin 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma/serum concentration-time curve 
AUC0-28day 
Area under the serum concentration-time curve 0-28day 
AUClast 
Area under the serum concentration-time curve from zero to last 
observed concentration time point 
A/G ratio 
Albumin-Globulin ratio 
BLQ 
Below the lower limit of quantification 
CBA 
Cell-based assay 
CK 
Creatine kinase 
Cmax 
Maximum concentration in plasma/serum 
COVID-19 
Coronavirus disease 2019 
CREA 
Creatinine 
CRP 
C reactive protein 
CTCAE 
Common terminology criteria for adverse events 
CyTOF 
Cytometry by time of flight 
D-Bil 
Direct bilirubin 
DCS 
Dual chamber syringe 
dcSSc 
Diffuse cutaneous SSc 
DLco 
Diffusing capacity of lung for carbon monoxide 
ECG 
Electrocardiogram 
ECL 
Electro Chemi Luminescence 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EULAR 
European League Against Rheumatism 
FAS 
Full analysis set 
FACIT-Fatigue 
Functional assessment of chronic illness therapy-Fatigue 
FEV1 
Forced expiratory volume in one second 
FSSG 
Frequency Scale for the Symptoms of GERD 
FU 
Follow up 
FVC 
Forced vital capacity 
GCP 
Good clinical practice 

Acronym/Abbreviation/ 
Technical term 
Full text/Definition 
γ-GT 
γ-Glutamyl transpeptidase 
HAQ-DI 
Health assessment questionnaire disability index 
Hb 
Hemoglobin 
HBc antibody 
Hepatitis B core antibody 
HBs antigen 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
hCG 
human chorionic gonadotrophin 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
HRCT 
High-resolution computed tomography 
Ht 
Hematocrit 
IL 
Interleukin 
IL-31RA 
Interleukin-31 receptor A 
IP 
Investigational product 
IRB 
Institutional review board 
JCOG 
Japan clinical oncology group 
KL-6 
Krebs von den lungen-6 
lcSSc 
Limited cutaneous SSc 
LDH 
Lactic acid dehydrogenase 
LDL-C 
Low density lipoprotein cholesterol 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA/J 
Medical dictionary for regulatory activities / Japanese edition 
mRSS 
Modified rodman total skin thickness score 
nemolizumab 
Humanized anti-human interleukin-receptor A (IL-31RA) monoclonal 
antibody 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
PAH 
Pulmonary arterial hypertension 
PGA 
Physician’s global assessment 
Plt 
Platelet 
PT 
Preferred term 
PtGA 
Patient’s global assessment 
QFT-3G 
QuantiFERON-TB Gold 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SP-D 
Surfactant protein D 
SOC 
System organ class 
SSc 
Systemic sclerosis 
TARC 
Thymus and activation-regulated chemokine 

Acronym/Abbreviation/ 
Technical term 
Full text/Definition 
T-Bil 
Total-bilirubin 
TC 
Total cholesterol 
TG 
Triglyceride 
TLC 
Total lung capacity 
tmax 
Time to reach the maximum concentration in plasma/serum 
TP 
Total protein 
T-SPOT 
T-SPOT®.TB 
UA 
Uric acid 
UN 
Urea nitrogen 
VAS 
Visual analogue scale 
WBC 
White blood cell 
 
 
 

Synopsis-5 
Protocol Synopsis 
 
1. Study objectives 
 Primary Objective 
To exploratorily evaluate the efficacy of nemolizumab in systemic sclerosis (SSc) patients with moderate to 
severe skin thickening 
 
 Secondary Objective 
To evaluate the safety and pharmacokinetics of nemolizumab in SSc patients with moderate to severe skin 
thickening 
 
2. Study Design 
This is a phase II, single-arm, multiple-dose study consisting of a pre-treatment observation period (1-4 
weeks) and a treatment period (52 weeks). The pre-treatment observation period is from the day of screening 
to the day of study treatment initiation, and participants will visit the site a total of twice, for screening and 
for study treatment initiation. Treatment period is from the day of study treatment initiation   and every 4 
weeks thereafter. Participants having received study treatment will be followed up 84 days after the day of 
the last dose of study treatment. Follow-up period is from Visit17 (Week 52) or the day of discontinuation 
visit to the day of follow-up visit. 
 
Study phase: Phase II 
 
Study type: Open-label, single-arm, multiple-dose study 
Participants: SSc patients with moderate to severe skin thickening 
Target Sample Size: 8 participants 
 
Figure 2-1: Study Schema 
 
 
 
 
 
 
 
 
 
 
1） Pre-treatment observation period 
The investigator or subinvestigator will make observations and assessments at the screening visit 
specified in Table 4-1 after obtaining informed consent from the participant. 
  
2） Treatment period 
The investigator or subinvestigator will administer the investigational product (IP) (nemolizumab, 60 
mg/body) every 4 weeks (Q4W) at visits until Week 48 after making observations and assessments on 
the day of study treatment initiation specified in Table 4-1. In addition, the investigator or 
subinvestigator will make perform observations and assessments at each visit specified in Table 4-1. 
 
Treatment period (52 weeks) 
Follow-up period 
Nemolizumab 60 mg/body n = 8 
IC 
Screening 
Start 
 treatment 
Week 1 
Week 2 
Week 4 
Visit every 4 weeks 
Week 52 
Follow-up visit 
Pre-treatment 
observation period 

Synopsis-6 
3） Follow-up period 
All participants having received the IP will be scheduled to visit for follow-up 12 weeks after the day 
of the last dose of study treatment (the day of follow-up visit). On the day of the follow-up visit, the 
investigator or subinvestigator will evaluate the safety and efficacy after completion of study treatment 
for all participants. 
 
3. Target Indication and Inclusion and Exclusion Criteria for Patients 
 Target Indication 
SSc 
 
 Inclusion Criteria 
Participants must meet all of the following criteria for study entry: 
Inclusion Criteria 
Assessment timing  
Day of 
Informed 
Consent  
Day of 
Screening 
Day of 
treatment start 
1） Patients aged 20 to 70 years at the time of informed 
consent 
X 
– 
– 
2） Patients meeting the classification criteria for SSc in ACR 
and EULAR 2013 
X 
– 
– 
3） Patients with systemic sclerosis who have moderate to 
severe skin thickening, with mRSS of 10 to 22 on both the 
screening and treatment initiation dates 
– 
X 
X 
4） Patients considered by the investigator or subinvestigator 
to be competent to perform the protocol-specified self-
assessment 
X 
X 
X 
 
 Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from study entry: 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
1） Patients complicated with diseases considered inappropriate 
for participation in clinical trials, such as serious* 
cardiac/hepatic/renal/pulmonary/hematologic disease 
*Refer to the Criteria for Seriousness Classification of Adverse 
Drug Reactions. (PAB/SD Notification No.80 by the Director 
of Safety Division, Pharmaceutical Affairs Bureau, Ministry of 
Health and Welfare dated June 29, 1992) and the Common 
Terminology Criteria for Adverse Events v 5.0 Japanese JCOG 
version (CTCAE v 5.0-JCOG). 
X 
X 
X 
2） Patients complicated with congestive heart failure [New York 
Heart Association (NYHA) Functional Class III or IV] 
X 
X 
X 
3） Patients having any of the following complications or 
concomitant/concurrent diseases: 
a） Severe chronic pulmonary disease (including %FVC < 
60%, or %DLco < 40% on the day of screening, 
calculated from the New Reference Values for 
Spirometry in Japanese adults calculated with the LMS 
X 
X 
X 

Synopsis-7 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
Method (the Japanese Respiratory Society)”  
b） Serious complications associated with SSc other than 
interstitial lung disease* (e.g., renal crisis) 
* Interstitial lung disease is excluded if it falls under Item 
a) of 3)  
c） Poorly 
controlled 
asthma 
that 
requires 
steroids 
(systemic), intravenous infusion of aminophylline, 
subcutaneous injection of adrenaline 0.1%, oxygen 
inhalation, or antibody drugs  
d） Diseases to affect the assessment of SSc 
4） Patients with a history of malignant tumor, who are receiving 
no treatment and have had no recurrence /relapse for ≥5 years 
at the time of informed consent, or patients with a history of 
radical treatment for cervical intraepithelial neoplasia at the 
time of informed consent may be included in the study 
X 
X 
X 
5） Patients 
with 
Immune 
deficiency 
(e.g., 
congenital 
immunodeficiency, AIDS, or HIV). 
X 
X 
X 
6） Patients with a history or current hypersensitivity (including 
anaphylaxis) to immunoglobulin products (plasma-derived 
preparations or genetic recombinant monoclonal antibodies) 
X 
X 
X 
7） Patients weighing < 30.0 kg or > 120 kg on the day of study 
treatment initiation 
– 
– 
X 
8） Patients whose laboratory test values on the day of screening 
meet any of the following criteria: 
a） AST or ALT > 2 times the upper limit of normal 
b） Serum creatinine ≥2.0 mg/dL 
c） WBC <3000 cells/μL 
– 
– 
X 
9） Patients infected with hepatitis B virus (HBV) or hepatitis C 
virus (HCV) (Positive for HBs antigen or HBc antibody on the 
day of screening, positive for anti-HCV antibody on the day of 
screening) 
The allowed exceptions are as follows: 
 
Patients confirmed not to be infected with HBV at the 
time of the HBV-DNA test performed before study 
treatment initiation in the case of negative for HBs 
antigen and positive for HBc antibody in the hepatitis B 
test performed on the day of screening. 
 
Patients confirmed not to be infected with HCV at the 
time of the HCV-RNA test performed before study 
treatment initiation in the case of positive for anti-HCV 
antibody in the hepatitis C test performed on the day of 
screening 
– 
– 
X 
10） Patients with latent or active tuberculosis based on the result 
of the screening TB test. The allowed exception is patients 
deemed not to be infected with tuberculosis according to the 
“Guidelines for the use of interferon-γ release assay 
(Prevention Committee of the Japanese Society for 
Tuberculosis).  
– 
– 
X 
11） Patients with either of the following infectious diseases: 
 
Recurrent/chronic infections or other active infections 
X 
X 
X 

Synopsis-8 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
deemed by the investigator to possibly aggravated by 
participating in the study. 
 
Infections (including skin infections) requiring systemic 
antibiotics, antivirals, or antifungals within 7 days prior 
to the day of study treatment initiation. 
12） Patients who have received oral steroids (> 10 mg/day of 
prednisolone or equivalent), dosage of receiving oral steroids 
have been changed (from ≤ 10 mg/day of prednisolone or 
equivalent), or newly treated with oral steroids, within 14 days 
before the day of study treatment initiation 
– 
– 
X 
13） Patients who have received any of the following therapies 
within the indicated period prior to the day of study treatment 
initiation 
– 
(X)* 
X 
a） Within 365 days 
Cyclophosphamide 
b） Within 120 days or 5 
times the elimination 
half-life of the drug, 
whichever is longer 
Antibody drugs 
c） Within 28 days 
 
Live vaccines 
 
The 
following 
systemic 
medications: 
− Antifibrotic 
drugs 
(e.g., 
pirfenidone, nintedanib) 
− Immunosuppressants 
(e.g., 
cyclosporine, 
tacrolimus, 
azathioprine, mycophenolate 
mofetil, 
mizoribine, 
sulfasalazine, 
leflunomide, 
methotrexate, 
hydroxychloroquine, 
D-
penicillamine, sirolimus) 
− Tyrosine kinase inhibitors 
(e.g., imatinib) 
− JAK 
inhibitors 
(e.g., 
tofacitinib, upadacitinib) 
− Endothelin receptor agonists 
(e.g., bosentan, ambrisentan, 
macitentan) 
− Phosphodiesterase-5 
inhibitors (e.g., sildenafil, 
tadalafil) 
− Prostaglandin analogue (e.g., 
alprostadil, epoprostenol) 
− Riociguat 
 
Injections of corticosteroids 
(excluding joint injections) 
 
Phototherapy 

Synopsis-9 
*The exclusion criteria will be assessed with the expected date of study treatment initiation as the starting 
point.
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
 
High-dose 
intravenous 
immunoglobulin therapy 
14） Patients who are within 120 days from the end of participation 
in other clinical trials or post-marketing clinical studies (i.e., 
the last day of administration of another IP or post-marketing 
clinical study drug) until the day of study treatment initiation, 
or participating in other clinical trials or post-marketing 
clinical studies 
– 
(X)* 
X 
15） Women who are pregnant, breastfeeding, possibly pregnant, 
or unwilling to use appropriate contraception measures as 
instructed by the investigator during the study period 
X 
X 
X 
16） Patients who meet any of the following criteria: 
a） Having not met eligibility for participation when 
participating in this study in the past 
d） Having previously received nemolizumab (including 
placebo) 
X 
X 
X 
17） Patients with confirmed or suspected COVID-19 
– 
X 
X 
18） Patients with a history of confirmed or suspected COVID-19 
excluding those meeting any of the following criteria: 
• At least 20 days after the onset of symptoms and at 
least 72 hours after the resolution of symptoms. 
• Confirmed not to carry SARS-Cov-2. 
– 
X 
X 
19） Patients found to have close contacts with COVID-19 patients 
within 14 days before the day of study treatment initiation  
– 
– 
X 
20） Other patients who are considered ineligible for the study by 
the investigator 
X 
X 
X 

Synopsis-13 
e Not to be performed if refused by the participant. 
If any of the following treatment-emergent adverse events occurs, photographs of the affected skin areas of the adverse event should be taken while the event (at least once) is 
occurring and at the final outcome evaluation, in addition to the scheduled visit (i.e., the day of study treatment initiation).  
• Atopic dermatitis 
• Adverse events with skin symptoms of edematous erythema or scaling 
• Any other adverse event for which the investigator or subinvestigator considers that photography is necessary. 
f To be performed on female participants excluding those who never become pregnant. 
g May be conducted on another day after the day of screening before the day of study treatment initiation 
h • Hepatitis B 
The participants who test negative for HBs antigen and positive for HBc antibody will undergo HBV-DNA measurement before the day of study treatment initiation. The participants 
enrolled through HBV-DNA measurement will undergo HBV-DNA measurement once every three months. 
・ 
Hepatitis C 
The participants who test positive for the anti-HCV antibody will undergo HCV-RNA measurement before the day of study treatment initiation. The participants enrolled through 
HCV-RNA measurement will undergo HCV-RNA measurement once every three months. 
i To be administered after all observation/tests are performed. If the IP cannot be administered within the window indicated, the next dose should be administered 14 days or later 
after the day of the previous dose. 
j Participants who discontinued the study will visit the site 84 days (±7 days) after the day of the last dose of study treatment for observation/tests at FU shown in Table 4-1. Participants 
discontinued the study before study treatment initiation need not to undergo observation/tests scheduled on the day of visit for discontinuation. 

Synopsis-14 
5. Treatment Method 
 Method of Administration 
The investigator or subinvestigator will slowly administer the IP, nemolizumab (one DCS [0.6 ml]) 
subcutaneously to the upper arm, abdomen, or thigh of the participants. The IP may be administered by a 
person qualified to administer it under the instruction of the investigator or subinvestigator.  
 
 Treatment Period 
52 weeks 
All participants who have received at least one dose of the IP will visit the site 12 weeks after the day of the 
last dose of study treatment for follow-up. 
 
 Concomitant Medications and Therapies  
5.3.1  Restricted Concomitant Medications 
The following medications may be continued at a stable dose if used for at least 14 days before the day of 
study treatment initiation. However, the dose may be reduced at the discretion of the investigator or 
subinvestigator, and after dose reduction, the dose may be increased up to that used at the day of study 
treatment initiation. 
•Oral steroids (≤ 10 mg/day of prednisolone or equivalent) 
 
5.3.2  Prohibited Concomitant Medications and Therapies  
Concomitant use of medications and therapies listed below is prohibited in this study.  
- 
From the day of study treatment initiation to Week 52 or to the physical examination on the day of visit 
for discontinuation 
1） The following systemic medications: 
a） Antifibrotic drugs (e.g., pirfenidone, nintedanib) 
b） Immunosuppressants 
(e.g., 
cyclophosphamide, 
cyclosporine, 
tacrolimus, 
azathioprine, 
mycophenolate mofetil, mizoribine, sulfasalazine, leflunomide, methotrexate, hydroxychloroquine, 
D-penicillamine, sirolimus) 
c） Tyrosine kinase inhibitors (e.g., imatinib) 
d） JAK inhibitors (e.g., tofacitinib, upadacitinib) 
e） Endothelin receptor agonists (e.g., bosentan, ambrisentan, macitentan) 
f） Phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil) 
g） Prostaglandin analogues (e.g., alprostadil, epoprostenol) 
h） Riociguat 
2） Injections of corticosteroids (excluding joint injections) 
3） Phototherapy 
4） High-dose intravenous immunoglobulin therapy 
5） Antibody drugs 
6） Live vaccines 
 
- 
From the day of study treatment initiation to the day of follow-up visit 
1） Other drugs and medical devices under development 
 
 

Synopsis-15 
6. Study Discontinuation of Individual Participants  
 Discontinuation Criteria 
1） Use of other antibody drugs by Week 52 visit 
2） Use of live vaccines by Week 52 visit 
3） The investigator or subinvestigator determined that an adverse event which would prevent the 
continuation of the study has occurred. 
4） The participant is found to fail to meet any of the inclusion criteria or to meet any of the exclusion 
criteria. 
5） The participant is found to be pregnant. 
6） The investigator or subinvestigator has determined that the participant should be withdrawn from the 
study due to inadequate response to the IP. 
7） The participant requests to withdraw from the study. 
8） The participant no longer visits the medical institution, and the study cannot be continued. 
9） The participant has died. 
10） The sponsor has determined the participant discontinuation from the study due to significant protocol 
deviations. 
11） The sponsor has prematurely terminated the study. 
12） The investigator or subinvestigator has determined to withdraw the participant from the study for any 
other reasons. 
 
7. Efficacy Evaluation 
 Primary Endpoint 
Change from baseline in mRSS at Week 24 
 
 Other Endpoints 
1） Change from baseline in mRSS at Week 52 
2） Change from baseline in HAQ-DI at Week 52 
3） Change from baseline in HAQ-DI at Week 24 
4） Change from baseline in %FVC at Week 52 
5） Change from baseline in %FVC at Week 24 
6） Change from baseline in DLco at Week 52 
7） Change from baseline in DLco at Week 24 
8） Change from baseline in PGA at Week 52 
9） Change from baseline in PGA at Week 24 
10） Change from baseline in PtGA at Week 52 
11） Change from baseline in PtGA at Week 24 
12） ACR-CRISS at Week 52 
13） ACR-CRISS at Week 24 
14） Change from baseline in the number of digital ulcers at Week 52 
15） Change from baseline in the number of digital ulcers at Week 24 
16） Time-course change in the following items: 
a） HAQ-DI 
b） FACIT-Fatigue 
c） FSSG 
d） FVC 

Synopsis-16 
e） %FVC 
f） DLco 
g） %DLco 
h） TLC 
i） FEV1 
j） Severity evaluation of lung lesion 
k） PGA 
l） PtGA 
m） ACR-CRISS 
n） The number of digital ulcers 
 
8. Safety Evaluation 
 Assessments for Safety Evaluations 
1） Adverse events 
a） Symptoms and signs 
b） Abnormal laboratory test values 
c） Abnormal vital signs 
d） Abnormal electrocardiograms 
2） Laboratory test values 
3） Vital signs 
4） Electrocardiogram 
5） Echocardiography 
 
9. Target Sample Size 
8 participants 
 
10. Study Period 
December 2021 to November 2024

 
Table of Contents 
 
1. Introduction ........................................................................................................... 22 
 Background of Development ................................................................................................ 22 
1.1.1 Pathophysiology and epidemiology of systemic sclerosis ............................................. 22 
1.1.2 Therapeutic treatment of systemic sclerosis and its issues .......................................... 22 
1.1.3 Summary description and significance of the development of nemolizumab ............... 22 
 Guidelines, Consultation with Pharmaceuticals and Medical Devices Agency (PMDA), 
etc., Referenced for Study Planning .................................................................................... 23 
2. Study objectives ................................................................................................... 24 
 Primary Objective ................................................................................................................. 24 
 Secondary Objective............................................................................................................. 24 
3. Study Design ........................................................................................................ 24 
4. Target Indication and Inclusion and Exclusion Criteria for Participants ................. 25 
 Target Indication ................................................................................................................... 25 
 Inclusion Criteria ................................................................................................................... 25 
 Exclusion criteria ................................................................................................................... 25 
5. Study Discontinuation of Individual Participants ................................................... 29 
 Discontinuation criteria ......................................................................................................... 29 
 Procedure for Discontinuation .............................................................................................. 30 
5.2.1 Discontinuation before Enrollment ................................................................................. 30 
5.2.2 Discontinuation after Enrollment .................................................................................... 30 
 Handling of Participants Who Fail to Visit the Study Site ..................................................... 30 
5.3.1 Participants Discontinuing Study Site Visit Between the Day of Informed Consent and 
the Day of Enrollment ................................................................................................... 30 
5.3.2 Participants Discontinuing Study Site Visit in the Period after the Enrollment up to 
Visit 17 (Week 52) ......................................................................................................... 30 
5.3.3 Participants Discontinuing Study Site Visit during the Follow-up Period ...................... 30 
6. Participant Enrollment........................................................................................... 31 
 Informed Consent ................................................................................................................. 31 
 Notification when the Participant is Treated by Another Doctor ........................................... 31 
 Enrollment Procedure of Participants ................................................................................... 31 
7. Investigational Product ......................................................................................... 31 
 Name, Dosage Form, and Strength of the IP ....................................................................... 31 
 Packaging and Labeling ....................................................................................................... 32 
7.2.1 Packaging ...................................................................................................................... 32 
7.2.2 Labeling .......................................................................................................................... 32 
 Storage and Management of Investigational Products ........................................................ 32 
8. Treatment Method ................................................................................................ 32 
 Dispensing of Investigational Products ................................................................................ 32 
 Preparation of Investigational Products ............................................................................... 32 
 Method of Administration ...................................................................................................... 32 
 Concomitant Medications and Therapies ............................................................................. 33 
8.4.1 Restricted Concomitant Medications ............................................................................. 33 
8.4.2 Duration and Method of Inspection ................................................................................ 33 

 
8.4.3 Prohibited Concomitant Medications and Therapies ..................................................... 33 
8.4.4 Instructions to participants ............................................................................................. 34 
9. Study Procedures and Assessments and the Schedule ....................................... 35 
 Schedule of Study Procedures and Assessments ............................................................... 35 
 Definition of the Days of Observation, Tests, and Sample Collection .................................. 39 
9.2.1 Day of Informed Consent ............................................................................................... 39 
9.2.2 Day of screening ............................................................................................................ 39 
9.2.3 Day of Study Treatment Initiation ................................................................................... 39 
9.2.4 Day of Assessment (Weeks 1, 2, 4, 8, 12, through 52) ................................................. 39 
9.2.5 Day of Study Treatment ................................................................................................. 39 
9.2.6 Day of Discontinuation ................................................................................................... 39 
9.2.7 Day of Discontinuation Visit ........................................................................................... 39 
9.2.8 Day of Follow-up Visit .................................................................................................... 39 
 Observation, Tests and Sample Collection........................................................................... 39 
9.3.1 Participant Demographics .............................................................................................. 39 
9.3.2 Prior and Concomitant Medications and Therapies ...................................................... 40 
9.3.3 Body Weight ................................................................................................................... 41 
9.3.4 Efficacy Evaluation ......................................................................................................... 41 
9.3.5 Safety Evaluation ........................................................................................................... 43 
9.3.6 Laboratory tests ............................................................................................................. 44 
9.3.7 Pharmacokinetics ........................................................................................................... 46 
9.3.8 Immunogenicity .............................................................................................................. 46 
9.3.9 Biomarker measurement ................................................................................................ 46 
9.3.10 Comprehensive measurement of autoantibodies ........................................................ 47 
9.3.11 CyTOF measurement ................................................................................................... 47 
9.3.12 Assessment of Adverse Events ................................................................................... 47 
9.3.13 Investigation of Malfunction of DCS ............................................................................ 47 
9.3.14 Amount of Blood and Urine Samples to be Collected ................................................. 48 
10. Efficacy Evaluation ............................................................................................. 49 
 Efficacy Assessments ......................................................................................................... 49 
10.1.1 Assessment of Skin Findings ....................................................................................... 49 
10.1.2 Respiratory Function Test ............................................................................................ 49 
10.1.3 Chest HRCT ................................................................................................................. 49 
10.1.4 Severity Classification of Lung Lesion ......................................................................... 49 
10.1.5 ACR-CRISS .................................................................................................................. 50 
10.1.6 The Number of Digital Ulcers ....................................................................................... 50 
10.1.7 Patient-reported outcome ............................................................................................ 50 
10.1.8 Global improvement rating ........................................................................................... 51 
 Efficacy Endpoints .............................................................................................................. 51 
10.2.1 Primary Endpoint ......................................................................................................... 51 
10.2.2 Other Endpoints ........................................................................................................... 51 
 Rationale for Efficacy Endpoints ........................................................................................ 52 
11. Safety Evaluation ................................................................................................ 54 
 Assessments for Safety Evaluations .................................................................................. 54 
 Definition of Adverse Events ............................................................................................... 54 
 Definitions of Safety Endpoints ........................................................................................... 55 

 
 Review and reporting of adverse events ............................................................................ 56 
 Review and reporting of serious adverse events ............................................................... 58 
 Reporting of adverse events of special interests (AESIs) .................................................. 58 
 Photography ........................................................................................................................ 58 
 Reporting of the Pregnancy of the Participant .................................................................... 58 
 Rationale for Safety Endpoints ........................................................................................... 59 
 Follow-up of Adverse Events ............................................................................................ 59 
 Malfunctions of DCS ......................................................................................................... 59 
11.11.1 Reporting of Malfunctions of DCS .............................................................................. 59 
11.11.2 Collection and Reporting of Malfunction Information on DCS occurring at the Stage 
of Use on Participants ................................................................................................... 59 
11.11.3 Storage of Malfunctioning DCS .................................................................................. 59 
 Anticipated Adverse Drug Reactions ................................................................................ 59 
12. Biomarkers ......................................................................................................... 60 
 Measurements of Biomarkers............................................................................................. 60 
 Blood Biomarker Outcome Measures ................................................................................ 60 
 Measurement Method and Reporting of Results................................................................ 61 
13. Pharmacokinetics ............................................................................................... 61 
 Pharmacokinetic Measurements ........................................................................................ 61 
 Pharmacokinetic Outcome Measures ................................................................................ 61 
 Measurement Method and Reporting of Results................................................................ 61 
14. Immunogenicity .................................................................................................. 62 
 Immunogenicity Measurements ......................................................................................... 62 
 Immunogenicity Outcome Measures .................................................................................. 62 
 Measurement Method and Reporting of Results................................................................ 62 
15. Comprehensive Measurement of Autoantibodies ............................................... 62 
 Measurement Method and Reporting of Results................................................................ 62 
16. CyTOF measurement ......................................................................................... 63 
 Measurement Method and Reporting of Results................................................................ 63 
17. Statistical Analysis .............................................................................................. 63 
 Analysis Sets ...................................................................................................................... 63 
17.1.1 Efficacy Analysis Set (Full Analysis Set: FAS) ............................................................. 63 
17.1.2 Safety Analysis Set ...................................................................................................... 64 
17.1.3 Pharmacokinetics Analysis Set .................................................................................... 64 
17.1.4 Biomarker Analysis Set ................................................................................................ 64 
 Data Handling ..................................................................................................................... 64 
17.2.1 Common Rules ............................................................................................................ 64 
17.2.2 Data Handling on Pharmacokinetics ........................................................................... 64 
 Statistical Analysis Plan ...................................................................................................... 65 
17.3.1 Demographic and Other Baseline Characteristics, and Severity of Primary Disease 65 
17.3.2 Efficacy Analysis .......................................................................................................... 65 
17.3.3 Safety Analysis ............................................................................................................. 66 
17.3.4 Analyses of Drug Concentrations and Pharmacokinetic Parameters ......................... 66 
17.3.5 Analysis of Immunogenicity ......................................................................................... 67 
17.3.6 Analysis of Biomarker .................................................................................................. 67 

 
 Determination of Sample Size ............................................................................................ 67 
17.4.1 Target Sample Size ...................................................................................................... 67 
17.4.2 Rationale for Sample Size ........................................................................................... 67 
 Data Review ....................................................................................................................... 67 
18. Agreement on the Protocol and Protocol Deviation/Amendment ........................ 68 
 Agreement of and Compliance with the Protocol ............................................................... 68 
 Protocol Deviation/Amendment .......................................................................................... 68 
19. Case Report Form .............................................................................................. 69 
 Data to be collected in CRF................................................................................................ 69 
19.1.1 Participants assigned to treatment .............................................................................. 69 
19.1.2 Participants Who Discontinue the Study before study entry after screening and 
those Who Discontinue the Study before enrollment ................................................... 70 
 Source Data for Information Entered in Case Report Form ............................................... 70 
 Information in the Case Report Forms Treated as Source Data ........................................ 71 
 Guidelines for Preparation of Case Report Form ............................................................... 71 
 Modification and Amendment to Case Report Forms ........................................................ 71 
20. Follow-up report of adverse events of special interest ........................................ 71 
21. Direct Access to Source Documents .................................................................. 72 
22. Quality Control and Quality Assurance ............................................................... 72 
23. Completion, Discontinuation, or Interruption of the Study ................................... 72 
 Completion of the Study ..................................................................................................... 72 
 Discontinuation or Interruption of the Study ....................................................................... 72 
24. Archiving of Records ........................................................................................... 73 
25. Publication Policy ............................................................................................... 73 
26. Use of study-related data .................................................................................... 73 
27. Ethics .................................................................................................................. 74 
 Institutional Review Board .................................................................................................. 74 
 Ethical Conduct of the Study .............................................................................................. 74 
 Protection of Participants’ Confidentiality ........................................................................... 74 
 Participant Selection and Informed Consent ...................................................................... 74 
27.4.1 Participant Selection .................................................................................................... 74 
27.4.2 Informed Consent ........................................................................................................ 74 
27.4.3 Explanations to Participants ........................................................................................ 75 
28. Payments ............................................................................................................ 76 
29. Compensation for Injuries ................................................................................... 76 
30. Responses to COVID-19 .................................................................................... 76 
 If participants are found to have confirmed COVID-19 (including asymptomatic pathogen 
carriers) or suspected COVID-19, or found to have been in close contact with a confirmed 
or suspected COVID-19 patient ........................................................................................... 76 
 Discontinuation of the study due to the influence of COVID-19 ......................................... 77 
 Deviations from the protocol due to the influence of COVID-19 ........................................ 77 
31. Study Period ....................................................................................................... 77 
32. Administrative Structure ...................................................................................... 77 
 Sponsor............................................................................................................................... 77 

 
 Sponsor Organization ......................................................................................................... 77 
 Study Sites and Investigators ............................................................................................. 78 
 Medical Expert .................................................................................................................... 78 
 Contract Research Organization ........................................................................................ 78 
33. Contact Information ............................................................................................ 78 
 Contact Information ............................................................................................................ 78 
 Emergency Contact (Saturdays and Sundays, National Holidays, Nights) ....................... 79 
34. References ......................................................................................................... 80 
 
 
 
 

22 
1. Introduction 
 Background of Development 
1.1.1  Pathophysiology and epidemiology of systemic sclerosis 
Systemic scleroderma (SSc) is a systemic autoimmune disease characterized by fibrosis and vasculopathy 
of skin and various internal organs such as lung and classified as a connective tissue disease. Skin fibrosis, a 
common symptom in patients with SSc, is considered to be excessive deposition of the extracellular matrix 
mainly composed of collagen. 1) In Japan, SSc is designated as an intractable disease; according to the 
information of the Japan Intractable Diseases Information Center, the number of SSc patients is about 20,000. 
2) The male-to-female ratio of patients is 1:12 and is more prevalent in women between the ages of 30 and 
50 years. 
SSc is classified as either diffuse cutaneous systemic scleroderma (dcSSc) in which skin thickening 
extends to the proximal extremities (i.e. the upper arms and the thighs) or the trunk or limited cutaneous 
systemic scleroderma (lcSSc) in which skin thickening is limited to the distal extremities (i.e. the forearms 
and the lower legs) and the face.3) In dcSSc patients, as skin thickening progresses, visceral involvement such 
as in the lungs, gastrointestinal tract, kidneys, and heart, and joint flexion contracture progress. In dcSSc in 
particular, it is widely recognized that the degree of skin thickening correlates with that of fibrotic lesions in 
internal organs, and higher severity of skin thickening has been reported to be associated with higher rates of 
visceral involvement including in the lungs and lower survivals. 4), 5), 6) In addition, fibrosis of internal organs, 
as well as skin thickening, develops at an early stage, in which slight tissue damage accumulates and 
progresses to irreversible organ damage. Therefore, treatment should be initiated as early as possible, 
especially in patients in whom the condition is predicted to become severe. In lcSSc patients, on the other 
hand, skin thickening progresses slowly and are not eligible for aggressive treatment. However, lcSSc with 
the possibility of rapid and widespread progression of skin thickening may be eligible for treatment.7) 
 
1.1.2  Therapeutic treatment of systemic sclerosis and its issues 
The etiology of SSc has not been clarified, and the main treatment methods are symptomatic treatments 
and disease-modifying drugs that inhibit disease progression. The progression and sites of involvement of 
SSc are different for each patient, and accordingly, the treatment method is selected based on the symptom 
of each patient. 
Diagnostic Criteria, Severity Classification and Guidelines of Systemic Sclerosis7) state that oral 
corticosteroids are thought to be empirically valid for patients with progressing skin thickening at an early 
stage but that they have risk factors for inducing renal crisis. Cyclophosphamide is the most recommended 
treatment option for both skin thickening and interstitial lung disease in patients with SSc; however, it has a 
problem of difficulty in long-term administration because of its carcinogenicity, immunosuppression, and 
side effects of drug such as hemorrhagic cystitis. Other drugs for SSc symptoms are prostacyclin, endothelin 
receptor antagonists, and phosphodiesterase-5 inhibitors for the treatment of pulmonary hypertension, 
calcium channel blockers for the treatment of cardiac involvement, intravenous prostaglandin E1 or 
prostacyclin for the treatment of disturbed blood flow in the fingers, and proton pump inhibitors for the 
treatment of reflux esophagitis. However, due to limited efficacy or safety issues of these therapeutic agents, 
the disease burden remains high and there is a great unmet medical need. 
 
1.1.3  Summary description and significance of the development of nemolizumab 
Nemolizumab is a monoclonal antibody that recognizes interleukin-31 receptor A (IL-31RA) in humans, 
which competitively inhibits the binding of interleukin-31 (IL-31) to its receptor, thereby blocking 
subsequent signal transduction into the cells. Nemolizumab was initially developed by 
 
Co., Ltd.; the worldwide development and marketing rights, except in Japan and Taiwan, 

23 
were granted to 
 in 2016, while the development and marketing rights in the field of skin 
diseases in Japan were granted to 
 
IL-31 is a cytokine produced mainly from activated T cells. IL-31 is present at higher levels in serum in 
SSc than in healthy individuals; IL-31 positive cells were identified in inflammatory infiltrates in fibrotic 
lesions in the skin and lungs8). Moreover, an in vitro study with dermal fibroblasts from healthy individuals 
showed IL-31 increased collagen production in these cells, and IL-31 administration to mice induced skin 
and lung fibrosis in an in vivo study, suggesting that IL-31 induces skin and lung fibrosis via inducing 
collagen production in fibroblasts8).These results indicate that IL-31 is a key cytokine involved in the 
development of SSc, and therefore, nemolizumab is expected to inhibit the progression of or ameliorate of 
skin and pulmonary fibrosis in SSc. 
From the above, nemolizumab is considered to be a possible new treatment option for SSc. Thus, this study 
has been developed to explore the efficacy and safety of nemolizumab in SSc patients. 
 
 Guidelines, Consultation with Pharmaceuticals and Medical Devices Agency (PMDA), etc., 
Referenced for Study Planning 
 
This study has been planned in reference to the “Diagnostic criteria, severity classification and guidelines of 
systemic sclerosis.” 

25 
All participants having received the IP will be scheduled to visit for follow-up 12 weeks after the day 
of the last dose of study treatment (the day of follow-up visit). On the day of the follow-up visit, the 
investigator or subinvestigator will evaluate the safety and efficacy after completion of study treatment 
for all participants. 
 
4. Target Indication and Inclusion and Exclusion Criteria for Participants 
The investigator or subinvestigator will ensure before enrollment that all inclusion criteria are met and none 
of the exclusion criteria are met. 
 
 Target Indication 
SSc 
 
 Inclusion Criteria 
Participants must meet all of the following criteria for study entry: 
Inclusion Criteria 
Assessment timing  
Day of 
Informed 
Consent  
Day of 
Screening 
Day of 
treatment start 
1） Patients aged 20 to 70 years at the time of informed 
consent 
X 
– 
– 
2） Patients meeting the classification criteria for SSc in ACR 
and EULAR 2013 
X 
– 
– 
3） Patients with systemic sclerosis who have moderate to 
severe skin thickening, with mRSS of 10 to 22 on both the 
screening and treatment initiation dates 
– 
X 
X 
4） Patients considered by the investigator or subinvestigator 
to be competent to perform the protocol-specified self-
assessment 
X 
X 
X 
 
 Rationale for inclusion criteria 
1) 
Established for safety consideration and to select patients with a sufficient capacity 
for judgment 
2) 
Established to standardize the diagnostic criteria for SSc for participants 
3) 
Established to include only patients with moderate to severe symptoms who are 
considered to be target patients for this drug. 
4) 
Established to select patients who can comply with the protocol-specified 
activities. 
 
 Exclusion criteria 
Participants who meet any of the following criteria will be excluded from study entry: 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
1） Patients complicated with diseases considered inappropriate 
for participation in clinical trials, such as serious* 
cardiac/hepatic/renal/pulmonary/hematologic disease 
*Refer to the Criteria for Seriousness Classification of Adverse 
Drug Reactions. (PAB/SD Notification No.80 by the Director 
X 
X 
X 

26 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
of Safety Division, Pharmaceutical Affairs Bureau, Ministry of 
Health and Welfare dated June 29, 1992) and the Common 
Terminology Criteria for Adverse Events v 5.0 Japanese JCOG 
version (CTCAE v 5.0-JCOG). 
2） Patients complicated with congestive heart failure [New York 
Heart Association (NYHA) Functional Class III or IV] 
X 
X 
X 
3） Patients having any of the following complications or 
concomitant/concurrent diseases: 
a） Severe chronic pulmonary disease (including %FVC < 
60%, or %DLco < 40% on the day of screening, 
calculated from the New Reference Values for 
Spirometry in Japanese adults calculated with the LMS 
Method (the Japanese Respiratory Society)”  
b） Serious complications associated with SSc other than 
interstitial lung disease* (e.g., renal crisis) 
* Interstitial lung disease is excluded if it falls under Item 
a) of3)  
c） Poorly controlled asthma that requires steroids 
(systemic), intravenous infusion of aminophylline, 
subcutaneous injection of adrenaline 0.1%, oxygen 
inhalation, or antibody drugs  
d） Diseases to affect the assessment of SSc 
X 
X 
X 
4） Patients with a history of malignant tumor, who are receiving 
no treatment and have had no recurrence /relapse for ≥5 years 
at the time of informed consent, or patients with a history of 
radical treatment for cervical intraepithelial neoplasia at the 
time of informed consent may be included in the study 
X 
X 
X 
5） Patients 
with 
Immune 
deficiency 
(e.g., 
congenital 
immunodeficiency, AIDS, or HIV). 
X 
X 
X 
6） Patients with a history or current hypersensitivity (including 
anaphylaxis) to immunoglobulin products (plasma-derived 
preparations or genetic recombinant monoclonal antibodies) 
X 
X 
X 
7） Patients weighing < 30.0 kg or > 120 kg on the day of study 
treatment initiation 
– 
– 
X 
8） Patients whose laboratory test values on the day of screening 
meet any of the following criteria: 
a） AST or ALT > 2 times the upper limit of normal 
b） Serum creatinine ≥2.0 mg/dL 
c） WBC <3000 cells/μL 
– 
– 
X 
9） Patients infected with hepatitis B virus (HBV) or hepatitis C 
virus (HCV) (Positive for HBs antigen or HBc antibody on the 
day of screening, positive for anti-HCV antibody on the day of 
screening) 
The allowed exceptions are as follows: 
 
Patients confirmed not to be infected with HBs at the time 
of the HBV-DNA test performed before study treatment 
initiation in the case of negative for HBs antigen and 
positive for HBc antibody in the hepatitis B test 
– 
– 
X 

27 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
performed on the day of screening. 
 
Patients confirmed not to be infected with HCV at the 
time of the HCV-RNA test performed before study 
treatment initiation in the case of positive for anti-HCV 
antibody in the hepatitis C test performed on the day of 
screening 
10） Patients with latent or active tuberculosis based on the result 
of the screening TB test. The allowed exception is patients 
deemed not to be infected with tuberculosis according to the 
“Guidelines for the use of interferon-γ release assay 
(Prevention Committee of the Japanese Society for 
Tuberculosis). 
– 
– 
X 
11） Patients with either of the following infectious diseases: 
 
Recurrent/chronic infections or other active infections 
deemed by the investigator to possibly aggravated by 
participating in the study 
 
Infections (including skin infections) requiring systemic 
antibiotics, antivirals, or antifungals within 7 days prior 
to the day of study treatment initiation. 
X 
X 
X 
12） Patients who have received oral steroids (> 10 mg/day of 
prednisolone or equivalent), dosage of receiving oral steroids 
have been changed (from ≤ 10 mg/day of prednisolone or 
equivalent), or newly treated with oral steroids, within 14 days 
before the day of study treatment initiation 
– 
– 
X 
13） Patients who have received any of the following therapies 
within the indicated period prior to the day of study treatment 
initiation 
– 
(X)* 
X 
a） Within 365 days 
Cyclophosphamide 
b） Within 120 days or 5 
times the elimination 
half-life of the drug, 
whichever is longer 
Antibody drugs 
c） Within 28 days 
i. 
Live vaccines 
ii. 
The 
following 
systemic 
medications: 
− Antifibrotic 
drugs 
(e.g., 
pirfenidone, nintedanib) 
− Immunosuppressants 
(e.g., 
cyclosporine, 
tacrolimus, 
azathioprine, mycophenolate 
mofetil, 
mizoribine, 
sulfasalazine, 
leflunomide, 
methotrexate, 
hydroxychloroquine, 
D-
penicillamine, sirolimus) 
− Tyrosine kinase inhibitors 
(e.g., imatinib) 

28 
*The exclusion criteria will be assessed with the expected date of study treatment initiation as the starting 
point. 
 
 Rationale for exclusion criteria 
1) to 6), 8) to 11), 15), 
and 17) to 19) 
Established considering the safety of participants  
7) 
Since the dose in this study is 60 mg/body, the upper body weight limit was set 
not to be lower than the dose (0.5 mg/kg) proven effective in the studies 
conducted to date in patients with atopic dermatitis, in view of efficacy. The lower 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
− JAK 
inhibitors 
(e.g., 
tofacitinib, upadacitinib) 
− Endothelin receptor agonists 
(e.g., bosentan, ambrisentan, 
macitentan) 
− Phosphodiesterase-5 
inhibitors (e.g., sildenafil, 
tadalafil) 
− Prostaglandin analogue (e.g., 
alprostadil, epoprostenol) 
− Riociguat 
iii. Injections of corticosteroids 
(excluding joint injections) 
iv. Phototherapy 
v. High-dose 
intravenous 
immunoglobulin therapy 
14） Patients who are within 120 days from the end of participation 
in other clinical trials or post-marketing clinical studies (i.e., 
the last day of administration of another IP or post-marketing 
clinical study drug) until the day of study treatment initiation, 
or participating in other clinical trials or post-marketing 
clinical studies 
– 
(X)* 
X 
15） Women who are pregnant, breastfeeding, possibly pregnant, 
or unwilling to use appropriate contraception measures as 
instructed by the investigator during the study period 
X 
X 
X 
16） Patients who meet any of the following criteria: 
a） Having not met eligibility for participation when 
participating in this study in the past 
b） Having previously received nemolizumab (including 
placebo) 
X 
X 
X 
17） Patients with confirmed or suspected COVID-19 
– 
X 
X 
18） Patients with a history of confirmed or suspected COVID-19 
excluding those meeting any of the following criteria: 
• At least 20 days after the onset of symptoms and at 
least 72 hours after the resolution of symptoms. 
• Confirmed not to carry SARS-Cov-2. 
– 
X 
X 
19） Patients found to have close contacts with COVID-19 patients 
within 14 days before the day of study treatment initiation 
– 
– 
X 
20） Other patients who are considered ineligible for the study by 
the investigator 
X 
X 
X 

29 
limit of body weight was set to ensure the safety of participants so that the 
exposure does not exceed that at the maximum dose (2.0 mg/kg) confirmed to be 
tolerated after repeated administration of IP. 
12) 
Established considering the impact on the efficacy of the IP and to ensure the 
safety of the participants.  
13) a), b), c) ii), iii), 
v),14) 
Established considering the impact on the efficacy and safety evaluation of the IP. 
The period was considered necessary for washout based on the duration of 
treatment effect and half-live of each drug and therapy. 
13) c), i) 
Established considering the impact on the safety evaluation of the IP. The period 
was considered necessary for washout based on the duration of treatment effect 
and half-live of each drug 
13) c), iv) 
Established considering the impact on the efficacy evaluation of the IP. The period 
was considered necessary for washout based on the duration of treatment effect 
and half-live of each therapy. 
16) 
 
1) Established to exclude patients ineligible for this study 
2) Established to exclude the impact on the evaluation of efficacy and safety 
20) 
Established as a general criterion to exclude patients considered ineligible for this 
study by the investigator or subinvestigator. 
 
5.  Study Discontinuation of Individual Participants 
The investigator or subinvestigator will withdraw the participant signing informed consent from the study 
and take appropriate measures if participant meets any of the following discontinuation criteria before 
observation/tests at Visit 17 (Week 52). Even if the participant requests withdrawal from the study, the 
participant’s data will be used. 
 
 Discontinuation criteria 
1） Use of other antibody drugs by Week 52 visit 
2） Use of live vaccines by Week 52 visit 
3） The investigator or subinvestigator determined that an adverse event which would prevent the 
continuation of the study has occurred. 
4） The participant is found to fail to meet any of the inclusion criteria or to meet any of the exclusion 
criteria. 
5） The participant is found to be pregnant. 
6） The investigator or subinvestigator has determined that the participant should be withdrawn from the 
study due to inadequate response to the IP. 
7） The participant requests to withdraw from the study. 
8） The participant no longer visits the medical institution, and the study cannot be continued 
9） The participant has died. 
10） The sponsor has determined the participant discontinuation from the study due to significant protocol 
deviations. 
The sponsor has prematurely terminated the study. 
The investigator or subinvestigator has determined to withdraw the participant from the study for any other 
reasons. 
 
 Rationale for discontinuation criteria 
1) to 3), 5) 
Established considering the safety of the participants 
4) 
Established because the participants are considered ineligible for the study 
6) 
Established to reduce disadvantages for the participants 

30 
7) 
Established because it is considered the rights of participants 
8) to 11) 
Established for contingencies 
12) 
Established to allow participant discontinuation from the study at the discretion of the 
investigator or subinvestigator. 
 
 Procedure for Discontinuation 
5.2.1  Discontinuation before Enrollment 
1） For the participant not led to enrollment because of not satisfying the inclusion criteria, meeting any of 
the exclusion criteria or other reasons, the investigator or subinvestigator will explain the reason to 
withdraw the participant from the study, take appropriate action for the participant. The investigator or 
subinvestigator will ascertain and record the date of discontinuation and the reason for discontinuation 
in the source documents. A visit for discontinuation and observation/tests scheduled on the day of visit 
for discontinuation will not be performed. 
2） The investigator, subinvestigator, or CRC will record the data for the items described in Section 19.1.2 
in the CRF. 
 
5.2.2  Discontinuation after Enrollment 
1） The investigator or subinvestigator will explain the reason to withdraw the participant from the study 
and take appropriate action, ascertain and record the reason for discontinuation in the source documents. 
2） The investigator or subinvestigator will perform the observation/tests scheduled on the day of visit for 
discontinuation. When determining to discontinue the study on a day other than the day of the visit, the 
investigator or subinvestigator will instruct the participant to come to the study site as early as possible. 
However, if the day of visit for discontinuation is on or after 77 days from the last dose of study treatment.  
3） The investigator, subinvestigator, or CRC will record the data of the items described in Section 19.1.1 in 
the CRF. 
 
 Handling of Participants Who Fail to Visit the Study Site 
5.3.1  Participants Discontinuing Study Site Visit Between the Day of Informed Consent and the 
Day of Enrollment 
When a participant discontinues visiting the study site after the day of informed consent but before enrollment, 
the investigator or subinvestigator will perform follow-up of the participant through contact with him/her by 
telephone, letter or other means to record the method and the result of follow-up, reason(s) for not visiting 
with the date of such information obtained, presence or absence of adverse events, and other information 
obtained in the source document.  
 
5.3.2  Participants Discontinuing Study Site Visit in the Period after the Enrollment up to Visit 17 
(Week 52) 
If a participant discontinues visiting the study site after assigned to treatment, the investigator or 
subinvestigator will identify the whereabouts of the participant as far as possible and encourage him/her to 
visit the study site. If the participant dose not visit the study site, the investigator or subinvestigator will 
perform follow-up of the participant through contact with him/her by telephone, letter, or other means to 
document the method of follow-up, reason(s) for not visiting with the date of such information obtained, 
presence or absence of adverse events, and other information obtained. 
 
5.3.3  Participants Discontinuing Study Site Visit during the Follow-up Period 
The participant who cannot visit the study site within the window of the follow-up visit will be encouraged 
to visit the study site on the nearest day to the window. If the participant does not visit the study site, the 
investigator or subinvestigator will perform follow up of the participant through contact with him/her by 
telephone, letter, and other means to document the method of follow-up, reason(s) for not visiting with the 

31 
date of such information obtained, the presence or absence of adverse events, and other information obtained. 
 
6. Participant Enrollment 
 Informed Consent 
The investigator or subinvestigator will fully explain the study to participants who are considered eligible for 
the study and obtain written consent before the procedures for the study (see Section 27.4 for the method and 
points to note for obtaining informed consent).  
The investigator or subinvestigator will record the participant information on the participant screening log 
and provide the participant identification code. The participant identification will be AF001-XXX and will 
be coded in order of informed consent acquisition. Each participant will use the same participant 
identification code from informed consent to completion of the study. 
 
 Notification when the Participant is Treated by Another Doctor 
The investigator or subinvestigator will ask participants whether or not they are being treated by another 
doctor. When a participant is being treated by another doctor, the investigator or subinvestigator will notify 
the doctor of his/her participation in the study after obtaining his/her consent. In addition, the investigator or 
subinvestigator will record this notification to the doctor in the medical record, etc. 
 
 Enrollment Procedure of Participants 
1） For first and second registration. 
For participants considered eligible for the study on the day of screening and on the day of study 
treatment initiation, the investigator or subinvestigator will enter the necessary information in the 
source documents, and then fill out a registration form and fax it to the sponsor. The registration form 
should be filled out and faxed after the source documents have been prepared, which can be performed 
by the CRC. 
 
2） For discontinuation before assigned to treatment 
For participants discontinued from the study after informed consent but before second registration, the 
investigator or subinvestigator will enter the necessary information in the source documents, and then 
fill out a registration form and fax it to the sponsor. The registration form should be filled out and 
faxed after the source documents have been prepared, which can be performed by the CRC. 
 
3） Correction of entries in the source documents 
When an error is found in the information registered, the investigator or subinvestigator will correct 
the data in the source document and enter the necessary information in a registration form as needed, 
and then fax it to the sponsor to correct such data. The registration form should be filled out and faxed 
after the source documents have been corrected, which can be performed by the CRC. 
 
7. Investigational Product 
 Name, Dosage Form, and Strength of the IP 
Name, dosage form, and strength of the IPs are indicated in Table 7-1. 
 
 
 

32 
Table 7-1  Name, dosage form and strength of investigational product 
Name of 
investigational 
product 
Formulation 
Active ingredient and strength 
(Per DCS) 
Storage condition 
(Before preparation) 
Nemolizumab 
Injection 
(DCS) 
nemolizumab 75 mg (lyophilized) 
Nemolizumab is overfilled to ensure injectable 
nemolizumab 60 mg from one DCS in 
consideration of the loss of the prepared drug 
solution during administration. The active 
ingredient level after preparation is 100 
mg/mL. 
2°C to 8°C 
Protection from light 
 
 Packaging and Labeling 
7.2.1  Packaging 
One DCS of the IP is contained in a small box. 
 
7.2.2  Labeling 
The small box is labeled with a statement for clinical study use only, the name and address of the sponsor, 
identification number, lot number, and storage method. 
 
 Storage and Management of Investigational Products 
The investigational product manager at each study site will store and manage the IPs according to the 
“Operating Procedure for Investigational Product Management” prepared by the sponsor and other 
procedures specified at each site. 
 
8. Treatment Method 
 Dispensing of Investigational Products 
The investigator or subinvestigator will dispense one DCS of the IP at the following visits: 
<Dispensing visits> 
Day of study treatment initiation, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 
 
 Preparation of Investigational Products 
The investigator or subinvestigator, the investigational product manager or the person in charge of preparation 
of the IP will prepare injection solutions of IPs according to the “Standard Operating Procedure for 
Investigational Product Management.”  
 
 Method of Administration 
On the days of administration (see Table 9-1: Schedule), the investigator or subinvestigator will 
subcutaneously inject one DCS (0.6-mL) of nemolizumab slowly to the participant either in the upper arm, 
abdomen, or thigh. The IP may be administered by a person qualified to administer it under the instruction 
of the investigator or subinvestigator. 
 
 Precautions 
- 
The IP will be administered after all observation/tests scheduled at the visit have been completed. 
- 
The IP will be administered within the window of the specified visit. However, if the IP cannot be 
administered within the window, the next dose should be administered 14 days or later after the 

33 
previous dose. 
- 
If the participant’s body weight is lower than 30.0 kg on the day of administration, the IP must not 
be administered. 
 
 Rationale for selection> 
1） Dosage: 60 mg/body Q4W 
A phase III study in Japanese patients with atopic dermatitis has demonstrated the long-term safety of 
nemolizumab 60 mg/body Q4W. This study has been designed to exploratorily evaluate the efficacy of 
nemolizumab in SSc patients at 60 mg/body Q4W which has shown the long-term efficacy in SSc 
patients.  
 
2） Treatment Period 
The treatment period has been set at 52 weeks because long-term observation is required to evaluate the 
efficacy of nemolizumab on skin thickening in SSc patients in an exploratory manner. 
 
3） Day of Follow-up Visit 
Considering the serum elimination half-life after a single dose of nemolizumab ranges from 12.6 to 
14.6 days in patients with atopic dermatitis, the day of follow-up visit has been set to collect 
information such as the occurrence of adverse events on the day of 5 times the elimination half-life 
(84 days ± 7 days) from the day of the last dose. 
 
 Concomitant Medications and Therapies 
8.4.1  Restricted Concomitant Medications 
The following medications may be continued at a stable dose if used for at least 14 days before the day of 
study treatment initiation. However, the dose may be reduced at the discretion of the investigator or 
subinvestigator, and after dose reduction, the dose may be increased up to that used at the day of study 
treatment initiation. 
•Oral steroids (≤ 10 mg/day of prednisolone or equivalent) 
 
8.4.2  Duration and Method of Inspection 
The investigator or subinvestigator will collect the information of concomitant medications/therapies by 
interviewing participants according to Section.9.3.2  
 
8.4.3  Prohibited Concomitant Medications and Therapies 
Concomitant use of medications and therapies listed below is prohibited in this study.  
- 
From the day of study treatment initiation to Week 52 or to the physical examination on the day of visit 
for discontinuation 
1） The following systemic medications: 
a） Antifibrotic drugs (e.g., pirfenidone, nintedanib) 
b） Immunosuppressants 
(e.g., 
cyclophosphamide, 
cyclosporine, 
tacrolimus, 
azathioprine, 
mycophenolate mofetil, mizoribine, sulfasalazine, leflunomide, methotrexate, hydroxychloroquine, 
D-penicillamine, sirolimus) 
c） Tyrosine kinase inhibitors (e.g., imatinib) 
d） JAK inhibitors (e.g., tofacitinib, upadacitinib) 
e） Endothelin receptor agonists (e.g., bosentan, ambrisentan, macitentan) 
f） Phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil) 

34 
g） Prostaglandin analogues (e.g., alprostadil, epoprostenol) 
h） Riociguat 
2） Injections of corticosteroids (excluding joint injections) 
3） Phototherapy 
4） High-dose intravenous immunoglobulin therapy 
5） Antibody drugs 
6） Live vaccines 
 
 Rationale for selection 
1) 2) 4) 5) 
Established considering the impact on the efficacy of the IP and the safety of participants 
3)  
Established considering the impact on the efficacy evaluation of the IP 
6) 
Established considering the safety of participants 
 
- 
From the day of study treatment initiation to the day of follow-up visit 
1） Other drugs and medical devices under development 
 
 Rationale for selection 
1)  
Established considering the safety of participants and the impact on the efficacy of the IP. 
 
8.4.4  Instructions to participants 
The investigator or subinvestigator will examine the implementation status of the treatment of SSc at each 
visit and give instructions to the participants on treatment of SSc according to the therapeutic guidance 
specified in Sections 8.4.1 and 8.4.3.

38 
e Not to be performed if refused by the participant. 
If any of the following treatment-emergent adverse events occurs, photographs of the affected skin areas of the adverse event should be taken while the event (at least once) is 
occurring and at the final outcome evaluation, in addition to the scheduled visit (i.e., the day of study treatment initiation). The photography on the scheduled visit (day of study 
treatment initiation) will be performed according to Section 9.3.5.4  
• Atopic dermatitis 
• Adverse events with skin symptoms of edematous erythema or scaling 
• Any other adverse event for which the investigator or subinvestigator considers that photography is necessary. 
f To be performed on female participants excluding those who never become pregnant. 
g May be conducted on another day after the day of screening before the day of study treatment initiation 
h • Hepatitis B 
The participants who test negative for HBs antigen and positive for HBc antibody will undergo HBV-DNA measurement before the day of study treatment initiation. The participants 
enrolled through HBV-DNA measurement will undergo HBV-DNA measurement once every three months. 
• Hepatitis C 
The participants who test positive for anti-HCV antibody will undergo HCV-RNA measurement before the day of study treatment initiation. The participants enrolled through HCV-
RNA measurement will undergo HCV-RNA measurement once every three months. 
i To be administered after all observation/tests are performed. If the IP cannot be administered within the window indicated, the next dose should be administered 14 days or later 
after the day of the previous dose. 
j Participants who discontinued the study will visit the site 84 days (±7 days) after the day of the last dose of study treatment for observation/tests at FU shown in Table 4-1. Participants 
discontinued the study before study treatment initiation need not to undergo observation/tests scheduled on the day of visit for discontinuation. 

39 
 Definition of the Days of Observation, Tests, and Sample Collection 
The days of observation, tests, and sample collection will be defined as follows. Table 9-1 shows the visit 
window of the assessment day. 
 
9.2.1  Day of Informed Consent 
The day when informed consent is obtained from the participant is defined as the day of informed consent.  
 
9.2.2  Day of screening 
The day of screening is defined as the day of first registration after completion of protocol-specified 
assessments. The day of informed consent may be the same day as the day of screening. 
All observation/tests scheduled for the day of screening must be performed on the same day. The tuberculosis 
test may be performed after the day of screening; however, the test result should be reviewed before the day 
of study treatment initiation. 
 
9.2.3  Day of Study Treatment Initiation 
The day of study treatment initiation is defined as the day when the participant is enrolled after completion 
of protocol-specified assessments. All assessments scheduled for the day of study treatment initiation must 
be performed on the same day. 
The day of study treatment initiation is Day 1, and the day before the day of study treatment initiation is Day 
-1. 
 
9.2.4  Day of Assessment (Weeks 1, 2, 4, 8, 12, through 52) 
Week 1 through Week 52 are days when participants visit the study site for protocol-specified 
observation/tests. 
 
9.2.5  Day of Study Treatment 
The day of study treatment is defined as the day when the IP is administered to the participant according to 
the schedule of Table 9-1 after the protocol-specified assessments are implemented. 
 
9.2.6  Day of Discontinuation 
The day of discontinuation is defined as the day when the investigator or subinvestigator determines to 
withdraw the participant from the study. 
 
9.2.7  Day of Discontinuation Visit 
The day of visit for discontinuation is defined as the day when the protocol-specified observation/tests 
scheduled for discontinuation are performed for the participant who is determined to be withdrawn from the 
study after study treatment initiation and visit the study site for the procedure. 
 
9.2.8  Day of Follow-up Visit  
The day of follow-up visit is defined as the day when the protocol-specified observation/tests are performed 
for the participant who visits the study site 84 days (±7 days) after the day of the last dose of study treatment. 
 
 Observation, Tests and Sample Collection  
9.3.1  Participant Demographics 
The investigator or subinvestigator will perform following assessments on the day of informed consent, the 
day of screening and the day of study treatment initiation. 

40 
1） Assessments on the day of informed consent 
 
Primary disease (diagnosis) 
 
Time of onset of primary disease 
 
Classification of primary disease (diffuse cutaneous SSc [dcSSc] or limited cutaneous SSc 
[lcSSc]) 
 
Main therapy given for SSc in the past 
 
Date of birth 
 
Sex 
 
Complication (any disease which is ongoing at the time of informed consent) 
 
Race 
 
Inclusion and exclusion criteria (see “4. Target Indication and Inclusion and Exclusion Criteria 
for Participants”) 
 
2） Assessments on the day of screening 
 
Inclusion and exclusion criteria (see “4. Target Indication and Inclusion and Exclusion Criteria 
for Participants”) 
 
Height 
 
3） Assessments on the day of study treatment initiation 
 
Inclusion and exclusion criteria (see “4. Target Indication and Inclusion and Exclusion Criteria 
for Participants”) 
 
9.3.2  Prior and Concomitant Medications and Therapies 
9.3.2.1  Prior and concomitant medications 
The investigator or subinvestigator will review the following medications for each participant: 
1） Medications intended to treat SSc 
 
Used from 28 days before the day of study treatment initiation to the physical examination at the 
follow-up visit 
2） Medications intended to treat adverse events 
a） Medications intended to treat adverse events of special interest defined in Section 11.6 : 
Used from the day of study treatment initiation (after initiating study treatment) to the final 
outcome evaluation. 
b） Medications intended to treat adverse events except for 1): 
Used from the day of study treatment initiation (after initiating study treatment) to the physical 
examination at the follow-up visit.  
3） All concomitant medications other than 1), and 2) 
 
Used from the day of study treatment initiation (after initiating study treatment) to Week 52 or 
the day of discontinuation visit. 
 
Information to be 
obtained 
Presence or absence of concomitant medications, and the drug name, dosage, drug 
use classification, start and end dates of use, and indication for use of each 
concomitant medication 
Notes 
The following information is not required to be collected: 
 Diagnostic agents, infusions, fluid replacement, nutritional agents, disinfectants, 
anesthetics for surgery, laxatives and suppository for barium examination (unless 
these drugs were used for treatment or are included in the prohibited concomitant 
medications) 
 Dosage of 3)  
 Among medications of 1), those newly used in participants who discontinued 

41 
from the study on or after the physical examination at the discontinuation visit. 
 
9.3.2.2  Prior and concomitant therapies 
The investigator or subinvestigator will collect the data of the following therapies: 
1） Therapies to treat SSc 
 
Performed from 28 days before the day of study treatment initiation to the physical examination 
at the follow-up visit. 
2） Concomitant therapies intended to treat adverse events 
a） Concomitant therapies intended to treat adverse events of special interest defined in Section 11.6  
 
Performed from the day of study treatment initiation (after initiating study treatment) to the final 
outcome evaluation. 
b） Concomitant therapies intended to treat adverse events except for 1) 
 
Performed from the day of study treatment initiation (after initiating study treatment) to the 
physical examination at the follow-up visit.  
c） Prohibited concomitant therapies 
 
Performed from the day of study treatment initiation (after initiating study treatment) to Week 52 
or the day of discontinuation visit. 
 
Information to 
be obtained 
Presence or absence of therapy, and the name of therapy, site to which concomitant 
therapy is applied, start and end dates of application and purpose of use of concomitant 
therapy  
Notes 
Among therapies of 1), those newly performed to participants who discontinued from 
the study on or after the physical examination at the discontinuation visit are not 
required. 
 
9.3.3  Body Weight 
The investigator or subinvestigator will measure the body weight of participants at the following timepoints: 
Data to be 
obtained 
Body weight 
Time points 
Day of screening, Day of study treatment initiation, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44 and 48  
Notes 
 On the days of study treatment, measurement will be performed, and the results will be 
reviewed before administration of IP. 
 Participants weighing less than 30.0 kg on the day of study treatment are not allowed 
to receive study treatment. 
 
9.3.4  Efficacy Evaluation 
9.3.4.1  Evaluation of Skin Findings 
The investigator or subinvestigator will perform the following assessments: 
Assessment 
mRSS  
Time points 
Day of screening, Day of study treatment initiation, Week 4, 12, 24, and 36, Week 52 or 
Day of discontinuation visit, Day of follow-up visit 
Notes 
 On the day of study treatment, assessment will be performed before the treatment. 
 mRSS assessment will be performed by a skilled physician experienced in scoring skin 
sclerosis. 
 In principle, the same investigator or subinvestigator will perform assessment 
throughout the study period for each participant in order to minimize inter-assessor 
variability. 

42 
 
9.3.4.2  Respiratory function test 
Spirometry will be performed according to the separately specified procedure. 
Assessment 
 
Forced vital capacity (FVC) and %FVC 
 
Diffusing capacity of lung for carbon monoxide (DLco) and % DLco 
 
Total lung capacity (TLC) and forced expiratory volume in one second (FEV1) 
Time points 
Day of screening, Week 12, and 24, Week 52 or Day of discontinuation visit 
Notes 
 
If the %FVC decreases by ≥ 15% from baseline, %FVC will be measured again 
within 1 month to examine whether the %FVC decreases by ≥ 15% from baseline or 
not. 
 
9.3.4.3  Chest HRCT 
HRCT will be performed according to the regulations or procedures or the test manual of the study site. 
Time points 
 
Day of screening, Week 24, Week 52 or Day of discontinuation visit 
Notes 
If having been performed within 1 month of the specified timepoint, it is not necessary to 
be performed at the specified timepoints, and the results within 1 month will be 
substituted. 
 
9.3.4.4  Severity of pulmonary lesions 
The investigator or subinvestigator will evaluate the severity of pulmonary lesions based on the results of 
respiratory function test and chest HRCT according to 10.1.4 . 
Time points 
Day of screening, Week 24, Week 52 or Day of discontinuation visit 
 
9.3.4.5  ACR-CRISS 
The investigator or subinvestigator will assess whether the participant fall under the following criteria: 
Evaluations 
 
Onset of scleroderma renal crisis 
 
Interstitial lung disease with a decline in %FVC ≥15% (requiring reconfirmation 
within 1 month), and %FVC of 80% or less 
 
Onset of left ventricular failure requiring treatment (defined as left ventricular 
ejection fraction ≤45%) * 
 
Onset of pulmonary arterial hypertension requiring right heart catheterization * 
*Caused by SSc 
Time points 
Week 12 and 24, Week 52 or Day of discontinuation visit 
 
9.3.4.6  The Number of Digital Ulcers 
The investigator or subinvestigator will count the number of digital ulcers. 
 
Time points 
 
Day of screening, Day of study treatment initiation, Week 12, 24 and 36, Week 52 
or Day of discontinuation visit 
Notes 
 
In principle, the same investigator or subinvestigator will perform assessment 
throughout the study period for each participant in order to minimize inter-assessor 
variability. 
 
 
 

43 
9.3.4.7  Patient-reported outcome 
The participants will perform the following assessments: 
Evaluations 
HAQ-DI, FACIT-Fatigue and FSSG 
Time points 
Day of study treatment initiation, Week 12, 24, and 36, Week 52 or Day of discontinuation 
visit 
Notes 
 
The participants will perform each assessment before receiving the examination and 
evaluation by the physician at the above visits. 
 
The investigator or subinvestigator must not attend the assessments by the 
participants. 
 
9.3.4.8  Global improvement rating 
9.3.4.8.1  Patient’s Global Assessment (PtGA) 
The participants will assess the overall condition of SSc using a visual analog scale (VAS). 
 
Time points 
Day of study treatment initiation, Week 12, 24, and 36, Week 52 or Day of discontinuation 
visit 
Notes 
 
The participants will perform each assessment before receiving the examination and 
evaluation by the physician at the above visits. 
 
The investigator or subinvestigator must not attend the assessments by the 
participants. 
 
9.3.4.8.2  Physician’s Global Assessment (PGA) 
The investigator or subinvestigator will assess the overall condition of SSc of each participant using a VAS. 
 
Time points 
Day of study treatment initiation, Week 12, 24, and 36, Week 52 or Day of discontinuation 
visit 
Notes 
 
In principle, the same investigator or subinvestigator will perform assessment 
throughout the study period for each participant in order to minimize inter-assessor 
variability. 
 
9.3.5  Safety Evaluation 
9.3.5.1  Vital signs 
The investigator or subinvestigator will perform the following measurements: 
Measurements Body temperature, pulse rate, and blood pressure (systolic/diastolic) 
Time points 
Day of screening, Day of study treatment initiation, Week 1, 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44 and 48, Week 52 or Day of discontinuation visit, Day of follow-up visit 
Notes 
 On the day of study treatment, measurements will be performed, and the results will 
be reviewed before the treatment.  
 The vital signs will be measured at rest in the sitting position. 
 
9.3.5.2  ECG 
The investigator or subinvestigator will perform the following measurements: 
Measurements PR interval, QRS interval, QT interval, heart rate and presence or absence of 
abnormalities 
Time points 
Day of screening, Week 24, Week 52 or Day of discontinuation visit 

44 
Notes 
 
On the day of study treatment, measurements will be performed, and the results will 
be reviewed before the treatment. 
 
The same electrocardiograph will be used for each participant at each measurement 
whenever possible. 
 
ECG will be performed at rest in the supine position.  
 
9.3.5.3  Echocardiography 
Echocardiography will be performed according to the regulations, procedures, or the test manual of the study 
site. 
Time points 
Day of screening, Week 24, Week 52 or Day of discontinuation visit 
Notes 
 
On the day of study treatment, measurements will be performed, and the results 
will be reviewed before the treatment.  
 
9.3.5.4  Photography 
The investigator or subinvestigator will perform photography according to the separately specified procedure. 
Sites to be 
Photographed 
1） Anterior and dorsal views of the upper body (excluding the face)  
2） Skin appearance of adverse events 
Time points 
1） Day of study treatment initiation 
2） Duration of the following adverse events (at least once occurrence) after study 
treatment initiation and at the final outcome evaluation: 
 
Atopic dermatitis 
 
Adverse events with skin symptoms accompanied by edematous erythema 
or scaling 
 
Any other adverse event for which the investigator or subinvestigator 
considers that photography is necessary. 
Notes 
 1) and 2): 
 
The photos will be retained by the study site and collected by the sponsor. 
When personal information can be identified from the photos, the photos must 
be collected with the personal information being masked. 
 
Photography will not be performed if refused by the participant. 
 
9.3.6  Laboratory tests 
Laboratory tests will be performed at the central laboratory. The investigator or subinvestigator will collect 
blood and urine samples from participants before study treatment initiation and submit them to the central 
laboratory. Tuberculosis test may be performed in an in-hospital laboratory. 
1） Hematology and serum chemistry tests 
2） Immunological tests (thymus and activation-regulated chemokines [TARC]) 
3） Urinalysis 
Time points 
Day of screening, Day of study treatment initiation, Week 1, 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44 and 48, Week 52 or Day of discontinuation visit, Day of follow-up visit 
Notes 
1) 2) and 3): 
 
On the day of study treatment, blood and urine will be collected before the treatment. 
 
The test result should be reviewed before the next study treatment. 
1) and 2): 
 
When aggregation or coagulation is observed in “Plt” because of a reason other than 
manual technique, blood will be collected into a blood collecting tube containing 
3.2% sodium citrate in addition to a conventional blood collection tube from the next 
visit. 
 
 

45 
4） Pregnancy test 
Time points 
Day of screening 
Notes 
 
The test will be performed on female participants. However, those who are 
considered unable to become pregnant (e.g., menopausal women* and women who 
have had total hysterectomy) will be excluded. 
*: Defined as those who are amenorrhea for at least 12 months without any medical 
reason. 
 
5） Tuberculosis test 
Time points 
Day of screening 
Notes 
 
If the test cannot be performed on the day of screening, it may be performed on 
another day after the day of screening but before study treatment initiation. In such 
cases, the rest results should be reviewed before administration of IP on the day of 
study treatment initiation. 
 
6） Hepatitis B and C tests 
Time points 
a） Day of screening 
b） Week 12, 24, 36 and 48, Day of follow-up visit 
Notes 
a） The participants who test negative for HBs antigen and positive for HBc antibody 
on the day of screening will undergo HBV-DNA measurement before the day of 
study treatment initiation. The participants who test positive for anti-HCV antibody 
on the day of screening will undergo HCV-RNA measurement before the day of 
study treatment initiation. 
b） The participants enrolled through HBV-DNA measurement before the day of study 
treatment initiation will undergo HBV-DNA measurement once every three months. 
The participants enrolled through HCV-RNA measurement before the day of study 
treatment initiation will undergo HCV-RNA measurement once every three months. 
 
7） Antinuclear antibodies test 
Time points 
Day of study treatment initiation 
Notes 
 
Blood will be collected before administration of IP on the day of study treatment 
initiation 
 
 
 

47 
On the day of study treatment, blood will be collected before the treatment 
 
9.3.10  Comprehensive measurement of autoantibodies 
The investigator or subinvestigator will collect blood samples for comprehensive measurement of 
autoantibodies. The measurement will be performed centrally. 
Time points 
Day of study treatment initiation, Week 24, Week 52 or Day of discontinuation visit 
Notes 
 
On the day of study treatment, blood will be collected before the treatment. 
 
9.3.11  CyTOF measurement 
The investigator or subinvestigator will collect blood samples for central measurement of CyTOF. 
Time points 
Day of study treatment initiation, Week 24, Week 52 or Day of discontinuation visit 
Notes 
 
On the day of study treatment, blood will be collected before the treatment. 
 
9.3.12  Assessment of Adverse Events 
The investigator or sub-investigator will assess the adverse events according to the procedure described in 
“11.4 Review and reporting of adverse events.” 
 
9.3.13  Investigation of Malfunction of DCS 
The investigator or subinvestigator will investigate malfunction of DCS according to "11.11 Malfunctions 
of DCS.”  

50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 10-1  Severity classification of lung lesion 
 
10.1.5  ACR-CRISS 
ACR-CRISS is a composite outcome measure that is calculated as an index taking a value ranging from 0 to 
1 for the probability of improving for participants based on the presence or absence of renal, pulmonary, and 
cardiac impairments and changes in the 5 core set items (mRSS, %FVC, PGA, PtGA, and HAQ-DI). 
Participants are considered improved and not improved when their ACR-CRISS is ≥ 0.6 and < 0.6, 
respectively. If participants meet any of the following criteria, the probability of improving is 0.0. The 
investigator or subinvestigator will assess whether participants met or not met the following criteria at 
specified visits. If patients do not meet any of the following criteria, an ACR-CRISS score will be calculated 
using the formula shown in 17.3.2 2). 
• Onset of scleroderma renal crisis 
• Decline in FVC% ≥15% (requiring reevaluation within 1 month), and %FVC of 80% or less 
• Onset of left ventricular failure requiring treatment (defined as left ventricular ejection fraction 
≤45%) * 
• Onset of pulmonary arterial hypertension requiring right heart catheterization * 
* Caused by SSc  
 
10.1.6  The Number of Digital Ulcers 
The investigator or subinvestigator will count the number of digital ulcers. 
 
10.1.7  Patient-reported outcome 
1） HAQ-DI  
Findings compatible with interstitial lung disease on 
chest HRCT 
Extent of any interstitial lung disease lesions on 
chest HRCT 
Forced vital capacity (FVC) predicted 
Requirement of oxygen supplementation  
Yes 
>20% 
<70% 
No 
0 (normal) 
≤ 20% 
1 (mild) 
≥ 70% 
2 (moderate) 
No 
3 (severe) 
Yes 
4 (very severe) 

51 
Participants will assess the degree of their difficulty in performing actions of eight functional categories 
(dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities) using HAQ-DI 
(Health assessment questionnaire disability index, Japanese version)9) on a 4-point scale of 0 (Without any 
difficulty), 1 (Without some difficulty), 2 (Without much difficulty), and 3 (Unable to do). 
 
2） FACIT-Fatigue 
Participants will assess their fatigue over the past 7 days using FACIT-Fatigue Scale, Japanese version 
10) on a 5-point scale from 0 (not at all) to 4 (very much). 
 
3） FSSG. 
Participants will assess their gastroesophageal reflux disease using Frequency Scale for the Symptoms 
of GERD (FSSG) 11) on a 5-point scale from 0 (never) to 4 (always). 
 
10.1.8  Global improvement rating 
1） PtGA 
Participants will assess their general health status associated with SSc at visit using a 10-cm visual 
analog scale (VAS) from 0 (the best status) to 10 (the worst status) 12). The investigator or 
subinvestigator or the clinical trial collaborator will measure the length (cm) from the left end to the 
first decimal place and record it. 
 
2）  PGA 
The investigator or subinvestigator will assess participants’ general health status associated with SSc 
in terms of Severity, Damage, and Overall disease using a 10-cm VAS from 0 (the best status) to 10 
(the worst status) 12). The investigator (or subinvestigator) or the clinical trial collaborator will measure 
and record the length (cm) from the left end to the first decimal place. 
 
 Efficacy Endpoints 
10.2.1  Primary Endpoint  
Change from baseline in mRSS at Week 24 
 
10.2.2  Other Endpoints 
1） Change from baseline in mRSS at Week 52 
2） Change from baseline in HAQ-DI at Week 52 
3） Change from baseline in HAQ-DI at Week 24 
4） Change from baseline in %FVC at Week 52 
5） Change from baseline in %FVC at Week 24 
6） Change from baseline in DLco at Week 52 
7） Change from baseline in DLco at Week 24 
8） Change from baseline in PGA at Week 52 
9） Change from baseline in PGA at Week 24 
10） Change from baseline in PtGA at Week 52 
11） Change from baseline in PtGA at Week 24 
12） ACR-CRISS at Week 52 
13） ACR-CRISS at Week 24 
14） Change from baseline in the number of digital ulcers at Week 52 

52 
15） Change from baseline in the number of digital ulcers at Week 24 
16） Time-course changes in the following parameters: 
a） HAQ-DI 
b） FACIT-Fatigue 
c） FSSG 
d） FVC 
e） %FVC 
f） DLco 
g） %DLco 
h） TLC 
i） FEV1 
j） Severity assessment of lung lesion 
k） PGA 
l） PtGA 
m） ACR-CRISS 
n） The number of digital ulcers 
 
 Rationale for Efficacy Endpoints 
1） mRSS 
mRSS is used internationally to assess severity of SSc13), 14). Moreover, mRSS is generally considered 
to be correlated with visceral involvement, etc. and change over a relatively short period of time by 
receiving treatment, etc. Therefore, change from baseline in mRSS at Week 24 has been selected as 
primary endpoint to evaluate the efficacy of this drug on SSc. Since SSc has a chronic course, change 
from baseline in mRSS at Week 52 has been also selected as an efficacy endpoint to discuss the clinical 
significance of this drug. 
 
2） Respiratory Function Test 
FVC in respiratory function tests has been shown to be a useful indicator for predicting vital prognosis 
in interstitial lung disease associated with SSc15) . %FVC and %DLco are useful parameters for 
screening pulmonary hypertension associated with SSc16). Therefore, this test has been selected to 
evaluate the efficacy of this drug on lung lesion in an exploratory manner and to ensure the safety of 
participants. 
 
3） Chest HRCT 
Interstitial lung disease in SSc patients has been reported to be detected 50% to 60% by HRCT17). 
Interstitial lung disease is the most common cause of death in SSc patients18). Interstitial lung disease 
often occurs from the early stage of SSc, and therefore, it is useful to predict prognosis and determine 
whether the treatment is feasible for the patient. Moreover, the guidelines recommend to predict the 
risk of progression to end-stage pulmonary disease and determine whether the treatment is feasible for 
the patient by the fibrotic finding in HRCT and the extent of the lesion or of the entire lesion in 
conjunction with FVC-predicted values in respiratory function tests7). Based on the above, this test has 
been selected to evaluate the efficacy of this drug on lung lesion in an exploratory manner and to 
ensure the safety of participants. 
 
4） Severity Classification of Lung Lesion  

53 
The Guidelines for Diagnostic Criteria, Severity Classification and Clinical Practice of Systemic 
Sclerosis recommend to predict the risk of progression to end-stage pulmonary disease and determine 
whether the treatment is feasible for the patient by the fibrotic finding in HRCT, the extent of the lesion 
or of the entire lesion and FVC predictive value in respiratory function tests7). This parameter has been 
selected to evaluate the efficacy of this drug on lung lesion in an exploratory manner and to ensure the 
safety of participants. 
 
5） ACR-CRISS 
ACR-CRISS is a composite response index for clinical trials in early diffuse cutaneous SSc 19), which 
is generally used in clinical trials in SSc patients. This index has been selected to evaluate the efficacy 
of this drug on SSc in an exploratory manner. 
 
6） The number of digital ulcers 
Ulcers of the fingers and toes are complications of vascular disorder, one of the conditions of SSc, 
which occur frequently (35-60%) and arise from the early stage of the disease; therefore, they are 
considered to reflect the condition of SSc. Moreover, the ulcers are often refractory and recurrent, 
which is directly related to participants’ activities of daily living (ADL) and decreased QOL. 
Accordingly, this parameter has been selected to evaluate the efficacy of this drug on SSc in an 
exploratory manner. 
 
7） HAQ-DI 
HAQ is a convenient self-administered questionnaire assessing physical function for activities of daily 
living. It was originally developed to evaluate the effect of rheumatoid arthritis on activities of daily 
living; however, it has been reported that HAQ-DI correlates with the degree of skin thickening, 
cardiac involvement, renal involvement, etc., also in SSc20). Moreover, along with mRSS, it is a widely 
used standard method to evaluate SSc. Based on the above, HAQ-DI has been selected to evaluate the 
efficacy of this drug on SSc in an exploratory manner. 
 
8） FACIT-Fatigue 
FACIT-Fatigue is a health-related quality of life that assesses fatigue and its impact on daily activities 
and functions in chronic diseases. Shortness of breath and fatigue occur in interstitial lung disease and 
pulmonary hypertension associated with SSc. FACIT-Fatigue has been proven to be reliable and useful 
in various diseases including SSc10). Thus, FACIT-Fatigue has been selected to evaluate the effects of 
this drug on fatigue and on daily living and functions in SSc, a chronic disease, in an exploratory 
manner. 
 
9） FSSG 
FSSG is a useful questionnaire to objectively assess the symptoms of Japanese participants with 
gastroesophageal reflux disease11). In SSc, esophageal involvement is complicated at a high rate from 
the early stage of the disease, and 80% to 90% of SSc patients have reflux esophagitis 1). Esophageal 
involvements are also associated with the extent and duration of thickening1). Based on the above, 
FSSG has been selected to evaluate the efficacy of this drug on reflux esophagitis in SSc patients in 
an exploratory manner. 
 
10） Global improvement rating (PtGA, PGA) 
Global improvement rating is a widely used method to assess disease activity in clinical trials such as 

54 
in rheumatoid arthritis. This rating has been selected to evaluate the efficacy of this drug on SSc in an 
exploratory manner. 
 
11. Safety Evaluation 
 Assessments for Safety Evaluations 
1） Adverse events 
a） Symptoms and signs 
b） Abnormal laboratory test values 
c） Abnormal vital signs 
d） Abnormal electrocardiograms 
2） Laboratory test values 
3） Vital signs 
4） Electrocardiograms 
5） Echocardiography 
 
  Definition of Adverse Events 
1） Adverse events (AEs) 
An AE in the study will be defined as any undesirable or unexpected sign, symptom, disease, or 
aggravation of an existing condition occurring in a participant who is given an IP on or after the time of 
informed consent regardless of whether there is a causal relationship to the IP. The aggravation of diseases 
or symptoms that have occurred before the time of informed consent are also considered an AE. 
The following events are not considered AE: 
• Events for which medical treatment had been scheduled before the time of informed consent 
• Aggravation of primary disease 
 
2） Serious adverse events (SAEs) 
a） Results in death 
b） Is life-threatening 
c） Requires or prolongs inpatient hospitalization* 
*Excluding the following events; 
 
Any hospitalization that had been scheduled before the time of informed consent (e.g., 
hospitalization for surgeries and detailed examinations) 
 
Any hospitalization for examinations without any treatment (including bed rest treatment). 
d） Results in persistent or significant disability/incapacity 
e） Is a congenital anomaly/birth defect 
f） Is another medically important condition* 
*An important medical event that may not be immediately life-threatening or does not result in 
death or hospitalization but may jeopardize the safety of the patient or may require treatments 
to prevent one of the other outcomes listed in a) to e) above. 
e.g., bronchospasm requiring intensive care at an emergency room, blood dyscrasias or 
convulsions not leading to hospitalization, drug dependence, or drug abuse 
 
3） Adverse events of special interest (AESIs) 
AESIs in this study are defined as the following treatment-emergent events: 
a） AEs requiring discontinuation of study treatment 

55 
b） Injection-related reactions (including local and systemic injection site reactions) 
Injection-related reactions are defined as AEs which develop within 24 hours after administration 
of IP. 
c） Asthma 
d） Atopic dermatitis 
e） Skin symptoms with edematous erythema or scales 
f） Skin infections 
g） Non-skin infections 
h） Suspected infection of infectious pathogen from the IP 
 
 Rationale for selection 
b), c), d),  
f), and g) 
These events should be monitored carefully because of being included in “important 
potential risks” in nemolizumab. 
e) 
These are events of interest closely monitored by the sponsor based on the results of 
clinical studies of nemolizumab in patients with atopic dermatitis 
h) 
The event should be carefully investigated in biological products in general. 
 
 Definitions of Safety Endpoints 
1） Adverse events 
a） Symptoms and signs 
The investigator or subinvestigator will assess symptoms and signs in participants after the time of 
informed consent through the time of physical examination on the day of follow-up visit based on 
interview results and complaints from participants. 
b） Abnormal laboratory test values 
The investigator or subinvestigator will treat laboratory test results collected after the time of 
informed consent through the day of follow-up visit as AEs if the results meet any of the following 
criteria: 
i. 
Accompanied with clinical symptoms 
ii. 
Resulted in any change of study treatment (e.g., interruption or discontinuation of the IP). 
iii. 
Resulted in medical treatment (including change of concomitant medications/therapies). 
iv. 
Considered clinically significant by the investigator or subinvestigator. 
v. 
Total bilirubin is >2-fold the upper limit of the reference value, and ALT or AST is >3-fold the 
upper limit of the reference value 
vi. 
ALT or AST is >3-fold the upper limit of the reference value with clinical jaundice 
 
Individual abnormal changes in laboratory test findings will be reported as individual AEs in 
principle. However, a single abnormal laboratory test finding or two or more abnormal laboratory test 
findings that are related to each other may be reported collectively as a single event under a single 
diagnosis if it is considered appropriate by the investigator or sub-investigator. If individual abnormal 
changes in laboratory test findings are regarded by the investigator or subinvestigator as 
manifestations of a symptom or a sign reported as an AE, the changes may be reported collectively 
with the AE of the symptom or sign. 
Laboratory values may change depending on interindividual factors, such as sex, age, and lifestyle, 
and intraindividual factors, such as diurnal fluctuation, diet, exercise, body positioning, and sexual 
cycle. Therefore, the investigator or subinvestigator will determine whether the change in each 
laboratory test findings is a physiological change or an abnormal change after sufficiently taking into 

56 
consideration the demographics of each participant, such as the underlying disease and complication, 
baseline values, and the changes specific to each participant who have any periodic laboratory test 
before study participation. 
 
c） Abnormal vital signs 
The investigator or subinvestigator will treat measurement results collected after the time of 
informed consent through the day of follow-up visit as AEs if the results meet any of the following 
criteria: 
i. 
Accompanied with clinical symptoms 
ii. 
Resulted in any change of study treatment (e.g., interruption or discontinuation of the IP). 
iii. 
Resulted in medical treatment (including change of concomitant medications/therapies). 
iv. 
Considered clinically significant by the investigator or subinvestigator. 
 
d） Abnormal electrocardiograms 
The investigator or subinvestigator will assess AEs based on the results collected after the time of 
informed consent through the day of follow-up visit  
 
e） Echocardiography 
Echocardiographic images will be assessed for cardiac morphology, cardiac motion and blood flow 
during cardiac contraction and relaxation, and other parameters. The investigator or subinvestigator 
will record the presence or absence of abnormalities in the source documents. 
 
 Review and reporting of adverse events 
The investigator or subinvestigator will assess the items shown in Table 11-1 regarding AEs occurring from 
after obtaining informed consent to the day of follow-up visit and fill the necessary information in the case 
report forms (CRFs). 
The investigator or subinvestigator will report the SAEs according to Section 11.5 and the AESIs according 
to Section 11.6 to the sponsor. The investigator or subinvestigator will promptly report the other AEs to the 
sponsor. 
 
 
 

57 
Table 11-1 Assessments for adverse events 
Assessments 
Details of assessment 
Name of adverse event 
Disease name/symptom, classification of the site of occurrence of adverse events 
Onset date 
Classification of onset date, Onset date 
Action 
on 
investigational 
product 
Treatment discontinuation, Treatment interruption, Dose reduction, No dose change, Not 
applicable, Unknown 
Treatment for the event 
Presence or absence of treatment 
Outcomes and 
Date 
of 
outcome/Date 
of 
outcome obtained 
Recovered/Resolved, 
Recovering/Resolving, 
Not 
Recovered/Not 
Resolved, 
Recovered/Resolved with sequelae, Death, and Unknown 
End date of AE, whether the AE is ongoing or not 
Severity 
Mild 
Transient, requiring minimal treatment and not interfering with daily 
life 
Moderate 
Specified treatments relieve symptoms and do not result in 
permanent or significant disability but interfere with daily life 
Severe 
Significant effect on advanced clinical condition or requiring 
intensive care or no longer allowing daily life. 
Seriousness 
Serious/Non-serious 
 
Definition of serious 
adverse 
events 
in 
Section 13.2 
1. Results in death 
2. Life-threatening 
3. Requires or prolongs inpatient hospitalization 
4. Results in persistent or significant disability/incapacity 
5. Is a congenital anomaly/birth defect 
6. Is another medically important condition 
Causal 
relationship 
with 
investigational product 
Causality classification (according to the following causality classification), and 
rationale 
 
Causality 
classification* 
Not related 
Causal relationship is unlikely because the adverse event has no 
plausible temporal relationship to administration of IP, or the 
event can be explained by another factor.  
The rationale for no causal relationship is required to be described. 
 
 
Related 
Causal relationship is presumed because there is a plausible 
temporal relationship between the onset of the adverse event and 
administration of investigational drug, and the event cannot be 
readily explained by another factor. 
The rationale for the causal relationship should be described if it is 
necessary to be explained.  
*The following guidance can be taken into consideration on causality assessment: resolution of the event after discontinuation 
of IP; recurrence after restarting of IP; established causal relationship with IP or similar drugs; no confounding risk factors; 
consistency with the amount and duration of exposure to IP; almost clearly explainable involvement of the IP based on the 
correct past medical history; no reasonable possibility of causal relationship with concomitant therapy, etc. 

58 
 Review and reporting of serious adverse events 
1） The investigator will report any serious adverse events to the sponsor within 24 hours of getting to know 
the occurrence of the event. The investigator will report detailed information to the sponsor by using 
the “Report of Serious Adverse Events” form within 2 days of getting to know the occurrence of the 
event (the date the event was known is regarded as day 0). The study site’s own form may be used 
instead of the "Report of Serious Adverse Events". For additional reporting, new serious information 
(e.g., change in the name of the adverse event, causal relationship, outcome information, the severity 
category, etc.) should be reported to the sponsor according to the above rules when it becomes known. 
2） The investigator will report the event to the study site according to the study site’s operating procedures. 
3） The investigator will provide any additional information (e.g., autopsy reports, late-stage medical 
records, and other necessary information) on reported serious adverse events, as requested by the 
sponsor. 
 
 Reporting of adverse events of special interests (AESIs) 
The investigator should report to the sponsor promptly when an AESI is noted. For atopic dermatitis and skin 
symptoms with edematous erythema or scaling, the necessary information (details of the symptoms/signs and 
the basis for determining the causal relationship with the IP) should be stated in the CRF. Any additional 
information should be provided, as requested by the sponsor. 
At the time of physical examination on the day of follow-up visit, the final outcome of any AESI “not 
recovered/not resolved” falling under 1) below should be obtained according to 2). Concomitant medications 
and therapies will also be collected according to Sections 9.3.2.1 and 9.3.2.2 . 
1） AESIs to be obtained 
a） AEs requiring discontinuation of study treatment 
b） Asthma 
c） Atopic dermatitis  
d） Skin symptoms with edematous erythema or scales 
2） Period to obtain AESIs 
AESIs should be collected until the earlier of the following dates to obtain the final outcome 
information (the outcome and the date of outcome/outcome obtained). 
• Date of recovering or recovered 
• Date 6 months after the last dose of IP 
 
 Photography 
Among AESIs, "atopic dermatitis" and "skin symptoms with edematous erythema or scales" will be 
photographed to examine the detailed skin findings of the events. Other adverse events of which the principal 
investigator or subinvestigator considers it necessary to take photographs will also be photographed. 
The photographs taken will be used as a record of the occurrence of adverse event and a reference for safety 
evaluation. 
 
 Reporting of the Pregnancy of the Participant 
1） If obtaining the information on the pregnancy of the participant who received the IP, the investigator 
or subinvestigator must immediately discontinue study treatment and take appropriate action for the 
participant, and follow up the participant until the completion of the pregnancy (e.g., delivery). 
2） The investigator or subinvestigator will also report detailed information to the sponsor by using the 
“Report for Pregnancies during the Study” form. 
3） Participant pregnancies are not regarded as adverse events. 

60 
12. Biomarkers 
 Measurements of Biomarkers 
1） Variable to be measured 
a） IL-31 
b） KL-6, SP-D, NT-proBNP 
c） Exploratory biomarkers 
 
2） Collection of blood samples 
a） Blood samples will be collected on the day of study treatment initiation, at Week 4, 8, 12, 16, 20, 
24, and 36, and Week 52 or on the day of visit for discontinuation. On the days of study treatment, 
blood samples will be collected before administration of IP. 
b） Blood samples will be collected on the day of study treatment initiation, at Week 4, 12, 24, and 36, 
and Week 52 or the day of visit for discontinuation. On the days of study treatment, blood samples 
will be collected before administration of IP. 
c） Blood samples will be collected on the day of study treatment initiation, at Week 12, 24, and Week 
52 or the day of visit for discontinuation. On the days of study treatment, blood samples will be 
collected before administration of IP.  
 
The collected blood samples will be centrifuged to separate the serum, and the serum samples will be 
stored frozen until measured. The amount of blood collected, centrifugal conditions, and storage 
conditions are specified in a separate operating procedure. 
 
 Blood Biomarker Outcome Measures 
1） Serum IL-31 level 
 Rationale for selection 
Since IL-31 is one of the cytokines considered to be involved in the disease state of SSc8),this has 
been selected to evaluate the changes after administration of nemolizumab.  
 
2） KL-6 and SP-D 
 Rationale for selection 
KL-6 and SP-D have been used as sensitive markers for interstitial pneumonitis in examination and 
measuring of disease progression or as a prognostic predictor in clinical practice. Moreover, increased 
levels of these have been reported to be associated with inflammatory pathological conditions such 
as ground-glass opacities on HRCT and elevated proportions of inflammatory cells in 
bronchoalveolar lavage fluid 21). Based on the above, these have been selected in terms of safety 
protection of participants. 
 
3） NT-proBN 
 Rationale for selection 
NT-proBNP is critical as a serological marker of pulmonary hypertension because it elevates in 
correlation with its severity in patients with SSc-PAH22). It is also important as a serological marker 
for overall some sort of because it elevates in the presence of any myocardial damage even without 
pulmonary hypertension23). Therefore, it has been set in terms of ensuring safety of participants. 
 
4） Exploratory biomarkers 

61 
As exploratory biomarkers, IL-1α, IL-4, IL-6, IL-8, IL-13, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, 
IL-17F, and IL-23 levels will be measured; however, cytokines for which adequate performance of 
the assay methods could not be validated will not be measured. 
 Rationale for selection 
The major cytokines considered to be involved in pathological conditions of SSc have been selected 
to evaluate the changes after nemolizumab administration. 
 
 Measurement Method and Reporting of Results 
1） Measurement methods 
a） IL-31 and exploratory biomarkers will be measured using the Enzyme-Linked Immuno Sorbent 
Assay (ELISA) method. The measurements will be performed by 
 Corporation 
according to its assay protocol. 
b） KL-6, SP-D and NT-proBNP will be measured by 
 Corporation according to its assay 
protocol.  
c） Exploratory biomarkers will be measured using the Electro Chemi-Luminescence (ECL) method. 
The measurements will be performed by 
 Corporation according to its assay protocol. 
 
2） Report of measurement results 
a） IL-31, KL-6, SP-D, NT-proBNP and exploratory biomakers 
 Corporation will prepare and submit a report of analysis results to the sponsor. 
 
13. Pharmacokinetics 
 Pharmacokinetic Measurements 
1） Variable to be measured 
Serum concentration of nemolizumab 
2） Collection of blood samples 
Blood samples will be collected on the day of study treatment initiation, at Week 1, 2, 4, 8, 12, 16, 20, 
24, and 36, Week 52 or on the day of visit for discontinuation, and on the day of follow up. On the 
days of study treatment, blood samples will be collected before administration of IP. 
The collected blood samples will be centrifuged to separate the serum, and the serum samples will be 
stored frozen until measured. The amount of blood collected, centrifugal conditions, and storage 
conditions are specified in a separate operating procedure. 
 
 Pharmacokinetic Outcome Measures 
1） Serum concentration of nemolizumab 
2） Pharmacokinetic parameters: Cmax、tmax、AUC0-28day、AUClast 
 
 Rationale for selection 
Parameters necessary and evaluable to examine pharmacokinetics of nemolizumab have been selected in 
reference to “Clinical pharmacokinetic studies on drugs (PFSB/ELD No.796 of June 1, 2001).” 
 
 Measurement Method and Reporting of Results 
1） Measurement method 
Serum concentration of nemolizumab will be measured using the ELISA method. The measurements 
will be performed by 
 Laboratories, Ltd. according to its assay protocol.  

62 
2） Report of measurement results 
 Laboratories, Ltd. will prepare and submit a report of analysis results to the 
sponsor. 
 
14. Immunogenicity 
 Immunogenicity Measurements 
1） Variable be measured 
Serum anti-nemolizumab antibody 
2） Collection of blood samples 
Blood samples will be collected on the day of study treatment initiation, at Week 24 and 36, Week 52 
or on the day of visit for discontinuation, and on the day of follow up. On the days of study treatment, 
blood samples will be collected before administration of IP.  
The collected blood samples will be centrifuged to separate the serum, and the serum samples will be 
stored frozen until measured. The amount of blood collected, centrifugal conditions, and storage 
conditions are specified in a separate operating procedure. 
 
 Immunogenicity Outcome Measures 
1） Serum anti-nemolizumab antibody 
2） Neutralizing antibody concentrations 
 
 Rationale for selection 
The variables have been selected to evaluate the effects of the development of anti-nemolizumab 
antibodies to efficacy and safety in participants. 
 
 Measurement Method and Reporting of Results 
1） Measurement method 
The serum anti-nemolizumab antibody will be measured using the ECL method. When anti-
nemolizumab antibodies are detected, their characteristics will be determined using the cell-based 
assay (CBA) method. The measurement will be performed by 
 Corporation according 
to its assay protocol. 
 
2） Report of measurement results 
 Corporation will prepare and submit a report of analysis results to the sponsor. 
 
15. Comprehensive Measurement of Autoantibodies 
Comprehensive measurement of autoantibodies will be performed to determine the disease state of SSc 
and explore the patient-group for whom nemolizumab is effective. 
 
 Measurement Method and Reporting of Results 
1） Collection of blood samples 
Blood samples will be collected on the day of study treatment initiation, at Week 24, and Week 52 or 
on the day of visit for discontinuation. On the days of study treatment, blood samples will be collected 
before administration of IP. 
The collected blood samples will be centrifuged to separate the serum, and the serum samples will be 
stored frozen until measured. The amount of blood collected, centrifugal conditions, and storage 

63 
conditions are specified in a separate operating procedure. 
 
2） Measurement method 
Autoantibodies will be measured comprehensively using HuPEX™ protein array. The measurement 
will be performed by
 Corporation according to its assay protocol. 
 
3） Report of measurement results 
Corporation will prepare and submit a report of analysis results to the sponsor. 
Measurement results will not be included in the clinical study report and will be summarized in a 
separate report. 
 
16. CyTOF measurement 
CyTOF measurement will be performed to explore the mechanism of action of nemolizumab in SSc. 
 
 Measurement Method and Reporting of Results 
1） Collection of blood samples 
Blood samples will be collected on the day of study treatment initiation, at Week 24, and Week 52 or 
on the day of visit for discontinuation. On the days of study treatment, blood samples will be collected 
before administration of IP.  
PBMC preparation of collected blood samples will be performed by the day following sample 
collection. The amount of blood to be collected and storage conditions are specified in a separate 
operating procedure. 
 
2） Measurement method 
Measurement will be performed by 
, Inc. according 
to its assay protocol. 
 
3） Report of measurement results 
, Inc. will prepare and submit a report of analysis 
results to the sponsor. Measurement results will not be included in the clinical study report and will be 
summarized in a separate report. 
 
17. Statistical Analysis 
The major plans for statistical analyses are presented below. The details are provided in the Statistical 
Analysis Plan. This plan will be fixed prior to database lock on through discussions on data review etc.  
 
 Analysis Sets 
17.1.1  Efficacy Analysis Set (Full Analysis Set: FAS) 
The efficacy analysis set includes all participants assigned to treatment except for those who meet any of the 
following criteria: 
1） Participants who are found not to have SSc 
2） Participants who have received no dose of nemolizumab at all after assigned to treatment   
3） Participants with no efficacy data at all after assigned to treatment   
 

64 
17.1.2  Safety Analysis Set 
The safety analysis set includes all participants assigned to treatment except for those who meet any of the 
following criteria: 
a） Participants who have received no dose of nemolizumab at all after assigned to treatment 
2） Participants with no safety data at all after assigned to treatment 
 
17.1.3  Pharmacokinetics Analysis Set 
The pharmacokinetics analysis set includes all participants assigned to treatment except for those who meet 
any of the following criteria: 
1) Participants who have received no dose of nemolizumab at all after assigned to treatment 
2) Participants with no pharmacokinetic data at all after assigned to treatment 
 
17.1.4  Biomarker Analysis Set 
The biomarker analysis set includes all participants assigned to treatment except for those who meet any of 
the following criteria: 
1) Participants who have received no dose of nemolizumab at all after assigned to treatment 
2) Participants with no biomarker data at all after assigned to treatment 
 
 Data Handling 
17.2.1  Common Rules 
a） Handling of missing values 
The missing values will not be imputed. 
 
2） Handling of data on the day of visit for discontinuation 
The data measured or evaluated on the day of visit for discontinuation will be handled as the data of 
the relevant evaluation period if the visit is within the allowance of any visit for evaluation period. 
However, such data will not be included in the analysis if another data has been obtained in the 
relevant evaluation period. 
 
17.2.2  Data Handling on Pharmacokinetics 
1) Handling of values below the lower limit of quantification (BLQ) and missing values for serum drug 
concentration data 
Values BLQ will be handled as follows and missing values will not be imputed. 
a) 
Tabulation: They will be reported as BLQ. 
b) Changes over time and profiles and summary statistics: They will be replaced by 0. However, 
if the number of participants with BLQ values exceeds half number of participants in 
pharmacokinetic analysis set, the summary statistics of serum drug concentrations at that time 
point will not be calculated and reported as N.C. (not calculated).  
 
2) Handling of pharmacokinetic parameters not calculable 
Parameters not calculable should be handled as follows: 
a) 
Tabulation: They will be reported as N.C. 
b) Summary statistic: They will be left missing. However, if the number of unevaluable 
participants for a pharmacokinetic parameter exceeds half of participants to be evaluated, the 
summary statistic of the parameter will not be calculated and reported as N.C. 
 

66 
 
𝛥𝛥mRSS: mRSS change 
𝛥𝛥FVC%: Percent FVC change 
𝛥𝛥pt−glob, 𝛥𝛥MD−glob :  Patient’s / Physician’s Global assessment change (cm) 
𝛥𝛥HAQ−DI: HAQ-DI Score change 
 
The score of participants occurring any of the following events is 0: 
 Onset of scleroderma renal crisis 
 Decline in FVC% ≥15% (requiring reevaluation within 1 month), and %FVC of 80% or less 
 Onset of left ventricular failure requiring treatment (defined as left ventricular ejection fraction ≤45%) 
* 
 Onset of pulmonary arterial hypertension requiring right heart catheterization * 
*Caused by SSc 
 
17.3.3  Safety Analysis 
The following variables will be summarized on the safety analysis set: 
1） Adverse events 
The following data will be collected and tabulated for AEs and separately for the treatment-related AEs. 
a） The number of participants included in the safety analysis set, and the number of participants 
with, and the number of occurrences of AEs, AEs by severity (mild, moderate, and severe), 
SAEs (total, fatal, and non-fatal), and AESIs will be calculated. 
b） The number of participants with AEs will be calculated by SOC and PT using MedDRA/J. 
c） For AESIs, the number of participants with AESIs, the number of participants with AESIs by 
PT will be calculated by the category. 
 
2） Laboratory test values 
a） Laboratory test values throughout the treatment period 
For the continuous variables, summary statistics will be calculated by laboratory parameter and 
time point. For the categorical variables, the number of participants will be calculated by category. 
The percentage of participants will be calculated using the number of observed participants at 
each time point. 
b） Changes in individual participants during the treatment period 
A spaghetti plot will be created for each participant using individual test values by laboratory 
parameter of continuous variables. 
 
3） Vital signs, physical findings, and other assessments related to safety 
a） Vital signs, electrocardiogram and echocardiography throughout the study period 
For the continuous variables, summary statistics will be calculated by vital sign, electrocardiogram 
parameter, and echocardiography parameter. For the categorical variables, the number and 
percentage of participants will be calculated by category. The percentage of participants will be 
calculated using the number of observed participants at each time point. 
 
17.3.4  Analyses of Drug Concentrations and Pharmacokinetic Parameters 
The following variables will be summarized on the pharmacokinetic analysis set. 
1） Serum concentrations of nemolizumab 

67 
a） Summary statistics including coefficient of variation and geometric mean of serum 
nemolizumab concentrations will be calculated by time point. 
b） The serum nemolizumab concentration-time profile will be created using mean serum drug 
concentrations and their standard deviations. 
c） The serum nemolizumab concentration-time profile will be created by participant. 
d） The serum nemolizumab concentration-time profile will be created by participant where 
participants who tested positive for the first time after study treatment (in blue), those who had 
tested positive since before treatment (in red), and those who tested negative at all time points 
(in black) for anti-nemolizumab antibodies in serum in the confirmatory test will be identified 
by color. 
2） Pharmacokinetic parameters (Cmax, tmax, AUC0-28Day, and AUClast) 
Summary statistics including coefficient of variation and geometric mean of parameters will be 
calculated. 
 
17.3.5  Analysis of Immunogenicity 
The following variables will be tabulated from the pharmacokinetics analysis set. 
1） Serum anti-nemolizumab antibody 
a） The percentage of participants with positive serum anti-nemolizumab antibodies will be 
calculated by test (Screening, Confirmatory, and Neutralizing) and time point. The positive rate 
in the Confirmatory test and the Neutralizing test is based on the number of participants having 
undergone the screening test. 
b） The number of and the percentage of participants who tested positive for anti-nemolizumab 
antibodies will be determined in this study. According to Shankar's definition,24) among 
participants who tested positive for anti-nemolizumab antibodies for the first time after study 
treatment or both before and after study treatment, a positive participant is defined as a 
participant with a ≥ 4-fold increase in difference in antibody titer. 
 
17.3.6  Analysis of Biomarker 
Details will be described in the Statistical Analysis Plan. 
 
 Determination of Sample Size 
17.4.1  Target Sample Size 
The target sample size for this study is 8 participants.  
 
17.4.2  Rationale for Sample Size 
The number of participants required to determine the efficacy of this drug for SSc was set at 8. Since no 
statistical evaluation is planned, the number is not based on the level of significance and power. 
 
 Data Review 
Data review will be performed before data fixation. In the data review, the appropriateness of data handling 
and analysis methods, etc., will be examined, and analysis sets, data handling, and an analysis plan will be 
determined. If a change in the statistical analysis plan is required after data review, the statistical analysis 
plan will be revised and documented. 

68 
18. Agreement on the Protocol and Protocol Deviation/Amendment 
 Agreement of and Compliance with the Protocol 
The investigator will, before the sponsor requests to conduct the study at the study site, agree in writing with 
the sponsor on the contents of the protocol and conducting the study in compliance with the protocol. The 
investigator will do the same when the protocol is revised through discussion with the sponsor or according 
to the instructions of the head of the study site on the basis of the opinion of the institutional review board 
(IRB). 
 
 Protocol Deviation/Amendment 
1） The investigator or subinvestigator should not deviate from or amend the protocol without prior written 
agreement with the sponsor and without written approval based on a prior review by the IRB. However, 
the investigator or subinvestigator may deviate from or amend the protocol without prior agreement with 
the sponsor or without prior approval from the IRB in the following cases where: 
a） it is medically unavoidable to avoid immediate danger to a participant 
b） it is on administrative matters of the study (e.g., change of the name of study site, change of the 
address or phone number of study site, and change of job title of the investigator) 
 
2） The investigator or subinvestigator will record all deviations from the protocol. The investigator will 
prepare a document only for deviations from the protocol to avoid immediate danger to the participant 
with the reason for deviation or for other medically unavoidable reasons and immediately submit it to 
the sponsor and the head of the study site. The investigator will also submit the document to the IRB via 
the head of the study site, obtain approval from the IRB, and obtain in writing approval of the head of 
the study site and agreement of the sponsor. 
 
3） If the protocol amendment is appropriate when the investigator is unable to comply with the protocol to 
avoid any immediate hazard to participants or due to other unavoidable medical reasons, the investigator 
will submit a draft amendment to the protocol to the sponsor as soon as possible to obtain written 
approval of the sponsor. Furthermore, the investigator will submit a draft amendment to the protocol to 
the head of the study site, obtain approval from the IRB and the head of the study site. 

69 
19. Case Report Form 
The EDC system (Table 19-1) will be used in this study. The original CRFs will be those generated in the 
EDC system. The validated EDC system will be used in this study. 
The data and audit trails entered in EDC system by the investigator, subinvestigator involved in CRF 
preparation, and CRCs are stored in the EDC server. 
 
Table 19-1 EDC system 
Name of EDC system 
 
Name of EDC system development Company 
 
Input method 
Data entry via the web 
Input terminal 
Personal computer available at study sites 
 
 Data to be collected in CRF 
The data to be collected in the CRFs is shown below. 
 
19.1.1  Participants assigned to treatment 
1） Date of written informed consent 
2） Visit dates 
3） Participant demographics 
4） Major therapies received for SSc in the past  
5） Inclusion and exclusion criteria 
6） Complications 
7） Concomitant Medications/Concomitant Therapies 
8） Patient-reported Outcomes 
9） Global improvement rating  
10） mRSS 
11） The number of digital ulcers 
12） Respiratory function test 
13） Electrocardiogram 
14） Echocardiography 
15） HRCT 
16） Severity of pulmonary lesions 
17） ACR-CRISS 
18） Vital signs 
19） Body weight 
20） Laboratory tests 
21） Biomarkers 
22） Serum nemolizumab levels  
23） Immunogenicity measurement 
24） Comprehensive measurements of autoantibodies 
25） CyTOF measurement 
26） Dosing status of IP  
27） Adverse events 
Information on outcome of an adverse event is to be collected until the follow-up visit. 
28） The details of adverse events of atopic dermatitis and skin symptoms with edematous erythema or 

70 
scaling as well as the basis for determining the causal relationship with the IP 
29） Malfunction of DCS 
30） Status of study entry after screening, enrollment, completion/discontinuation of the study 
completion status of study entry after screening, completion status of enrollment, study completion 
status, date of completion, date and reason for discontinuation if discontinued, and impact of COVID-
19 
31） Follow-up visit 
Whether there was a follow-up visit or not, date of follow-up visit, date of determination and reason 
if no follow-up visit, and impact of COVID-19 
32） Others 
a） Comment on each assessment 
b） Unscheduled visits 
 
19.1.2  Participants Who Discontinue the Study before study entry after screening and those Who 
Discontinue the Study before enrollment 
The following data will be collected and documented in the CRF for respective participants: 
1) to 6) for participants having discontinued the study before study entry after screening 
1) to 6) and 7) to 16) for participants having discontinued the study before enrollment 
1） Date of written informed consent 
2） Visit dates 
3） Participant demographics 
4） Inclusion and exclusion criteria 
5） Adverse events 
6） Date of and reason for discontinuation 
7） mRSS 
8） The number of digital ulcers 
9） Respiratory function test 
10） Vital signs 
11） Body weight 
12） Severity of pulmonary lesions 
13） HRCT 
14） Echocardiography 
15） Electrocardiograms 
16） Laboratory tests 
 
 Source Data for Information Entered in Case Report Form 
Source data for information entered in the case report forms are as follows: 
1） Medical records 
2） Laboratory test slips 
3） Serious Adverse Event Report (copy) 
4） Serious Adverse Event and Device Malfunction Report (copy) 
5） Informed consent forms 
6） Participant screening logs 
7） IP accountability records 
8） ECG measurement results 

71 
9） Respiratory function test 
10） Patient QOL questionnaire (paper) 
 
 Information in the Case Report Forms Treated as Source Data  
Any information of the following items described only in the CRF will be treated as the original data. 
1） Presence or absence of data for each item 
2） Indication of drug/therapy 
3） Seriousness and severity of adverse event, causality of adverse event to IP, and presence or absence of 
abnormal laboratory changes 
4） Date of and reason for study discontinuation 
5） All comments 
 
 Guidelines for Preparation of Case Report Form 
The investigator, subinvestigator involved in CRF preparation, and CRCs will have to receive training before 
preparing CRFs. The sponsor will create an account management table to specify the authority given to each 
person in the place of a list of signatures/seals. 
1） The investigator or subinvestigator will accurately prepare CRFs based on the source documents of 
enrolled participants according to the “Guidance for CRF Preparation.” 
2） The investigator or subinvestigator will promptly prepare the CRF once the evaluation of the 
participant at each visit is completed. 
3） CRCs may fill out or transcript and correct CRFs on the basis of the source documents. The 
investigator will review the entries, transcriptions, and corrections made by CRCs and electronically 
sign the CRFs. 
4） The investigator will review the CRFs prepared at the study site and electronically sign the CRFs. 
5） The investigator will submit the CRFs to the sponsor. In addition, the investigator will obtain a copy 
of the CRFs from the sponsor at the end of the study and retain them electronically. 
6） If data in the CRF shows a discrepancy with the source document, the investigator will prepare a 
document explaining the discrepancy and submit it to the sponsor. The investigator will also retain a 
copy of the record. 
 
 Modification and Amendment to Case Report Forms 
1） The investigator, subinvestigator, or CRCs will amend the CRFs according to the “Guidance for CRF 
Preparation” provided by the sponsor. 
2） The investigator will review the modifications or amendments made by the subinvestigator or, CRCs 
and electronically sign the CRF. 
 
20. Follow-up report of adverse events of special interest 
For adverse events of interest falling under those specified in Section 11.6 1) which are “not recovered/not 
resolved” at the time of physical examination on the day of follow-up visit, the investigator will report their 
following information from after the physical examination of the follow-up visit to the time of obtaining the 
final outcome in the format separately specified by the sponsor. 
1） Outcome and date of outcome/date of outcome obtained 
2） Drugs used for the adverse event 
3） Therapies performed for the adverse event 
 

72 
21. Direct Access to Source Documents 
The investigator, subinvestigator, and the head of the study site will allow study monitoring, the sponsor’s 
audit, and inspections by the IRB and regulatory authorities, and their direct access to all study-related 
documents, including the source documents. 
When regulations on direct access are stipulated at the study site, they will be followed. 
 
22. Quality Control and Quality Assurance 
Risk management of this study will be performed based on the risk management plan prepared according to 
the standard operating procedures of 
 
 
1） Monitoring 
The CRA will request the investigator and subinvestigator, etc. to comply with the GCP, related 
regulatory notifications, and study protocol throughout the study period, and will then assess their 
compliance. If any deviation from the GCP, related regulatory notifications, and the study protocol is 
found by monitoring, the CRA will inform the investigator immediately and the head of the study site 
as necessary and take appropriate measures to prevent the recurrence of the deviation. Furthermore, 
on the basis of direct access to the source documents, the CRA will verify whether the CRFs are 
completed accurately and are consistent with the source documents. 
 
2） Quality control 
a） Standardization of assessments 
Prior to the start of the study, the sponsor will explain the standards of the assessment and the 
protocol to the investigator and subinvestigator, etc. 
 
3） Quality control of CRF data 
The quality control of CRF data will be performed according to the SOPs of Maruho Co., Ltd. When 
necessary, a case review meeting may be held by the medical expert and the sponsor to determine the 
handling of individual cases. 
 
4） Audit 
The auditor will assess whether the study is being conducted in accordance with GCP, the protocol, 
and relevant operating procedures separately and independently from the monitoring and quality 
control activities performed by the clinical study department. The auditor will also assess whether the 
study is being conducted properly and that the reliability of the study data is being maintained by direct 
access to study-related documents and records or other methods. 
 
23. Completion, Discontinuation, or Interruption of the Study 
 Completion of the Study 
Upon the completion of the study, the investigator will report the completion and a summary of study results 
in writing to the head of the study site. Once receiving the report of study completion from the investigator, 
the head of the study site will notify the IRB and the sponsor of the fact the summary of study results. 
 
 Discontinuation or Interruption of the Study 
The investigator will, when interrupting or discontinuing the study at his/her own discretion, promptly report 
it and the reason in writing to the head of the study site. Once receiving the report of study discontinuation 

73 
or interruption from the investigator, the head of the study site will promptly notify the IRB and the sponsor 
of the fact and the reason in writing. 
The sponsor will, when deciding the discontinuation or interruption of the study or the termination of 
development of the IP, promptly notify the head of the study site of the fact and the reason in writing. Once 
receiving a notification of interruption or discontinuation of the study or the termination of development from 
the sponsor, the head of the study site will promptly notify the investigator and the IRB of the fact and the 
reason in writing. 
 
24. Archiving of Records 
1） Study site 
The head of the study site should retain the documents and records related to this study to be archived 
at the study site (hereinafter, the study-related records) until the elapse of 15 years after either the date 
of the marketing approval of the investigational drug or the date of decision of discontinuation of the 
development of the investigational drug. 
For archiving the study-related records, the head of the study site will assign a storage manager. The 
head of the study site and the storage manager must take necessary measures so that these records are 
not lost or disposed of during the retention period and that they can be presented at the request of the 
sponsor, regulatory authorities, etc. 
When the retention period of records to be archived at the study site expires, the sponsor will promptly 
notify the head of the study site of the fact. 
2） Sponsor 
The sponsor should retain the study-related records to be archived at the sponsor site until the elapse 
of 15 years after either the date of the marketing approval of the investigational drug or the date of the 
decision of discontinuation of the development of the investigational drug. 
 
25. Publication Policy 
1） The study site may not disclose or divulge data on the study provided by the sponsor or information 
such as study results to any third party without prior permission of the sponsor. If intending to publish 
the information obtained from the study to external parties such as academic conferences, the study 
site must obtain prior permission from the sponsor. 
2） The founder of the IRB shall accept the sponsor’s request (if any) for prior checking of a summary of 
the meeting minutes specified in Article 28, Paragraph 2-6 of the GCP to ensure the summary does not 
include the description infringing on the sponsor’s intellectual property rights. When necessary, the 
founder may publish the summary after taking appropriate measures such as data masking. 
3） The sponsor may freely use information obtained from this study for application for marketing 
approval for the test drug, product summary, promotional materials, publications, presentations at 
academic societies, and other materials to be submitted to the Ministry of Health, Labour, and Welfare. 
4） When publishing information, sufficient attention must be paid to participant privacy. 
 
26. Use of study-related data 
1） The sponsor may use information obtained from this study (the study-related data) for application for 
marketing approval for the test drug, product summary, promotional materials, publications, 
presentations at academic societies, and other materials to be submitted to the Ministry of Health, 
Labor, and Welfare.  
2） The sponsor may use the study-related data for the research and development of other than the test 

74 
drug and otherwise academic research when considered necessary. 
 
27. Ethics 
 Institutional Review Board 
Prior to the execution of the clinical study agreement, the IRB will review the contents of the protocol, 
informed consent form, and other explanatory documents, as well as the appropriateness of conducting the 
study. After the execution of the clinical study agreement, the IRB will continuously review the 
appropriateness of continuing the study. 
 
 Ethical Conduct of the Study 
This study shall be conducted in compliance with the Ministerial Ordinance on Good Clinical Practice for 
Drugs and related notifications, the ethical principles based on the Declaration of Helsinki, and the protocol. 
 
 Protection of Participants’ Confidentiality 
To protect the participants’ confidentiality, the investigator or subinvestigator will use participant 
identification codes instead of names to identify participants when completing CRFs and reporting adverse 
events and other study-related data to the sponsor. The sponsor’s CRA and auditors will similarly protect any 
confidential participant information obtained during the course of the study in accordance with the provisions 
of Article 80-2, Paragraph 10 of the Act on Securing Quality, Efficacy, and Safety of Products Including 
Pharmaceuticals”. 
 
 Participant Selection and Informed Consent 
27.4.1  Participant Selection 
During the selection of participants, the investigator or subinvestigator should carefully consider the 
advisability of asking for a patient to participate in the study taking into consideration the health condition, 
symptoms, age, sex, ability to consent, dependency on the investigator or subinvestigator, and status of 
participation in other clinical studies from the viewpoints of human rights protection and based on the 
protocol-specified inclusion and exclusion criteria. If a patient who is visiting another hospital is enrolled in 
the study, the investigator or subinvestigator will consider eligibility for study participation after examining 
the details of the medical treatment. 
 
27.4.2  Informed Consent 
1） Prior to the assessment for study participation, the investigator or subinvestigator will fully explain 
the study to each participant by using the informed consent form and other explanatory documents 
that describe the items provided in “27.4.3 Explanations to Participants.” After this explanation, 
written voluntary consent to participate in the study will be obtained from the participant personally. 
2） In cooperation with the sponsor, the investigator will prepare the informed consent and other 
explanatory documents that will be used to obtain the participants’ consent to participate in the study 
and revise them as needed. The prepared or revised informed consent form and other explanatory 
documents should be approved by the IRB before use. 
3） The investigator will comply with the ethical principles when preparing or revising the informed 
consent form and other explanatory documents. 
4） The investigator or subinvestigator who provided the explanation, and the participant will each sign 
and date on the informed consent form. If a CRC makes a supplemental explanation, the CRC will 
also sign and date on the form. 
5） The investigator or subinvestigator will provide the participant with the signed and dated informed 

75 
consent form (copy), and other explanatory documents before the participant participates in the study.  
6） The investigator, subinvestigator, and CRC should not put pressure or unjustified influence on the 
participants to participate or continue participating in the study.  
7） The informed consent form and other explanatory documents for the participants or information 
provided orally when explaining the study must not contain any words or suggestions that cause the 
participants to relinquish their rights. Furthermore, the consent materials and explanation must not 
contain any words or suggestions that absolve the investigator, subinvestigator, CRC, study site, or 
sponsor of their legal responsibilities. 
8） Nontechnical vocabulary that the participants can understand should be used as much as possible 
during the verbal explanation and in written explanation and the informed consent form. 
9） The investigator or subinvestigator will provide the participant with the opportunity to ask questions 
and sufficient time to decide whether to participate in the study before obtaining the participant’s 
consent. The investigator, subinvestigator, or CRC (as someone providing additional explanation) 
must answer all questions to the satisfaction of the participant. 
10） If information is obtained that could potentially affect the participants’ willingness to continue 
participating the study, the investigator or subinvestigator must promptly give the information to the 
participants and ask whether the participants are willing to continue participating the study. In such 
cases, the fact that this information has been given to the participants will be recorded in the source 
documents. 
11） If significant new information that may be related to the participants’ consent is obtained, the 
investigator should promptly revise the informed consent form and other explanatory documents for 
the participants on the basis of this information. 
12） When the informed consent form and other explanatory documents for participants are revised, the 
investigator or subinvestigator will promptly give the information which the amendment is based on 
to participants and ask whether the participants are willing to continue participation in the study. 
Furthermore, the investigator or subinvestigator will again explain the study using the revised 
informed consent form and other explanatory documents for participants and obtain voluntary written 
informed consent to continue participation in the study from each participant. The investigator or 
subinvestigator will provide the participants with the newly signed and dated revised informed 
consent form (copy) and the other explanatory documents.  
 
27.4.3  Explanations to Participants 
1） This study is being conducted for the purpose of investigation (i.e., this study involves research). 
2） Study objective 
3） Name, job title, and contact information of the investigator. 
4） The study method (including the investigative aspect of the study, the participant inclusion criteria, 
and the probability of being assigned to each treatment) 
5） The expected benefits to the participant’s physical and mental health and the expected disadvantages 
to the participant of the IP 
6） The presence or absence of other treatments available to the participant and the expected important 
benefits and risks of the treatments 
7） The participant’s scheduled duration of participation in the study 
8） Participation in the study is voluntary, and the participant can refuse or withdraw consent to participate 
in the study at any time. 
9） The participant will not undergo any disadvantages as a result of refusing or withdrawing consent to 

76 
participate in the study, and the participant will not lose any benefits that the participant should receive 
if he or she does not participate in the study. 
10） The CRAs, auditors, and the IRB which deliberated the protocol, and regulatory authorities will have 
direct access to medical records and similar documents on the condition that the participant’s 
confidentiality will be protected. At such times, the participant’s confidentiality will be protected. The 
participant allows direct access to such materials by signing the informed consent form. 
11） The participant’s confidentiality will be protected if the study results are published. 
12） The consultation service to the study site where the participant should make inquiries or should 
contact if the participant desires further information regarding the study or participant’s rights or if 
study-related injury occurs. 
13） The compensation and treatment available to the participant in the event of study-related injury. 
14） The types of IRBs that review the appropriateness of the study, the matters reviewed by each IRB, 
and other matters related to the IRBs involved in this study. 
15） Matters to be communicated to participants on this study 
 
The planned number of participants in the study 
 
If information is obtained that could potentially affect the participant’s willingness to continue 
participating the study, that information will be promptly reported to the participant. 
 
The conditions or reasons to withdraw participants from the study 
 
Information for the financial responsibility of the participant in the study 
 
Information related to payments to the participant 
 
Instructions to be followed by the participant 
 
Study staff will obtain medical information from other physicians with the consent of the 
participant. 
 
28. Payments 
Measures taken to reduce the participant’s financial burden resulting from participation in the study (if any) 
should be stipulated in writing after a discussion with the study site. Provisions for other necessary expenses 
will also be stipulated in writing after another discussion with each study site. 
 
29. Compensation for Injuries 
If a participant suffers from an injury attributable to the study and seeks compensation from the study site, 
the sponsor shall be fully responsible for the compensation unless the injury is due to an intentional error or 
a medical error by the study site. Prior to conducting the study, the sponsor will purchase product liability 
insurance for the IP as a measure to compensate for injuries. 
 
30. Responses to COVID-19 
 If participants are found to have confirmed COVID-19 (including asymptomatic pathogen 
carriers) or suspected COVID-19, or found to have been in close contact with a confirmed or 
suspected COVID-19 patient 
1） Administration of investigational product 
a） The investigator or subinvestigator should not administer the IP unless it is confirmed that the 
participant meets the following criteria on the day of administration: 
i. 
For participants who have confirmed (including asymptomatic pathogen carriers) or 
suspected COVID-19 
 
At least 20 days after the onset of symptoms and 72 hours after the symptoms have 

77 
resolved: or 
 
The symptoms have resolved, and the participant has been confirmed not to carry the 
pathogen. 
ii. 
For participants having been in close contact with a confirmed or suspected COVID-19 
patient 
 
At least 15 days after close contact  
 
 Discontinuation of the study due to the influence of COVID-19 
If the study has been discontinued due to the influence of COVID-19, the investigator or subinvestigator will 
record in the source document and the CRF that the study was discontinued due to COVID-19. 
 
 Deviations from the protocol due to the influence of COVID-19 
If a protocol deviation has occurred due to the influence of COVID-19, the investigator or subinvestigator 
will keep a record in the source document so as to make it clear that the deviation occurred due to the 
influence of COVID-19. 
 
31. Study Period 
December 2021 to November 2024 
 
32. Administrative Structure 
 Sponsor 
, Representative Director, President & CEO, Maruho Co., Ltd. 
 Osaka 
 
 
 Sponsor Organization 
1） Head of Clinical Trial 
, General Manager, Clinical Development Department, Maruho Co., Ltd 
 
Major roles: 
a）
 
b）
 
c） 
 
 
2） Clinical Trial Supervisor 
, Clinical Development Department, Maruho Co., Ltd. 
 
Major roles: 
 
 
3） Medical Safety Officer 
, MD, PhD, Senior Medical Director, Maruho Co., Ltd. 
 
Major roles: 
a） 
 
b）
 

78 
 
 
4） Clinical Research Associate Leader 
, Clinical Development Department, Maruho Co., Ltd. 
 
Major roles: 
 
 
 Study Sites and Investigators 
Study Center：The University of 
, 
 Tokyo 
 
Investigator：
 
 
 Medical Expert 
 
Professor, Department of Dermatology, 
, The 
University of 
 
 
 Contract Research Organization 
1）  Clinical Testing Laboratory 
Corporation, 
 Tokyo 
 
 
 
2） Biomarker Measurement Institution 
 Corporation, 
 Tokyo
 
 
 
 
3） Anti-Drug Antibody Measurement Institution 
Corporation, 
Tokyo 
 
 
 
 
4） Drug Concentration Measurement Institution 
 Laboratories, Ltd., 
 Tokyo 
 
 
 
5） Autoantibody Measurement Institution 
 Corporation, 
Tokyo 135-0064 
 
 
6） CyTOF Measurement Institution 
 Research Center, Inc.,
, Tokyo
 
 
 
33. Contact Information 
 Contact Information 
, Clinical Development Department, Maruho Co., Ltd. 

79 
 Kyoto 
 
TEL 
 (dial in) 
FAX 
 
 
 Emergency Contact (Saturdays and Sundays, National Holidays, Nights) 
 Clinical Development Department, Maruho Co., Ltd. TEL 
 
, Clinical Development Department, Maruho Co., Ltd. TEL 
 
 
 
 

80 
34. References 
1) Sato S. Basics and Clinics of Scleroderma-From Understanding of Clinical Conditions to Current 
Diagnosis. Article in Japanese. Iyaku (Medicine and Drug) Journal Co., Ltd. (2016). 
2) Japan Intractable Diseases Research Foundation [Internet]. Website of Japan Intractable Diseases 
Information Center [cited 2021 Sep 29]. Available from: https://www.nanbyou.or.jp/ 
3) LeRoy E C, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger T A, et al,. Scleroderma (systemic 
sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988 Feb; 15(2): 202-5. 
4) Clements P J, Hurwitz E L, Wong W K, Seibold J R, Mayes M, White B, et al. Skin thickness score as 
a predictor and correlate of outcome in systemic sclerosis: high-dose versus low-dose penicillamine 
trial. Arthritis Rheum. 2000 Nov; 43(11): 2445-54. 
5) Steen V D, Medsger T A. Severe organ involvement in systemic sclerosis with diffuse scleroderma. 
Arthritis Rheum. 2000 Nov; 43(11):2437-44. 
6) Walker U A, Tyndall A, Czirjak L, Denton C, Farge-Bancel D, Kowal-Bielecka O, et al. Clinical risk 
assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials 
And Research group database. Ann Rheum Dis. 2007 Jun; 66(6): 754-63. 
7) Asano Y, Jinnin M, Kawaguchi Y, Kuwana M, Goto D, Sato S, et al. Diagnostic Criteria, Severity 
Classification and Guidelines of Systemic Sclerosis. Jpn J Dermatol. 2016 (126); 1831-96. 
8) Boddor Y, Henry L, Zeinab T, Sara Z, Henrique R, Bahja A A, et al. Interleukin-31 promotes pathogenic 
mechanisms underlying skin and lung fibrosis in scleroderma. Rheumatology (Oxford). 2020 Sep 1; 
59(9): 2625-36. 
9) Matsuda Y, Singh G, Yamanaka H, Tanaka E, Urano W, Taniguchi A, et al. Validation of a Japanese 
version of the Stanford Health Assessment Questionnaire in 3,763 patients with rheumatoid arthritis. 
Arthritis Rheum. 2003 Dec 15;49(6):784-8. 
10) FACIT 
group 
[Internet]. 
FACIT-Fatigue 
[cited 
2021 
Sep 
29]. 
Available 
from: 
https://www.facit.org/measures/FACIT-Fatigue 
11) Kusano M, Shimoyama Y, Sugimoto S, et al. Development and evaluation of FSSG: frequency scale 
fot he symptoms of GERD. J Gastroenterol 2004; 39 :888-91. 
12) Guidelines for Clinical Evaluation of Antirheumatoid Drugs, Notification No. 0217001 of the 
Evaluation and Licensing Division, PFSB dated February 17, 2006  
13) Clements P, Lachenbruch P, Siebold J, White B, Weiner S, Martin R, et al. Inter and intraobserver 
variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol. 1995 
Jul; 22(7) 1281-5. 
14) Clements P J, Lachenburch P A, Seibold J R, Zee B, Steen V D, Brennan P, et al. Skin thickness score 
in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol. 
1993 Non; 20(11): 1892-6. 
15) Nicole S L G, Sujia R D, Srihari V, David M H, Susan J C, Toby M M, et al. Interstitial lung disease in 
systemic sclerosis: a simple staging system. Am J Respir Crit Care Med.2008 Jun 1; 177(11): 1248-54. 
16) Coghlan G G, Denton C P, Grunig E, Bonderman D, Distler O, Khanna D, et al. Evidence-based 
detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 
2014 Jul; 73(7): 1340-9. 
17) Steele R, Hudson M, Lo E, Baron M, Canadian Scleroderma Research Group. Clinical decision rule to 
predict the presence of interstitial lung disease in systemic sclerosis. Arthritis Cae Res (Hoboken). 2012 
Apr; 64(4): 519-24. 
18) Steen V D, Medsger T A. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 
2007Jul; 66(7): 940-4. 
19) Khanna D, Berrocal V J, Giannini E H, Seibold J R, Merkel P A, Mayse M D, et al. The American 

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College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse 
Cutaneous Systemic Sclerosis. Arthritis Rheumatol. 2016 Feb; 68(2): 299-311. 
20) Steen V D, Medsger Jr T A. The value of the Health Assessment Questionnaire and special patient-
generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum. 1997 
Nov; 40(11): 1984-91. 
21) Hant F N, Ludwicka-Bradley A, Wang H J, Li N, Elashoff R, Tashkin D P, Silver R M. Surfactant 
protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. J 
Rheumatol. 2009 Apr; 36(4): 773-80. 
22) Cavagna L, Caporali R, Klersy C, Ghio S, Albertini R, Scelsi L. Comparison of brain natriuretic peptide 
(BNP) and NT-proBNP in screening for pulmonary arterial hypertension in patients with systemic 
sclerosis. J Rheumatol. 2010 Oct; 37(10): 2064-70. 
23) Allanore Y, Wahbi K, Borderie D, Weber S, Kahan A, Meune C. N-terminal pro-brain natriuretic peptide 
in systemic sclerosis: a new cornerstone of cardiovascular assessment?. Ann Rheum Dis. 2009 
Dec;68(12):1885-9. 
24) Shankar, G., Arkin, S., Cocea, L., Devanarayan, V., Kirshner, S., Kromminga, A., et al. Assessment and 
reporting of the clinical immunogenicity of therapeutic proteins and peptides—harmonized terminology 
and tactical recommendations. The AAPS journal. 2014; 16(4): 658-673. 
 

List of Definitions of Abbreviations and Technical Terms 
 
Acronym/Abbreviation/ 
Technical term 
Full text/Definition 
ACR-CRISS 
American College of Rheumatology Combined Response Index in 
diffuse cutaneous Systemic Sclerosis 
ADL 
Activities of daily living 
AE 
Adverse events 
AIDS 
Acquired immunodeficiency syndrome 
ALB 
Albumin 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma/serum concentration-time curve 
AUC0-28day 
Area under the serum concentration-time curve 0-28day 
AUClast 
Area under the serum concentration-time curve from zero to last 
observed concentration time point 
A/G ratio 
Albumin-Globulin ratio 
BLQ 
Below the lower limit of quantification 
CBA 
Cell-based assay 
CK 
Creatine kinase 
Cmax 
Maximum concentration in plasma/serum 
COVID-19 
Coronavirus disease 2019 
CREA 
Creatinine 
CRP 
C reactive protein 
CTCAE 
Common terminology criteria for adverse events 
CyTOF 
Cytometry by time of flight 
D-Bil 
Direct bilirubin 
DCS 
Dual chamber syringe 
dcSSc 
Diffuse cutaneous SSc 
DLco 
Diffusing capacity of lung for carbon monoxide 
ECG 
Electrocardiogram 
ECL 
Electro Chemi Luminescence 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EULAR 
European League Against Rheumatism 
FAS 
Full analysis set 
FACIT-Fatigue 
Functional assessment of chronic illness therapy-Fatigue 
FEV1 
Forced expiratory volume in one second 
FSSG 
Frequency Scale for the Symptoms of GERD 
FU 
Follow up 
FVC 
Forced vital capacity 
GCP 
Good clinical practice 

Acronym/Abbreviation/ 
Technical term 
Full text/Definition 
γ-GT 
γ-Glutamyl transpeptidase 
HAQ-DI 
Health assessment questionnaire disability index 
Hb 
Hemoglobin 
HBc antibody 
Hepatitis B core antibody 
HBs antigen 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
hCG 
human chorionic gonadotrophin 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
HRCT 
High-resolution computed tomography 
Ht 
Hematocrit 
IL 
Interleukin 
IL-31RA 
Interleukin-31 receptor A 
IP 
Investigational product 
IRB 
Institutional review board 
JCOG 
Japan clinical oncology group 
KL-6 
Krebs von den lungen-6 
lcSSc 
Limited cutaneous SSc 
LDH 
Lactic acid dehydrogenase 
LDL-C 
Low density lipoprotein cholesterol 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA/J 
Medical dictionary for regulatory activities / Japanese edition 
mRSS 
Modified rodman total skin thickness score 
nemolizumab 
Humanized anti-human interleukin-receptor A (IL-31RA) monoclonal 
antibody 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
PAH 
Pulmonary arterial hypertension 
PGA 
Physician’s global assessment 
Plt 
Platelet 
PT 
Preferred term 
PtGA 
Patient’s global assessment 
QFT-3G 
QuantiFERON-TB Gold 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SP-D 
Surfactant protein D 
SOC 
System organ class 
SSc 
Systemic sclerosis 
TARC 
Thymus and activation-regulated chemokine 

Acronym/Abbreviation/ 
Technical term 
Full text/Definition 
T-Bil 
Total-bilirubin 
TC 
Total cholesterol 
TG 
Triglyceride 
TLC 
Total lung capacity 
tmax 
Time to reach the maximum concentration in plasma/serum 
TP 
Total protein 
T-SPOT 
T-SPOT®.TB 
UA 
Uric acid 
UN 
Urea nitrogen 
VAS 
Visual analogue scale 
WBC 
White blood cell 
 
 
 

Synopsis-5 
Protocol Synopsis 
 
1. Study objectives 
 Primary Objective 
To exploratorily evaluate the efficacy of nemolizumab in systemic sclerosis (SSc) patients with moderate to 
severe skin thickening 
 
 Secondary Objective 
To evaluate the safety and pharmacokinetics of nemolizumab in SSc patients with moderate to severe skin 
thickening 
 
2. Study Design 
This is a phase II, single-arm, multiple-dose study consisting of a pre-treatment observation period (1-4 
weeks) and a treatment period (52 weeks). The pre-treatment observation period is from the day of screening 
to the day of study treatment initiation, and participants will visit the site a total of twice, for screening and 
for study treatment initiation. Treatment period is from the day of study treatment initiation   and every 4 
weeks thereafter. Participants having received study treatment will be followed up 84 days after the day of 
the last dose of study treatment. Follow-up period is from Visit17 (Week 52) or the day of discontinuation 
visit to the day of follow-up visit. 
 
Study phase: Phase II 
 
Study type: Open-label, single-arm, multiple-dose study 
Participants: SSc patients with moderate to severe skin thickening 
Target Sample Size: 8 participants 
 
Figure 2-1: Study Schema 
 
 
 
 
 
 
 
 
 
 
1） Pre-treatment observation period 
The investigator or subinvestigator will make observations and assessments at the screening visit 
specified in Table 4-1 after obtaining informed consent from the participant. 
  
2） Treatment period 
The investigator or subinvestigator will administer the investigational product (IP) (nemolizumab, 60 
mg/body) every 4 weeks (Q4W) at visits until Week 48 after making observations and assessments on 
the day of study treatment initiation specified in Table 4-1. In addition, the investigator or 
subinvestigator will make perform observations and assessments at each visit specified in Table 4-1. 
 
Treatment period (52 weeks) 
Follow-up period 
Nemolizumab 60 mg/body n = 8 
IC 
Screening 
Start 
 treatment 
Week 1 
Week 2 
Week 4 
Visit every 4 weeks 
Week 52 
Follow-up visit 
Pre-treatment 
observation period 

Synopsis-6 
3） Follow-up period 
All participants having received the IP will be scheduled to visit for follow-up 12 weeks after the day 
of the last dose of study treatment (the day of follow-up visit). On the day of the follow-up visit, the 
investigator or subinvestigator will evaluate the safety and efficacy after completion of study treatment 
for all participants. 
 
3. Target Indication and Inclusion and Exclusion Criteria for Patients 
 Target Indication 
SSc 
 
 Inclusion Criteria 
Participants must meet all of the following criteria for study entry: 
Inclusion Criteria 
Assessment timing  
Day of 
Informed 
Consent  
Day of 
Screening 
Day of 
treatment start 
1） Patients aged 20 to 70 years at the time of informed 
consent 
X 
– 
– 
2） Patients meeting the classification criteria for SSc in ACR 
and EULAR 2013 
X 
– 
– 
3） Patients with systemic sclerosis who have moderate to 
severe skin thickening, with mRSS of 10 to 22 on both the 
screening and treatment initiation dates 
– 
X 
X 
4） Patients considered by the investigator or subinvestigator 
to be competent to perform the protocol-specified self-
assessment 
X 
X 
X 
 
 Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from study entry: 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
1） Patients complicated with diseases considered inappropriate 
for participation in clinical trials, such as serious* 
cardiac/hepatic/renal/pulmonary/hematologic disease 
*Refer to the Criteria for Seriousness Classification of Adverse 
Drug Reactions. (PAB/SD Notification No.80 by the Director 
of Safety Division, Pharmaceutical Affairs Bureau, Ministry of 
Health and Welfare dated June 29, 1992) and the Common 
Terminology Criteria for Adverse Events v 5.0 Japanese JCOG 
version (CTCAE v 5.0-JCOG). 
X 
X 
X 
2） Patients complicated with congestive heart failure [New York 
Heart Association (NYHA) Functional Class III or IV] 
X 
X 
X 
3） Patients having any of the following complications or 
concomitant/concurrent diseases: 
a） Severe chronic pulmonary disease (including %FVC < 
60%, or %DLco < 40% on the day of screening, 
calculated from the New Reference Values for 
Spirometry in Japanese adults calculated with the LMS 
X 
X 
X 

Synopsis-7 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
Method (the Japanese Respiratory Society)”  
b） Serious complications associated with SSc other than 
interstitial lung disease* (e.g., renal crisis) 
* Interstitial lung disease is excluded if it falls under Item 
a) of 3)  
c） Poorly 
controlled 
asthma 
that 
requires 
steroids 
(systemic), intravenous infusion of aminophylline, 
subcutaneous injection of adrenaline 0.1%, oxygen 
inhalation, or antibody drugs  
d） Diseases to affect the assessment of SSc 
4） Patients with a history of malignant tumor, who are receiving 
no treatment and have had no recurrence /relapse for ≥5 years 
at the time of informed consent, or patients with a history of 
radical treatment for cervical intraepithelial neoplasia at the 
time of informed consent may be included in the study 
X 
X 
X 
5） Patients 
with 
Immune 
deficiency 
(e.g., 
congenital 
immunodeficiency, AIDS, or HIV). 
X 
X 
X 
6） Patients with a history or current hypersensitivity (including 
anaphylaxis) to immunoglobulin products (plasma-derived 
preparations or genetic recombinant monoclonal antibodies) 
X 
X 
X 
7） Patients weighing < 30.0 kg or > 120 kg on the day of study 
treatment initiation 
– 
– 
X 
8） Patients whose laboratory test values on the day of screening 
meet any of the following criteria: 
a） AST or ALT > 2 times the upper limit of normal 
b） Serum creatinine ≥2.0 mg/dL 
c） WBC <3000 cells/μL 
– 
– 
X 
9） Patients infected with hepatitis B virus (HBV) or hepatitis C 
virus (HCV) (Positive for HBs antigen or HBc antibody on the 
day of screening, positive for anti-HCV antibody on the day of 
screening) 
The allowed exceptions are as follows: 
 
Patients confirmed not to be infected with HBV at the 
time of the HBV-DNA test performed before study 
treatment initiation in the case of negative for HBs 
antigen and positive for HBc antibody in the hepatitis B 
test performed on the day of screening. 
 
Patients confirmed not to be infected with HCV at the 
time of the HCV-RNA test performed before study 
treatment initiation in the case of positive for anti-HCV 
antibody in the hepatitis C test performed on the day of 
screening 
– 
– 
X 
10） Patients with latent or active tuberculosis based on the result 
of the screening TB test. The allowed exception is patients 
deemed not to be infected with tuberculosis according to the 
“Guidelines for the use of interferon-γ release assay 
(Prevention Committee of the Japanese Society for 
Tuberculosis).  
– 
– 
X 
11） Patients with either of the following infectious diseases: 
 
Recurrent/chronic infections or other active infections 
X 
X 
X 

Synopsis-8 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
deemed by the investigator to possibly aggravated by 
participating in the study. 
 
Infections (including skin infections) requiring systemic 
antibiotics, antivirals, or antifungals within 7 days prior 
to the day of study treatment initiation. 
12） Patients who have received oral steroids (> 10 mg/day of 
prednisolone or equivalent), dosage of receiving oral steroids 
have been changed (from ≤ 10 mg/day of prednisolone or 
equivalent), or newly treated with oral steroids, within 14 days 
before the day of study treatment initiation 
– 
– 
X 
13） Patients who have received any of the following therapies 
within the indicated period prior to the day of study treatment 
initiation 
– 
(X)* 
X 
a） Within 365 days 
Cyclophosphamide 
b） Within 120 days or 5 
times the elimination 
half-life of the drug, 
whichever is longer 
Antibody drugs 
c） Within 28 days 
 
Live vaccines 
 
The 
following 
systemic 
medications: 
− Antifibrotic 
drugs 
(e.g., 
pirfenidone, nintedanib) 
− Immunosuppressants 
(e.g., 
cyclosporine, 
tacrolimus, 
azathioprine, mycophenolate 
mofetil, 
mizoribine, 
sulfasalazine, 
leflunomide, 
methotrexate, 
hydroxychloroquine, 
D-
penicillamine, sirolimus) 
− Tyrosine kinase inhibitors 
(e.g., imatinib) 
− JAK 
inhibitors 
(e.g., 
tofacitinib, upadacitinib) 
− Endothelin receptor agonists 
(e.g., bosentan, ambrisentan, 
macitentan) 
− Phosphodiesterase-5 
inhibitors (e.g., sildenafil, 
tadalafil) 
− Prostaglandin analogue (e.g., 
alprostadil, epoprostenol) 
− Riociguat 
 
Injections of corticosteroids 
(excluding joint injections) 
 
Phototherapy 

Synopsis-9 
*The exclusion criteria will be assessed with the expected date of study treatment initiation as the starting 
point.
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
 
High-dose 
intravenous 
immunoglobulin therapy 
14） Patients who are within 120 days from the end of participation 
in other clinical trials or post-marketing clinical studies (i.e., 
the last day of administration of another IP or post-marketing 
clinical study drug) until the day of study treatment initiation, 
or participating in other clinical trials or post-marketing 
clinical studies 
– 
(X)* 
X 
15） Women who are pregnant, breastfeeding, possibly pregnant, 
or unwilling to use appropriate contraception measures as 
instructed by the investigator during the study period 
X 
X 
X 
16） Patients who meet any of the following criteria: 
a） Having not met eligibility for participation when 
participating in this study in the past 
d） Having previously received nemolizumab (including 
placebo) 
X 
X 
X 
17） Patients with confirmed or suspected COVID-19 
– 
X 
X 
18） Patients with a history of confirmed or suspected COVID-19 
excluding those meeting any of the following criteria: 
• At least 20 days after the onset of symptoms and at 
least 72 hours after the resolution of symptoms. 
• Confirmed not to carry SARS-Cov-2. 
– 
X 
X 
19） Patients found to have close contacts with COVID-19 patients 
within 14 days before the day of study treatment initiation  
– 
– 
X 
20） Other patients who are considered ineligible for the study by 
the investigator 
X 
X 
X 

Synopsis-13 
e Not to be performed if refused by the participant. 
If any of the following treatment-emergent adverse events occurs, photographs of the affected skin areas of the adverse event should be taken while the event (at least once) is 
occurring and at the final outcome evaluation, in addition to the scheduled visit (i.e., the day of study treatment initiation).  
• Atopic dermatitis 
• Adverse events with skin symptoms of edematous erythema or scaling 
• Any other adverse event for which the investigator or subinvestigator considers that photography is necessary. 
f To be performed on female participants excluding those who never become pregnant. 
g May be conducted on another day after the day of screening before the day of study treatment initiation 
h • Hepatitis B 
The participants who test negative for HBs antigen and positive for HBc antibody will undergo HBV-DNA measurement before the day of study treatment initiation. The participants 
enrolled through HBV-DNA measurement will undergo HBV-DNA measurement once every three months. 
・ 
Hepatitis C 
The participants who test positive for the anti-HCV antibody will undergo HCV-RNA measurement before the day of study treatment initiation. The participants enrolled through 
HCV-RNA measurement will undergo HCV-RNA measurement once every three months. 
i To be administered after all observation/tests are performed. If the IP cannot be administered within the window indicated, the next dose should be administered 14 days or later 
after the day of the previous dose. 
j Participants who discontinued the study will visit the site 84 days (±7 days) after the day of the last dose of study treatment for observation/tests at FU shown in Table 4-1. Participants 
discontinued the study before study treatment initiation need not to undergo observation/tests scheduled on the day of visit for discontinuation. 

Synopsis-14 
5. Treatment Method 
 Method of Administration 
The investigator or subinvestigator will slowly administer the IP, nemolizumab (one DCS [0.6 ml]) 
subcutaneously to the upper arm, abdomen, or thigh of the participants. The IP may be administered by a 
person qualified to administer it under the instruction of the investigator or subinvestigator.  
 
 Treatment Period 
52 weeks 
All participants who have received at least one dose of the IP will visit the site 12 weeks after the day of the 
last dose of study treatment for follow-up. 
 
 Concomitant Medications and Therapies  
5.3.1  Restricted Concomitant Medications 
The following medications may be continued at a stable dose if used for at least 14 days before the day of 
study treatment initiation. However, the dose may be reduced at the discretion of the investigator or 
subinvestigator, and after dose reduction, the dose may be increased up to that used at the day of study 
treatment initiation. 
•Oral steroids (≤ 10 mg/day of prednisolone or equivalent) 
 
5.3.2  Prohibited Concomitant Medications and Therapies  
Concomitant use of medications and therapies listed below is prohibited in this study.  
- 
From the day of study treatment initiation to Week 52 or to the physical examination on the day of visit 
for discontinuation 
1） The following systemic medications: 
a） Antifibrotic drugs (e.g., pirfenidone, nintedanib) 
b） Immunosuppressants 
(e.g., 
cyclophosphamide, 
cyclosporine, 
tacrolimus, 
azathioprine, 
mycophenolate mofetil, mizoribine, sulfasalazine, leflunomide, methotrexate, hydroxychloroquine, 
D-penicillamine, sirolimus) 
c） Tyrosine kinase inhibitors (e.g., imatinib) 
d） JAK inhibitors (e.g., tofacitinib, upadacitinib) 
e） Endothelin receptor agonists (e.g., bosentan, ambrisentan, macitentan) 
f） Phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil) 
g） Prostaglandin analogues (e.g., alprostadil, epoprostenol) 
h） Riociguat 
2） Injections of corticosteroids (excluding joint injections) 
3） Phototherapy 
4） High-dose intravenous immunoglobulin therapy 
5） Antibody drugs 
6） Live vaccines 
 
- 
From the day of study treatment initiation to the day of follow-up visit 
1） Other drugs and medical devices under development 
 
 

Synopsis-15 
6. Study Discontinuation of Individual Participants  
 Discontinuation Criteria 
1） Use of other antibody drugs by Week 52 visit 
2） Use of live vaccines by Week 52 visit 
3） The investigator or subinvestigator determined that an adverse event which would prevent the 
continuation of the study has occurred. 
4） The participant is found to fail to meet any of the inclusion criteria or to meet any of the exclusion 
criteria. 
5） The participant is found to be pregnant. 
6） The investigator or subinvestigator has determined that the participant should be withdrawn from the 
study due to inadequate response to the IP. 
7） The participant requests to withdraw from the study. 
8） The participant no longer visits the medical institution, and the study cannot be continued. 
9） The participant has died. 
10） The sponsor has determined the participant discontinuation from the study due to significant protocol 
deviations. 
11） The sponsor has prematurely terminated the study. 
12） The investigator or subinvestigator has determined to withdraw the participant from the study for any 
other reasons. 
 
7. Efficacy Evaluation 
 Primary Endpoint 
Change from baseline in mRSS at Week 24 
 
 Other Endpoints 
1） Change from baseline in mRSS at Week 52 
2） Change from baseline in HAQ-DI at Week 52 
3） Change from baseline in HAQ-DI at Week 24 
4） Change from baseline in %FVC at Week 52 
5） Change from baseline in %FVC at Week 24 
6） Change from baseline in DLco at Week 52 
7） Change from baseline in DLco at Week 24 
8） Change from baseline in PGA at Week 52 
9） Change from baseline in PGA at Week 24 
10） Change from baseline in PtGA at Week 52 
11） Change from baseline in PtGA at Week 24 
12） ACR-CRISS at Week 52 
13） ACR-CRISS at Week 24 
14） Change from baseline in the number of digital ulcers at Week 52 
15） Change from baseline in the number of digital ulcers at Week 24 
16） Time-course change in the following items: 
a） HAQ-DI 
b） FACIT-Fatigue 
c） FSSG 
d） FVC 

Synopsis-16 
e） %FVC 
f） DLco 
g） %DLco 
h） TLC 
i） FEV1 
j） Severity evaluation of lung lesion 
k） PGA 
l） PtGA 
m） ACR-CRISS 
n） The number of digital ulcers 
 
8. Safety Evaluation 
 Assessments for Safety Evaluations 
1） Adverse events 
a） Symptoms and signs 
b） Abnormal laboratory test values 
c） Abnormal vital signs 
d） Abnormal electrocardiograms 
2） Laboratory test values 
3） Vital signs 
4） Electrocardiogram 
5） Echocardiography 
 
9. Target Sample Size 
8 participants 
 
10. Study Period 
December 2021 to October 2023

 
Table of Contents 
 
1. Introduction ........................................................................................................... 22 
 Background of Development ................................................................................................ 22 
1.1.1 Pathophysiology and epidemiology of systemic sclerosis ............................................. 22 
1.1.2 Therapeutic treatment of systemic sclerosis and its issues .......................................... 22 
1.1.3 Summary description and significance of the development of nemolizumab ............... 22 
 Guidelines, Consultation with Pharmaceuticals and Medical Devices Agency (PMDA), 
etc., Referenced for Study Planning .................................................................................... 23 
2. Study objectives ................................................................................................... 24 
 Primary Objective ................................................................................................................. 24 
 Secondary Objective............................................................................................................. 24 
3. Study Design ........................................................................................................ 24 
4. Target Indication and Inclusion and Exclusion Criteria for Participants ................. 25 
 Target Indication ................................................................................................................... 25 
 Inclusion Criteria ................................................................................................................... 25 
 Exclusion criteria ................................................................................................................... 25 
5. Study Discontinuation of Individual Participants ................................................... 29 
 Discontinuation criteria ......................................................................................................... 29 
 Procedure for Discontinuation .............................................................................................. 30 
5.2.1 Discontinuation before Enrollment ................................................................................. 30 
5.2.2 Discontinuation after Enrollment .................................................................................... 30 
 Handling of Participants Who Fail to Visit the Study Site ..................................................... 30 
5.3.1 Participants Discontinuing Study Site Visit Between the Day of Informed Consent and 
the Day of Enrollment ................................................................................................... 30 
5.3.2 Participants Discontinuing Study Site Visit in the Period after the Enrollment up to 
Visit 17 (Week 52) ......................................................................................................... 30 
5.3.3 Participants Discontinuing Study Site Visit during the Follow-up Period ...................... 30 
6. Participant Enrollment........................................................................................... 31 
 Informed Consent ................................................................................................................. 31 
 Notification when the Participant is Treated by Another Doctor ........................................... 31 
 Enrollment Procedure of Participants ................................................................................... 31 
7. Investigational Product ......................................................................................... 31 
 Name, Dosage Form, and Strength of the IP ....................................................................... 31 
 Packaging and Labeling ....................................................................................................... 32 
7.2.1 Packaging ...................................................................................................................... 32 
7.2.2 Labeling .......................................................................................................................... 32 
 Storage and Management of Investigational Products ........................................................ 32 
8. Treatment Method ................................................................................................ 32 
 Dispensing of Investigational Products ................................................................................ 32 
 Preparation of Investigational Products ............................................................................... 32 
 Method of Administration ...................................................................................................... 32 
 Concomitant Medications and Therapies ............................................................................. 33 
8.4.1 Restricted Concomitant Medications ............................................................................. 33 
8.4.2 Duration and Method of Inspection ................................................................................ 33 

 
8.4.3 Prohibited Concomitant Medications and Therapies ..................................................... 33 
8.4.4 Instructions to participants ............................................................................................. 34 
9. Study Procedures and Assessments and the Schedule ....................................... 35 
 Schedule of Study Procedures and Assessments ............................................................... 35 
 Definition of the Days of Observation, Tests, and Sample Collection .................................. 39 
9.2.1 Day of Informed Consent ............................................................................................... 39 
9.2.2 Day of screening ............................................................................................................ 39 
9.2.3 Day of Study Treatment Initiation ................................................................................... 39 
9.2.4 Day of Assessment (Weeks 1, 2, 4, 8, 12, through 52) ................................................. 39 
9.2.5 Day of Study Treatment ................................................................................................. 39 
9.2.6 Day of Discontinuation ................................................................................................... 39 
9.2.7 Day of Discontinuation Visit ........................................................................................... 39 
9.2.8 Day of Follow-up Visit .................................................................................................... 39 
 Observation, Tests and Sample Collection........................................................................... 39 
9.3.1 Participant Demographics .............................................................................................. 39 
9.3.2 Prior and Concomitant Medications and Therapies ...................................................... 40 
9.3.3 Body Weight ................................................................................................................... 41 
9.3.4 Efficacy Evaluation ......................................................................................................... 41 
9.3.5 Safety Evaluation ........................................................................................................... 43 
9.3.6 Laboratory tests ............................................................................................................. 44 
9.3.7 Pharmacokinetics ........................................................................................................... 46 
9.3.8 Immunogenicity .............................................................................................................. 46 
9.3.9 Biomarker measurement ................................................................................................ 46 
9.3.10 Comprehensive measurement of autoantibodies ........................................................ 47 
9.3.11 CyTOF measurement ................................................................................................... 47 
9.3.12 Assessment of Adverse Events ................................................................................... 47 
9.3.13 Investigation of Malfunction of DCS ............................................................................ 47 
9.3.14 Amount of Blood and Urine Samples to be Collected ................................................. 48 
10. Efficacy Evaluation ............................................................................................. 49 
 Efficacy Assessments ......................................................................................................... 49 
10.1.1 Assessment of Skin Findings ....................................................................................... 49 
10.1.2 Respiratory Function Test ............................................................................................ 49 
10.1.3 Chest HRCT ................................................................................................................. 49 
10.1.4 Severity Classification of Lung Lesion ......................................................................... 49 
10.1.5 ACR-CRISS .................................................................................................................. 50 
10.1.6 The Number of Digital Ulcers ....................................................................................... 50 
10.1.7 Patient-reported outcome ............................................................................................ 50 
10.1.8 Global improvement rating ........................................................................................... 51 
 Efficacy Endpoints .............................................................................................................. 51 
10.2.1 Primary Endpoint ......................................................................................................... 51 
10.2.2 Other Endpoints ........................................................................................................... 51 
 Rationale for Efficacy Endpoints ........................................................................................ 52 
11. Safety Evaluation ................................................................................................ 54 
 Assessments for Safety Evaluations .................................................................................. 54 
 Definition of Adverse Events ............................................................................................... 54 
 Definitions of Safety Endpoints ........................................................................................... 55 

 
 Review and reporting of adverse events ............................................................................ 56 
 Review and reporting of serious adverse events ............................................................... 58 
 Reporting of adverse events of special interests (AESIs) .................................................. 58 
 Photography ........................................................................................................................ 58 
 Reporting of the Pregnancy of the Participant .................................................................... 58 
 Rationale for Safety Endpoints ........................................................................................... 59 
 Follow-up of Adverse Events ............................................................................................ 59 
 Malfunctions of DCS ......................................................................................................... 59 
11.11.1 Reporting of Malfunctions of DCS .............................................................................. 59 
11.11.2 Collection and Reporting of Malfunction Information on DCS occurring at the Stage 
of Use on Participants ................................................................................................... 59 
11.11.3 Storage of Malfunctioning DCS .................................................................................. 59 
 Anticipated Adverse Drug Reactions ................................................................................ 59 
12. Biomarkers ......................................................................................................... 60 
 Measurements of Biomarkers............................................................................................. 60 
 Blood Biomarker Outcome Measures ................................................................................ 60 
 Measurement Method and Reporting of Results................................................................ 61 
13. Pharmacokinetics ............................................................................................... 61 
 Pharmacokinetic Measurements ........................................................................................ 61 
 Pharmacokinetic Outcome Measures ................................................................................ 61 
 Measurement Method and Reporting of Results................................................................ 61 
14. Immunogenicity .................................................................................................. 62 
 Immunogenicity Measurements ......................................................................................... 62 
 Immunogenicity Outcome Measures .................................................................................. 62 
 Measurement Method and Reporting of Results................................................................ 62 
15. Comprehensive Measurement of Autoantibodies ............................................... 62 
 Measurement Method and Reporting of Results................................................................ 62 
16. CyTOF measurement ......................................................................................... 63 
 Measurement Method and Reporting of Results................................................................ 63 
17. Statistical Analysis .............................................................................................. 63 
 Analysis Sets ...................................................................................................................... 63 
17.1.1 Efficacy Analysis Set (Full Analysis Set: FAS) ............................................................. 63 
17.1.2 Safety Analysis Set ...................................................................................................... 64 
17.1.3 Pharmacokinetics Analysis Set .................................................................................... 64 
17.1.4 Biomarker Analysis Set ................................................................................................ 64 
 Data Handling ..................................................................................................................... 64 
17.2.1 Common Rules ............................................................................................................ 64 
17.2.2 Data Handling on Pharmacokinetics ........................................................................... 64 
 Statistical Analysis Plan ...................................................................................................... 65 
17.3.1 Demographic and Other Baseline Characteristics, and Severity of Primary Disease 65 
17.3.2 Efficacy Analysis .......................................................................................................... 65 
17.3.3 Safety Analysis ............................................................................................................. 66 
17.3.4 Analyses of Drug Concentrations and Pharmacokinetic Parameters ......................... 66 
17.3.5 Analysis of Immunogenicity ......................................................................................... 67 
17.3.6 Analysis of Biomarker .................................................................................................. 67 

 
 Determination of Sample Size ............................................................................................ 67 
17.4.1 Target Sample Size ...................................................................................................... 67 
17.4.2 Rationale for Sample Size ........................................................................................... 67 
 Data Review ....................................................................................................................... 67 
18. Agreement on the Protocol and Protocol Deviation/Amendment ........................ 68 
 Agreement of and Compliance with the Protocol ............................................................... 68 
 Protocol Deviation/Amendment .......................................................................................... 68 
19. Case Report Form .............................................................................................. 69 
 Data to be collected in CRF................................................................................................ 69 
19.1.1 Participants assigned to treatment .............................................................................. 69 
19.1.2 Participants Who Discontinue the Study before study entry after screening and 
those Who Discontinue the Study before enrollment ................................................... 70 
 Source Data for Information Entered in Case Report Form ............................................... 70 
 Information in the Case Report Forms Treated as Source Data ........................................ 71 
 Guidelines for Preparation of Case Report Form ............................................................... 71 
 Modification and Amendment to Case Report Forms ........................................................ 71 
20. Follow-up report of adverse events of special interest ........................................ 71 
21. Direct Access to Source Documents .................................................................. 72 
22. Quality Control and Quality Assurance ............................................................... 72 
23. Completion, Discontinuation, or Interruption of the Study ................................... 72 
 Completion of the Study ..................................................................................................... 72 
 Discontinuation or Interruption of the Study ....................................................................... 72 
24. Archiving of Records ........................................................................................... 73 
25. Publication Policy ............................................................................................... 73 
26. Use of study-related data .................................................................................... 73 
27. Ethics .................................................................................................................. 74 
 Institutional Review Board .................................................................................................. 74 
 Ethical Conduct of the Study .............................................................................................. 74 
 Protection of Participants’ Confidentiality ........................................................................... 74 
 Participant Selection and Informed Consent ...................................................................... 74 
27.4.1 Participant Selection .................................................................................................... 74 
27.4.2 Informed Consent ........................................................................................................ 74 
27.4.3 Explanations to Participants ........................................................................................ 75 
28. Payments ............................................................................................................ 76 
29. Compensation for Injuries ................................................................................... 76 
30. Responses to COVID-19 .................................................................................... 76 
 If participants are found to have confirmed COVID-19 (including asymptomatic pathogen 
carriers) or suspected COVID-19, or found to have been in close contact with a confirmed 
or suspected COVID-19 patient ........................................................................................... 76 
 Discontinuation of the study due to the influence of COVID-19 ......................................... 78 
 Deviations from the protocol due to the influence of COVID-19 ........................................ 78 
31. Study Period ....................................................................................................... 78 
32. Administrative Structure ...................................................................................... 78 
 Sponsor............................................................................................................................... 78 

 
 Sponsor Organization ......................................................................................................... 78 
 Study Sites and Investigators ............................................................................................. 79 
 Medical Expert .................................................................................................................... 79 
 Contract Research Organization ........................................................................................ 79 
33. Contact Information ............................................................................................ 80 
 Contact Information ............................................................................................................ 80 
 Emergency Contact (Saturdays and Sundays, National Holidays, Nights) ....................... 80 
34. References ......................................................................................................... 81 
 
 
 
 

22 
1. Introduction 
 Background of Development 
1.1.1  Pathophysiology and epidemiology of systemic sclerosis 
Systemic scleroderma (SSc) is a systemic autoimmune disease characterized by fibrosis and vasculopathy 
of skin and various internal organs such as lung and classified as a connective tissue disease. Skin fibrosis, a 
common symptom in patients with SSc, is considered to be excessive deposition of the extracellular matrix 
mainly composed of collagen. 1) In Japan, SSc is designated as an intractable disease; according to the 
information of the Japan Intractable Diseases Information Center, the number of SSc patients is about 20,000. 
2) The male-to-female ratio of patients is 1:12 and is more prevalent in women between the ages of 30 and 
50 years. 
SSc is classified as either diffuse cutaneous systemic scleroderma (dcSSc) in which skin thickening 
extends to the proximal extremities (i.e. the upper arms and the thighs) or the trunk or limited cutaneous 
systemic scleroderma (lcSSc) in which skin thickening is limited to the distal extremities (i.e. the forearms 
and the lower legs) and the face.3) In dcSSc patients, as skin thickening progresses, visceral involvement such 
as in the lungs, gastrointestinal tract, kidneys, and heart, and joint flexion contracture progress. In dcSSc in 
particular, it is widely recognized that the degree of skin thickening correlates with that of fibrotic lesions in 
internal organs, and higher severity of skin thickening has been reported to be associated with higher rates of 
visceral involvement including in the lungs and lower survivals. 4), 5), 6) In addition, fibrosis of internal organs, 
as well as skin thickening, develops at an early stage, in which slight tissue damage accumulates and 
progresses to irreversible organ damage. Therefore, treatment should be initiated as early as possible, 
especially in patients in whom the condition is predicted to become severe. In lcSSc patients, on the other 
hand, skin thickening progresses slowly and are not eligible for aggressive treatment. However, lcSSc with 
the possibility of rapid and widespread progression of skin thickening may be eligible for treatment.7) 
 
1.1.2  Therapeutic treatment of systemic sclerosis and its issues 
The etiology of SSc has not been clarified, and the main treatment methods are symptomatic treatments 
and disease-modifying drugs that inhibit disease progression. The progression and sites of involvement of 
SSc are different for each patient, and accordingly, the treatment method is selected based on the symptom 
of each patient. 
Diagnostic Criteria, Severity Classification and Guidelines of Systemic Sclerosis7) state that oral 
corticosteroids are thought to be empirically valid for patients with progressing skin thickening at an early 
stage but that they have risk factors for inducing renal crisis. Cyclophosphamide is the most recommended 
treatment option for both skin thickening and interstitial lung disease in patients with SSc; however, it has a 
problem of difficulty in long-term administration because of its carcinogenicity, immunosuppression, and 
side effects of drug such as hemorrhagic cystitis. Other drugs for SSc symptoms are prostacyclin, endothelin 
receptor antagonists, and phosphodiesterase-5 inhibitors for the treatment of pulmonary hypertension, 
calcium channel blockers for the treatment of cardiac involvement, intravenous prostaglandin E1 or 
prostacyclin for the treatment of disturbed blood flow in the fingers, and proton pump inhibitors for the 
treatment of reflux esophagitis. However, due to limited efficacy or safety issues of these therapeutic agents, 
the disease burden remains high and there is a great unmet medical need. 
 
1.1.3  Summary description and significance of the development of nemolizumab 
Nemolizumab is a monoclonal antibody that recognizes interleukin-31 receptor A (IL-31RA) in humans, 
which competitively inhibits the binding of interleukin-31 (IL-31) to its receptor, thereby blocking 
subsequent signal transduction into the cells. Nemolizumab was initially developed by 
 
 Co., Ltd.; the worldwide development and marketing rights, except in Japan and Taiwan, 

23 
were granted to 
 in 2016, while the development and marketing rights in the field of skin 
diseases in Japan were granted to 
. 
IL-31 is a cytokine produced mainly from activated T cells. IL-31 is present at higher levels in serum in 
SSc than in healthy individuals; IL-31 positive cells were identified in inflammatory infiltrates in fibrotic 
lesions in the skin and lungs8). Moreover, an in vitro study with dermal fibroblasts from healthy individuals 
showed IL-31 increased collagen production in these cells, and IL-31 administration to mice induced skin 
and lung fibrosis in an in vivo study, suggesting that IL-31 induces skin and lung fibrosis via inducing 
collagen production in fibroblasts8).These results indicate that IL-31 is a key cytokine involved in the 
development of SSc, and therefore, nemolizumab is expected to inhibit the progression of or ameliorate of 
skin and pulmonary fibrosis in SSc. 
From the above, nemolizumab is considered to be a possible new treatment option for SSc. Thus, this study 
has been developed to explore the efficacy and safety of nemolizumab in SSc patients. 
 
 Guidelines, Consultation with Pharmaceuticals and Medical Devices Agency (PMDA), etc., 
Referenced for Study Planning 
 
This study has been planned in reference to the “Diagnostic criteria, severity classification and guidelines of 
systemic sclerosis.” 

25 
All participants having received the IP will be scheduled to visit for follow-up 12 weeks after the day 
of the last dose of study treatment (the day of follow-up visit). On the day of the follow-up visit, the 
investigator or subinvestigator will evaluate the safety and efficacy after completion of study treatment 
for all participants. 
 
4. Target Indication and Inclusion and Exclusion Criteria for Participants 
The investigator or subinvestigator will ensure before enrollment that all inclusion criteria are met and none 
of the exclusion criteria are met. 
 
 Target Indication 
SSc 
 
 Inclusion Criteria 
Participants must meet all of the following criteria for study entry: 
Inclusion Criteria 
Assessment timing  
Day of 
Informed 
Consent  
Day of 
Screening 
Day of 
treatment start 
1） Patients aged 20 to 70 years at the time of informed 
consent 
X 
– 
– 
2） Patients meeting the classification criteria for SSc in ACR 
and EULAR 2013 
X 
– 
– 
3） Patients with systemic sclerosis who have moderate to 
severe skin thickening, with mRSS of 10 to 22 on both the 
screening and treatment initiation dates 
– 
X 
X 
4） Patients considered by the investigator or subinvestigator 
to be competent to perform the protocol-specified self-
assessment 
X 
X 
X 
 
 Rationale for inclusion criteria 
1) 
Established for safety consideration and to select patients with a sufficient capacity 
for judgment 
2) 
Established to standardize the diagnostic criteria for SSc for participants 
3) 
Established to include only patients with moderate to severe symptoms who are 
considered to be target patients for this drug. 
4) 
Established to select patients who can comply with the protocol-specified 
activities. 
 
 Exclusion criteria 
Participants who meet any of the following criteria will be excluded from study entry: 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
1） Patients complicated with diseases considered inappropriate 
for participation in clinical trials, such as serious* 
cardiac/hepatic/renal/pulmonary/hematologic disease 
*Refer to the Criteria for Seriousness Classification of Adverse 
Drug Reactions. (PAB/SD Notification No.80 by the Director 
X 
X 
X 

26 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
of Safety Division, Pharmaceutical Affairs Bureau, Ministry of 
Health and Welfare dated June 29, 1992) and the Common 
Terminology Criteria for Adverse Events v 5.0 Japanese JCOG 
version (CTCAE v 5.0-JCOG). 
2） Patients complicated with congestive heart failure [New York 
Heart Association (NYHA) Functional Class III or IV] 
X 
X 
X 
3） Patients having any of the following complications or 
concomitant/concurrent diseases: 
a） Severe chronic pulmonary disease (including %FVC < 
60%, or %DLco < 40% on the day of screening, 
calculated from the New Reference Values for 
Spirometry in Japanese adults calculated with the LMS 
Method (the Japanese Respiratory Society)”  
b） Serious complications associated with SSc other than 
interstitial lung disease* (e.g., renal crisis) 
* Interstitial lung disease is excluded if it falls under Item 
a) of3)  
c） Poorly controlled asthma that requires steroids 
(systemic), intravenous infusion of aminophylline, 
subcutaneous injection of adrenaline 0.1%, oxygen 
inhalation, or antibody drugs  
d） Diseases to affect the assessment of SSc 
X 
X 
X 
4） Patients with a history of malignant tumor, who are receiving 
no treatment and have had no recurrence /relapse for ≥5 years 
at the time of informed consent, or patients with a history of 
radical treatment for cervical intraepithelial neoplasia at the 
time of informed consent may be included in the study 
X 
X 
X 
5） Patients 
with 
Immune 
deficiency 
(e.g., 
congenital 
immunodeficiency, AIDS, or HIV). 
X 
X 
X 
6） Patients with a history or current hypersensitivity (including 
anaphylaxis) to immunoglobulin products (plasma-derived 
preparations or genetic recombinant monoclonal antibodies) 
X 
X 
X 
7） Patients weighing < 30.0 kg or > 120 kg on the day of study 
treatment initiation 
– 
– 
X 
8） Patients whose laboratory test values on the day of screening 
meet any of the following criteria: 
a） AST or ALT > 2 times the upper limit of normal 
b） Serum creatinine ≥2.0 mg/dL 
c） WBC <3000 cells/μL 
– 
– 
X 
9） Patients infected with hepatitis B virus (HBV) or hepatitis C 
virus (HCV) (Positive for HBs antigen or HBc antibody on the 
day of screening, positive for anti-HCV antibody on the day of 
screening) 
The allowed exceptions are as follows: 
 
Patients confirmed not to be infected with HBs at the time 
of the HBV-DNA test performed before study treatment 
initiation in the case of negative for HBs antigen and 
positive for HBc antibody in the hepatitis B test 
– 
– 
X 

27 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
performed on the day of screening. 
 
Patients confirmed not to be infected with HCV at the 
time of the HCV-RNA test performed before study 
treatment initiation in the case of positive for anti-HCV 
antibody in the hepatitis C test performed on the day of 
screening 
10） Patients with latent or active tuberculosis based on the result 
of the screening TB test. The allowed exception is patients 
deemed not to be infected with tuberculosis according to the 
“Guidelines for the use of interferon-γ release assay 
(Prevention Committee of the Japanese Society for 
Tuberculosis). 
– 
– 
X 
11） Patients with either of the following infectious diseases: 
 
Recurrent/chronic infections or other active infections 
deemed by the investigator to possibly aggravated by 
participating in the study 
 
Infections (including skin infections) requiring systemic 
antibiotics, antivirals, or antifungals within 7 days prior 
to the day of study treatment initiation. 
X 
X 
X 
12） Patients who have received oral steroids (> 10 mg/day of 
prednisolone or equivalent), dosage of receiving oral steroids 
have been changed (from ≤ 10 mg/day of prednisolone or 
equivalent), or newly treated with oral steroids, within 14 days 
before the day of study treatment initiation 
– 
– 
X 
13） Patients who have received any of the following therapies 
within the indicated period prior to the day of study treatment 
initiation 
– 
(X)* 
X 
a） Within 365 days 
Cyclophosphamide 
b） Within 120 days or 5 
times the elimination 
half-life of the drug, 
whichever is longer 
Antibody drugs 
c） Within 28 days 
i. 
Live vaccines 
ii. 
The 
following 
systemic 
medications: 
− Antifibrotic 
drugs 
(e.g., 
pirfenidone, nintedanib) 
− Immunosuppressants 
(e.g., 
cyclosporine, 
tacrolimus, 
azathioprine, mycophenolate 
mofetil, 
mizoribine, 
sulfasalazine, 
leflunomide, 
methotrexate, 
hydroxychloroquine, 
D-
penicillamine, sirolimus) 
− Tyrosine kinase inhibitors 
(e.g., imatinib) 

28 
*The exclusion criteria will be assessed with the expected date of study treatment initiation as the starting 
point. 
 
 Rationale for exclusion criteria 
1) to 6), 8) to 11), 15), 
and 17) to 19) 
Established considering the safety of participants  
7) 
Since the dose in this study is 60 mg/body, the upper body weight limit was set 
not to be lower than the dose (0.5 mg/kg) proven effective in the studies 
conducted to date in patients with atopic dermatitis, in view of efficacy. The lower 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
− JAK 
inhibitors 
(e.g., 
tofacitinib, upadacitinib) 
− Endothelin receptor agonists 
(e.g., bosentan, ambrisentan, 
macitentan) 
− Phosphodiesterase-5 
inhibitors (e.g., sildenafil, 
tadalafil) 
− Prostaglandin analogue (e.g., 
alprostadil, epoprostenol) 
− Riociguat 
iii. Injections of corticosteroids 
(excluding joint injections) 
iv. Phototherapy 
v. High-dose 
intravenous 
immunoglobulin therapy 
14） Patients who are within 120 days from the end of participation 
in other clinical trials or post-marketing clinical studies (i.e., 
the last day of administration of another IP or post-marketing 
clinical study drug) until the day of study treatment initiation, 
or participating in other clinical trials or post-marketing 
clinical studies 
– 
(X)* 
X 
15） Women who are pregnant, breastfeeding, possibly pregnant, 
or unwilling to use appropriate contraception measures as 
instructed by the investigator during the study period 
X 
X 
X 
16） Patients who meet any of the following criteria: 
a） Having not met eligibility for participation when 
participating in this study in the past 
b） Having previously received nemolizumab (including 
placebo) 
X 
X 
X 
17） Patients with confirmed or suspected COVID-19 
– 
X 
X 
18） Patients with a history of confirmed or suspected COVID-19 
excluding those meeting any of the following criteria: 
• At least 20 days after the onset of symptoms and at 
least 72 hours after the resolution of symptoms. 
• Confirmed not to carry SARS-Cov-2. 
– 
X 
X 
19） Patients found to have close contacts with COVID-19 patients 
within 14 days before the day of study treatment initiation 
– 
– 
X 
20） Other patients who are considered ineligible for the study by 
the investigator 
X 
X 
X 

29 
limit of body weight was set to ensure the safety of participants so that the 
exposure does not exceed that at the maximum dose (2.0 mg/kg) confirmed to be 
tolerated after repeated administration of IP. 
12) 
Established considering the impact on the efficacy of the IP and to ensure the 
safety of the participants.  
13) a), b), c) ii), iii), 
v),14) 
Established considering the impact on the efficacy and safety evaluation of the IP. 
The period was considered necessary for washout based on the duration of 
treatment effect and half-live of each drug and therapy. 
13) c), i) 
Established considering the impact on the safety evaluation of the IP. The period 
was considered necessary for washout based on the duration of treatment effect 
and half-live of each drug 
13) c), iv) 
Established considering the impact on the efficacy evaluation of the IP. The period 
was considered necessary for washout based on the duration of treatment effect 
and half-live of each therapy. 
16) 
 
1) Established to exclude patients ineligible for this study 
2) Established to exclude the impact on the evaluation of efficacy and safety 
20) 
Established as a general criterion to exclude patients considered ineligible for this 
study by the investigator or subinvestigator. 
 
5.  Study Discontinuation of Individual Participants 
The investigator or subinvestigator will withdraw the participant signing informed consent from the study 
and take appropriate measures if participant meets any of the following discontinuation criteria before 
observation/tests at Visit 17 (Week 52). Even if the participant requests withdrawal from the study, the 
participant’s data will be used. 
 
 Discontinuation criteria 
1） Use of other antibody drugs by Week 52 visit 
2） Use of live vaccines by Week 52 visit 
3） The investigator or subinvestigator determined that an adverse event which would prevent the 
continuation of the study has occurred. 
4） The participant is found to fail to meet any of the inclusion criteria or to meet any of the exclusion 
criteria. 
5） The participant is found to be pregnant. 
6） The investigator or subinvestigator has determined that the participant should be withdrawn from the 
study due to inadequate response to the IP. 
7） The participant requests to withdraw from the study. 
8） The participant no longer visits the medical institution, and the study cannot be continued 
9） The participant has died. 
10） The sponsor has determined the participant discontinuation from the study due to significant protocol 
deviations. 
The sponsor has prematurely terminated the study. 
The investigator or subinvestigator has determined to withdraw the participant from the study for any other 
reasons. 
 
 Rationale for discontinuation criteria 
1) to 3), 5) 
Established considering the safety of the participants 
4) 
Established because the participants are considered ineligible for the study 
6) 
Established to reduce disadvantages for the participants 

30 
7) 
Established because it is considered the rights of participants 
8) to 11) 
Established for contingencies 
12) 
Established to allow participant discontinuation from the study at the discretion of the 
investigator or subinvestigator. 
 
 Procedure for Discontinuation 
5.2.1  Discontinuation before Enrollment 
1） For the participant not led to enrollment because of not satisfying the inclusion criteria, meeting any of 
the exclusion criteria or other reasons, the investigator or subinvestigator will explain the reason to 
withdraw the participant from the study, take appropriate action for the participant. The investigator or 
subinvestigator will ascertain and record the date of discontinuation and the reason for discontinuation 
in the source documents. A visit for discontinuation and observation/tests scheduled on the day of visit 
for discontinuation will not be performed. 
2） The investigator, subinvestigator, or CRC will record the data for the items described in Section 19.1.2 
in the CRF. 
 
5.2.2  Discontinuation after Enrollment 
1） The investigator or subinvestigator will explain the reason to withdraw the participant from the study 
and take appropriate action, ascertain and record the reason for discontinuation in the source documents. 
2） The investigator or subinvestigator will perform the observation/tests scheduled on the day of visit for 
discontinuation. When determining to discontinue the study on a day other than the day of the visit, the 
investigator or subinvestigator will instruct the participant to come to the study site as early as possible. 
However, if the day of visit for discontinuation is on or after 77 days from the last dose of study treatment.  
3） The investigator, subinvestigator, or CRC will record the data of the items described in Section 19.1.1 in 
the CRF. 
 
 Handling of Participants Who Fail to Visit the Study Site 
5.3.1  Participants Discontinuing Study Site Visit Between the Day of Informed Consent and the 
Day of Enrollment 
When a participant discontinues visiting the study site after the day of informed consent but before enrollment, 
the investigator or subinvestigator will perform follow-up of the participant through contact with him/her by 
telephone, letter or other means to record the method and the result of follow-up, reason(s) for not visiting 
with the date of such information obtained, presence or absence of adverse events, and other information 
obtained in the source document.  
 
5.3.2  Participants Discontinuing Study Site Visit in the Period after the Enrollment up to Visit 17 
(Week 52) 
If a participant discontinues visiting the study site after assigned to treatment, the investigator or 
subinvestigator will identify the whereabouts of the participant as far as possible and encourage him/her to 
visit the study site. If the participant dose not visit the study site, the investigator or subinvestigator will 
perform follow-up of the participant through contact with him/her by telephone, letter, or other means to 
document the method of follow-up, reason(s) for not visiting with the date of such information obtained, 
presence or absence of adverse events, and other information obtained. 
 
5.3.3  Participants Discontinuing Study Site Visit during the Follow-up Period 
The participant who cannot visit the study site within the window of the follow-up visit will be encouraged 
to visit the study site on the nearest day to the window. If the participant does not visit the study site, the 
investigator or subinvestigator will perform follow up of the participant through contact with him/her by 
telephone, letter, and other means to document the method of follow-up, reason(s) for not visiting with the 

31 
date of such information obtained, the presence or absence of adverse events, and other information obtained. 
 
6. Participant Enrollment 
 Informed Consent 
The investigator or subinvestigator will fully explain the study to participants who are considered eligible for 
the study and obtain written consent before the procedures for the study (see Section 27.4 for the method and 
points to note for obtaining informed consent).  
The investigator or subinvestigator will record the participant information on the participant screening log 
and provide the participant identification code. The participant identification will be AF001-XXX and will 
be coded in order of informed consent acquisition. Each participant will use the same participant 
identification code from informed consent to completion of the study. 
 
 Notification when the Participant is Treated by Another Doctor 
The investigator or subinvestigator will ask participants whether or not they are being treated by another 
doctor. When a participant is being treated by another doctor, the investigator or subinvestigator will notify 
the doctor of his/her participation in the study after obtaining his/her consent. In addition, the investigator or 
subinvestigator will record this notification to the doctor in the medical record, etc. 
 
 Enrollment Procedure of Participants 
1） For first and second registration. 
For participants considered eligible for the study on the day of screening and on the day of study 
treatment initiation, the investigator or subinvestigator will enter the necessary information in the 
source documents, and then fill out a registration form and fax it to the sponsor. The registration form 
should be filled out and faxed after the source documents have been prepared, which can be performed 
by the CRC. 
 
2） For discontinuation before assigned to treatment 
For participants discontinued from the study after informed consent but before second registration, the 
investigator or subinvestigator will enter the necessary information in the source documents, and then 
fill out a registration form and fax it to the sponsor. The registration form should be filled out and 
faxed after the source documents have been prepared, which can be performed by the CRC. 
 
3） Correction of entries in the source documents 
When an error is found in the information registered, the investigator or subinvestigator will correct 
the data in the source document and enter the necessary information in a registration form as needed, 
and then fax it to the sponsor to correct such data. The registration form should be filled out and faxed 
after the source documents have been corrected, which can be performed by the CRC. 
 
7. Investigational Product 
 Name, Dosage Form, and Strength of the IP 
Name, dosage form, and strength of the IPs are indicated in Table 7-1. 
 
 
 

32 
Table 7-1  Name, dosage form and strength of investigational product 
Name of 
investigational 
product 
Formulation 
Active ingredient and strength 
(Per DCS) 
Storage condition 
(Before preparation) 
Nemolizumab 
Injection 
(DCS) 
nemolizumab 75 mg (lyophilized) 
Nemolizumab is overfilled to ensure injectable 
nemolizumab 60 mg from one DCS in 
consideration of the loss of the prepared drug 
solution during administration. The active 
ingredient level after preparation is 100 
mg/mL. 
2°C to 8°C 
Protection from light 
 
 Packaging and Labeling 
7.2.1  Packaging 
One DCS of the IP is contained in a small box. 
 
7.2.2  Labeling 
The small box is labeled with a statement for clinical study use only, the name and address of the sponsor, 
identification number, lot number, and storage method. 
 
 Storage and Management of Investigational Products 
The investigational product manager at each study site will store and manage the IPs according to the 
“Operating Procedure for Investigational Product Management” prepared by the sponsor and other 
procedures specified at each site. 
 
8. Treatment Method 
 Dispensing of Investigational Products 
The investigator or subinvestigator will dispense one DCS of the IP at the following visits: 
<Dispensing visits> 
Day of study treatment initiation, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 
 
 Preparation of Investigational Products 
The investigator or subinvestigator, the investigational product manager or the person in charge of preparation 
of the IP will prepare injection solutions of IPs according to the “Standard Operating Procedure for 
Investigational Product Management.”  
 
 Method of Administration 
On the days of administration (see Table 9-1: Schedule), the investigator or subinvestigator will 
subcutaneously inject one DCS (0.6-mL) of nemolizumab slowly to the participant either in the upper arm, 
abdomen, or thigh. The IP may be administered by a person qualified to administer it under the instruction 
of the investigator or subinvestigator. 
 
 Precautions 
- 
The IP will be administered after all observation/tests scheduled at the visit have been completed. 
- 
The IP will be administered within the window of the specified visit. However, if the IP cannot be 
administered within the window, the next dose should be administered 14 days or later after the 

33 
previous dose. 
- 
If the participant’s body weight is lower than 30.0 kg on the day of administration, the IP must not 
be administered. 
 
 Rationale for selection> 
1） Dosage: 60 mg/body Q4W 
A phase III study in Japanese patients with atopic dermatitis has demonstrated the long-term safety of 
nemolizumab 60 mg/body Q4W. This study has been designed to exploratorily evaluate the efficacy of 
nemolizumab in SSc patients at 60 mg/body Q4W which has shown the long-term efficacy in SSc 
patients.  
 
2） Treatment Period 
The treatment period has been set at 52 weeks because long-term observation is required to evaluate the 
efficacy of nemolizumab on skin thickening in SSc patients in an exploratory manner. 
 
3） Day of Follow-up Visit 
Considering the serum elimination half-life after a single dose of nemolizumab ranges from 12.6 to 
14.6 days in patients with atopic dermatitis, the day of follow-up visit has been set to collect 
information such as the occurrence of adverse events on the day of 5 times the elimination half-life 
(84 days ± 7 days) from the day of the last dose. 
 
 Concomitant Medications and Therapies 
8.4.1  Restricted Concomitant Medications 
The following medications may be continued at a stable dose if used for at least 14 days before the day of 
study treatment initiation. However, the dose may be reduced at the discretion of the investigator or 
subinvestigator, and after dose reduction, the dose may be increased up to that used at the day of study 
treatment initiation. 
•Oral steroids (≤ 10 mg/day of prednisolone or equivalent) 
 
8.4.2  Duration and Method of Inspection 
The investigator or subinvestigator will collect the information of concomitant medications/therapies by 
interviewing participants according to Section.9.3.2  
 
8.4.3  Prohibited Concomitant Medications and Therapies 
Concomitant use of medications and therapies listed below is prohibited in this study.  
- 
From the day of study treatment initiation to Week 52 or to the physical examination on the day of visit 
for discontinuation 
1） The following systemic medications: 
a） Antifibrotic drugs (e.g., pirfenidone, nintedanib) 
b） Immunosuppressants 
(e.g., 
cyclophosphamide, 
cyclosporine, 
tacrolimus, 
azathioprine, 
mycophenolate mofetil, mizoribine, sulfasalazine, leflunomide, methotrexate, hydroxychloroquine, 
D-penicillamine, sirolimus) 
c） Tyrosine kinase inhibitors (e.g., imatinib) 
d） JAK inhibitors (e.g., tofacitinib, upadacitinib) 
e） Endothelin receptor agonists (e.g., bosentan, ambrisentan, macitentan) 
f） Phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil) 

34 
g） Prostaglandin analogues (e.g., alprostadil, epoprostenol) 
h） Riociguat 
2） Injections of corticosteroids (excluding joint injections) 
3） Phototherapy 
4） High-dose intravenous immunoglobulin therapy 
5） Antibody drugs 
6） Live vaccines 
 
 Rationale for selection 
1) 2) 4) 5) 
Established considering the impact on the efficacy of the IP and the safety of participants 
3)  
Established considering the impact on the efficacy evaluation of the IP 
6) 
Established considering the safety of participants 
 
- 
From the day of study treatment initiation to the day of follow-up visit 
1） Other drugs and medical devices under development 
 
 Rationale for selection 
1)  
Established considering the safety of participants and the impact on the efficacy of the IP. 
 
8.4.4  Instructions to participants 
The investigator or subinvestigator will examine the implementation status of the treatment of SSc at each 
visit and give instructions to the participants on treatment of SSc according to the therapeutic guidance 
specified in Sections 8.4.1 and 8.4.3.

38 
e Not to be performed if refused by the participant. 
If any of the following treatment-emergent adverse events occurs, photographs of the affected skin areas of the adverse event should be taken while the event (at least once) is 
occurring and at the final outcome evaluation, in addition to the scheduled visit (i.e., the day of study treatment initiation). The photography on the scheduled visit (day of study 
treatment initiation) will be performed according to Section 9.3.5.4  
• Atopic dermatitis 
• Adverse events with skin symptoms of edematous erythema or scaling 
• Any other adverse event for which the investigator or subinvestigator considers that photography is necessary. 
f To be performed on female participants excluding those who never become pregnant. 
g May be conducted on another day after the day of screening before the day of study treatment initiation 
h • Hepatitis B 
The participants who test negative for HBs antigen and positive for HBc antibody will undergo HBV-DNA measurement before the day of study treatment initiation. The participants 
enrolled through HBV-DNA measurement will undergo HBV-DNA measurement once every three months. 
• Hepatitis C 
The participants who test positive for anti-HCV antibody will undergo HCV-RNA measurement before the day of study treatment initiation. The participants enrolled through HCV-
RNA measurement will undergo HCV-RNA measurement once every three months. 
i To be administered after all observation/tests are performed. If the IP cannot be administered within the window indicated, the next dose should be administered 14 days or later 
after the day of the previous dose. 
j Participants who discontinued the study will visit the site 84 days (±7 days) after the day of the last dose of study treatment for observation/tests at FU shown in Table 4-1. Participants 
discontinued the study before study treatment initiation need not to undergo observation/tests scheduled on the day of visit for discontinuation. 

39 
 Definition of the Days of Observation, Tests, and Sample Collection 
The days of observation, tests, and sample collection will be defined as follows. Table 9-1 shows the visit 
window of the assessment day. 
 
9.2.1  Day of Informed Consent 
The day when informed consent is obtained from the participant is defined as the day of informed consent.  
 
9.2.2  Day of screening 
The day of screening is defined as the day of first registration after completion of protocol-specified 
assessments. The day of informed consent may be the same day as the day of screening. 
All observation/tests scheduled for the day of screening must be performed on the same day. The tuberculosis 
test may be performed after the day of screening; however, the test result should be reviewed before the day 
of study treatment initiation. 
 
9.2.3  Day of Study Treatment Initiation 
The day of study treatment initiation is defined as the day when the participant is enrolled after completion 
of protocol-specified assessments. All assessments scheduled for the day of study treatment initiation must 
be performed on the same day. 
The day of study treatment initiation is Day 1, and the day before the day of study treatment initiation is Day 
-1. 
 
9.2.4  Day of Assessment (Weeks 1, 2, 4, 8, 12, through 52) 
Week 1 through Week 52 are days when participants visit the study site for protocol-specified 
observation/tests. 
 
9.2.5  Day of Study Treatment 
The day of study treatment is defined as the day when the IP is administered to the participant according to 
the schedule of Table 9-1 after the protocol-specified assessments are implemented. 
 
9.2.6  Day of Discontinuation 
The day of discontinuation is defined as the day when the investigator or subinvestigator determines to 
withdraw the participant from the study. 
 
9.2.7  Day of Discontinuation Visit 
The day of visit for discontinuation is defined as the day when the protocol-specified observation/tests 
scheduled for discontinuation are performed for the participant who is determined to be withdrawn from the 
study after study treatment initiation and visit the study site for the procedure. 
 
9.2.8  Day of Follow-up Visit  
The day of follow-up visit is defined as the day when the protocol-specified observation/tests are performed 
for the participant who visits the study site 84 days (±7 days) after the day of the last dose of study treatment. 
 
 Observation, Tests and Sample Collection  
9.3.1  Participant Demographics 
The investigator or subinvestigator will perform following assessments on the day of informed consent, the 
day of screening and the day of study treatment initiation. 

40 
1） Assessments on the day of informed consent 
 
Primary disease (diagnosis) 
 
Time of onset of primary disease 
 
Classification of primary disease (diffuse cutaneous SSc [dcSSc] or limited cutaneous SSc 
[lcSSc]) 
 
Main therapy given for SSc in the past 
 
Date of birth 
 
Sex 
 
Complication (any disease which is ongoing at the time of informed consent) 
 
Race 
 
Inclusion and exclusion criteria (see “4. Target Indication and Inclusion and Exclusion Criteria 
for Participants”) 
 
2） Assessments on the day of screening 
 
Inclusion and exclusion criteria (see “4. Target Indication and Inclusion and Exclusion Criteria 
for Participants”) 
 
Height 
 
3） Assessments on the day of study treatment initiation 
 
Inclusion and exclusion criteria (see “4. Target Indication and Inclusion and Exclusion Criteria 
for Participants”) 
 
9.3.2  Prior and Concomitant Medications and Therapies 
9.3.2.1  Prior and concomitant medications 
The investigator or subinvestigator will review the following medications for each participant: 
1） Medications intended to treat SSc 
 
Used from 28 days before the day of study treatment initiation to the physical examination at the 
follow-up visit 
2） Medications intended to treat adverse events 
a） Medications intended to treat adverse events of special interest defined in Section 11.6 : 
Used from the day of study treatment initiation (after initiating study treatment) to the final 
outcome evaluation. 
b） Medications intended to treat adverse events except for 1): 
Used from the day of study treatment initiation (after initiating study treatment) to the physical 
examination at the follow-up visit.  
3） All concomitant medications other than 1), and 2) 
 
Used from the day of study treatment initiation (after initiating study treatment) to Week 52 or 
the day of discontinuation visit. 
 
Information to be 
obtained 
Presence or absence of concomitant medications, and the drug name, dosage, drug 
use classification, start and end dates of use, and indication for use of each 
concomitant medication 
Notes 
The following information is not required to be collected: 
 Diagnostic agents, infusions, fluid replacement, nutritional agents, disinfectants, 
anesthetics for surgery, laxatives and suppository for barium examination (unless 
these drugs were used for treatment or are included in the prohibited concomitant 
medications) 
 Dosage of 3)  
 Among medications of 1), those newly used in participants who discontinued 

41 
from the study on or after the physical examination at the discontinuation visit. 
 
9.3.2.2  Prior and concomitant therapies 
The investigator or subinvestigator will collect the data of the following therapies: 
1） Therapies to treat SSc 
 
Performed from 28 days before the day of study treatment initiation to the physical examination 
at the follow-up visit. 
2） Concomitant therapies intended to treat adverse events 
a） Concomitant therapies intended to treat adverse events of special interest defined in Section 11.6  
 
Performed from the day of study treatment initiation (after initiating study treatment) to the final 
outcome evaluation. 
b） Concomitant therapies intended to treat adverse events except for 1) 
 
Performed from the day of study treatment initiation (after initiating study treatment) to the 
physical examination at the follow-up visit.  
c） Prohibited concomitant therapies 
 
Performed from the day of study treatment initiation (after initiating study treatment) to Week 52 
or the day of discontinuation visit. 
 
Information to 
be obtained 
Presence or absence of therapy, and the name of therapy, site to which concomitant 
therapy is applied, start and end dates of application and purpose of use of concomitant 
therapy  
Notes 
Among therapies of 1), those newly performed to participants who discontinued from 
the study on or after the physical examination at the discontinuation visit are not 
required. 
 
9.3.3  Body Weight 
The investigator or subinvestigator will measure the body weight of participants at the following timepoints: 
Data to be 
obtained 
Body weight 
Time points 
Day of screening, Day of study treatment initiation, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44 and 48  
Notes 
 On the days of study treatment, measurement will be performed, and the results will be 
reviewed before administration of IP. 
 Participants weighing less than 30.0 kg on the day of study treatment are not allowed 
to receive study treatment. 
 
9.3.4  Efficacy Evaluation 
9.3.4.1  Evaluation of Skin Findings 
The investigator or subinvestigator will perform the following assessments: 
Assessment 
mRSS  
Time points 
Day of screening, Day of study treatment initiation, Week 4, 12, 24, and 36, Week 52 or 
Day of discontinuation visit, Day of follow-up visit 
Notes 
 On the day of study treatment, assessment will be performed before the treatment. 
 mRSS assessment will be performed by a skilled physician experienced in scoring skin 
sclerosis. 
 In principle, the same investigator or subinvestigator will perform assessment 
throughout the study period for each participant in order to minimize inter-assessor 
variability. 

42 
 
9.3.4.2  Respiratory function test 
Spirometry will be performed according to the separately specified procedure. 
Assessment 
 
Forced vital capacity (FVC) and %FVC 
 
Diffusing capacity of lung for carbon monoxide (DLco) and % DLco 
 
Total lung capacity (TLC) and forced expiratory volume in one second (FEV1) 
Time points 
Day of screening, Week 12, and 24, Week 52 or Day of discontinuation visit 
Notes 
 
If the %FVC decreases by ≥ 15% from baseline, %FVC will be measured again 
within 1 month to examine whether the %FVC decreases by ≥ 15% from baseline or 
not. 
 
9.3.4.3  Chest HRCT 
HRCT will be performed according to the regulations or procedures or the test manual of the study site. 
Time points 
 
Day of screening, Week 24, Week 52 or Day of discontinuation visit 
Notes 
If having been performed within 1 month of the specified timepoint, it is not necessary to 
be performed at the specified timepoints, and the results within 1 month will be 
substituted. 
 
9.3.4.4  Severity of pulmonary lesions 
The investigator or subinvestigator will evaluate the severity of pulmonary lesions based on the results of 
respiratory function test and chest HRCT according to 10.1.4 . 
Time points 
Day of screening, Week 24, Week 52 or Day of discontinuation visit 
 
9.3.4.5  ACR-CRISS 
The investigator or subinvestigator will assess whether the participant fall under the following criteria: 
Evaluations 
 
Onset of scleroderma renal crisis 
 
Interstitial lung disease with a decline in %FVC ≥15% (requiring reconfirmation 
within 1 month), and %FVC of 80% or less 
 
Onset of left ventricular failure requiring treatment (defined as left ventricular 
ejection fraction ≤45%) * 
 
Onset of pulmonary arterial hypertension requiring right heart catheterization * 
*Caused by SSc 
Time points 
Week 12 and 24, Week 52 or Day of discontinuation visit 
 
9.3.4.6  The Number of Digital Ulcers 
The investigator or subinvestigator will count the number of digital ulcers. 
 
Time points 
 
Day of screening, Day of study treatment initiation, Week 12, 24 and 36, Week 52 
or Day of discontinuation visit 
Notes 
 
In principle, the same investigator or subinvestigator will perform assessment 
throughout the study period for each participant in order to minimize inter-assessor 
variability. 
 
 
 

43 
9.3.4.7  Patient-reported outcome 
The participants will perform the following assessments: 
Evaluations 
HAQ-DI, FACIT-Fatigue and FSSG 
Time points 
Day of study treatment initiation, Week 12, 24, and 36, Week 52 or Day of discontinuation 
visit 
Notes 
 
The participants will perform each assessment before receiving the examination and 
evaluation by the physician at the above visits. 
 
The investigator or subinvestigator must not attend the assessments by the 
participants. 
 
9.3.4.8  Global improvement rating 
9.3.4.8.1  Patient’s Global Assessment (PtGA) 
The participants will assess the overall condition of SSc using a visual analog scale (VAS). 
 
Time points 
Day of study treatment initiation, Week 12, 24, and 36, Week 52 or Day of discontinuation 
visit 
Notes 
 
The participants will perform each assessment before receiving the examination and 
evaluation by the physician at the above visits. 
 
The investigator or subinvestigator must not attend the assessments by the 
participants. 
 
9.3.4.8.2  Physician’s Global Assessment (PGA) 
The investigator or subinvestigator will assess the overall condition of SSc of each participant using a VAS. 
 
Time points 
Day of study treatment initiation, Week 12, 24, and 36, Week 52 or Day of discontinuation 
visit 
Notes 
 
In principle, the same investigator or subinvestigator will perform assessment 
throughout the study period for each participant in order to minimize inter-assessor 
variability. 
 
9.3.5  Safety Evaluation 
9.3.5.1  Vital signs 
The investigator or subinvestigator will perform the following measurements: 
Measurements Body temperature, pulse rate, and blood pressure (systolic/diastolic) 
Time points 
Day of screening, Day of study treatment initiation, Week 1, 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44 and 48, Week 52 or Day of discontinuation visit, Day of follow-up visit 
Notes 
 On the day of study treatment, measurements will be performed, and the results will 
be reviewed before the treatment.  
 The vital signs will be measured at rest in the sitting position. 
 
9.3.5.2  ECG 
The investigator or subinvestigator will perform the following measurements: 
Measurements PR interval, QRS interval, QT interval, heart rate and presence or absence of 
abnormalities 
Time points 
Day of screening, Week 24, Week 52 or Day of discontinuation visit 

44 
Notes 
 
On the day of study treatment, measurements will be performed, and the results will 
be reviewed before the treatment. 
 
The same electrocardiograph will be used for each participant at each measurement 
whenever possible. 
 
ECG will be performed at rest in the supine position.  
 
9.3.5.3  Echocardiography 
Echocardiography will be performed according to the regulations, procedures, or the test manual of the study 
site. 
Time points 
Day of screening, Week 24, Week 52 or Day of discontinuation visit 
Notes 
 
On the day of study treatment, measurements will be performed, and the results 
will be reviewed before the treatment.  
 
9.3.5.4  Photography 
The investigator or subinvestigator will perform photography according to the separately specified procedure. 
Sites to be 
Photographed 
1） Anterior and dorsal views of the upper body (excluding the face)  
2） Skin appearance of adverse events 
Time points 
1） Day of study treatment initiation 
2） Duration of the following adverse events (at least once occurrence) after study 
treatment initiation and at the final outcome evaluation: 
 
Atopic dermatitis 
 
Adverse events with skin symptoms accompanied by edematous erythema 
or scaling 
 
Any other adverse event for which the investigator or subinvestigator 
considers that photography is necessary. 
Notes 
 1) and 2): 
 
The photos will be retained by the study site and collected by the sponsor. 
When personal information can be identified from the photos, the photos must 
be collected with the personal information being masked. 
 
Photography will not be performed if refused by the participant. 
 
9.3.6  Laboratory tests 
Laboratory tests will be performed at the central laboratory. The investigator or subinvestigator will collect 
blood and urine samples from participants before study treatment initiation and submit them to the central 
laboratory. Tuberculosis test may be performed in an in-hospital laboratory. 
1） Hematology and serum chemistry tests 
2） Immunological tests (thymus and activation-regulated chemokines [TARC]) 
3） Urinalysis 
Time points 
Day of screening, Day of study treatment initiation, Week 1, 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44 and 48, Week 52 or Day of discontinuation visit, Day of follow-up visit 
Notes 
1) 2) and 3): 
 
On the day of study treatment, blood and urine will be collected before the treatment. 
 
The test result should be reviewed before the next study treatment. 
1) and 2): 
 
When aggregation or coagulation is observed in “Plt” because of a reason other than 
manual technique, blood will be collected into a blood collecting tube containing 
3.2% sodium citrate in addition to a conventional blood collection tube from the next 
visit. 
 
 

45 
4） Pregnancy test 
Time points 
Day of screening 
Notes 
 
The test will be performed on female participants. However, those who are 
considered unable to become pregnant (e.g., menopausal women* and women who 
have had total hysterectomy) will be excluded. 
*: Defined as those who are amenorrhea for at least 12 months without any medical 
reason. 
 
5） Tuberculosis test 
Time points 
Day of screening 
Notes 
 
If the test cannot be performed on the day of screening, it may be performed on 
another day after the day of screening but before study treatment initiation. In such 
cases, the rest results should be reviewed before administration of IP on the day of 
study treatment initiation. 
 
6） Hepatitis B and C tests 
Time points 
a） Day of screening 
b） Week 12, 24, 36 and 48, Day of follow-up visit 
Notes 
a） The participants who test negative for HBs antigen and positive for HBc antibody 
on the day of screening will undergo HBV-DNA measurement before the day of 
study treatment initiation. The participants who test positive for anti-HCV antibody 
on the day of screening will undergo HCV-RNA measurement before the day of 
study treatment initiation. 
b） The participants enrolled through HBV-DNA measurement before the day of study 
treatment initiation will undergo HBV-DNA measurement once every three months. 
The participants enrolled through HCV-RNA measurement before the day of study 
treatment initiation will undergo HCV-RNA measurement once every three months. 
 
7） Antinuclear antibodies test 
Time points 
Day of study treatment initiation 
Notes 
 
Blood will be collected before administration of IP on the day of study treatment 
initiation 
 
 
 

47 
On the day of study treatment, blood will be collected before the treatment 
 
9.3.10  Comprehensive measurement of autoantibodies 
The investigator or subinvestigator will collect blood samples for comprehensive measurement of 
autoantibodies. The measurement will be performed centrally. 
Time points 
Day of study treatment initiation, Week 24, Week 52 or Day of discontinuation visit 
Notes 
 
On the day of study treatment, blood will be collected before the treatment. 
 
9.3.11  CyTOF measurement 
The investigator or subinvestigator will collect blood samples for central measurement of CyTOF. 
Time points 
Day of study treatment initiation, Week 24, Week 52 or Day of discontinuation visit 
Notes 
 
On the day of study treatment, blood will be collected before the treatment. 
 
9.3.12  Assessment of Adverse Events 
The investigator or sub-investigator will assess the adverse events according to the procedure described in 
“11.4 Review and reporting of adverse events.” 
 
9.3.13  Investigation of Malfunction of DCS 
The investigator or subinvestigator will investigate malfunction of DCS according to "11.11 Malfunctions 
of DCS.”  

50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 10-1  Severity classification of lung lesion 
 
10.1.5  ACR-CRISS 
ACR-CRISS is a composite outcome measure that is calculated as an index taking a value ranging from 0 to 
1 for the probability of improving for participants based on the presence or absence of renal, pulmonary, and 
cardiac impairments and changes in the 5 core set items (mRSS, %FVC, PGA, PtGA, and HAQ-DI). 
Participants are considered improved and not improved when their ACR-CRISS is ≥ 0.6 and < 0.6, 
respectively. If participants meet any of the following criteria, the probability of improving is 0.0. The 
investigator or subinvestigator will assess whether participants met or not met the following criteria at 
specified visits. If patients do not meet any of the following criteria, an ACR-CRISS score will be calculated 
using the formula shown in 17.3.2 2). 
• Onset of scleroderma renal crisis 
• Decline in FVC% ≥15% (requiring reevaluation within 1 month), and %FVC of 80% or less 
• Onset of left ventricular failure requiring treatment (defined as left ventricular ejection fraction 
≤45%) * 
• Onset of pulmonary arterial hypertension requiring right heart catheterization * 
* Caused by SSc  
 
10.1.6  The Number of Digital Ulcers 
The investigator or subinvestigator will count the number of digital ulcers. 
 
10.1.7  Patient-reported outcome 
1） HAQ-DI  
Findings compatible with interstitial lung disease on 
chest HRCT 
Extent of any interstitial lung disease lesions on 
chest HRCT 
Forced vital capacity (FVC) predicted 
Requirement of oxygen supplementation  
Yes 
>20% 
<70% 
No 
0 (normal) 
≤ 20% 
1 (mild) 
≥ 70% 
2 (moderate) 
No 
3 (severe) 
Yes 
4 (very severe) 

51 
Participants will assess the degree of their difficulty in performing actions of eight functional categories 
(dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities) using HAQ-DI 
(Health assessment questionnaire disability index, Japanese version)9) on a 4-point scale of 0 (Without any 
difficulty), 1 (Without some difficulty), 2 (Without much difficulty), and 3 (Unable to do). 
 
2） FACIT-Fatigue 
Participants will assess their fatigue over the past 7 days using FACIT-Fatigue Scale, Japanese version 
10) on a 5-point scale from 0 (not at all) to 4 (very much). 
 
3） FSSG. 
Participants will assess their gastroesophageal reflux disease using Frequency Scale for the Symptoms 
of GERD (FSSG) 11) on a 5-point scale from 0 (never) to 4 (always). 
 
10.1.8  Global improvement rating 
1） PtGA 
Participants will assess their general health status associated with SSc at visit using a 10-cm visual 
analog scale (VAS) from 0 (the best status) to 10 (the worst status) 12). The investigator or 
subinvestigator or the clinical trial collaborator will measure the length (cm) from the left end to the 
first decimal place and record it. 
 
2）  PGA 
The investigator or subinvestigator will assess participants’ general health status associated with SSc 
in terms of Severity, Damage, and Overall disease using a 10-cm VAS from 0 (the best status) to 10 
(the worst status) 12). The investigator (or subinvestigator) or the clinical trial collaborator will measure 
and record the length (cm) from the left end to the first decimal place. 
 
 Efficacy Endpoints 
10.2.1  Primary Endpoint  
Change from baseline in mRSS at Week 24 
 
10.2.2  Other Endpoints 
1） Change from baseline in mRSS at Week 52 
2） Change from baseline in HAQ-DI at Week 52 
3） Change from baseline in HAQ-DI at Week 24 
4） Change from baseline in %FVC at Week 52 
5） Change from baseline in %FVC at Week 24 
6） Change from baseline in DLco at Week 52 
7） Change from baseline in DLco at Week 24 
8） Change from baseline in PGA at Week 52 
9） Change from baseline in PGA at Week 24 
10） Change from baseline in PtGA at Week 52 
11） Change from baseline in PtGA at Week 24 
12） ACR-CRISS at Week 52 
13） ACR-CRISS at Week 24 
14） Change from baseline in the number of digital ulcers at Week 52 

52 
15） Change from baseline in the number of digital ulcers at Week 24 
16） Time-course changes in the following parameters: 
a） HAQ-DI 
b） FACIT-Fatigue 
c） FSSG 
d） FVC 
e） %FVC 
f） DLco 
g） %DLco 
h） TLC 
i） FEV1 
j） Severity assessment of lung lesion 
k） PGA 
l） PtGA 
m） ACR-CRISS 
n） The number of digital ulcers 
 
 Rationale for Efficacy Endpoints 
1） mRSS 
mRSS is used internationally to assess severity of SSc13), 14). Moreover, mRSS is generally considered 
to be correlated with visceral involvement, etc. and change over a relatively short period of time by 
receiving treatment, etc. Therefore, change from baseline in mRSS at Week 24 has been selected as 
primary endpoint to evaluate the efficacy of this drug on SSc. Since SSc has a chronic course, change 
from baseline in mRSS at Week 52 has been also selected as an efficacy endpoint to discuss the clinical 
significance of this drug. 
 
2） Respiratory Function Test 
FVC in respiratory function tests has been shown to be a useful indicator for predicting vital prognosis 
in interstitial lung disease associated with SSc15) . %FVC and %DLco are useful parameters for 
screening pulmonary hypertension associated with SSc16). Therefore, this test has been selected to 
evaluate the efficacy of this drug on lung lesion in an exploratory manner and to ensure the safety of 
participants. 
 
3） Chest HRCT 
Interstitial lung disease in SSc patients has been reported to be detected 50% to 60% by HRCT17). 
Interstitial lung disease is the most common cause of death in SSc patients18). Interstitial lung disease 
often occurs from the early stage of SSc, and therefore, it is useful to predict prognosis and determine 
whether the treatment is feasible for the patient. Moreover, the guidelines recommend to predict the 
risk of progression to end-stage pulmonary disease and determine whether the treatment is feasible for 
the patient by the fibrotic finding in HRCT and the extent of the lesion or of the entire lesion in 
conjunction with FVC-predicted values in respiratory function tests7). Based on the above, this test has 
been selected to evaluate the efficacy of this drug on lung lesion in an exploratory manner and to 
ensure the safety of participants. 
 
4） Severity Classification of Lung Lesion  

53 
The Guidelines for Diagnostic Criteria, Severity Classification and Clinical Practice of Systemic 
Sclerosis recommend to predict the risk of progression to end-stage pulmonary disease and determine 
whether the treatment is feasible for the patient by the fibrotic finding in HRCT, the extent of the lesion 
or of the entire lesion and FVC predictive value in respiratory function tests7). This parameter has been 
selected to evaluate the efficacy of this drug on lung lesion in an exploratory manner and to ensure the 
safety of participants. 
 
5） ACR-CRISS 
ACR-CRISS is a composite response index for clinical trials in early diffuse cutaneous SSc 19), which 
is generally used in clinical trials in SSc patients. This index has been selected to evaluate the efficacy 
of this drug on SSc in an exploratory manner. 
 
6） The number of digital ulcers 
Ulcers of the fingers and toes are complications of vascular disorder, one of the conditions of SSc, 
which occur frequently (35-60%) and arise from the early stage of the disease; therefore, they are 
considered to reflect the condition of SSc. Moreover, the ulcers are often refractory and recurrent, 
which is directly related to participants’ activities of daily living (ADL) and decreased QOL. 
Accordingly, this parameter has been selected to evaluate the efficacy of this drug on SSc in an 
exploratory manner. 
 
7） HAQ-DI 
HAQ is a convenient self-administered questionnaire assessing physical function for activities of daily 
living. It was originally developed to evaluate the effect of rheumatoid arthritis on activities of daily 
living; however, it has been reported that HAQ-DI correlates with the degree of skin thickening, 
cardiac involvement, renal involvement, etc., also in SSc20). Moreover, along with mRSS, it is a widely 
used standard method to evaluate SSc. Based on the above, HAQ-DI has been selected to evaluate the 
efficacy of this drug on SSc in an exploratory manner. 
 
8） FACIT-Fatigue 
FACIT-Fatigue is a health-related quality of life that assesses fatigue and its impact on daily activities 
and functions in chronic diseases. Shortness of breath and fatigue occur in interstitial lung disease and 
pulmonary hypertension associated with SSc. FACIT-Fatigue has been proven to be reliable and useful 
in various diseases including SSc10). Thus, FACIT-Fatigue has been selected to evaluate the effects of 
this drug on fatigue and on daily living and functions in SSc, a chronic disease, in an exploratory 
manner. 
 
9） FSSG 
FSSG is a useful questionnaire to objectively assess the symptoms of Japanese participants with 
gastroesophageal reflux disease11). In SSc, esophageal involvement is complicated at a high rate from 
the early stage of the disease, and 80% to 90% of SSc patients have reflux esophagitis 1). Esophageal 
involvements are also associated with the extent and duration of thickening1). Based on the above, 
FSSG has been selected to evaluate the efficacy of this drug on reflux esophagitis in SSc patients in 
an exploratory manner. 
 
10） Global improvement rating (PtGA, PGA) 
Global improvement rating is a widely used method to assess disease activity in clinical trials such as 

54 
in rheumatoid arthritis. This rating has been selected to evaluate the efficacy of this drug on SSc in an 
exploratory manner. 
 
11. Safety Evaluation 
 Assessments for Safety Evaluations 
1） Adverse events 
a） Symptoms and signs 
b） Abnormal laboratory test values 
c） Abnormal vital signs 
d） Abnormal electrocardiograms 
2） Laboratory test values 
3） Vital signs 
4） Electrocardiograms 
5） Echocardiography 
 
  Definition of Adverse Events 
1） Adverse events (AEs) 
An AE in the study will be defined as any undesirable or unexpected sign, symptom, disease, or 
aggravation of an existing condition occurring in a participant who is given an IP on or after the time of 
informed consent regardless of whether there is a causal relationship to the IP. The aggravation of diseases 
or symptoms that have occurred before the time of informed consent are also considered an AE. 
The following events are not considered AE: 
• Events for which medical treatment had been scheduled before the time of informed consent 
• Aggravation of primary disease 
 
2） Serious adverse events (SAEs) 
a） Results in death 
b） Is life-threatening 
c） Requires or prolongs inpatient hospitalization* 
*Excluding the following events; 
 
Any hospitalization that had been scheduled before the time of informed consent (e.g., 
hospitalization for surgeries and detailed examinations) 
 
Any hospitalization for examinations without any treatment (including bed rest treatment). 
d） Results in persistent or significant disability/incapacity 
e） Is a congenital anomaly/birth defect 
f） Is another medically important condition* 
*An important medical event that may not be immediately life-threatening or does not result in 
death or hospitalization but may jeopardize the safety of the patient or may require treatments 
to prevent one of the other outcomes listed in a) to e) above. 
e.g., bronchospasm requiring intensive care at an emergency room, blood dyscrasias or 
convulsions not leading to hospitalization, drug dependence, or drug abuse 
 
3） Adverse events of special interest (AESIs) 
AESIs in this study are defined as the following treatment-emergent events: 
a） AEs requiring discontinuation of study treatment 

55 
b） Injection-related reactions (including local and systemic injection site reactions) 
Injection-related reactions are defined as AEs which develop within 24 hours after administration 
of IP. 
c） Asthma 
d） Atopic dermatitis 
e） Skin symptoms with edematous erythema or scales 
f） Skin infections 
g） Non-skin infections 
h） Suspected infection of infectious pathogen from the IP 
 
 Rationale for selection 
b), c), d),  
f), and g) 
These events should be monitored carefully because of being included in “important 
potential risks” in nemolizumab. 
e) 
These are events of interest closely monitored by the sponsor based on the results of 
clinical studies of nemolizumab in patients with atopic dermatitis 
h) 
The event should be carefully investigated in biological products in general. 
 
 Definitions of Safety Endpoints 
1） Adverse events 
a） Symptoms and signs 
The investigator or subinvestigator will assess symptoms and signs in participants after the time of 
informed consent through the time of physical examination on the day of follow-up visit based on 
interview results and complaints from participants. 
b） Abnormal laboratory test values 
The investigator or subinvestigator will treat laboratory test results collected after the time of 
informed consent through the day of follow-up visit as AEs if the results meet any of the following 
criteria: 
i. 
Accompanied with clinical symptoms 
ii. 
Resulted in any change of study treatment (e.g., interruption or discontinuation of the IP). 
iii. 
Resulted in medical treatment (including change of concomitant medications/therapies). 
iv. 
Considered clinically significant by the investigator or subinvestigator. 
v. 
Total bilirubin is >2-fold the upper limit of the reference value, and ALT or AST is >3-fold the 
upper limit of the reference value 
vi. 
ALT or AST is >3-fold the upper limit of the reference value with clinical jaundice 
 
Individual abnormal changes in laboratory test findings will be reported as individual AEs in 
principle. However, a single abnormal laboratory test finding or two or more abnormal laboratory test 
findings that are related to each other may be reported collectively as a single event under a single 
diagnosis if it is considered appropriate by the investigator or sub-investigator. If individual abnormal 
changes in laboratory test findings are regarded by the investigator or subinvestigator as 
manifestations of a symptom or a sign reported as an AE, the changes may be reported collectively 
with the AE of the symptom or sign. 
Laboratory values may change depending on interindividual factors, such as sex, age, and lifestyle, 
and intraindividual factors, such as diurnal fluctuation, diet, exercise, body positioning, and sexual 
cycle. Therefore, the investigator or subinvestigator will determine whether the change in each 
laboratory test findings is a physiological change or an abnormal change after sufficiently taking into 

56 
consideration the demographics of each participant, such as the underlying disease and complication, 
baseline values, and the changes specific to each participant who have any periodic laboratory test 
before study participation. 
 
c） Abnormal vital signs 
The investigator or subinvestigator will treat measurement results collected after the time of 
informed consent through the day of follow-up visit as AEs if the results meet any of the following 
criteria: 
i. 
Accompanied with clinical symptoms 
ii. 
Resulted in any change of study treatment (e.g., interruption or discontinuation of the IP). 
iii. 
Resulted in medical treatment (including change of concomitant medications/therapies). 
iv. 
Considered clinically significant by the investigator or subinvestigator. 
 
d） Abnormal electrocardiograms 
The investigator or subinvestigator will assess AEs based on the results collected after the time of 
informed consent through the day of follow-up visit  
 
e） Echocardiography 
Echocardiographic images will be assessed for cardiac morphology, cardiac motion and blood flow 
during cardiac contraction and relaxation, and other parameters. The investigator or subinvestigator 
will record the presence or absence of abnormalities in the source documents. 
 
 Review and reporting of adverse events 
The investigator or subinvestigator will assess the items shown in Table 11-1 regarding AEs occurring from 
after obtaining informed consent to the day of follow-up visit and fill the necessary information in the case 
report forms (CRFs). 
The investigator or subinvestigator will report the SAEs according to Section 11.5 and the AESIs according 
to Section 11.6 to the sponsor. The investigator or subinvestigator will promptly report the other AEs to the 
sponsor. 
 
 
 

57 
Table 11-1 Assessments for adverse events 
Assessments 
Details of assessment 
Name of adverse event 
Disease name/symptom, classification of the site of occurrence of adverse events 
Onset date 
Classification of onset date, Onset date 
Action 
on 
investigational 
product 
Treatment discontinuation, Treatment interruption, Dose reduction, No dose change, Not 
applicable, Unknown 
Treatment for the event 
Presence or absence of treatment 
Outcomes and 
Date 
of 
outcome/Date 
of 
outcome obtained 
Recovered/Resolved, 
Recovering/Resolving, 
Not 
Recovered/Not 
Resolved, 
Recovered/Resolved with sequelae, Death, and Unknown 
End date of AE, whether the AE is ongoing or not 
Severity 
Mild 
Transient, requiring minimal treatment and not interfering with daily 
life 
Moderate 
Specified treatments relieve symptoms and do not result in 
permanent or significant disability but interfere with daily life 
Severe 
Significant effect on advanced clinical condition or requiring 
intensive care or no longer allowing daily life. 
Seriousness 
Serious/Non-serious 
 
Definition of serious 
adverse 
events 
in 
Section 13.2 
1. Results in death 
2. Life-threatening 
3. Requires or prolongs inpatient hospitalization 
4. Results in persistent or significant disability/incapacity 
5. Is a congenital anomaly/birth defect 
6. Is another medically important condition 
Causal 
relationship 
with 
investigational product 
Causality classification (according to the following causality classification), and 
rationale 
 
Causality 
classification* 
Not related 
Causal relationship is unlikely because the adverse event has no 
plausible temporal relationship to administration of IP, or the 
event can be explained by another factor.  
The rationale for no causal relationship is required to be described. 
 
 
Related 
Causal relationship is presumed because there is a plausible 
temporal relationship between the onset of the adverse event and 
administration of investigational drug, and the event cannot be 
readily explained by another factor. 
The rationale for the causal relationship should be described if it is 
necessary to be explained.  
*The following guidance can be taken into consideration on causality assessment: resolution of the event after discontinuation 
of IP; recurrence after restarting of IP; established causal relationship with IP or similar drugs; no confounding risk factors; 
consistency with the amount and duration of exposure to IP; almost clearly explainable involvement of the IP based on the 
correct past medical history; no reasonable possibility of causal relationship with concomitant therapy, etc. 

58 
 Review and reporting of serious adverse events 
1） The investigator will report any serious adverse events to the sponsor within 24 hours of getting to know 
the occurrence of the event. The investigator will report detailed information to the sponsor by using 
the “Report of Serious Adverse Events” form within 2 days of getting to know the occurrence of the 
event (the date the event was known is regarded as day 0). The study site’s own form may be used 
instead of the "Report of Serious Adverse Events". For additional reporting, new serious information 
(e.g., change in the name of the adverse event, causal relationship, outcome information, the severity 
category, etc.) should be reported to the sponsor according to the above rules when it becomes known. 
2） The investigator will report the event to the study site according to the study site’s operating procedures. 
3） The investigator will provide any additional information (e.g., autopsy reports, late-stage medical 
records, and other necessary information) on reported serious adverse events, as requested by the 
sponsor. 
 
 Reporting of adverse events of special interests (AESIs) 
The investigator should report to the sponsor promptly when an AESI is noted. For atopic dermatitis and skin 
symptoms with edematous erythema or scaling, the necessary information (details of the symptoms/signs and 
the basis for determining the causal relationship with the IP) should be stated in the CRF. Any additional 
information should be provided, as requested by the sponsor. 
At the time of physical examination on the day of follow-up visit, the final outcome of any AESI “not 
recovered/not resolved” falling under 1) below should be obtained according to 2). Concomitant medications 
and therapies will also be collected according to Sections 9.3.2.1 and 9.3.2.2 . 
1） AESIs to be obtained 
a） AEs requiring discontinuation of study treatment 
b） Asthma 
c） Atopic dermatitis  
d） Skin symptoms with edematous erythema or scales 
2） Period to obtain AESIs 
AESIs should be collected until the earlier of the following dates to obtain the final outcome 
information (the outcome and the date of outcome/outcome obtained). 
• Date of recovering or recovered 
• Date 6 months after the last dose of IP 
 
 Photography 
Among AESIs, "atopic dermatitis" and "skin symptoms with edematous erythema or scales" will be 
photographed to examine the detailed skin findings of the events. Other adverse events of which the principal 
investigator or subinvestigator considers it necessary to take photographs will also be photographed. 
The photographs taken will be used as a record of the occurrence of adverse event and a reference for safety 
evaluation. 
 
 Reporting of the Pregnancy of the Participant 
1） If obtaining the information on the pregnancy of the participant who received the IP, the investigator 
or subinvestigator must immediately discontinue study treatment and take appropriate action for the 
participant, and follow up the participant until the completion of the pregnancy (e.g., delivery). 
2） The investigator or subinvestigator will also report detailed information to the sponsor by using the 
“Report for Pregnancies during the Study” form. 
3） Participant pregnancies are not regarded as adverse events. 

60 
12. Biomarkers 
 Measurements of Biomarkers 
1） Variable to be measured 
a） IL-31 
b） KL-6, SP-D, NT-proBNP 
c） Exploratory biomarkers 
 
2） Collection of blood samples 
a） Blood samples will be collected on the day of study treatment initiation, at Week 4, 8, 12, 16, 20, 
24, and 36, and Week 52 or on the day of visit for discontinuation. On the days of study treatment, 
blood samples will be collected before administration of IP. 
b） Blood samples will be collected on the day of study treatment initiation, at Week 4, 12, 24, and 36, 
and Week 52 or the day of visit for discontinuation. On the days of study treatment, blood samples 
will be collected before administration of IP. 
c） Blood samples will be collected on the day of study treatment initiation, at Week 12, 24, and Week 
52 or the day of visit for discontinuation. On the days of study treatment, blood samples will be 
collected before administration of IP.  
 
The collected blood samples will be centrifuged to separate the serum, and the serum samples will be 
stored frozen until measured. The amount of blood collected, centrifugal conditions, and storage 
conditions are specified in a separate operating procedure. 
 
 Blood Biomarker Outcome Measures 
1） Serum IL-31 level 
 Rationale for selection 
Since IL-31 is one of the cytokines considered to be involved in the disease state of SSc8),this has 
been selected to evaluate the changes after administration of nemolizumab.  
 
2） KL-6 and SP-D 
 Rationale for selection 
KL-6 and SP-D have been used as sensitive markers for interstitial pneumonitis in examination and 
measuring of disease progression or as a prognostic predictor in clinical practice. Moreover, increased 
levels of these have been reported to be associated with inflammatory pathological conditions such 
as ground-glass opacities on HRCT and elevated proportions of inflammatory cells in 
bronchoalveolar lavage fluid 21). Based on the above, these have been selected in terms of safety 
protection of participants. 
 
3） NT-proBN 
 Rationale for selection 
NT-proBNP is critical as a serological marker of pulmonary hypertension because it elevates in 
correlation with its severity in patients with SSc-PAH22). It is also important as a serological marker 
for overall some sort of because it elevates in the presence of any myocardial damage even without 
pulmonary hypertension23). Therefore, it has been set in terms of ensuring safety of participants. 
 
4） Exploratory biomarkers 

61 
As exploratory biomarkers, IL-1α, IL-4, IL-6, IL-8, IL-13, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, 
IL-17F, and IL-23 levels will be measured; however, cytokines for which adequate performance of 
the assay methods could not be validated will not be measured. 
 Rationale for selection 
The major cytokines considered to be involved in pathological conditions of SSc have been selected 
to evaluate the changes after nemolizumab administration. 
 
 Measurement Method and Reporting of Results 
1） Measurement methods 
a） IL-31 and exploratory biomarkers will be measured using the Enzyme-Linked Immuno Sorbent 
Assay (ELISA) method. The measurements will be performed by 
 Corporation 
according to its assay protocol. 
b） KL-6, SP-D and NT-proBNP will be measured by 
 Corporation according to its assay 
protocol.  
c） Exploratory biomarkers will be measured using the Electro Chemi-Luminescence (ECL) method. 
The measurements will be performed by
 Corporation according to its assay protocol. 
 
2） Report of measurement results 
a） IL-31, KL-6, SP-D, NT-proBNP and exploratory biomakers 
 Corporation will prepare and submit a report of analysis results to the sponsor. 
 
13. Pharmacokinetics 
 Pharmacokinetic Measurements 
1） Variable to be measured 
Serum concentration of nemolizumab 
2） Collection of blood samples 
Blood samples will be collected on the day of study treatment initiation, at Week 1, 2, 4, 8, 12, 16, 20, 
24, and 36, Week 52 or on the day of visit for discontinuation, and on the day of follow up. On the 
days of study treatment, blood samples will be collected before administration of IP. 
The collected blood samples will be centrifuged to separate the serum, and the serum samples will be 
stored frozen until measured. The amount of blood collected, centrifugal conditions, and storage 
conditions are specified in a separate operating procedure. 
 
 Pharmacokinetic Outcome Measures 
1） Serum concentration of nemolizumab 
2） Pharmacokinetic parameters: Cmax、tmax、AUC0-28day、AUClast 
 
 Rationale for selection 
Parameters necessary and evaluable to examine pharmacokinetics of nemolizumab have been selected in 
reference to “Clinical pharmacokinetic studies on drugs (PFSB/ELD No.796 of June 1, 2001).” 
 
 Measurement Method and Reporting of Results 
1） Measurement method 
Serum concentration of nemolizumab will be measured using the ELISA method. The measurements 
will be performed by 
 Laboratories, Ltd. according to its assay protocol.  

62 
2） Report of measurement results 
 Laboratories, Ltd. will prepare and submit a report of analysis results to the 
sponsor. 
 
14. Immunogenicity 
 Immunogenicity Measurements 
1） Variable be measured 
Serum anti-nemolizumab antibody 
2） Collection of blood samples 
Blood samples will be collected on the day of study treatment initiation, at Week 24 and 36, Week 52 
or on the day of visit for discontinuation, and on the day of follow up. On the days of study treatment, 
blood samples will be collected before administration of IP.  
The collected blood samples will be centrifuged to separate the serum, and the serum samples will be 
stored frozen until measured. The amount of blood collected, centrifugal conditions, and storage 
conditions are specified in a separate operating procedure. 
 
 Immunogenicity Outcome Measures 
1） Serum anti-nemolizumab antibody 
2） Neutralizing antibody concentrations 
 
 Rationale for selection 
The variables have been selected to evaluate the effects of the development of anti-nemolizumab 
antibodies to efficacy and safety in participants. 
 
 Measurement Method and Reporting of Results 
1） Measurement method 
The serum anti-nemolizumab antibody will be measured using the ECL method. When anti-
nemolizumab antibodies are detected, their characteristics will be determined using the cell-based 
assay (CBA) method. The measurement will be performed by 
 Corporation according 
to its assay protocol. 
 
2） Report of measurement results 
 Corporation will prepare and submit a report of analysis results to the sponsor. 
 
15. Comprehensive Measurement of Autoantibodies 
Comprehensive measurement of autoantibodies will be performed to determine the disease state of SSc 
and explore the patient-group for whom nemolizumab is effective. 
 
 Measurement Method and Reporting of Results 
1） Collection of blood samples 
Blood samples will be collected on the day of study treatment initiation, at Week 24, and Week 52 or 
on the day of visit for discontinuation. On the days of study treatment, blood samples will be collected 
before administration of IP. 
The collected blood samples will be centrifuged to separate the serum, and the serum samples will be 
stored frozen until measured. The amount of blood collected, centrifugal conditions, and storage 

63 
conditions are specified in a separate operating procedure. 
 
2） Measurement method 
Autoantibodies will be measured comprehensively using HuPEX™ protein array. The measurement 
will be performed by P
Corporation according to its assay protocol. 
 
3） Report of measurement results 
Corporation will prepare and submit a report of analysis results to the sponsor. 
Measurement results will not be included in the clinical study report and will be summarized in a 
separate report. 
 
16. CyTOF measurement 
CyTOF measurement will be performed to explore the mechanism of action of nemolizumab in SSc. 
 
 Measurement Method and Reporting of Results 
1） Collection of blood samples 
Blood samples will be collected on the day of study treatment initiation, at Week 24, and Week 52 or 
on the day of visit for discontinuation. On the days of study treatment, blood samples will be collected 
before administration of IP.  
PBMC preparation of collected blood samples will be performed by the day following sample 
collection. The amount of blood to be collected and storage conditions are specified in a separate 
operating procedure. 
 
2） Measurement method 
Measurement will be performed by 
, Inc. according 
to its assay protocol. 
 
3） Report of measurement results 
. will prepare and submit a report of analysis 
results to the sponsor. Measurement results will not be included in the clinical study report and will be 
summarized in a separate report. 
 
17. Statistical Analysis 
The major plans for statistical analyses are presented below. The details are provided in the Statistical 
Analysis Plan. This plan will be fixed prior to database lock on through discussions on data review etc.  
 
 Analysis Sets 
17.1.1  Efficacy Analysis Set (Full Analysis Set: FAS) 
The efficacy analysis set includes all participants assigned to treatment except for those who meet any of the 
following criteria: 
1） Participants who are found not to have SSc 
2） Participants who have received no dose of nemolizumab at all after assigned to treatment   
3） Participants with no efficacy data at all after assigned to treatment   
 

64 
17.1.2  Safety Analysis Set 
The safety analysis set includes all participants assigned to treatment except for those who meet any of the 
following criteria: 
a） Participants who have received no dose of nemolizumab at all after assigned to treatment 
2） Participants with no safety data at all after assigned to treatment 
 
17.1.3  Pharmacokinetics Analysis Set 
The pharmacokinetics analysis set includes all participants assigned to treatment except for those who meet 
any of the following criteria: 
1) Participants who have received no dose of nemolizumab at all after assigned to treatment 
2) Participants with no pharmacokinetic data at all after assigned to treatment 
 
17.1.4  Biomarker Analysis Set 
The biomarker analysis set includes all participants assigned to treatment except for those who meet any of 
the following criteria: 
1) Participants who have received no dose of nemolizumab at all after assigned to treatment 
2) Participants with no biomarker data at all after assigned to treatment 
 
 Data Handling 
17.2.1  Common Rules 
a） Handling of missing values 
The missing values will not be imputed. 
 
2） Handling of data on the day of visit for discontinuation 
The data measured or evaluated on the day of visit for discontinuation will be handled as the data of 
the relevant evaluation period if the visit is within the allowance of any visit for evaluation period. 
However, such data will not be included in the analysis if another data has been obtained in the 
relevant evaluation period. 
 
17.2.2  Data Handling on Pharmacokinetics 
1) Handling of values below the lower limit of quantification (BLQ) and missing values for serum drug 
concentration data 
Values BLQ will be handled as follows and missing values will not be imputed. 
a) 
Tabulation: They will be reported as BLQ. 
b) Changes over time and profiles and summary statistics: They will be replaced by 0. However, 
if the number of participants with BLQ values exceeds half number of participants in 
pharmacokinetic analysis set, the summary statistics of serum drug concentrations at that time 
point will not be calculated and reported as N.C. (not calculated).  
 
2) Handling of pharmacokinetic parameters not calculable 
Parameters not calculable should be handled as follows: 
a) 
Tabulation: They will be reported as N.C. 
b) Summary statistic: They will be left missing. However, if the number of unevaluable 
participants for a pharmacokinetic parameter exceeds half of participants to be evaluated, the 
summary statistic of the parameter will not be calculated and reported as N.C. 
 

66 
 
𝛥𝛥mRSS: mRSS change 
𝛥𝛥FVC%: Percent FVC change 
𝛥𝛥pt−glob, 𝛥𝛥MD−glob :  Patient’s / Physician’s Global assessment change (cm) 
𝛥𝛥HAQ−DI: HAQ-DI Score change 
 
The score of participants occurring any of the following events is 0: 
 Onset of scleroderma renal crisis 
 Decline in FVC% ≥15% (requiring reevaluation within 1 month), and %FVC of 80% or less 
 Onset of left ventricular failure requiring treatment (defined as left ventricular ejection fraction ≤45%) 
* 
 Onset of pulmonary arterial hypertension requiring right heart catheterization * 
*Caused by SSc 
 
17.3.3  Safety Analysis 
The following variables will be summarized on the safety analysis set: 
1） Adverse events 
The following data will be collected and tabulated for AEs and separately for the treatment-related AEs. 
a） The number of participants included in the safety analysis set, and the number of participants 
with, and the number of occurrences of AEs, AEs by severity (mild, moderate, and severe), 
SAEs (total, fatal, and non-fatal), and AESIs will be calculated. 
b） The number of participants with AEs will be calculated by SOC and PT using MedDRA/J. 
c） For AESIs, the number of participants with AESIs, the number of participants with AESIs by 
PT will be calculated by the category. 
 
2） Laboratory test values 
a） Laboratory test values throughout the treatment period 
For the continuous variables, summary statistics will be calculated by laboratory parameter and 
time point. For the categorical variables, the number of participants will be calculated by category. 
The percentage of participants will be calculated using the number of observed participants at 
each time point. 
b） Changes in individual participants during the treatment period 
A spaghetti plot will be created for each participant using individual test values by laboratory 
parameter of continuous variables. 
 
3） Vital signs, physical findings, and other assessments related to safety 
a） Vital signs, electrocardiogram and echocardiography throughout the study period 
For the continuous variables, summary statistics will be calculated by vital sign, electrocardiogram 
parameter, and echocardiography parameter. For the categorical variables, the number and 
percentage of participants will be calculated by category. The percentage of participants will be 
calculated using the number of observed participants at each time point. 
 
17.3.4  Analyses of Drug Concentrations and Pharmacokinetic Parameters 
The following variables will be summarized on the pharmacokinetic analysis set. 
1） Serum concentrations of nemolizumab 

67 
a） Summary statistics including coefficient of variation and geometric mean of serum 
nemolizumab concentrations will be calculated by time point. 
b） The serum nemolizumab concentration-time profile will be created using mean serum drug 
concentrations and their standard deviations. 
c） The serum nemolizumab concentration-time profile will be created by participant. 
d） The serum nemolizumab concentration-time profile will be created by participant where 
participants who tested positive for the first time after study treatment (in blue), those who had 
tested positive since before treatment (in red), and those who tested negative at all time points 
(in black) for anti-nemolizumab antibodies in serum in the confirmatory test will be identified 
by color. 
2） Pharmacokinetic parameters (Cmax, tmax, AUC0-28Day, and AUClast) 
Summary statistics including coefficient of variation and geometric mean of parameters will be 
calculated. 
 
17.3.5  Analysis of Immunogenicity 
The following variables will be tabulated from the pharmacokinetics analysis set. 
1） Serum anti-nemolizumab antibody 
a） The percentage of participants with positive serum anti-nemolizumab antibodies will be 
calculated by test (Screening, Confirmatory, and Neutralizing) and time point. The positive rate 
in the Confirmatory test and the Neutralizing test is based on the number of participants having 
undergone the screening test. 
b） The number of and the percentage of participants who tested positive for anti-nemolizumab 
antibodies will be determined in this study. According to Shankar's definition,24) among 
participants who tested positive for anti-nemolizumab antibodies for the first time after study 
treatment or both before and after study treatment, a positive participant is defined as a 
participant with a ≥ 4-fold increase in difference in antibody titer. 
 
17.3.6  Analysis of Biomarker 
Details will be described in the Statistical Analysis Plan. 
 
 Determination of Sample Size 
17.4.1  Target Sample Size 
The target sample size for this study is 8 participants.  
 
17.4.2  Rationale for Sample Size 
The number of participants required to determine the efficacy of this drug for SSc was set at 8. Since no 
statistical evaluation is planned, the number is not based on the level of significance and power. 
 
 Data Review 
Data review will be performed before data fixation. In the data review, the appropriateness of data handling 
and analysis methods, etc., will be examined, and analysis sets, data handling, and an analysis plan will be 
determined. If a change in the statistical analysis plan is required after data review, the statistical analysis 
plan will be revised and documented. 

68 
18. Agreement on the Protocol and Protocol Deviation/Amendment 
 Agreement of and Compliance with the Protocol 
The investigator will, before the sponsor requests to conduct the study at the study site, agree in writing with 
the sponsor on the contents of the protocol and conducting the study in compliance with the protocol. The 
investigator will do the same when the protocol is revised through discussion with the sponsor or according 
to the instructions of the head of the study site on the basis of the opinion of the institutional review board 
(IRB). 
 
 Protocol Deviation/Amendment 
1） The investigator or subinvestigator should not deviate from or amend the protocol without prior written 
agreement with the sponsor and without written approval based on a prior review by the IRB. However, 
the investigator or subinvestigator may deviate from or amend the protocol without prior agreement with 
the sponsor or without prior approval from the IRB in the following cases where: 
a） it is medically unavoidable to avoid immediate danger to a participant 
b） it is on administrative matters of the study (e.g., change of the name of study site, change of the 
address or phone number of study site, and change of job title of the investigator) 
 
2） The investigator or subinvestigator will record all deviations from the protocol. The investigator will 
prepare a document only for deviations from the protocol to avoid immediate danger to the participant 
with the reason for deviation or for other medically unavoidable reasons and immediately submit it to 
the sponsor and the head of the study site. The investigator will also submit the document to the IRB via 
the head of the study site, obtain approval from the IRB, and obtain in writing approval of the head of 
the study site and agreement of the sponsor. 
 
3） If the protocol amendment is appropriate when the investigator is unable to comply with the protocol to 
avoid any immediate hazard to participants or due to other unavoidable medical reasons, the investigator 
will submit a draft amendment to the protocol to the sponsor as soon as possible to obtain written 
approval of the sponsor. Furthermore, the investigator will submit a draft amendment to the protocol to 
the head of the study site, obtain approval from the IRB and the head of the study site. 

69 
19. Case Report Form 
The EDC system (Table 19-1) will be used in this study. The original CRFs will be those generated in the 
EDC system. The validated EDC system will be used in this study. 
The data and audit trails entered in EDC system by the investigator, subinvestigator involved in CRF 
preparation, and CRCs are stored in the EDC server. 
 
Table 19-1 EDC system 
Name of EDC system 
 
Name of EDC system development Company 
. 
Input method 
Data entry via the web 
Input terminal 
Personal computer available at study sites 
 
 Data to be collected in CRF 
The data to be collected in the CRFs is shown below. 
 
19.1.1  Participants assigned to treatment 
1） Date of written informed consent 
2） Visit dates 
3） Participant demographics 
4） Major therapies received for SSc in the past  
5） Inclusion and exclusion criteria 
6） Complications 
7） Concomitant Medications/Concomitant Therapies 
8） Patient-reported Outcomes 
9） Global improvement rating  
10） mRSS 
11） The number of digital ulcers 
12） Respiratory function test 
13） Electrocardiogram 
14） Echocardiography 
15） HRCT 
16） Severity of pulmonary lesions 
17） ACR-CRISS 
18） Vital signs 
19） Body weight 
20） Laboratory tests 
21） Biomarkers 
22） Serum nemolizumab levels  
23） Immunogenicity measurement 
24） Comprehensive measurements of autoantibodies 
25） CyTOF measurement 
26） Dosing status of IP  
27） Adverse events 
Information on outcome of an adverse event is to be collected until the follow-up visit. 
28） The details of adverse events of atopic dermatitis and skin symptoms with edematous erythema or 

70 
scaling as well as the basis for determining the causal relationship with the IP 
29） Malfunction of DCS 
30） Status of study entry after screening, enrollment, completion/discontinuation of the study 
completion status of study entry after screening, completion status of enrollment, study completion 
status, date of completion, date and reason for discontinuation if discontinued, and impact of COVID-
19 
31） Follow-up visit 
Whether there was a follow-up visit or not, date of follow-up visit, date of determination and reason 
if no follow-up visit, and impact of COVID-19 
32） Others 
a） Comment on each assessment 
b） Unscheduled visits 
 
19.1.2  Participants Who Discontinue the Study before study entry after screening and those Who 
Discontinue the Study before enrollment 
The following data will be collected and documented in the CRF for respective participants: 
1) to 6) for participants having discontinued the study before study entry after screening 
1) to 6) and 7) to 16) for participants having discontinued the study before enrollment 
1） Date of written informed consent 
2） Visit dates 
3） Participant demographics 
4） Inclusion and exclusion criteria 
5） Adverse events 
6） Date of and reason for discontinuation 
7） mRSS 
8） The number of digital ulcers 
9） Respiratory function test 
10） Vital signs 
11） Body weight 
12） Severity of pulmonary lesions 
13） HRCT 
14） Echocardiography 
15） Electrocardiograms 
16） Laboratory tests 
 
 Source Data for Information Entered in Case Report Form 
Source data for information entered in the case report forms are as follows: 
1） Medical records 
2） Laboratory test slips 
3） Serious Adverse Event Report (copy) 
4） Serious Adverse Event and Device Malfunction Report (copy) 
5） Informed consent forms 
6） Participant screening logs 
7） IP accountability records 
8） ECG measurement results 

71 
9） Respiratory function test 
10） Patient QOL questionnaire (paper) 
 
 Information in the Case Report Forms Treated as Source Data  
Any information of the following items described only in the CRF will be treated as the original data. 
1） Presence or absence of data for each item 
2） Indication of drug/therapy 
3） Seriousness and severity of adverse event, causality of adverse event to IP, and presence or absence of 
abnormal laboratory changes 
4） Date of and reason for study discontinuation 
5） All comments 
 
 Guidelines for Preparation of Case Report Form 
The investigator, subinvestigator involved in CRF preparation, and CRCs will have to receive training before 
preparing CRFs. The sponsor will create an account management table to specify the authority given to each 
person in the place of a list of signatures/seals. 
1） The investigator or subinvestigator will accurately prepare CRFs based on the source documents of 
enrolled participants according to the “Guidance for CRF Preparation.” 
2） The investigator or subinvestigator will promptly prepare the CRF once the evaluation of the 
participant at each visit is completed. 
3） CRCs may fill out or transcript and correct CRFs on the basis of the source documents. The 
investigator will review the entries, transcriptions, and corrections made by CRCs and electronically 
sign the CRFs. 
4） The investigator will review the CRFs prepared at the study site and electronically sign the CRFs. 
5） The investigator will submit the CRFs to the sponsor. In addition, the investigator will obtain a copy 
of the CRFs from the sponsor at the end of the study and retain them electronically. 
6） If data in the CRF shows a discrepancy with the source document, the investigator will prepare a 
document explaining the discrepancy and submit it to the sponsor. The investigator will also retain a 
copy of the record. 
 
 Modification and Amendment to Case Report Forms 
1） The investigator, subinvestigator, or CRCs will amend the CRFs according to the “Guidance for CRF 
Preparation” provided by the sponsor. 
2） The investigator will review the modifications or amendments made by the subinvestigator or, CRCs 
and electronically sign the CRF. 
 
20. Follow-up report of adverse events of special interest 
For adverse events of interest falling under those specified in Section 11.6 1) which are “not recovered/not 
resolved” at the time of physical examination on the day of follow-up visit, the investigator will report their 
following information from after the physical examination of the follow-up visit to the time of obtaining the 
final outcome in the format separately specified by the sponsor. 
1） Outcome and date of outcome/date of outcome obtained 
2） Drugs used for the adverse event 
3） Therapies performed for the adverse event 
 

72 
21. Direct Access to Source Documents 
The investigator, subinvestigator, and the head of the study site will allow study monitoring, the sponsor’s 
audit, and inspections by the IRB and regulatory authorities, and their direct access to all study-related 
documents, including the source documents. 
When regulations on direct access are stipulated at the study site, they will be followed. 
 
22. Quality Control and Quality Assurance 
Risk management of this study will be performed based on the risk management plan prepared according to 
the standard operating procedures of 
 
 
1） Monitoring 
The CRA will request the investigator and subinvestigator, etc. to comply with the GCP, related 
regulatory notifications, and study protocol throughout the study period, and will then assess their 
compliance. If any deviation from the GCP, related regulatory notifications, and the study protocol is 
found by monitoring, the CRA will inform the investigator immediately and the head of the study site 
as necessary and take appropriate measures to prevent the recurrence of the deviation. Furthermore, 
on the basis of direct access to the source documents, the CRA will verify whether the CRFs are 
completed accurately and are consistent with the source documents. 
 
2） Quality control 
a） Standardization of assessments 
Prior to the start of the study, the sponsor will explain the standards of the assessment and the 
protocol to the investigator and subinvestigator, etc. 
 
3） Quality control of CRF data 
The quality control of CRF data will be performed according to the SOPs of Maruho Co., Ltd. When 
necessary, a case review meeting may be held by the medical expert and the sponsor to determine the 
handling of individual cases. 
 
4） Audit 
The auditor will assess whether the study is being conducted in accordance with GCP, the protocol, 
and relevant operating procedures separately and independently from the monitoring and quality 
control activities performed by the clinical study department. The auditor will also assess whether the 
study is being conducted properly and that the reliability of the study data is being maintained by direct 
access to study-related documents and records or other methods. 
 
23. Completion, Discontinuation, or Interruption of the Study 
 Completion of the Study 
Upon the completion of the study, the investigator will report the completion and a summary of study results 
in writing to the head of the study site. Once receiving the report of study completion from the investigator, 
the head of the study site will notify the IRB and the sponsor of the fact the summary of study results. 
 
 Discontinuation or Interruption of the Study 
The investigator will, when interrupting or discontinuing the study at his/her own discretion, promptly report 
it and the reason in writing to the head of the study site. Once receiving the report of study discontinuation 

73 
or interruption from the investigator, the head of the study site will promptly notify the IRB and the sponsor 
of the fact and the reason in writing. 
The sponsor will, when deciding the discontinuation or interruption of the study or the termination of 
development of the IP, promptly notify the head of the study site of the fact and the reason in writing. Once 
receiving a notification of interruption or discontinuation of the study or the termination of development from 
the sponsor, the head of the study site will promptly notify the investigator and the IRB of the fact and the 
reason in writing. 
 
24. Archiving of Records 
1） Study site 
The head of the study site should retain the documents and records related to this study to be archived 
at the study site (hereinafter, the study-related records) until the elapse of 15 years after either the date 
of the marketing approval of the investigational drug or the date of decision of discontinuation of the 
development of the investigational drug. 
For archiving the study-related records, the head of the study site will assign a storage manager. The 
head of the study site and the storage manager must take necessary measures so that these records are 
not lost or disposed of during the retention period and that they can be presented at the request of the 
sponsor, regulatory authorities, etc. 
When the retention period of records to be archived at the study site expires, the sponsor will promptly 
notify the head of the study site of the fact. 
2） Sponsor 
The sponsor should retain the study-related records to be archived at the sponsor site until the elapse 
of 15 years after either the date of the marketing approval of the investigational drug or the date of the 
decision of discontinuation of the development of the investigational drug. 
 
25. Publication Policy 
1） The study site may not disclose or divulge data on the study provided by the sponsor or information 
such as study results to any third party without prior permission of the sponsor. If intending to publish 
the information obtained from the study to external parties such as academic conferences, the study 
site must obtain prior permission from the sponsor. 
2） The founder of the IRB shall accept the sponsor’s request (if any) for prior checking of a summary of 
the meeting minutes specified in Article 28, Paragraph 2-6 of the GCP to ensure the summary does not 
include the description infringing on the sponsor’s intellectual property rights. When necessary, the 
founder may publish the summary after taking appropriate measures such as data masking. 
3） The sponsor may freely use information obtained from this study for application for marketing 
approval for the test drug, product summary, promotional materials, publications, presentations at 
academic societies, and other materials to be submitted to the Ministry of Health, Labour, and Welfare. 
4） When publishing information, sufficient attention must be paid to participant privacy. 
 
26. Use of study-related data 
1） The sponsor may use information obtained from this study (the study-related data) for application for 
marketing approval for the test drug, product summary, promotional materials, publications, 
presentations at academic societies, and other materials to be submitted to the Ministry of Health, 
Labor, and Welfare.  
2） The sponsor may use the study-related data for the research and development of other than the test 

74 
drug and otherwise academic research when considered necessary. 
 
27. Ethics 
 Institutional Review Board 
Prior to the execution of the clinical study agreement, the IRB will review the contents of the protocol, 
informed consent form, and other explanatory documents, as well as the appropriateness of conducting the 
study. After the execution of the clinical study agreement, the IRB will continuously review the 
appropriateness of continuing the study. 
 
 Ethical Conduct of the Study 
This study shall be conducted in compliance with the Ministerial Ordinance on Good Clinical Practice for 
Drugs and related notifications, the ethical principles based on the Declaration of Helsinki, and the protocol. 
 
 Protection of Participants’ Confidentiality 
To protect the participants’ confidentiality, the investigator or subinvestigator will use participant 
identification codes instead of names to identify participants when completing CRFs and reporting adverse 
events and other study-related data to the sponsor. The sponsor’s CRA and auditors will similarly protect any 
confidential participant information obtained during the course of the study in accordance with the provisions 
of Article 80-2, Paragraph 10 of the Act on Securing Quality, Efficacy, and Safety of Products Including 
Pharmaceuticals”. 
 
 Participant Selection and Informed Consent 
27.4.1  Participant Selection 
During the selection of participants, the investigator or subinvestigator should carefully consider the 
advisability of asking for a patient to participate in the study taking into consideration the health condition, 
symptoms, age, sex, ability to consent, dependency on the investigator or subinvestigator, and status of 
participation in other clinical studies from the viewpoints of human rights protection and based on the 
protocol-specified inclusion and exclusion criteria. If a patient who is visiting another hospital is enrolled in 
the study, the investigator or subinvestigator will consider eligibility for study participation after examining 
the details of the medical treatment. 
 
27.4.2  Informed Consent 
1） Prior to the assessment for study participation, the investigator or subinvestigator will fully explain 
the study to each participant by using the informed consent form and other explanatory documents 
that describe the items provided in “27.4.3 Explanations to Participants.” After this explanation, 
written voluntary consent to participate in the study will be obtained from the participant personally. 
2） In cooperation with the sponsor, the investigator will prepare the informed consent and other 
explanatory documents that will be used to obtain the participants’ consent to participate in the study 
and revise them as needed. The prepared or revised informed consent form and other explanatory 
documents should be approved by the IRB before use. 
3） The investigator will comply with the ethical principles when preparing or revising the informed 
consent form and other explanatory documents. 
4） The investigator or subinvestigator who provided the explanation, and the participant will each sign 
and date on the informed consent form. If a CRC makes a supplemental explanation, the CRC will 
also sign and date on the form. 
5） The investigator or subinvestigator will provide the participant with the signed and dated informed 

75 
consent form (copy), and other explanatory documents before the participant participates in the study.  
6） The investigator, subinvestigator, and CRC should not put pressure or unjustified influence on the 
participants to participate or continue participating in the study.  
7） The informed consent form and other explanatory documents for the participants or information 
provided orally when explaining the study must not contain any words or suggestions that cause the 
participants to relinquish their rights. Furthermore, the consent materials and explanation must not 
contain any words or suggestions that absolve the investigator, subinvestigator, CRC, study site, or 
sponsor of their legal responsibilities. 
8） Nontechnical vocabulary that the participants can understand should be used as much as possible 
during the verbal explanation and in written explanation and the informed consent form. 
9） The investigator or subinvestigator will provide the participant with the opportunity to ask questions 
and sufficient time to decide whether to participate in the study before obtaining the participant’s 
consent. The investigator, subinvestigator, or CRC (as someone providing additional explanation) 
must answer all questions to the satisfaction of the participant. 
10） If information is obtained that could potentially affect the participants’ willingness to continue 
participating the study, the investigator or subinvestigator must promptly give the information to the 
participants and ask whether the participants are willing to continue participating the study. In such 
cases, the fact that this information has been given to the participants will be recorded in the source 
documents. 
11） If significant new information that may be related to the participants’ consent is obtained, the 
investigator should promptly revise the informed consent form and other explanatory documents for 
the participants on the basis of this information. 
12） When the informed consent form and other explanatory documents for participants are revised, the 
investigator or subinvestigator will promptly give the information which the amendment is based on 
to participants and ask whether the participants are willing to continue participation in the study. 
Furthermore, the investigator or subinvestigator will again explain the study using the revised 
informed consent form and other explanatory documents for participants and obtain voluntary written 
informed consent to continue participation in the study from each participant. The investigator or 
subinvestigator will provide the participants with the newly signed and dated revised informed 
consent form (copy) and the other explanatory documents.  
 
27.4.3  Explanations to Participants 
1） This study is being conducted for the purpose of investigation (i.e., this study involves research). 
2） Study objective 
3） Name, job title, and contact information of the investigator. 
4） The study method (including the investigative aspect of the study, the participant inclusion criteria, 
and the probability of being assigned to each treatment) 
5） The expected benefits to the participant’s physical and mental health and the expected disadvantages 
to the participant of the IP 
6） The presence or absence of other treatments available to the participant and the expected important 
benefits and risks of the treatments 
7） The participant’s scheduled duration of participation in the study 
8） Participation in the study is voluntary, and the participant can refuse or withdraw consent to participate 
in the study at any time. 
9） The participant will not undergo any disadvantages as a result of refusing or withdrawing consent to 

76 
participate in the study, and the participant will not lose any benefits that the participant should receive 
if he or she does not participate in the study. 
10） The CRAs, auditors, and the IRB which deliberated the protocol, and regulatory authorities will have 
direct access to medical records and similar documents on the condition that the participant’s 
confidentiality will be protected. At such times, the participant’s confidentiality will be protected. The 
participant allows direct access to such materials by signing the informed consent form. 
11） The participant’s confidentiality will be protected if the study results are published. 
12） The consultation service to the study site where the participant should make inquiries or should 
contact if the participant desires further information regarding the study or participant’s rights or if 
study-related injury occurs. 
13） The compensation and treatment available to the participant in the event of study-related injury. 
14） The types of IRBs that review the appropriateness of the study, the matters reviewed by each IRB, 
and other matters related to the IRBs involved in this study. 
15） Matters to be communicated to participants on this study 
 
The planned number of participants in the study 
 
If information is obtained that could potentially affect the participant’s willingness to continue 
participating the study, that information will be promptly reported to the participant. 
 
The conditions or reasons to withdraw participants from the study 
 
Information for the financial responsibility of the participant in the study 
 
Information related to payments to the participant 
 
Instructions to be followed by the participant 
 
Study staff will obtain medical information from other physicians with the consent of the 
participant. 
 
28. Payments 
Measures taken to reduce the participant’s financial burden resulting from participation in the study (if any) 
should be stipulated in writing after a discussion with the study site. Provisions for other necessary expenses 
will also be stipulated in writing after another discussion with each study site. 
 
29. Compensation for Injuries 
If a participant suffers from an injury attributable to the study and seeks compensation from the study site, 
the sponsor shall be fully responsible for the compensation unless the injury is due to an intentional error or 
a medical error by the study site. Prior to conducting the study, the sponsor will purchase product liability 
insurance for the IP as a measure to compensate for injuries. 
 
30. Responses to COVID-19 
Definitions of confirmed COVID-19 patients (including asymptomatic pathogen carriers), suspected 
COVID-19 patients, and persons in close contact with such patient follow the latest edition of the Treatment 
Guidelines for New Coronavirus Infections (COVID-19). 
 
 COVID-19-related instructions to participants 
The investigator or subinvestigator will instruct the participants in this study to promptly contact the study 
site if they are found to have confirmed COVID-19 (including asymptomatic pathogen carriers) or suspected 
COVID-19, or found to have been in close contact with a confirmed or suspected COVID-19 patient. 
 

78 
 
30.2.2  When staff at the study site who may have close contact with participants have confirmed 
COVID-19 (including asymptomatic pathogen carriers) or suspected COVID-19. 
(1) The investigator or subinvestigator will inform the participants in the study that staff at the study site 
who may have close contact with them are (or may be) infected with COVID-19, ask the safety of 
the subjects by telephone or other contact means, and document the result in the source documents. 
The investigator or subinvestigator will also provide response and instruction to the participants 
according to the instructions of the study site. 
(2) The investigator or subinvestigator will promptly inform the sponsor that staff at the study site who 
may have close contact with participants are (or may be) infected with COVID-19. 
 
 Discontinuation of the study due to the influence of COVID-19 
If the study has been discontinued due to the influence of COVID-19, the investigator or subinvestigator will 
record in the source document and the CRF that the study was discontinued due to COVID-19. 
 
 Deviations from the protocol due to the influence of COVID-19 
If a protocol deviation has occurred due to the influence of COVID-19, the investigator or subinvestigator 
will keep a record in the source document so as to make it clear that the deviation occurred due to the 
influence of COVID-19. 
 
31. Study Period 
December 2021 to October 2023 
 
32. Administrative Structure 
 Sponsor 
 Representative Director, President & CEO, Maruho Co., Ltd. 
, Osaka 
 
 
 Sponsor Organization 
1） Head of Clinical Trial 
, General Manager, Clinical Development Department, Maruho Co., Ltd 
 
Major roles: 
a） 
 
b）
 
c） 
 
 
2） Clinical Trial Supervisor 
, Clinical Development Department, Maruho Co., Ltd. 
 
Major roles: 
 
 
3） Medical Safety Officer 
, MD, PhD, Senior Medical Director, Maruho Co., Ltd. 

79 
 
Major roles: 
a） 
 
b）
 
 
 
4） Clinical Research Associate Leader 
 Clinical Development Department, Maruho Co., Ltd. 
 
Major roles: 
. 
 
 Study Sites and Investigators 
Study Center：The University of 
, 
 Tokyo 
 
Investigator：
 
 
 Medical Expert 
Shinichi Sato 
Professor, Department of Dermatology, 
, The 
University of 
 
 
 Contract Research Organization 
1）  Clinical Testing Laboratory 
Corporation, 
 Tokyo
 
 
 
2） Biomarker Measurement Institution 
Corporation, 
 Tokyo
 
 
 
 
3） Anti-Drug Antibody Measurement Institution 
 Corporation, 
 Tokyo
 
 
 
4） Drug Concentration Measurement Institution 
 Laboratories, Ltd.,
 Tokyo 
 
 
 
5） Autoantibody Measurement Institution 
 Corporation, 
 Tokyo 
 
 
 
6） CyTOF Measurement Institution 
, Inc., 
 Tokyo 
 
 

80 
 
33. Contact Information 
 Contact Information 
 Clinical Development Department, Maruho Co., Ltd. 
 Kyoto 
 
TEL 
 (dial in) 
FAX 
 
 
 Emergency Contact (Saturdays and Sundays, National Holidays, Nights) 
 Clinical Development Department, Maruho Co., Ltd. TEL 
 
, Clinical Development Department, Maruho Co., Ltd. TEL 
 
 
 
 

81 
34. References 
1) Sato S. Basics and Clinics of Scleroderma-From Understanding of Clinical Conditions to Current 
Diagnosis. Article in Japanese. Iyaku (Medicine and Drug) Journal Co., Ltd. (2016). 
2) Japan Intractable Diseases Research Foundation [Internet]. Website of Japan Intractable Diseases 
Information Center [cited 2021 Sep 29]. Available from: https://www.nanbyou.or.jp/ 
3) LeRoy E C, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger T A, et al,. Scleroderma (systemic 
sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988 Feb; 15(2): 202-5. 
4) Clements P J, Hurwitz E L, Wong W K, Seibold J R, Mayes M, White B, et al. Skin thickness score as 
a predictor and correlate of outcome in systemic sclerosis: high-dose versus low-dose penicillamine 
trial. Arthritis Rheum. 2000 Nov; 43(11): 2445-54. 
5) Steen V D, Medsger T A. Severe organ involvement in systemic sclerosis with diffuse scleroderma. 
Arthritis Rheum. 2000 Nov; 43(11):2437-44. 
6) Walker U A, Tyndall A, Czirjak L, Denton C, Farge-Bancel D, Kowal-Bielecka O, et al. Clinical risk 
assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials 
And Research group database. Ann Rheum Dis. 2007 Jun; 66(6): 754-63. 
7) Asano Y, Jinnin M, Kawaguchi Y, Kuwana M, Goto D, Sato S, et al. Diagnostic Criteria, Severity 
Classification and Guidelines of Systemic Sclerosis. Jpn J Dermatol. 2016 (126); 1831-96. 
8) Boddor Y, Henry L, Zeinab T, Sara Z, Henrique R, Bahja A A, et al. Interleukin-31 promotes pathogenic 
mechanisms underlying skin and lung fibrosis in scleroderma. Rheumatology (Oxford). 2020 Sep 1; 
59(9): 2625-36. 
9) Matsuda Y, Singh G, Yamanaka H, Tanaka E, Urano W, Taniguchi A, et al. Validation of a Japanese 
version of the Stanford Health Assessment Questionnaire in 3,763 patients with rheumatoid arthritis. 
Arthritis Rheum. 2003 Dec 15;49(6):784-8. 
10) FACIT 
group 
[Internet]. 
FACIT-Fatigue 
[cited 
2021 
Sep 
29]. 
Available 
from: 
https://www.facit.org/measures/FACIT-Fatigue 
11) Kusano M, Shimoyama Y, Sugimoto S, et al. Development and evaluation of FSSG: frequency scale 
fot he symptoms of GERD. J Gastroenterol 2004; 39 :888-91. 
12) Guidelines for Clinical Evaluation of Antirheumatoid Drugs, Notification No. 0217001 of the 
Evaluation and Licensing Division, PFSB dated February 17, 2006  
13) Clements P, Lachenbruch P, Siebold J, White B, Weiner S, Martin R, et al. Inter and intraobserver 
variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol. 1995 
Jul; 22(7) 1281-5. 
14) Clements P J, Lachenburch P A, Seibold J R, Zee B, Steen V D, Brennan P, et al. Skin thickness score 
in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol. 
1993 Non; 20(11): 1892-6. 
15) Nicole S L G, Sujia R D, Srihari V, David M H, Susan J C, Toby M M, et al. Interstitial lung disease in 
systemic sclerosis: a simple staging system. Am J Respir Crit Care Med.2008 Jun 1; 177(11): 1248-54. 
16) Coghlan G G, Denton C P, Grunig E, Bonderman D, Distler O, Khanna D, et al. Evidence-based 
detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. Ann Rheum Dis. 
2014 Jul; 73(7): 1340-9. 
17) Steele R, Hudson M, Lo E, Baron M, Canadian Scleroderma Research Group. Clinical decision rule to 
predict the presence of interstitial lung disease in systemic sclerosis. Arthritis Cae Res (Hoboken). 2012 
Apr; 64(4): 519-24. 
18) Steen V D, Medsger T A. Changes in causes of death in systemic sclerosis, 1972-2002. Ann Rheum Dis. 
2007Jul; 66(7): 940-4. 
19) Khanna D, Berrocal V J, Giannini E H, Seibold J R, Merkel P A, Mayse M D, et al. The American 

82 
College of Rheumatology Provisional Composite Response Index for Clinical Trials in Early Diffuse 
Cutaneous Systemic Sclerosis. Arthritis Rheumatol. 2016 Feb; 68(2): 299-311. 
20) Steen V D, Medsger Jr T A. The value of the Health Assessment Questionnaire and special patient-
generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum. 1997 
Nov; 40(11): 1984-91. 
21) Hant F N, Ludwicka-Bradley A, Wang H J, Li N, Elashoff R, Tashkin D P, Silver R M. Surfactant 
protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. J 
Rheumatol. 2009 Apr; 36(4): 773-80. 
22) Cavagna L, Caporali R, Klersy C, Ghio S, Albertini R, Scelsi L. Comparison of brain natriuretic peptide 
(BNP) and NT-proBNP in screening for pulmonary arterial hypertension in patients with systemic 
sclerosis. J Rheumatol. 2010 Oct; 37(10): 2064-70. 
23) Allanore Y, Wahbi K, Borderie D, Weber S, Kahan A, Meune C. N-terminal pro-brain natriuretic peptide 
in systemic sclerosis: a new cornerstone of cardiovascular assessment?. Ann Rheum Dis. 2009 
Dec;68(12):1885-9. 
24) Shankar, G., Arkin, S., Cocea, L., Devanarayan, V., Kirshner, S., Kromminga, A., et al. Assessment and 
reporting of the clinical immunogenicity of therapeutic proteins and peptides—harmonized terminology 
and tactical recommendations. The AAPS journal. 2014; 16(4): 658-673. 
 

List of Definitions of Abbreviations and Technical Terms 
 
Acronym/Abbreviation/ 
Technical term 
Full text/Definition 
ACR-CRISS 
American College of Rheumatology Combined Response Index in 
diffuse cutaneous Systemic Sclerosis 
ADL 
Activities of daily living 
AE 
Adverse events 
AIDS 
Acquired immunodeficiency syndrome 
ALB 
Albumin 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma/serum concentration-time curve 
AUC0-28day 
Area under the serum concentration-time curve 0-28day 
AUClast 
Area under the serum concentration-time curve from zero to last 
observed concentration time point 
A/G ratio 
Albumin-Globulin ratio 
BLQ 
Below the lower limit of quantification 
CBA 
Cell-based assay 
CK 
Creatine kinase 
Cmax 
Maximum concentration in plasma/serum 
COVID-19 
Coronavirus disease 2019 
CREA 
Creatinine 
CRP 
C reactive protein 
CTCAE 
Common terminology criteria for adverse events 
CyTOF 
Cytometry by time of flight 
D-Bil 
Direct bilirubin 
DCS 
Dual chamber syringe 
dcSSc 
Diffuse cutaneous SSc 
DLco 
Diffusing capacity of lung for carbon monoxide 
ECG 
Electrocardiogram 
ECL 
Electro Chemi Luminescence 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EULAR 
European League Against Rheumatism 
FAS 
Full analysis set 
FACIT-Fatigue 
Functional assessment of chronic illness therapy-Fatigue 
FEV1 
Forced expiratory volume in one second 
FSSG 
Frequency Scale for the Symptoms of GERD 
FU 
Follow up 
FVC 
Forced vital capacity 
GCP 
Good clinical practice 

Acronym/Abbreviation/ 
Technical term 
Full text/Definition 
γ-GT 
γ-Glutamyl transpeptidase 
HAQ-DI 
Health assessment questionnaire disability index 
Hb 
Hemoglobin 
HBc antibody 
Hepatitis B core antibody 
HBs antigen 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
hCG 
human chorionic gonadotrophin 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein cholesterol 
HIV 
Human immunodeficiency virus 
HRCT 
High-resolution computed tomography 
Ht 
Hematocrit 
IL 
Interleukin 
IL-31RA 
Interleukin-31 receptor A 
IP 
Investigational product 
IRB 
Institutional review board 
JCOG 
Japan clinical oncology group 
KL-6 
Krebs von den lungen-6 
lcSSc 
Limited cutaneous SSc 
LDH 
Lactic acid dehydrogenase 
LDL-C 
Low density lipoprotein cholesterol 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA/J 
Medical dictionary for regulatory activities / Japanese edition 
mRSS 
Modified rodman total skin thickness score 
nemolizumab 
Humanized anti-human interleukin-receptor A (IL-31RA) monoclonal 
antibody 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
PAH 
Pulmonary arterial hypertension 
PGA 
Physician’s global assessment 
Plt 
Platelet 
PT 
Preferred term 
PtGA 
Patient’s global assessment 
QFT-3G 
QuantiFERON-TB Gold 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SP-D 
Surfactant protein D 
SOC 
System organ class 
SSc 
Systemic sclerosis 
TARC 
Thymus and activation-regulated chemokine 

Acronym/Abbreviation/ 
Technical term 
Full text/Definition 
T-Bil 
Total-bilirubin 
TC 
Total cholesterol 
TG 
Triglyceride 
TLC 
Total lung capacity 
tmax 
Time to reach the maximum concentration in plasma/serum 
TP 
Total protein 
T-SPOT 
T-SPOT®.TB 
UA 
Uric acid 
UN 
Urea nitrogen 
VAS 
Visual analogue scale 
WBC 
White blood cell 
 
 
 

Synopsis-5 
Protocol Synopsis 
 
1. Study objectives 
 Primary Objective 
To exploratorily evaluate the efficacy of nemolizumab in systemic sclerosis (SSc) patients with moderate to 
severe skin thickening 
 
 Secondary Objective 
To evaluate the safety and pharmacokinetics of nemolizumab in SSc patients with moderate to severe skin 
thickening 
 
2. Study Design 
This is a phase II, single-arm, multiple-dose study consisting of a pre-treatment observation period (1-4 
weeks) and a treatment period (52 weeks). The pre-treatment observation period is from the day of screening 
to the day of study treatment initiation, and participants will visit the site a total of twice, for screening and 
for study treatment initiation. Treatment period is from the day of study treatment initiation   and every 4 
weeks thereafter. Participants having received study treatment will be followed up 84 days after the day of 
the last dose of study treatment. Follow-up period is from Visit17 (Week 52) or the day of discontinuation 
visit to the day of follow-up visit. 
 
Study phase: Phase II 
 
Study type: Open-label, single-arm, multiple-dose study 
Participants: SSc patients with moderate to severe skin thickening 
Target Sample Size: 8 participants 
 
Figure 2-1: Study Schema 
 
 
 
 
 
 
 
 
 
 
1） Pre-treatment observation period 
The investigator or subinvestigator will make observations and assessments at the screening visit 
specified in Table 4-1 after obtaining informed consent from the participant. 
  
2） Treatment period 
The investigator or subinvestigator will administer the investigational product (IP) (nemolizumab, 60 
mg/body) every 4 weeks (Q4W) at visits until Week 48 after making observations and assessments on 
the day of study treatment initiation specified in Table 4-1. In addition, the investigator or 
subinvestigator will make perform observations and assessments at each visit specified in Table 4-1. 
 
Treatment period (52 weeks) 
Follow-up period 
Nemolizumab 60 mg/body n = 8 
IC 
Screening 
Start 
 treatment 
Week 1 
Week 2 
Week 4 
Visit every 4 weeks 
Week 52 
Follow-up visit 
Pre-treatment 
observation period 

Synopsis-6 
3） Follow-up period 
All participants having received the IP will be scheduled to visit for follow-up 12 weeks after the day 
of the last dose of study treatment (the day of follow-up visit). On the day of the follow-up visit, the 
investigator or subinvestigator will evaluate the safety and efficacy after completion of study treatment 
for all participants. 
 
3. Target Indication and Inclusion and Exclusion Criteria for Patients 
 Target Indication 
SSc 
 
 Inclusion Criteria 
Participants must meet all of the following criteria for study entry: 
Inclusion Criteria 
Assessment timing  
Day of 
Informed 
Consent  
Day of 
Screening 
Day of 
treatment start 
1） Patients aged 20 to 70 years at the time of informed 
consent 
X 
– 
– 
2） Patients meeting the classification criteria for SSc in ACR 
and EULAR 2013 
X 
– 
– 
3） Patients with systemic sclerosis who have moderate to 
severe skin thickening, with mRSS of 10 to 22 on both the 
screening and treatment initiation dates 
– 
X 
X 
4） Patients considered by the investigator or subinvestigator 
to be competent to perform the protocol-specified self-
assessment 
X 
X 
X 
 
 Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from study entry: 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
1） Patients complicated with diseases considered inappropriate 
for participation in clinical trials, such as serious* 
cardiac/hepatic/renal/pulmonary/hematologic disease 
*Refer to the Criteria for Seriousness Classification of Adverse 
Drug Reactions. (PAB/SD Notification No.80 by the Director 
of Safety Division, Pharmaceutical Affairs Bureau, Ministry of 
Health and Welfare dated June 29, 1992) and the Common 
Terminology Criteria for Adverse Events v 5.0 Japanese JCOG 
version (CTCAE v 5.0-JCOG). 
X 
X 
X 
2） Patients complicated with congestive heart failure [New York 
Heart Association (NYHA) Functional Class III or IV] 
X 
X 
X 
3） Patients having any of the following complications or 
concomitant/concurrent diseases: 
a） Severe chronic pulmonary disease (including %FVC < 
60%, or %DLco < 40% on the day of screening, 
calculated from the New Reference Values for 
Spirometry in Japanese adults calculated with the LMS 
X 
X 
X 

Synopsis-7 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
Method (the Japanese Respiratory Society)”  
b） Serious complications associated with SSc other than 
interstitial lung disease* (e.g., renal crisis) 
* Interstitial lung disease is excluded if it falls under Item 
a) of 3)  
c） Poorly 
controlled 
asthma 
that 
requires 
steroids 
(systemic), intravenous infusion of aminophylline, 
subcutaneous injection of adrenaline 0.1%, oxygen 
inhalation, or antibody drugs  
d） Diseases to affect the assessment of SSc 
4） Patients with a history of malignant tumor, who are receiving 
no treatment and have had no recurrence /relapse for ≥5 years 
at the time of informed consent, or patients with a history of 
radical treatment for cervical intraepithelial neoplasia at the 
time of informed consent may be included in the study 
X 
X 
X 
5） Patients 
with 
Immune 
deficiency 
(e.g., 
congenital 
immunodeficiency, AIDS, or HIV). 
X 
X 
X 
6） Patients with a history or current hypersensitivity (including 
anaphylaxis) to immunoglobulin products (plasma-derived 
preparations or genetic recombinant monoclonal antibodies) 
X 
X 
X 
7） Patients weighing < 30.0 kg or > 120 kg on the day of study 
treatment initiation 
– 
– 
X 
8） Patients whose laboratory test values on the day of screening 
meet any of the following criteria: 
a） AST or ALT > 2 times the upper limit of normal 
b） Serum creatinine ≥2.0 mg/dL 
c） WBC <3000 cells/μL 
– 
– 
X 
9） Patients infected with hepatitis B virus (HBV) or hepatitis C 
virus (HCV) (Positive for HBs antigen or HBc antibody on the 
day of screening, positive for anti-HCV antibody on the day of 
screening) 
The allowed exceptions are as follows: 
 
Patients confirmed not to be infected with HBV at the 
time of the HBV-DNA test performed before study 
treatment initiation in the case of negative for HBs 
antigen and positive for HBc antibody in the hepatitis B 
test performed on the day of screening. 
 
Patients confirmed not to be infected with HCV at the 
time of the HCV-RNA test performed before study 
treatment initiation in the case of positive for anti-HCV 
antibody in the hepatitis C test performed on the day of 
screening 
– 
– 
X 
10） Patients with latent or active tuberculosis based on the result 
of the screening TB test. The allowed exception is patients 
deemed not to be infected with tuberculosis according to the 
“Guidelines for the use of interferon-γ release assay 
(Prevention Committee of the Japanese Society for 
Tuberculosis).  
– 
– 
X 
11） Patients with either of the following infectious diseases: 
 
Recurrent/chronic infections or other active infections 
X 
X 
X 

Synopsis-8 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
deemed by the investigator to possibly aggravated by 
participating in the study. 
 
Infections (including skin infections) requiring systemic 
antibiotics, antivirals, or antifungals within 7 days prior 
to the day of study treatment initiation. 
12） Patients who have received oral steroids (> 10 mg/day of 
prednisolone or equivalent), dosage of receiving oral steroids 
have been changed (from ≤ 10 mg/day of prednisolone or 
equivalent), or newly treated with oral steroids, within 14 days 
before the day of study treatment initiation 
– 
– 
X 
13） Patients who have received any of the following therapies 
within the indicated period prior to the day of study treatment 
initiation 
– 
(X)* 
X 
a） Within 365 days 
Cyclophosphamide 
b） Within 120 days or 5 
times the elimination 
half-life of the drug, 
whichever is longer 
Antibody drugs 
c） Within 28 days 
 
Live vaccines 
 
The 
following 
systemic 
medications: 
− Antifibrotic 
drugs 
(e.g., 
pirfenidone, nintedanib) 
− Immunosuppressants 
(e.g., 
cyclosporine, 
tacrolimus, 
azathioprine, mycophenolate 
mofetil, 
mizoribine, 
sulfasalazine, 
leflunomide, 
methotrexate, 
hydroxychloroquine, 
D-
penicillamine, sirolimus) 
− Tyrosine kinase inhibitors 
(e.g., imatinib) 
− JAK 
inhibitors 
(e.g., 
tofacitinib, upadacitinib) 
− Endothelin receptor agonists 
(e.g., bosentan, ambrisentan, 
macitentan) 
− Phosphodiesterase-5 
inhibitors (e.g., sildenafil, 
tadalafil) 
− Prostaglandin analogue (e.g., 
alprostadil, epoprostenol) 
− Riociguat 
 
Injections of corticosteroids 
(excluding joint injections) 
 
Phototherapy 

Synopsis-9 
*The exclusion criteria will be assessed with the expected date of study treatment initiation as the starting 
point.
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
 
High-dose 
intravenous 
immunoglobulin therapy 
14） Patients who are within 120 days from the end of participation 
in other clinical trials or post-marketing clinical studies (i.e., 
the last day of administration of another IP or post-marketing 
clinical study drug) until the day of study treatment initiation, 
or participating in other clinical trials or post-marketing 
clinical studies 
– 
(X)* 
X 
15） Women who are pregnant, breastfeeding, possibly pregnant, 
or unwilling to use appropriate contraception measures as 
instructed by the investigator during the study period 
X 
X 
X 
16） Patients who meet any of the following criteria: 
a） Having not met eligibility for participation when 
participating in this study in the past 
d） Having previously received nemolizumab (including 
placebo) 
X 
X 
X 
17） Patients with confirmed or suspected COVID-19 
– 
X 
X 
18） Patients with a history of confirmed or suspected COVID-19 
excluding those meeting any of the following criteria: 
• At least 20 days after the onset of symptoms and at 
least 72 hours after the resolution of symptoms. 
• Confirmed not to carry SARS-Cov-2. 
– 
X 
X 
19） Patients found to have close contacts with COVID-19 patients 
within 14 days before the day of study treatment initiation  
– 
– 
X 
20） Other patients who are considered ineligible for the study by 
the investigator 
X 
X 
X 

Synopsis-13 
e Not to be performed if refused by the participant. 
If any of the following treatment-emergent adverse events occurs, photographs of the affected skin areas of the adverse event should be taken while the event (at least once) is 
occurring and at the final outcome evaluation, in addition to the scheduled visit (i.e., the day of study treatment initiation).  
• Atopic dermatitis 
• Adverse events with skin symptoms of edematous erythema or scaling 
• Any other adverse event for which the investigator or subinvestigator considers that photography is necessary. 
f To be performed on female participants excluding those who never become pregnant. 
g May be conducted on another day after the day of screening before the day of study treatment initiation 
h To be administered after all observation/tests are performed. If the IP cannot be administered within the window indicated, the next dose should be administered 14 days or later 
after the day of the previous dose. 
i Participants who discontinued the study will visit the site 84 days (±7 days) after the day of the last dose of study treatment for observation/tests at FU shown in Table 4-1. Participants 
discontinued the study before study treatment initiation need not to undergo observation/tests scheduled on the day of visit for discontinuation. 

Synopsis-14 
5. Treatment Method 
 Method of Administration 
The investigator or subinvestigator will slowly administer the IP, nemolizumab (one DCS [0.6 ml]) 
subcutaneously to the upper arm, abdomen, or thigh of the participants. The IP may be administered by a 
person qualified to administer it under the instruction of the investigator or subinvestigator.  
 
 Treatment Period 
52 weeks 
All participants who have received at least one dose of the IP will visit the site 12 weeks after the day of the 
last dose of study treatment for follow-up. 
 
 Concomitant Medications and Therapies  
5.3.1  Restricted Concomitant Medications 
The following medications may be continued at a stable dose if used for at least 14 days before the day of 
study treatment initiation. However, the dose may be reduced at the discretion of the investigator or 
subinvestigator, and after dose reduction, the dose may be increased up to that used at the day of study 
treatment initiation. 
•Oral steroids (≤ 10 mg/day of prednisolone or equivalent) 
 
5.3.2  Prohibited Concomitant Medications and Therapies  
Concomitant use of medications and therapies listed below is prohibited in this study.  
- 
From the day of study treatment initiation to Week 52 or to the physical examination on the day of visit 
for discontinuation 
1） The following systemic medications: 
a） Antifibrotic drugs (e.g., pirfenidone, nintedanib) 
b） Immunosuppressants 
(e.g., 
cyclophosphamide, 
cyclosporine, 
tacrolimus, 
azathioprine, 
mycophenolate mofetil, mizoribine, sulfasalazine, leflunomide, methotrexate, hydroxychloroquine, 
D-penicillamine, sirolimus) 
c） Tyrosine kinase inhibitors (e.g., imatinib) 
d） JAK inhibitors (e.g., tofacitinib, upadacitinib) 
e） Endothelin receptor agonists (e.g., bosentan, ambrisentan, macitentan) 
f） Phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil) 
g） Prostaglandin analogues (e.g., alprostadil, epoprostenol) 
h） Riociguat 
2） Injections of corticosteroids (excluding joint injections) 
3） Phototherapy 
4） High-dose intravenous immunoglobulin therapy 
5） Antibody drugs 
6） Live vaccines 
 
- 
From the day of study treatment initiation to the day of follow-up visit 
1） Other drugs and medical devices under development 
 
 

Synopsis-15 
6. Study Discontinuation of Individual Participants  
 Discontinuation Criteria 
1） Use of other antibody drugs by Week 52 visit 
2） Use of live vaccines by Week 52 visit 
3） The investigator or subinvestigator determined that an adverse event which would prevent the 
continuation of the study has occurred. 
4） The participant is found to fail to meet any of the inclusion criteria or to meet any of the exclusion 
criteria. 
5） The participant is found to be pregnant. 
6） The investigator or subinvestigator has determined that the participant should be withdrawn from the 
study due to inadequate response to the IP. 
7） The participant requests to withdraw from the study. 
8） The participant no longer visits the medical institution, and the study cannot be continued. 
9） The participant has died. 
10） The sponsor has determined the participant discontinuation from the study due to significant protocol 
deviations. 
11） The sponsor has prematurely terminated the study. 
12） The investigator or subinvestigator has determined to withdraw the participant from the study for any 
other reasons. 
 
7. Efficacy Evaluation 
 Primary Endpoint 
Change from baseline in mRSS at Week 24 
 
 Other Endpoints 
1） Change from baseline in mRSS at Week 52 
2） Change from baseline in HAQ-DI at Week 52 
3） Change from baseline in HAQ-DI at Week 24 
4） Change from baseline in %FVC at Week 52 
5） Change from baseline in %FVC at Week 24 
6） Change from baseline in DLco at Week 52 
7） Change from baseline in DLco at Week 24 
8） Change from baseline in PGA at Week 52 
9） Change from baseline in PGA at Week 24 
10） Change from baseline in PtGA at Week 52 
11） Change from baseline in PtGA at Week 24 
12） ACR-CRISS at Week 52 
13） ACR-CRISS at Week 24 
14） Change from baseline in the number of digital ulcers at Week 52 
15） Change from baseline in the number of digital ulcers at Week 24 
16） Time-course change in the following items: 
a） HAQ-DI 
b） FACIT-Fatigue 
c） FSSG 
d） FVC 

Synopsis-16 
e） %FVC 
f） DLco 
g） %DLco 
h） TLC 
i） FEV1 
j） Severity evaluation of lung lesion 
k） PGA 
l） PtGA 
m） ACR-CRISS 
n） The number of digital ulcers 
 
8. Safety Evaluation 
 Assessments for Safety Evaluations 
1） Adverse events 
a） Symptoms and signs 
b） Abnormal laboratory test values 
c） Abnormal vital signs 
d） Abnormal electrocardiograms 
2） Laboratory test values 
3） Vital signs 
4） Electrocardiogram 
5） Echocardiography 
 
9. Target Sample Size 
8 participants 
 
10. Study Period 
December 2021 to October 2023

 
Table of Contents 
 
1. Introduction ........................................................................................................... 22 
 Background of Development ................................................................................................ 22 
1.1.1 Pathophysiology and epidemiology of systemic sclerosis ............................................. 22 
1.1.2 Therapeutic treatment of systemic sclerosis and its issues .......................................... 22 
1.1.3 Summary description and significance of the development of nemolizumab ............... 22 
 Guidelines, Consultation with Pharmaceuticals and Medical Devices Agency (PMDA), 
etc., Referenced for Study Planning .................................................................................... 23 
2. Study objectives ................................................................................................... 24 
 Primary Objective ................................................................................................................. 24 
 Secondary Objective............................................................................................................. 24 
3. Study Design ........................................................................................................ 24 
4. Target Indication and Inclusion and Exclusion Criteria for Participants ................. 25 
 Target Indication ................................................................................................................... 25 
 Inclusion Criteria ................................................................................................................... 25 
 Exclusion criteria ................................................................................................................... 25 
5. Study Discontinuation of Individual Participants ................................................... 29 
 Discontinuation criteria ......................................................................................................... 29 
 Procedure for Discontinuation .............................................................................................. 30 
5.2.1 Discontinuation before Enrollment ................................................................................. 30 
5.2.2 Discontinuation after Enrollment .................................................................................... 30 
 Handling of Participants Who Fail to Visit the Study Site ..................................................... 30 
5.3.1 Participants Discontinuing Study Site Visit Between the Day of Informed Consent and 
the Day of Enrollment ................................................................................................... 30 
5.3.2 Participants Discontinuing Study Site Visit in the Period after the Enrollment up to 
Visit 17 (Week 52) ......................................................................................................... 30 
5.3.3 Participants Discontinuing Study Site Visit during the Follow-up Period ...................... 30 
6. Participant Enrollment........................................................................................... 31 
 Informed Consent ................................................................................................................. 31 
 Notification when the Participant is Treated by Another Doctor ........................................... 31 
 Enrollment Procedure of Participants ................................................................................... 31 
7. Investigational Product ......................................................................................... 31 
 Name, Dosage Form, and Strength of the IP ....................................................................... 31 
 Packaging and Labeling ....................................................................................................... 32 
7.2.1 Packaging ...................................................................................................................... 32 
7.2.2 Labeling .......................................................................................................................... 32 
 Storage and Management of Investigational Products ........................................................ 32 
8. Treatment Method ................................................................................................ 32 
 Dispensing of Investigational Products ................................................................................ 32 
 Preparation of Investigational Products ............................................................................... 32 
 Method of Administration ...................................................................................................... 32 
 Concomitant Medications and Therapies ............................................................................. 33 
8.4.1 Restricted Concomitant Medications ............................................................................. 33 
8.4.2 Duration and Method of Inspection ................................................................................ 33 

 
8.4.3 Prohibited Concomitant Medications and Therapies ..................................................... 33 
8.4.4 Instructions to participants ............................................................................................. 34 
9. Study Procedures and Assessments and the Schedule ....................................... 35 
 Schedule of Study Procedures and Assessments ............................................................... 35 
 Definition of the Days of Observation, Tests, and Sample Collection .................................. 39 
9.2.1 Day of Informed Consent ............................................................................................... 39 
9.2.2 Day of screening ............................................................................................................ 39 
9.2.3 Day of Study Treatment Initiation ................................................................................... 39 
9.2.4 Day of Assessment (Weeks 1, 2, 4, 8, 12, through 52) ................................................. 39 
9.2.5 Day of Study Treatment ................................................................................................. 39 
9.2.6 Day of Discontinuation ................................................................................................... 39 
9.2.7 Day of Discontinuation Visit ........................................................................................... 39 
9.2.8 Day of Follow-up Visit .................................................................................................... 39 
 Observation, Tests and Sample Collection........................................................................... 39 
9.3.1 Participant Demographics .............................................................................................. 39 
9.3.2 Prior and Concomitant Medications and Therapies ...................................................... 40 
9.3.3 Body Weight ................................................................................................................... 41 
9.3.4 Efficacy Evaluation ......................................................................................................... 41 
9.3.5 Safety Evaluation ........................................................................................................... 43 
9.3.6 Laboratory tests ............................................................................................................. 44 
9.3.7 Pharmacokinetics ........................................................................................................... 46 
9.3.8 Immunogenicity .............................................................................................................. 46 
9.3.9 Biomarker measurement ................................................................................................ 46 
9.3.10 Comprehensive measurement of autoantibodies ........................................................ 47 
9.3.11 CyTOF measurement ................................................................................................... 47 
9.3.12 Assessment of Adverse Events ................................................................................... 47 
9.3.13 Investigation of Malfunction of DCS ............................................................................ 47 
9.3.14 Amount of Blood and Urine Samples to be Collected ................................................. 48 
10. Efficacy Evaluation ............................................................................................. 49 
 Efficacy Assessments ......................................................................................................... 49 
10.1.1 Assessment of Skin Findings ....................................................................................... 49 
10.1.2 Respiratory Function Test ............................................................................................ 49 
10.1.3 Chest HRCT ................................................................................................................. 49 
10.1.4 Severity Classification of Lung Lesion ......................................................................... 49 
10.1.5 ACR-CRISS .................................................................................................................. 50 
10.1.6 The Number of Digital Ulcers ....................................................................................... 50 
10.1.7 Patient-reported outcome ............................................................................................ 50 
10.1.8 Global improvement rating ........................................................................................... 51 
 Efficacy Endpoints .............................................................................................................. 51 
10.2.1 Primary Endpoint ......................................................................................................... 51 
10.2.2 Other Endpoints ........................................................................................................... 51 
 Rationale for Efficacy Endpoints ........................................................................................ 52 
11. Safety Evaluation ................................................................................................ 54 
 Assessments for Safety Evaluations .................................................................................. 54 
 Definition of Adverse Events ............................................................................................... 54 
 Definitions of Safety Endpoints ........................................................................................... 55 

 
 Review and reporting of adverse events ............................................................................ 56 
 Review and reporting of serious adverse events ............................................................... 58 
 Reporting of adverse events of special interests (AESIs) .................................................. 58 
 Photography ........................................................................................................................ 58 
 Reporting of the Pregnancy of the Participant .................................................................... 58 
 Rationale for Safety Endpoints ........................................................................................... 59 
 Follow-up of Adverse Events ............................................................................................ 59 
 Malfunctions of DCS ......................................................................................................... 59 
11.11.1 Reporting of Malfunctions of DCS .............................................................................. 59 
11.11.2 Collection and Reporting of Malfunction Information on DCS occurring at the Stage 
of Use on Participants ................................................................................................... 59 
11.11.3 Storage of Malfunctioning DCS .................................................................................. 59 
 Anticipated Adverse Drug Reactions ................................................................................ 59 
12. Biomarkers ......................................................................................................... 60 
 Measurements of Biomarkers............................................................................................. 60 
 Blood Biomarker Outcome Measures ................................................................................ 60 
 Measurement Method and Reporting of Results................................................................ 61 
13. Pharmacokinetics ............................................................................................... 61 
 Pharmacokinetic Measurements ........................................................................................ 61 
 Pharmacokinetic Outcome Measures ................................................................................ 61 
 Measurement Method and Reporting of Results................................................................ 61 
14. Immunogenicity .................................................................................................. 62 
 Immunogenicity Measurements ......................................................................................... 62 
 Immunogenicity Outcome Measures .................................................................................. 62 
 Measurement Method and Reporting of Results................................................................ 62 
15. Comprehensive Measurement of Autoantibodies ............................................... 62 
 Measurement Method and Reporting of Results................................................................ 62 
16. CyTOF measurement ......................................................................................... 63 
 Measurement Method and Reporting of Results................................................................ 63 
17. Statistical Analysis .............................................................................................. 63 
 Analysis Sets ...................................................................................................................... 63 
17.1.1 Efficacy Analysis Set (Full Analysis Set: FAS) ............................................................. 63 
17.1.2 Safety Analysis Set ...................................................................................................... 64 
17.1.3 Pharmacokinetics Analysis Set .................................................................................... 64 
17.1.4 Biomarker Analysis Set ................................................................................................ 64 
 Data Handling ..................................................................................................................... 64 
17.2.1 Common Rules ............................................................................................................ 64 
17.2.2 Data Handling on Pharmacokinetics ........................................................................... 64 
 Statistical Analysis Plan ...................................................................................................... 65 
17.3.1 Demographic and Other Baseline Characteristics, and Severity of Primary Disease 65 
17.3.2 Efficacy Analysis .......................................................................................................... 65 
17.3.3 Safety Analysis ............................................................................................................. 66 
17.3.4 Analyses of Drug Concentrations and Pharmacokinetic Parameters ......................... 66 
17.3.5 Analysis of Immunogenicity ......................................................................................... 67 
17.3.6 Analysis of Biomarker .................................................................................................. 67 

 
 Determination of Sample Size ............................................................................................ 67 
17.4.1 Target Sample Size ...................................................................................................... 67 
17.4.2 Rationale for Sample Size ........................................................................................... 67 
 Data Review ....................................................................................................................... 67 
18. Agreement on the Protocol and Protocol Deviation/Amendment ........................ 68 
 Agreement of and Compliance with the Protocol ............................................................... 68 
 Protocol Deviation/Amendment .......................................................................................... 68 
19. Case Report Form .............................................................................................. 69 
 Data to be collected in CRF................................................................................................ 69 
19.1.1 Participants assigned to treatment .............................................................................. 69 
19.1.2 Participants Who Discontinue the Study before study entry after screening and 
those Who Discontinue the Study before enrollment ................................................... 70 
 Source Data for Information Entered in Case Report Form ............................................... 70 
 Information in the Case Report Forms Treated as Source Data ........................................ 71 
 Guidelines for Preparation of Case Report Form ............................................................... 71 
 Modification and Amendment to Case Report Forms ........................................................ 71 
20. Follow-up report of adverse events of special interest ........................................ 71 
21. Direct Access to Source Documents .................................................................. 72 
22. Quality Control and Quality Assurance ............................................................... 72 
23. Completion, Discontinuation, or Interruption of the Study ................................... 72 
 Completion of the Study ..................................................................................................... 72 
 Discontinuation or Interruption of the Study ....................................................................... 72 
24. Archiving of Records ........................................................................................... 73 
25. Publication Policy ............................................................................................... 73 
26. Use of study-related data .................................................................................... 73 
27. Ethics .................................................................................................................. 74 
 Institutional Review Board .................................................................................................. 74 
 Ethical Conduct of the Study .............................................................................................. 74 
 Protection of Participants’ Confidentiality ........................................................................... 74 
 Participant Selection and Informed Consent ...................................................................... 74 
27.4.1 Participant Selection .................................................................................................... 74 
27.4.2 Informed Consent ........................................................................................................ 74 
27.4.3 Explanations to Participants ........................................................................................ 75 
28. Payments ............................................................................................................ 76 
29. Compensation for Injuries ................................................................................... 76 
30. Responses to COVID-19 .................................................................................... 76 
 If participants are found to have confirmed COVID-19 (including asymptomatic pathogen 
carriers) or suspected COVID-19, or found to have been in close contact with a confirmed 
or suspected COVID-19 patient ........................................................................................... 76 
 Discontinuation of the study due to the influence of COVID-19 ......................................... 78 
 Deviations from the protocol due to the influence of COVID-19 ........................................ 78 
31. Study Period ....................................................................................................... 78 
32. Administrative Structure ...................................................................................... 78 
 Sponsor............................................................................................................................... 78 

 
 Sponsor Organization ......................................................................................................... 78 
 Study Sites and Investigators ............................................................................................. 79 
 Medical Expert .................................................................................................................... 79 
 Contract Research Organization ........................................................................................ 79 
33. Contact Information ............................................................................................ 80 
 Contact Information ............................................................................................................ 80 
 Emergency Contact (Saturdays and Sundays, National Holidays, Nights) ....................... 80 
34. References ......................................................................................................... 81 
 
 
 
 

22 
1. Introduction 
 Background of Development 
1.1.1  Pathophysiology and epidemiology of systemic sclerosis 
Systemic scleroderma (SSc) is a systemic autoimmune disease characterized by fibrosis and vasculopathy 
of skin and various internal organs such as lung and classified as a connective tissue disease. Skin fibrosis, a 
common symptom in patients with SSc, is considered to be excessive deposition of the extracellular matrix 
mainly composed of collagen. 1) In Japan, SSc is designated as an intractable disease; according to the 
information of the Japan Intractable Diseases Information Center, the number of SSc patients is about 20,000. 
2) The male-to-female ratio of patients is 1:12 and is more prevalent in women between the ages of 30 and 
50 years. 
SSc is classified as either diffuse cutaneous systemic scleroderma (dcSSc) in which skin thickening 
extends to the proximal extremities (i.e. the upper arms and the thighs) or the trunk or limited cutaneous 
systemic scleroderma (lcSSc) in which skin thickening is limited to the distal extremities (i.e. the forearms 
and the lower legs) and the face.3) In dcSSc patients, as skin thickening progresses, visceral involvement such 
as in the lungs, gastrointestinal tract, kidneys, and heart, and joint flexion contracture progress. In dcSSc in 
particular, it is widely recognized that the degree of skin thickening correlates with that of fibrotic lesions in 
internal organs, and higher severity of skin thickening has been reported to be associated with higher rates of 
visceral involvement including in the lungs and lower survivals. 4), 5), 6) In addition, fibrosis of internal organs, 
as well as skin thickening, develops at an early stage, in which slight tissue damage accumulates and 
progresses to irreversible organ damage. Therefore, treatment should be initiated as early as possible, 
especially in patients in whom the condition is predicted to become severe. In lcSSc patients, on the other 
hand, skin thickening progresses slowly and are not eligible for aggressive treatment. However, lcSSc with 
the possibility of rapid and widespread progression of skin thickening may be eligible for treatment.7) 
 
1.1.2  Therapeutic treatment of systemic sclerosis and its issues 
The etiology of SSc has not been clarified, and the main treatment methods are symptomatic treatments 
and disease-modifying drugs that inhibit disease progression. The progression and sites of involvement of 
SSc are different for each patient, and accordingly, the treatment method is selected based on the symptom 
of each patient. 
Diagnostic Criteria, Severity Classification and Guidelines of Systemic Sclerosis7) state that oral 
corticosteroids are thought to be empirically valid for patients with progressing skin thickening at an early 
stage but that they have risk factors for inducing renal crisis. Cyclophosphamide is the most recommended 
treatment option for both skin thickening and interstitial lung disease in patients with SSc; however, it has a 
problem of difficulty in long-term administration because of its carcinogenicity, immunosuppression, and 
side effects of drug such as hemorrhagic cystitis. Other drugs for SSc symptoms are prostacyclin, endothelin 
receptor antagonists, and phosphodiesterase-5 inhibitors for the treatment of pulmonary hypertension, 
calcium channel blockers for the treatment of cardiac involvement, intravenous prostaglandin E1 or 
prostacyclin for the treatment of disturbed blood flow in the fingers, and proton pump inhibitors for the 
treatment of reflux esophagitis. However, due to limited efficacy or safety issues of these therapeutic agents, 
the disease burden remains high and there is a great unmet medical need. 
 
1.1.3  Summary description and significance of the development of nemolizumab 
Nemolizumab is a monoclonal antibody that recognizes interleukin-31 receptor A (IL-31RA) in humans, 
which competitively inhibits the binding of interleukin-31 (IL-31) to its receptor, thereby blocking 
subsequent signal transduction into the cells. Nemolizumab was initially developed by 
 
Co., Ltd.; the worldwide development and marketing rights, except in Japan and Taiwan, 

23 
were granted to
 in 2016, while the development and marketing rights in the field of skin 
diseases in Japan were granted to 
. 
IL-31 is a cytokine produced mainly from activated T cells. IL-31 is present at higher levels in serum in 
SSc than in healthy individuals; IL-31 positive cells were identified in inflammatory infiltrates in fibrotic 
lesions in the skin and lungs8). Moreover, an in vitro study with dermal fibroblasts from healthy individuals 
showed IL-31 increased collagen production in these cells, and IL-31 administration to mice induced skin 
and lung fibrosis in an in vivo study, suggesting that IL-31 induces skin and lung fibrosis via inducing 
collagen production in fibroblasts8).These results indicate that IL-31 is a key cytokine involved in the 
development of SSc, and therefore, nemolizumab is expected to inhibit the progression of or ameliorate of 
skin and pulmonary fibrosis in SSc. 
From the above, nemolizumab is considered to be a possible new treatment option for SSc. Thus, this study 
has been developed to explore the efficacy and safety of nemolizumab in SSc patients. 
 
 Guidelines, Consultation with Pharmaceuticals and Medical Devices Agency (PMDA), etc., 
Referenced for Study Planning 
 
This study has been planned in reference to the “Diagnostic criteria, severity classification and guidelines of 
systemic sclerosis.” 

25 
All participants having received the IP will be scheduled to visit for follow-up 12 weeks after the day 
of the last dose of study treatment (the day of follow-up visit). On the day of the follow-up visit, the 
investigator or subinvestigator will evaluate the safety and efficacy after completion of study treatment 
for all participants. 
 
4. Target Indication and Inclusion and Exclusion Criteria for Participants 
The investigator or subinvestigator will ensure before enrollment that all inclusion criteria are met and none 
of the exclusion criteria are met. 
 
 Target Indication 
SSc 
 
 Inclusion Criteria 
Participants must meet all of the following criteria for study entry: 
Inclusion Criteria 
Assessment timing  
Day of 
Informed 
Consent  
Day of 
Screening 
Day of 
treatment start 
1） Patients aged 20 to 70 years at the time of informed 
consent 
X 
– 
– 
2） Patients meeting the classification criteria for SSc in ACR 
and EULAR 2013 
X 
– 
– 
3） Patients with systemic sclerosis who have moderate to 
severe skin thickening, with mRSS of 10 to 22 on both the 
screening and treatment initiation dates 
– 
X 
X 
4） Patients considered by the investigator or subinvestigator 
to be competent to perform the protocol-specified self-
assessment 
X 
X 
X 
 
 Rationale for inclusion criteria 
1) 
Established for safety consideration and to select patients with a sufficient capacity 
for judgment 
2) 
Established to standardize the diagnostic criteria for SSc for participants 
3) 
Established to include only patients with moderate to severe symptoms who are 
considered to be target patients for this drug. 
4) 
Established to select patients who can comply with the protocol-specified 
activities. 
 
 Exclusion criteria 
Participants who meet any of the following criteria will be excluded from study entry: 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
1） Patients complicated with diseases considered inappropriate 
for participation in clinical trials, such as serious* 
cardiac/hepatic/renal/pulmonary/hematologic disease 
*Refer to the Criteria for Seriousness Classification of Adverse 
Drug Reactions. (PAB/SD Notification No.80 by the Director 
X 
X 
X 

26 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
of Safety Division, Pharmaceutical Affairs Bureau, Ministry of 
Health and Welfare dated June 29, 1992) and the Common 
Terminology Criteria for Adverse Events v 5.0 Japanese JCOG 
version (CTCAE v 5.0-JCOG). 
2） Patients complicated with congestive heart failure [New York 
Heart Association (NYHA) Functional Class III or IV] 
X 
X 
X 
3） Patients having any of the following complications or 
concomitant/concurrent diseases: 
a） Severe chronic pulmonary disease (including %FVC < 
60%, or %DLco < 40% on the day of screening, 
calculated from the New Reference Values for 
Spirometry in Japanese adults calculated with the LMS 
Method (the Japanese Respiratory Society)”  
b） Serious complications associated with SSc other than 
interstitial lung disease* (e.g., renal crisis) 
* Interstitial lung disease is excluded if it falls under Item 
a) of3)  
c） Poorly controlled asthma that requires steroids 
(systemic), intravenous infusion of aminophylline, 
subcutaneous injection of adrenaline 0.1%, oxygen 
inhalation, or antibody drugs  
d） Diseases to affect the assessment of SSc 
X 
X 
X 
4） Patients with a history of malignant tumor, who are receiving 
no treatment and have had no recurrence /relapse for ≥5 years 
at the time of informed consent, or patients with a history of 
radical treatment for cervical intraepithelial neoplasia at the 
time of informed consent may be included in the study 
X 
X 
X 
5） Patients 
with 
Immune 
deficiency 
(e.g., 
congenital 
immunodeficiency, AIDS, or HIV). 
X 
X 
X 
6） Patients with a history or current hypersensitivity (including 
anaphylaxis) to immunoglobulin products (plasma-derived 
preparations or genetic recombinant monoclonal antibodies) 
X 
X 
X 
7） Patients weighing < 30.0 kg or > 120 kg on the day of study 
treatment initiation 
– 
– 
X 
8） Patients whose laboratory test values on the day of screening 
meet any of the following criteria: 
a） AST or ALT > 2 times the upper limit of normal 
b） Serum creatinine ≥2.0 mg/dL 
c） WBC <3000 cells/μL 
– 
– 
X 
9） Patients infected with hepatitis B virus (HBV) or hepatitis C 
virus (HCV) (Positive for HBs antigen or HBc antibody on the 
day of screening, positive for anti-HCV antibody on the day of 
screening) 
The allowed exceptions are as follows: 
 
Patients confirmed not to be infected with HBs at the time 
of the HBV-DNA test performed before study treatment 
initiation in the case of negative for HBs antigen and 
positive for HBc antibody in the hepatitis B test 
– 
– 
X 

27 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
performed on the day of screening. 
 
Patients confirmed not to be infected with HCV at the 
time of the HCV-RNA test performed before study 
treatment initiation in the case of positive for anti-HCV 
antibody in the hepatitis C test performed on the day of 
screening 
10） Patients with latent or active tuberculosis based on the result 
of the screening TB test. The allowed exception is patients 
deemed not to be infected with tuberculosis according to the 
“Guidelines for the use of interferon-γ release assay 
(Prevention Committee of the Japanese Society for 
Tuberculosis). 
– 
– 
X 
11） Patients with either of the following infectious diseases: 
 
Recurrent/chronic infections or other active infections 
deemed by the investigator to possibly aggravated by 
participating in the study 
 
Infections (including skin infections) requiring systemic 
antibiotics, antivirals, or antifungals within 7 days prior 
to the day of study treatment initiation. 
X 
X 
X 
12） Patients who have received oral steroids (> 10 mg/day of 
prednisolone or equivalent), dosage of receiving oral steroids 
have been changed (from ≤ 10 mg/day of prednisolone or 
equivalent), or newly treated with oral steroids, within 14 days 
before the day of study treatment initiation 
– 
– 
X 
13） Patients who have received any of the following therapies 
within the indicated period prior to the day of study treatment 
initiation 
– 
(X)* 
X 
a） Within 365 days 
Cyclophosphamide 
b） Within 120 days or 5 
times the elimination 
half-life of the drug, 
whichever is longer 
Antibody drugs 
c） Within 28 days 
i. 
Live vaccines 
ii. 
The 
following 
systemic 
medications: 
− Antifibrotic 
drugs 
(e.g., 
pirfenidone, nintedanib) 
− Immunosuppressants 
(e.g., 
cyclosporine, 
tacrolimus, 
azathioprine, mycophenolate 
mofetil, 
mizoribine, 
sulfasalazine, 
leflunomide, 
methotrexate, 
hydroxychloroquine, 
D-
penicillamine, sirolimus) 
− Tyrosine kinase inhibitors 
(e.g., imatinib) 

28 
*The exclusion criteria will be assessed with the expected date of study treatment initiation as the starting 
point. 
 
 Rationale for exclusion criteria 
1) to 6), 8) to 11), 15), 
and 17) to 19) 
Established considering the safety of participants  
7) 
Since the dose in this study is 60 mg/body, the upper body weight limit was set 
not to be lower than the dose (0.5 mg/kg) proven effective in the studies 
conducted to date in patients with atopic dermatitis, in view of efficacy. The lower 
Exclusion Criteria 
Confirmation timing 
Day of 
informed 
consent 
Day of 
Screening 
Day of 
treatment 
start 
− JAK 
inhibitors 
(e.g., 
tofacitinib, upadacitinib) 
− Endothelin receptor agonists 
(e.g., bosentan, ambrisentan, 
macitentan) 
− Phosphodiesterase-5 
inhibitors (e.g., sildenafil, 
tadalafil) 
− Prostaglandin analogue (e.g., 
alprostadil, epoprostenol) 
− Riociguat 
iii. Injections of corticosteroids 
(excluding joint injections) 
iv. Phototherapy 
v. High-dose 
intravenous 
immunoglobulin therapy 
14） Patients who are within 120 days from the end of participation 
in other clinical trials or post-marketing clinical studies (i.e., 
the last day of administration of another IP or post-marketing 
clinical study drug) until the day of study treatment initiation, 
or participating in other clinical trials or post-marketing 
clinical studies 
– 
(X)* 
X 
15） Women who are pregnant, breastfeeding, possibly pregnant, 
or unwilling to use appropriate contraception measures as 
instructed by the investigator during the study period 
X 
X 
X 
16） Patients who meet any of the following criteria: 
a） Having not met eligibility for participation when 
participating in this study in the past 
b） Having previously received nemolizumab (including 
placebo) 
X 
X 
X 
17） Patients with confirmed or suspected COVID-19 
– 
X 
X 
18） Patients with a history of confirmed or suspected COVID-19 
excluding those meeting any of the following criteria: 
• At least 20 days after the onset of symptoms and at 
least 72 hours after the resolution of symptoms. 
• Confirmed not to carry SARS-Cov-2. 
– 
X 
X 
19） Patients found to have close contacts with COVID-19 patients 
within 14 days before the day of study treatment initiation 
– 
– 
X 
20） Other patients who are considered ineligible for the study by 
the investigator 
X 
X 
X 

29 
limit of body weight was set to ensure the safety of participants so that the 
exposure does not exceed that at the maximum dose (2.0 mg/kg) confirmed to be 
tolerated after repeated administration of IP. 
12) 
Established considering the impact on the efficacy of the IP and to ensure the 
safety of the participants.  
13) a), b), c) ii), iii), 
v),14) 
Established considering the impact on the efficacy and safety evaluation of the IP. 
The period was considered necessary for washout based on the duration of 
treatment effect and half-live of each drug and therapy. 
13) c), i) 
Established considering the impact on the safety evaluation of the IP. The period 
was considered necessary for washout based on the duration of treatment effect 
and half-live of each drug 
13) c), iv) 
Established considering the impact on the efficacy evaluation of the IP. The period 
was considered necessary for washout based on the duration of treatment effect 
and half-live of each therapy. 
16) 
 
1) Established to exclude patients ineligible for this study 
2) Established to exclude the impact on the evaluation of efficacy and safety 
20) 
Established as a general criterion to exclude patients considered ineligible for this 
study by the investigator or subinvestigator. 
 
5.  Study Discontinuation of Individual Participants 
The investigator or subinvestigator will withdraw the participant signing informed consent from the study 
and take appropriate measures if participant meets any of the following discontinuation criteria before 
observation/tests at Visit 17 (Week 52). Even if the participant requests withdrawal from the study, the 
participant’s data will be used. 
 
 Discontinuation criteria 
1） Use of other antibody drugs by Week 52 visit 
2） Use of live vaccines by Week 52 visit 
3） The investigator or subinvestigator determined that an adverse event which would prevent the 
continuation of the study has occurred. 
4） The participant is found to fail to meet any of the inclusion criteria or to meet any of the exclusion 
criteria. 
5） The participant is found to be pregnant. 
6） The investigator or subinvestigator has determined that the participant should be withdrawn from the 
study due to inadequate response to the IP. 
7） The participant requests to withdraw from the study. 
8） The participant no longer visits the medical institution, and the study cannot be continued 
9） The participant has died. 
10） The sponsor has determined the participant discontinuation from the study due to significant protocol 
deviations. 
The sponsor has prematurely terminated the study. 
The investigator or subinvestigator has determined to withdraw the participant from the study for any other 
reasons. 
 
 Rationale for discontinuation criteria 
1) to 3), 5) 
Established considering the safety of the participants 
4) 
Established because the participants are considered ineligible for the study 
6) 
Established to reduce disadvantages for the participants 

30 
7) 
Established because it is considered the rights of participants 
8) to 11) 
Established for contingencies 
12) 
Established to allow participant discontinuation from the study at the discretion of the 
investigator or subinvestigator. 
 
 Procedure for Discontinuation 
5.2.1  Discontinuation before Enrollment 
1） For the participant not led to enrollment because of not satisfying the inclusion criteria, meeting any of 
the exclusion criteria or other reasons, the investigator or subinvestigator will explain the reason to 
withdraw the participant from the study, take appropriate action for the participant. The investigator or 
subinvestigator will ascertain and record the date of discontinuation and the reason for discontinuation 
in the source documents. A visit for discontinuation and observation/tests scheduled on the day of visit 
for discontinuation will not be performed. 
2） The investigator, subinvestigator, or CRC will record the data for the items described in Section 19.1.2 
in the CRF. 
 
5.2.2  Discontinuation after Enrollment 
1） The investigator or subinvestigator will explain the reason to withdraw the participant from the study 
and take appropriate action, ascertain and record the reason for discontinuation in the source documents. 
2） The investigator or subinvestigator will perform the observation/tests scheduled on the day of visit for 
discontinuation. When determining to discontinue the study on a day other than the day of the visit, the 
investigator or subinvestigator will instruct the participant to come to the study site as early as possible. 
However, if the day of visit for discontinuation is on or after 77 days from the last dose of study treatment.  
3） The investigator, subinvestigator, or CRC will record the data of the items described in Section 19.1.1 in 
the CRF. 
 
 Handling of Participants Who Fail to Visit the Study Site 
5.3.1  Participants Discontinuing Study Site Visit Between the Day of Informed Consent and the 
Day of Enrollment 
When a participant discontinues visiting the study site after the day of informed consent but before enrollment, 
the investigator or subinvestigator will perform follow-up of the participant through contact with him/her by 
telephone, letter or other means to record the method and the result of follow-up, reason(s) for not visiting 
with the date of such information obtained, presence or absence of adverse events, and other information 
obtained in the source document.  
 
5.3.2  Participants Discontinuing Study Site Visit in the Period after the Enrollment up to Visit 17 
(Week 52) 
If a participant discontinues visiting the study site after assigned to treatment, the investigator or 
subinvestigator will identify the whereabouts of the participant as far as possible and encourage him/her to 
visit the study site. If the participant dose not visit the study site, the investigator or subinvestigator will 
perform follow-up of the participant through contact with him/her by telephone, letter, or other means to 
document the method of follow-up, reason(s) for not visiting with the date of such information obtained, 
presence or absence of adverse events, and other information obtained. 
 
5.3.3  Participants Discontinuing Study Site Visit during the Follow-up Period 
The participant who cannot visit the study site within the window of the follow-up visit will be encouraged 
to visit the study site on the nearest day to the window. If the participant does not visit the study site, the 
investigator or subinvestigator will perform follow up of the participant through contact with him/her by 
telephone, letter, and other means to document the method of follow-up, reason(s) for not visiting with the 

31 
date of such information obtained, the presence or absence of adverse events, and other information obtained. 
 
6. Participant Enrollment 
 Informed Consent 
The investigator or subinvestigator will fully explain the study to participants who are considered eligible for 
the study and obtain written consent before the procedures for the study (see Section 27.4 for the method and 
points to note for obtaining informed consent).  
The investigator or subinvestigator will record the participant information on the participant screening log 
and provide the participant identification code. The participant identification will be AF001-XXX and will 
be coded in order of informed consent acquisition. Each participant will use the same participant 
identification code from informed consent to completion of the study. 
 
 Notification when the Participant is Treated by Another Doctor 
The investigator or subinvestigator will ask participants whether or not they are being treated by another 
doctor. When a participant is being treated by another doctor, the investigator or subinvestigator will notify 
the doctor of his/her participation in the study after obtaining his/her consent. In addition, the investigator or 
subinvestigator will record this notification to the doctor in the medical record, etc. 
 
 Enrollment Procedure of Participants 
1） For first and second registration. 
For participants considered eligible for the study on the day of screening and on the day of study 
treatment initiation, the investigator or subinvestigator will enter the necessary information in the 
source documents, and then fill out a registration form and fax it to the sponsor. The registration form 
should be filled out and faxed after the source documents have been prepared, which can be performed 
by the CRC. 
 
2） For discontinuation before assigned to treatment 
For participants discontinued from the study after informed consent but before second registration, the 
investigator or subinvestigator will enter the necessary information in the source documents, and then 
fill out a registration form and fax it to the sponsor. The registration form should be filled out and 
faxed after the source documents have been prepared, which can be performed by the CRC. 
 
3） Correction of entries in the source documents 
When an error is found in the information registered, the investigator or subinvestigator will correct 
the data in the source document and enter the necessary information in a registration form as needed, 
and then fax it to the sponsor to correct such data. The registration form should be filled out and faxed 
after the source documents have been corrected, which can be performed by the CRC. 
 
7. Investigational Product 
 Name, Dosage Form, and Strength of the IP 
Name, dosage form, and strength of the IPs are indicated in Table 7-1. 
 
 
 

32 
Table 7-1  Name, dosage form and strength of investigational product 
Name of 
investigational 
product 
Formulation 
Active ingredient and strength 
(Per DCS) 
Storage condition 
(Before preparation) 
Nemolizumab 
Injection 
(DCS) 
nemolizumab 75 mg (lyophilized) 
Nemolizumab is overfilled to ensure injectable 
nemolizumab 60 mg from one DCS in 
consideration of the loss of the prepared drug 
solution during administration. The active 
ingredient level after preparation is 100 
mg/mL. 
2°C to 8°C 
Protection from light 
 
 Packaging and Labeling 
7.2.1  Packaging 
One DCS of the IP is contained in a small box. 
 
7.2.2  Labeling 
The small box is labeled with a statement for clinical study use only, the name and address of the sponsor, 
identification number, lot number, and storage method. 
 
 Storage and Management of Investigational Products 
The investigational product manager at each study site will store and manage the IPs according to the 
“Operating Procedure for Investigational Product Management” prepared by the sponsor and other 
procedures specified at each site. 
 
8. Treatment Method 
 Dispensing of Investigational Products 
The investigator or subinvestigator will dispense one DCS of the IP at the following visits: 
<Dispensing visits> 
Day of study treatment initiation, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 
 
 Preparation of Investigational Products 
The investigator or subinvestigator, the investigational product manager or the person in charge of preparation 
of the IP will prepare injection solutions of IPs according to the “Standard Operating Procedure for 
Investigational Product Management.”  
 
 Method of Administration 
On the days of administration (see Table 9-1: Schedule), the investigator or subinvestigator will 
subcutaneously inject one DCS (0.6-mL) of nemolizumab slowly to the participant either in the upper arm, 
abdomen, or thigh. The IP may be administered by a person qualified to administer it under the instruction 
of the investigator or subinvestigator. 
 
 Precautions 
- 
The IP will be administered after all observation/tests scheduled at the visit have been completed. 
- 
The IP will be administered within the window of the specified visit. However, if the IP cannot be 
administered within the window, the next dose should be administered 14 days or later after the 

33 
previous dose. 
- 
If the participant’s body weight is lower than 30.0 kg on the day of administration, the IP must not 
be administered. 
 
 Rationale for selection> 
1） Dosage: 60 mg/body Q4W 
A phase III study in Japanese patients with atopic dermatitis has demonstrated the long-term safety of 
nemolizumab 60 mg/body Q4W. This study has been designed to exploratorily evaluate the efficacy of 
nemolizumab in SSc patients at 60 mg/body Q4W which has shown the long-term efficacy in SSc 
patients.  
 
2） Treatment Period 
The treatment period has been set at 52 weeks because long-term observation is required to evaluate the 
efficacy of nemolizumab on skin thickening in SSc patients in an exploratory manner. 
 
3） Day of Follow-up Visit 
Considering the serum elimination half-life after a single dose of nemolizumab ranges from 12.6 to 
14.6 days in patients with atopic dermatitis, the day of follow-up visit has been set to collect 
information such as the occurrence of adverse events on the day of 5 times the elimination half-life 
(84 days ± 7 days) from the day of the last dose. 
 
 Concomitant Medications and Therapies 
8.4.1  Restricted Concomitant Medications 
The following medications may be continued at a stable dose if used for at least 14 days before the day of 
study treatment initiation. However, the dose may be reduced at the discretion of the investigator or 
subinvestigator, and after dose reduction, the dose may be increased up to that used at the day of study 
treatment initiation. 
•Oral steroids (≤ 10 mg/day of prednisolone or equivalent) 
 
8.4.2  Duration and Method of Inspection 
The investigator or subinvestigator will collect the information of concomitant medications/therapies by 
interviewing participants according to Section.9.3.2  
 
8.4.3  Prohibited Concomitant Medications and Therapies 
Concomitant use of medications and therapies listed below is prohibited in this study.  
- 
From the day of study treatment initiation to Week 52 or to the physical examination on the day of visit 
for discontinuation 
1） The following systemic medications: 
a） Antifibrotic drugs (e.g., pirfenidone, nintedanib) 
b） Immunosuppressants 
(e.g., 
cyclophosphamide, 
cyclosporine, 
tacrolimus, 
azathioprine, 
mycophenolate mofetil, mizoribine, sulfasalazine, leflunomide, methotrexate, hydroxychloroquine, 
D-penicillamine, sirolimus) 
c） Tyrosine kinase inhibitors (e.g., imatinib) 
d） JAK inhibitors (e.g., tofacitinib, upadacitinib) 
e） Endothelin receptor agonists (e.g., bosentan, ambrisentan, macitentan) 
f） Phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil) 

34 
g） Prostaglandin analogues (e.g., alprostadil, epoprostenol) 
h） Riociguat 
2） Injections of corticosteroids (excluding joint injections) 
3） Phototherapy 
4） High-dose intravenous immunoglobulin therapy 
5） Antibody drugs 
6） Live vaccines 
 
 Rationale for selection 
1) 2) 4) 5) 
Established considering the impact on the efficacy of the IP and the safety of participants 
3)  
Established considering the impact on the efficacy evaluation of the IP 
6) 
Established considering the safety of participants 
 
- 
From the day of study treatment initiation to the day of follow-up visit 
1） Other drugs and medical devices under development 
 
 Rationale for selection 
1)  
Established considering the safety of participants and the impact on the efficacy of the IP. 
 
8.4.4  Instructions to participants 
The investigator or subinvestigator will examine the implementation status of the treatment of SSc at each 
visit and give instructions to the participants on treatment of SSc according to the therapeutic guidance 
specified in Sections 8.4.1 and 8.4.3.

38 
e Not to be performed if refused by the participant. 
If any of the following treatment-emergent adverse events occurs, photographs of the affected skin areas of the adverse event should be taken while the event (at least once) is 
occurring and at the final outcome evaluation, in addition to the scheduled visit (i.e., the day of study treatment initiation). The photography on the scheduled visit (day of study 
treatment initiation) will be performed according to Section 9.3.5.4  
• Atopic dermatitis 
• Adverse events with skin symptoms of edematous erythema or scaling 
• Any other adverse event for which the investigator or subinvestigator considers that photography is necessary. 
f To be performed on female participants excluding those who never become pregnant. 
g May be conducted on another day after the day of screening before the day of study treatment initiation 
h To be administered after all observation/tests are performed. If the IP cannot be administered within the window indicated, the next dose should be administered 14 days or later 
after the day of the previous dose. 
i Participants who discontinued the study will visit the site 84 days (±7 days) after the day of the last dose of study treatment for observation/tests at FU shown in Table 4-1. Participants 
discontinued the study before study treatment initiation need not to undergo observation/tests scheduled on the day of visit for discontinuation. 

39 
 Definition of the Days of Observation, Tests, and Sample Collection 
The days of observation, tests, and sample collection will be defined as follows. Table 9-1 shows the visit 
window of the assessment day. 
 
9.2.1  Day of Informed Consent 
The day when informed consent is obtained from the participant is defined as the day of informed consent.  
 
9.2.2  Day of screening 
The day of screening is defined as the day of first registration after completion of protocol-specified 
assessments. The day of informed consent may be the same day as the day of screening. 
All observation/tests scheduled for the day of screening must be performed on the same day. The tuberculosis 
test may be performed after the day of screening; however, the test result should be reviewed before the day 
of study treatment initiation. 
 
9.2.3  Day of Study Treatment Initiation 
The day of study treatment initiation is defined as the day when the participant is enrolled after completion 
of protocol-specified assessments. All assessments scheduled for the day of study treatment initiation must 
be performed on the same day. 
The day of study treatment initiation is Day 1, and the day before the day of study treatment initiation is Day 
-1. 
 
9.2.4  Day of Assessment (Weeks 1, 2, 4, 8, 12, through 52) 
Week 1 through Week 52 are days when participants visit the study site for protocol-specified 
observation/tests. 
 
9.2.5  Day of Study Treatment 
The day of study treatment is defined as the day when the IP is administered to the participant according to 
the schedule of Table 9-1 after the protocol-specified assessments are implemented. 
 
9.2.6  Day of Discontinuation 
The day of discontinuation is defined as the day when the investigator or subinvestigator determines to 
withdraw the participant from the study. 
 
9.2.7  Day of Discontinuation Visit 
The day of visit for discontinuation is defined as the day when the protocol-specified observation/tests 
scheduled for discontinuation are performed for the participant who is determined to be withdrawn from the 
study after study treatment initiation and visit the study site for the procedure. 
 
9.2.8  Day of Follow-up Visit  
The day of follow-up visit is defined as the day when the protocol-specified observation/tests are performed 
for the participant who visits the study site 84 days (±7 days) after the day of the last dose of study treatment. 
 
 Observation, Tests and Sample Collection  
9.3.1  Participant Demographics 
The investigator or subinvestigator will perform following assessments on the day of informed consent, the 
day of screening and the day of study treatment initiation. 

40 
1） Assessments on the day of informed consent 
 
Primary disease (diagnosis) 
 
Time of onset of primary disease 
 
Classification of primary disease (diffuse cutaneous SSc [dcSSc] or limited cutaneous SSc 
[lcSSc]) 
 
Main therapy given for SSc in the past 
 
Date of birth 
 
Sex 
 
Complication (any disease which is ongoing at the time of informed consent) 
 
Race 
 
Inclusion and exclusion criteria (see “4. Target Indication and Inclusion and Exclusion Criteria 
for Participants”) 
 
2） Assessments on the day of screening 
 
Inclusion and exclusion criteria (see “4. Target Indication and Inclusion and Exclusion Criteria 
for Participants”) 
 
Height 
 
3） Assessments on the day of study treatment initiation 
 
Inclusion and exclusion criteria (see “4. Target Indication and Inclusion and Exclusion Criteria 
for Participants”) 
 
9.3.2  Prior and Concomitant Medications and Therapies 
9.3.2.1  Prior and concomitant medications 
The investigator or subinvestigator will review the following medications for each participant: 
1） Medications intended to treat SSc 
 
Used from 28 days before the day of study treatment initiation to the physical examination at the 
follow-up visit 
2） Medications intended to treat adverse events 
a） Medications intended to treat adverse events of special interest defined in Section 11.6 : 
Used from the day of study treatment initiation (after initiating study treatment) to the final 
outcome evaluation. 
b） Medications intended to treat adverse events except for 1): 
Used from the day of study treatment initiation (after initiating study treatment) to the physical 
examination at the follow-up visit.  
3） All concomitant medications other than 1), and 2) 
 
Used from the day of study treatment initiation (after initiating study treatment) to Week 52 or 
the day of discontinuation visit. 
 
Information to be 
obtained 
Presence or absence of concomitant medications, and the drug name, dosage, drug 
use classification, start and end dates of use, and indication for use of each 
concomitant medication 
Notes 
The following information is not required to be collected: 
 Diagnostic agents, infusions, fluid replacement, nutritional agents, disinfectants, 
anesthetics for surgery, laxatives and suppository for barium examination (unless 
these drugs were used for treatment or are included in the prohibited concomitant 
medications) 
 Dosage of 3)  
 Among medications of 1), those newly used in participants who discontinued 

41 
from the study on or after the physical examination at the discontinuation visit. 
 
9.3.2.2  Prior and concomitant therapies 
The investigator or subinvestigator will collect the data of the following therapies: 
1） Therapies to treat SSc 
 
Performed from 28 days before the day of study treatment initiation to the physical examination 
at the follow-up visit. 
2） Concomitant therapies intended to treat adverse events 
a） Concomitant therapies intended to treat adverse events of special interest defined in Section 11.6  
 
Performed from the day of study treatment initiation (after initiating study treatment) to the final 
outcome evaluation. 
b） Concomitant therapies intended to treat adverse events except for 1) 
 
Performed from the day of study treatment initiation (after initiating study treatment) to the 
physical examination at the follow-up visit.  
c） Prohibited concomitant therapies 
 
Performed from the day of study treatment initiation (after initiating study treatment) to Week 52 
or the day of discontinuation visit. 
 
Information to 
be obtained 
Presence or absence of therapy, and the name of therapy, site to which concomitant 
therapy is applied, start and end dates of application and purpose of use of concomitant 
therapy  
Notes 
Among therapies of 1), those newly performed to participants who discontinued from 
the study on or after the physical examination at the discontinuation visit are not 
required. 
 
9.3.3  Body Weight 
The investigator or subinvestigator will measure the body weight of participants at the following timepoints: 
Data to be 
obtained 
Body weight 
Time points 
Day of screening, Day of study treatment initiation, Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 
40, 44 and 48  
Notes 
 On the days of study treatment, measurement will be performed, and the results will be 
reviewed before administration of IP. 
 Participants weighing less than 30.0 kg on the day of study treatment are not allowed 
to receive study treatment. 
 
9.3.4  Efficacy Evaluation 
9.3.4.1  Evaluation of Skin Findings 
The investigator or subinvestigator will perform the following assessments: 
Assessment 
mRSS  
Time points 
Day of screening, Day of study treatment initiation, Week 4, 12, 24, and 36, Week 52 or 
Day of discontinuation visit, Day of follow-up visit 
Notes 
 On the day of study treatment, assessment will be performed before the treatment. 
 mRSS assessment will be performed by a skilled physician experienced in scoring skin 
sclerosis. 
 In principle, the same investigator or subinvestigator will perform assessment 
throughout the study period for each participant in order to minimize inter-assessor 
variability. 

42 
 
9.3.4.2  Respiratory function test 
Spirometry will be performed according to the separately specified procedure. 
Assessment 
 
Forced vital capacity (FVC) and %FVC 
 
Diffusing capacity of lung for carbon monoxide (DLco) and % DLco 
 
Total lung capacity (TLC) and forced expiratory volume in one second (FEV1) 
Time points 
Day of screening, Week 12, and 24, Week 52 or Day of discontinuation visit 
Notes 
 
If the %FVC decreases by ≥ 15% from baseline, %FVC will be measured again 
within 1 month to examine whether the %FVC decreases by ≥ 15% from baseline or 
not. 
 
9.3.4.3  Chest HRCT 
HRCT will be performed according to the regulations or procedures or the test manual of the study site. 
Time points 
 
Day of screening, Week 24, Week 52 or Day of discontinuation visit 
Notes 
If having been performed within 1 month of the specified timepoint, it is not necessary to 
be performed at the specified timepoints, and the results within 1 month will be 
substituted. 
 
9.3.4.4  Severity of pulmonary lesions 
The investigator or subinvestigator will evaluate the severity of pulmonary lesions based on the results of 
respiratory function test and chest HRCT according to 10.1.4 . 
Time points 
Day of screening, Week 24, Week 52 or Day of discontinuation visit 
 
9.3.4.5  ACR-CRISS 
The investigator or subinvestigator will assess whether the participant fall under the following criteria: 
Evaluations 
 
Onset of scleroderma renal crisis 
 
Interstitial lung disease with a decline in %FVC ≥15% (requiring reconfirmation 
within 1 month), and %FVC of 80% or less 
 
Onset of left ventricular failure requiring treatment (defined as left ventricular 
ejection fraction ≤45%) * 
 
Onset of pulmonary arterial hypertension requiring right heart catheterization * 
*Caused by SSc 
Time points 
Week 12 and 24, Week 52 or Day of discontinuation visit 
 
9.3.4.6  The Number of Digital Ulcers 
The investigator or subinvestigator will count the number of digital ulcers. 
 
Time points 
 
Day of screening, Day of study treatment initiation, Week 12, 24 and 36, Week 52 
or Day of discontinuation visit 
Notes 
 
In principle, the same investigator or subinvestigator will perform assessment 
throughout the study period for each participant in order to minimize inter-assessor 
variability. 
 
 
 

43 
9.3.4.7  Patient-reported outcome 
The participants will perform the following assessments: 
Evaluations 
HAQ-DI, FACIT-Fatigue and FSSG 
Time points 
Day of study treatment initiation, Week 12, 24, and 36, Week 52 or Day of discontinuation 
visit 
Notes 
 
The participants will perform each assessment before receiving the examination and 
evaluation by the physician at the above visits. 
 
The investigator or subinvestigator must not attend the assessments by the 
participants. 
 
9.3.4.8  Global improvement rating 
9.3.4.8.1  Patient’s Global Assessment (PtGA) 
The participants will assess the overall condition of SSc using a visual analog scale (VAS). 
 
Time points 
Day of study treatment initiation, Week 12, 24, and 36, Week 52 or Day of discontinuation 
visit 
Notes 
 
The participants will perform each assessment before receiving the examination and 
evaluation by the physician at the above visits. 
 
The investigator or subinvestigator must not attend the assessments by the 
participants. 
 
9.3.4.8.2  Physician’s Global Assessment (PGA) 
The investigator or subinvestigator will assess the overall condition of SSc of each participant using a VAS. 
 
Time points 
Day of study treatment initiation, Week 12, 24, and 36, Week 52 or Day of discontinuation 
visit 
Notes 
 
In principle, the same investigator or subinvestigator will perform assessment 
throughout the study period for each participant in order to minimize inter-assessor 
variability. 
 
9.3.5  Safety Evaluation 
9.3.5.1  Vital signs 
The investigator or subinvestigator will perform the following measurements: 
Measurements Body temperature, pulse rate, and blood pressure (systolic/diastolic) 
Time points 
Day of screening, Day of study treatment initiation, Week 1, 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44 and 48, Week 52 or Day of discontinuation visit, Day of follow-up visit 
Notes 
 On the day of study treatment, measurements will be performed, and the results will 
be reviewed before the treatment.  
 The vital signs will be measured at rest in the sitting position. 
 
9.3.5.2  ECG 
The investigator or subinvestigator will perform the following measurements: 
Measurements PR interval, QRS interval, QT interval, heart rate and presence or absence of 
abnormalities 
Time points 
Day of screening, Week 24, Week 52 or Day of discontinuation visit 

44 
Notes 
 
On the day of study treatment, measurements will be performed, and the results will 
be reviewed before the treatment. 
 
The same electrocardiograph will be used for each participant at each measurement 
whenever possible. 
 
ECG will be performed at rest in the supine position.  
 
9.3.5.3  Echocardiography 
Echocardiography will be performed according to the regulations, procedures, or the test manual of the study 
site. 
Time points 
Day of screening, Week 24, Week 52 or Day of discontinuation visit 
Notes 
 
On the day of study treatment, measurements will be performed, and the results 
will be reviewed before the treatment.  
 
9.3.5.4  Photography 
The investigator or subinvestigator will perform photography according to the separately specified procedure. 
Sites to be 
Photographed 
1） Anterior and dorsal views of the upper body (excluding the face)  
2） Skin appearance of adverse events 
Time points 
1） Day of study treatment initiation 
2） Duration of the following adverse events (at least once occurrence) after study 
treatment initiation and at the final outcome evaluation: 
 
Atopic dermatitis 
 
Adverse events with skin symptoms accompanied by edematous erythema 
or scaling 
 
Any other adverse event for which the investigator or subinvestigator 
considers that photography is necessary. 
Notes 
 1) and 2): 
 
The photos will be retained by the study site and collected by the sponsor. 
When personal information can be identified from the photos, the photos must 
be collected with the personal information being masked. 
 
Photography will not be performed if refused by the participant. 
 
9.3.6  Laboratory tests 
Laboratory tests will be performed at the central laboratory. The investigator or subinvestigator will collect 
blood and urine samples from participants before study treatment initiation and submit them to the central 
laboratory. Tuberculosis test may be performed in an in-hospital laboratory. 
1） Hematology and serum chemistry tests 
2） Immunological tests (thymus and activation-regulated chemokines [TARC]) 
3） Urinalysis 
Time points 
Day of screening, Day of study treatment initiation, Week 1, 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44 and 48, Week 52 or Day of discontinuation visit, Day of follow-up visit 
Notes 
1) 2) and 3): 
 
On the day of study treatment, blood and urine will be collected before the treatment. 
 
The test result should be reviewed before the next study treatment. 
1) and 2): 
 
When aggregation or coagulation is observed in “Plt” because of a reason other than 
manual technique, blood will be collected into a blood collecting tube containing 
3.2% sodium citrate in addition to a conventional blood collection tube from the next 
visit. 
 
 

45 
4） Pregnancy test 
Time points 
Day of screening 
Notes 
 
The test will be performed on female participants. However, those who are 
considered unable to become pregnant (e.g., menopausal women* and women who 
have had total hysterectomy) will be excluded. 
*: Defined as those who are amenorrhea for at least 12 months without any medical 
reason. 
 
5） Tuberculosis test 
Time points 
Day of screening 
Notes 
 
If the test cannot be performed on the day of screening, it may be performed on 
another day after the day of screening but before study treatment initiation. In such 
cases, the rest results should be reviewed before administration of IP on the day of 
study treatment initiation. 
 
6） Hepatitis B and C tests 
Time points 
Day of screening 
Notes 
The participants who test negative for HBs antigen and positive for HBc antibody on the 
day of screening will undergo HBV-DNA measurement before the day of study treatment 
initiation. The participants who test positive for anti-HCV antibody on the day of 
screening will undergo HCV-RNA measurement before the day of study treatment 
initiation. 
 
7） Antinuclear antibodies test 
Time points 
Day of study treatment initiation 
Notes 
 
Blood will be collected before administration of IP on the day of study treatment 
initiation 
 
 
 

47 
On the day of study treatment, blood will be collected before the treatment 
 
9.3.10  Comprehensive measurement of autoantibodies 
The investigator or subinvestigator will collect blood samples for comprehensive measurement of 
autoantibodies. The measurement will be performed centrally. 
Time points 
Day of study treatment initiation, Week 24, Week 52 or Day of discontinuation visit 
Notes 
 
On the day of study treatment, blood will be collected before the treatment. 
 
9.3.11  CyTOF measurement 
The investigator or subinvestigator will collect blood samples for central measurement of CyTOF. 
Time points 
Day of study treatment initiation, Week 24, Week 52 or Day of discontinuation visit 
Notes 
 
On the day of study treatment, blood will be collected before the treatment. 
 
9.3.12  Assessment of Adverse Events 
The investigator or sub-investigator will assess the adverse events according to the procedure described in 
“11.4 Review and reporting of adverse events.” 
 
9.3.13  Investigation of Malfunction of DCS 
The investigator or subinvestigator will investigate malfunction of DCS according to "11.11 Malfunctions 
of DCS.”  

50 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 10-1  Severity classification of lung lesion 
 
10.1.5  ACR-CRISS 
ACR-CRISS is a composite outcome measure that is calculated as an index taking a value ranging from 0 to 
1 for the probability of improving for participants based on the presence or absence of renal, pulmonary, and 
cardiac impairments and changes in the 5 core set items (mRSS, %FVC, PGA, PtGA, and HAQ-DI). 
Participants are considered improved and not improved when their ACR-CRISS is ≥ 0.6 and < 0.6, 
respectively. If participants meet any of the following criteria, the probability of improving is 0.0. The 
investigator or subinvestigator will assess whether participants met or not met the following criteria at 
specified visits. If patients do not meet any of the following criteria, an ACR-CRISS score will be calculated 
using the formula shown in 17.3.2 2). 
• Onset of scleroderma renal crisis 
• Decline in FVC% ≥15% (requiring reevaluation within 1 month), and %FVC of 80% or less 
• Onset of left ventricular failure requiring treatment (defined as left ventricular ejection fraction 
≤45%) * 
• Onset of pulmonary arterial hypertension requiring right heart catheterization * 
* Caused by SSc  
 
10.1.6  The Number of Digital Ulcers 
The investigator or subinvestigator will count the number of digital ulcers. 
 
10.1.7  Patient-reported outcome 
1） HAQ-DI  
Findings compatible with interstitial lung disease on 
chest HRCT 
Extent of any interstitial lung disease lesions on 
chest HRCT 
Forced vital capacity (FVC) predicted 
Requirement of oxygen supplementation  
Yes 
>20% 
<70% 
No 
0 (normal) 
≤ 20% 
1 (mild) 
≥ 70% 
2 (moderate) 
No 
3 (severe) 
Yes 
4 (very severe) 

51 
Participants will assess the degree of their difficulty in performing actions of eight functional categories 
(dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities) using HAQ-DI 
(Health assessment questionnaire disability index, Japanese version)9) on a 4-point scale of 0 (Without any 
difficulty), 1 (Without some difficulty), 2 (Without much difficulty), and 3 (Unable to do). 
 
2） FACIT-Fatigue 
Participants will assess their fatigue over the past 7 days using FACIT-Fatigue Scale, Japanese version 
10) on a 5-point scale from 0 (not at all) to 4 (very much). 
 
3） FSSG. 
Participants will assess their gastroesophageal reflux disease using Frequency Scale for the Symptoms 
of GERD (FSSG) 11) on a 5-point scale from 0 (never) to 4 (always). 
 
10.1.8  Global improvement rating 
1） PtGA 
Participants will assess their general health status associated with SSc at visit using a 10-cm visual 
analog scale (VAS) from 0 (the best status) to 10 (the worst status) 12). The investigator or 
subinvestigator or the clinical trial collaborator will measure the length (cm) from the left end to the 
first decimal place and record it. 
 
2）  PGA 
The investigator or subinvestigator will assess participants’ general health status associated with SSc 
in terms of Severity, Damage, and Overall disease using a 10-cm VAS from 0 (the best status) to 10 
(the worst status) 12). The investigator (or subinvestigator) or the clinical trial collaborator will measure 
and record the length (cm) from the left end to the first decimal place. 
 
 Efficacy Endpoints 
10.2.1  Primary Endpoint  
Change from baseline in mRSS at Week 24 
 
10.2.2  Other Endpoints 
1） Change from baseline in mRSS at Week 52 
2） Change from baseline in HAQ-DI at Week 52 
3） Change from baseline in HAQ-DI at Week 24 
4） Change from baseline in %FVC at Week 52 
5） Change from baseline in %FVC at Week 24 
6） Change from baseline in DLco at Week 52 
7） Change from baseline in DLco at Week 24 
8） Change from baseline in PGA at Week 52 
9） Change from baseline in PGA at Week 24 
10） Change from baseline in PtGA at Week 52 
11） Change from baseline in PtGA at Week 24 
12） ACR-CRISS at Week 52 
13） ACR-CRISS at Week 24 
14） Change from baseline in the number of digital ulcers at Week 52 

52 
15） Change from baseline in the number of digital ulcers at Week 24 
16） Time-course changes in the following parameters: 
a） HAQ-DI 
b） FACIT-Fatigue 
c） FSSG 
d） FVC 
e） %FVC 
f） DLco 
g） %DLco 
h） TLC 
i） FEV1 
j） Severity assessment of lung lesion 
k） PGA 
l） PtGA 
m） ACR-CRISS 
n） The number of digital ulcers 
 
 Rationale for Efficacy Endpoints 
1） mRSS 
mRSS is used internationally to assess severity of SSc13), 14). Moreover, mRSS is generally considered 
to be correlated with visceral involvement, etc. and change over a relatively short period of time by 
receiving treatment, etc. Therefore, change from baseline in mRSS at Week 24 has been selected as 
primary endpoint to evaluate the efficacy of this drug on SSc. Since SSc has a chronic course, change 
from baseline in mRSS at Week 52 has been also selected as an efficacy endpoint to discuss the clinical 
significance of this drug. 
 
2） Respiratory Function Test 
FVC in respiratory function tests has been shown to be a useful indicator for predicting vital prognosis 
in interstitial lung disease associated with SSc15) . %FVC and %DLco are useful parameters for 
screening pulmonary hypertension associated with SSc16). Therefore, this test has been selected to 
evaluate the efficacy of this drug on lung lesion in an exploratory manner and to ensure the safety of 
participants. 
 
3） Chest HRCT 
Interstitial lung disease in SSc patients has been reported to be detected 50% to 60% by HRCT17). 
Interstitial lung disease is the most common cause of death in SSc patients18). Interstitial lung disease 
often occurs from the early stage of SSc, and therefore, it is useful to predict prognosis and determine 
whether the treatment is feasible for the patient. Moreover, the guidelines recommend to predict the 
risk of progression to end-stage pulmonary disease and determine whether the treatment is feasible for 
the patient by the fibrotic finding in HRCT and the extent of the lesion or of the entire lesion in 
conjunction with FVC-predicted values in respiratory function tests7). Based on the above, this test has 
been selected to evaluate the efficacy of this drug on lung lesion in an exploratory manner and to 
ensure the safety of participants. 
 
4） Severity Classification of Lung Lesion  

53 
The Guidelines for Diagnostic Criteria, Severity Classification and Clinical Practice of Systemic 
Sclerosis recommend to predict the risk of progression to end-stage pulmonary disease and determine 
whether the treatment is feasible for the patient by the fibrotic finding in HRCT, the extent of the lesion 
or of the entire lesion and FVC predictive value in respiratory function tests7). This parameter has been 
selected to evaluate the efficacy of this drug on lung lesion in an exploratory manner and to ensure the 
safety of participants. 
 
5） ACR-CRISS 
ACR-CRISS is a composite response index for clinical trials in early diffuse cutaneous SSc 19), which 
is generally used in clinical trials in SSc patients. This index has been selected to evaluate the efficacy 
of this drug on SSc in an exploratory manner. 
 
6） The number of digital ulcers 
Ulcers of the fingers and toes are complications of vascular disorder, one of the conditions of SSc, 
which occur frequently (35-60%) and arise from the early stage of the disease; therefore, they are 
considered to reflect the condition of SSc. Moreover, the ulcers are often refractory and recurrent, 
which is directly related to participants’ activities of daily living (ADL) and decreased QOL. 
Accordingly, this parameter has been selected to evaluate the efficacy of this drug on SSc in an 
exploratory manner. 
 
7） HAQ-DI 
HAQ is a convenient self-administered questionnaire assessing physical function for activities of daily 
living. It was originally developed to evaluate the effect of rheumatoid arthritis on activities of daily 
living; however, it has been reported that HAQ-DI correlates with the degree of skin thickening, 
cardiac involvement, renal involvement, etc., also in SSc20). Moreover, along with mRSS, it is a widely 
used standard method to evaluate SSc. Based on the above, HAQ-DI has been selected to evaluate the 
efficacy of this drug on SSc in an exploratory manner. 
 
8） FACIT-Fatigue 
FACIT-Fatigue is a health-related quality of life that assesses fatigue and its impact on daily activities 
and functions in chronic diseases. Shortness of breath and fatigue occur in interstitial lung disease and 
pulmonary hypertension associated with SSc. FACIT-Fatigue has been proven to be reliable and useful 
in various diseases including SSc10). Thus, FACIT-Fatigue has been selected to evaluate the effects of 
this drug on fatigue and on daily living and functions in SSc, a chronic disease, in an exploratory 
manner. 
 
9） FSSG 
FSSG is a useful questionnaire to objectively assess the symptoms of Japanese participants with 
gastroesophageal reflux disease11). In SSc, esophageal involvement is complicated at a high rate from 
the early stage of the disease, and 80% to 90% of SSc patients have reflux esophagitis 1). Esophageal 
involvements are also associated with the extent and duration of thickening1). Based on the above, 
FSSG has been selected to evaluate the efficacy of this drug on reflux esophagitis in SSc patients in 
an exploratory manner. 
 
10） Global improvement rating (PtGA, PGA) 
Global improvement rating is a widely used method to assess disease activity in clinical trials such as 

54 
in rheumatoid arthritis. This rating has been selected to evaluate the efficacy of this drug on SSc in an 
exploratory manner. 
 
11. Safety Evaluation 
 Assessments for Safety Evaluations 
1） Adverse events 
a） Symptoms and signs 
b） Abnormal laboratory test values 
c） Abnormal vital signs 
d） Abnormal electrocardiograms 
2） Laboratory test values 
3） Vital signs 
4） Electrocardiograms 
5） Echocardiography 
 
  Definition of Adverse Events 
1） Adverse events (AEs) 
An AE in the study will be defined as any undesirable or unexpected sign, symptom, disease, or 
aggravation of an existing condition occurring in a participant who is given an IP on or after the time of 
informed consent regardless of whether there is a causal relationship to the IP. The aggravation of diseases 
or symptoms that have occurred before the time of informed consent are also considered an AE. 
The following events are not considered AE: 
• Events for which medical treatment had been scheduled before the time of informed consent 
• Aggravation of primary disease 
 
2） Serious adverse events (SAEs) 
a） Results in death 
b） Is life-threatening 
c） Requires or prolongs inpatient hospitalization* 
*Excluding the following events; 
 
Any hospitalization that had been scheduled before the time of informed consent (e.g., 
hospitalization for surgeries and detailed examinations) 
 
Any hospitalization for examinations without any treatment (including bed rest treatment). 
d） Results in persistent or significant disability/incapacity 
e） Is a congenital anomaly/birth defect 
f） Is another medically important condition* 
*An important medical event that may not be immediately life-threatening or does not result in 
death or hospitalization but may jeopardize the safety of the patient or may require treatments 
to prevent one of the other outcomes listed in a) to e) above. 
e.g., bronchospasm requiring intensive care at an emergency room, blood dyscrasias or 
convulsions not leading to hospitalization, drug dependence, or drug abuse 
 
3） Adverse events of special interest (AESIs) 
AESIs in this study are defined as the following treatment-emergent events: 
a） AEs requiring discontinuation of study treatment 

55 
b） Injection-related reactions (including local and systemic injection site reactions) 
Injection-related reactions are defined as AEs which develop within 24 hours after administration 
of IP. 
c） Asthma 
d） Atopic dermatitis 
e） Skin symptoms with edematous erythema or scales 
f） Skin infections 
g） Non-skin infections 
h） Suspected infection of infectious pathogen from the IP 
 
 Rationale for selection 
b), c), d),  
f), and g) 
These events should be monitored carefully because of being included in “important 
potential risks” in nemolizumab. 
e) 
These are events of interest closely monitored by the sponsor based on the results of 
clinical studies of nemolizumab in patients with atopic dermatitis 
h) 
The event should be carefully investigated in biological products in general. 
 
 Definitions of Safety Endpoints 
1） Adverse events 
a） Symptoms and signs 
The investigator or subinvestigator will assess symptoms and signs in participants after the time of 
informed consent through the time of physical examination on the day of follow-up visit based on 
interview results and complaints from participants. 
b） Abnormal laboratory test values 
The investigator or subinvestigator will treat laboratory test results collected after the time of 
informed consent through the day of follow-up visit as AEs if the results meet any of the following 
criteria: 
i. 
Accompanied with clinical symptoms 
ii. 
Resulted in any change of study treatment (e.g., interruption or discontinuation of the IP). 
iii. 
Resulted in medical treatment (including change of concomitant medications/therapies). 
iv. 
Considered clinically significant by the investigator or subinvestigator. 
v. 
Total bilirubin is >2-fold the upper limit of the reference value, and ALT or AST is >3-fold the 
upper limit of the reference value 
vi. 
ALT or AST is >3-fold the upper limit of the reference value with clinical jaundice 
 
Individual abnormal changes in laboratory test findings will be reported as individual AEs in 
principle. However, a single abnormal laboratory test finding or two or more abnormal laboratory test 
findings that are related to each other may be reported collectively as a single event under a single 
diagnosis if it is considered appropriate by the investigator or sub-investigator. If individual abnormal 
changes in laboratory test findings are regarded by the investigator or subinvestigator as 
manifestations of a symptom or a sign reported as an AE, the changes may be reported collectively 
with the AE of the symptom or sign. 
Laboratory values may change depending on interindividual factors, such as sex, age, and lifestyle, 
and intraindividual factors, such as diurnal fluctuation, diet, exercise, body positioning, and sexual 
cycle. Therefore, the investigator or subinvestigator will determine whether the change in each 
laboratory test findings is a physiological change or an abnormal change after sufficiently taking into 

56 
consideration the demographics of each participant, such as the underlying disease and complication, 
baseline values, and the changes specific to each participant who have any periodic laboratory test 
before study participation. 
 
c） Abnormal vital signs 
The investigator or subinvestigator will treat measurement results collected after the time of 
informed consent through the day of follow-up visit as AEs if the results meet any of the following 
criteria: 
i. 
Accompanied with clinical symptoms 
ii. 
Resulted in any change of study treatment (e.g., interruption or discontinuation of the IP). 
iii. 
Resulted in medical treatment (including change of concomitant medications/therapies). 
iv. 
Considered clinically significant by the investigator or subinvestigator. 
 
d） Abnormal electrocardiograms 
The investigator or subinvestigator will assess AEs based on the results collected after the time of 
informed consent through the day of follow-up visit  
 
e） Echocardiography 
Echocardiographic images will be assessed for cardiac morphology, cardiac motion and blood flow 
during cardiac contraction and relaxation, and other parameters. The investigator or subinvestigator 
will record the presence or absence of abnormalities in the source documents. 
 
 Review and reporting of adverse events 
The investigator or subinvestigator will assess the items shown in Table 11-1 regarding AEs occurring from 
after obtaining informed consent to the day of follow-up visit and fill the necessary information in the case 
report forms (CRFs). 
The investigator or subinvestigator will report the SAEs according to Section 11.5 and the AESIs according 
to Section 11.6 to the sponsor. The investigator or subinvestigator will promptly report the other AEs to the 
sponsor. 
 
 
 

57 
Table 11-1 Assessments for adverse events 
Assessments 
Details of assessment 
Name of adverse event 
Disease name/symptom, classification of the site of occurrence of adverse events 
Onset date 
Classification of onset date, Onset date 
Action 
on 
investigational 
product 
Treatment discontinuation, Treatment interruption, Dose reduction, No dose change, Not 
applicable, Unknown 
Treatment for the event 
Presence or absence of treatment 
Outcomes and 
Date 
of 
outcome/Date 
of 
outcome obtained 
Recovered/Resolved, 
Recovering/Resolving, 
Not 
Recovered/Not 
Resolved, 
Recovered/Resolved with sequelae, Death, and Unknown 
End date of AE, whether the AE is ongoing or not 
Severity 
Mild 
Transient, requiring minimal treatment and not interfering with daily 
life 
Moderate 
Specified treatments relieve symptoms and do not result in 
permanent or significant disability but interfere with daily life 
Severe 
Significant effect on advanced clinical condition or requiring 
intensive care or no longer allowing daily life. 
Seriousness 
Serious/Non-serious 
 
Definition of serious 
adverse 
events 
in 
Section 13.2 
1. Results in death 
2. Life-threatening 
3. Requires or prolongs inpatient hospitalization 
4. Results in persistent or significant disability/incapacity 
5. Is a congenital anomaly/birth defect 
6. Is another medically important condition 
Causal 
relationship 
with 
investigational product 
Causality classification (according to the following causality classification), and 
rationale 
 
Causality 
classification* 
Not related 
Causal relationship is unlikely because the adverse event has no 
plausible temporal relationship to administration of IP, or the 
event can be explained by another factor.  
The rationale for no causal relationship is required to be described. 
 
 
Related 
Causal relationship is presumed because there is a plausible 
temporal relationship between the onset of the adverse event and 
administration of investigational drug, and the event cannot be 
readily explained by another factor. 
The rationale for the causal relationship should be described if it is 
necessary to be explained.  
*The following guidance can be taken into consideration on causality assessment: resolution of the event after discontinuation 
of IP; recurrence after restarting of IP; established causal relationship with IP or similar drugs; no confounding risk factors; 
consistency with the amount and duration of exposure to IP; almost clearly explainable involvement of the IP based on the 
correct past medical history; no reasonable possibility of causal relationship with concomitant therapy, etc. 

58 
 Review and reporting of serious adverse events 
1） The investigator will report any serious adverse events to the sponsor within 24 hours of getting to know 
the occurrence of the event. The investigator will report detailed information to the sponsor by using 
the “Report of Serious Adverse Events” form within 2 days of getting to know the occurrence of the 
event (the date the event was known is regarded as day 0). The study site’s own form may be used 
instead of the "Report of Serious Adverse Events". For additional reporting, new serious information 
(e.g., change in the name of the adverse event, causal relationship, outcome information, the severity 
category, etc.) should be reported to the sponsor according to the above rules when it becomes known. 
2） The investigator will report the event to the study site according to the study site’s operating procedures. 
3） The investigator will provide any additional information (e.g., autopsy reports, late-stage medical 
records, and other necessary information) on reported serious adverse events, as requested by the 
sponsor. 
 
 Reporting of adverse events of special interests (AESIs) 
The investigator should report to the sponsor promptly when an AESI is noted. For atopic dermatitis and skin 
symptoms with edematous erythema or scaling, the necessary information (details of the symptoms/signs and 
the basis for determining the causal relationship with the IP) should be stated in the CRF. Any additional 
information should be provided, as requested by the sponsor. 
At the time of physical examination on the day of follow-up visit, the final outcome of any AESI “not 
recovered/not resolved” falling under 1) below should be obtained according to 2). Concomitant medications 
and therapies will also be collected according to Sections 9.3.2.1 and 9.3.2.2 . 
1） AESIs to be obtained 
a） AEs requiring discontinuation of study treatment 
b） Asthma 
c） Atopic dermatitis  
d） Skin symptoms with edematous erythema or scales 
2） Period to obtain AESIs 
AESIs should be collected until the earlier of the following dates to obtain the final outcome 
information (the outcome and the date of outcome/outcome obtained). 
• Date of recovering or recovered 
• Date 6 months after the last dose of IP 
 
 Photography 
Among AESIs, "atopic dermatitis" and "skin symptoms with edematous erythema or scales" will be 
photographed to examine the detailed skin findings of the events. Other adverse events of which the principal 
investigator or subinvestigator considers it necessary to take photographs will also be photographed. 
The photographs taken will be used as a record of the occurrence of adverse event and a reference for safety 
evaluation. 
 
 Reporting of the Pregnancy of the Participant 
1） If obtaining the information on the pregnancy of the participant who received the IP, the investigator 
or subinvestigator must immediately discontinue study treatment and take appropriate action for the 
participant, and follow up the participant until the completion of the pregnancy (e.g., delivery). 
2） The investigator or subinvestigator will also report detailed information to the sponsor by using the 
“Report for Pregnancies during the Study” form. 
3） Participant pregnancies are not regarded as adverse events. 

60 
12. Biomarkers 
 Measurements of Biomarkers 
1） Variable to be measured 
a） IL-31 
b） KL-6, SP-D, NT-proBNP 
c） Exploratory biomarkers 
 
2） Collection of blood samples 
a） Blood samples will be collected on the day of study treatment initiation, at Week 4, 8, 12, 16, 20, 
24, and 36, and Week 52 or on the day of visit for discontinuation. On the days of study treatment, 
blood samples will be collected before administration of IP. 
b） Blood samples will be collected on the day of study treatment initiation, at Week 4, 12, 24, and 36, 
and Week 52 or the day of visit for discontinuation. On the days of study treatment, blood samples 
will be collected before administration of IP. 
c） Blood samples will be collected on the day of study treatment initiation, at Week 12, 24, and Week 
52 or the day of visit for discontinuation. On the days of study treatment, blood samples will be 
collected before administration of IP.  
 
The collected blood samples will be centrifuged to separate the serum, and the serum samples will be 
stored frozen until measured. The amount of blood collected, centrifugal conditions, and storage 
conditions are specified in a separate operating procedure. 
 
 Blood Biomarker Outcome Measures 
1） Serum IL-31 level 
 Rationale for selection 
Since IL-31 is one of the cytokines considered to be involved in the disease state of SSc8),this has 
been selected to evaluate the changes after administration of nemolizumab.  
 
2） KL-6 and SP-D 
 Rationale for selection 
KL-6 and SP-D have been used as sensitive markers for interstitial pneumonitis in examination and 
measuring of disease progression or as a prognostic predictor in clinical practice. Moreover, increased 
levels of these have been reported to be associated with inflammatory pathological conditions such 
as ground-glass opacities on HRCT and elevated proportions of inflammatory cells in 
bronchoalveolar lavage fluid 21). Based on the above, these have been selected in terms of safety 
protection of participants. 
 
3） NT-proBN 
 Rationale for selection 
NT-proBNP is critical as a serological marker of pulmonary hypertension because it elevates in 
correlation with its severity in patients with SSc-PAH22). It is also important as a serological marker 
for overall some sort of because it elevates in the presence of any myocardial damage even without 
pulmonary hypertension23). Therefore, it has been set in terms of ensuring safety of participants. 
 
4） Exploratory biomarkers 

61 
As exploratory biomarkers, IL-1α, IL-4, IL-6, IL-8, IL-13, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, 
IL-17F, and IL-23 levels will be measured; however, cytokines for which adequate performance of 
the assay methods could not be validated will not be measured. 
 Rationale for selection 
The major cytokines considered to be involved in pathological conditions of SSc have been selected 
to evaluate the changes after nemolizumab administration. 
 
 Measurement Method and Reporting of Results 
1） Measurement methods 
a） IL-31 and exploratory biomarkers will be measured using the Enzyme-Linked Immuno Sorbent 
Assay (ELISA) method. The measurements will be performed by 
 Corporation 
according to its assay protocol. 
b） KL-6, SP-D and NT-proBNP will be measured by 
 Corporation according to its assay 
protocol.  
c） Exploratory biomarkers will be measured using the Electro Chemi-Luminescence (ECL) method. 
The measurements will be performed by 
 Corporation according to its assay protocol. 
 
2） Report of measurement results 
a） IL-31, KL-6, SP-D, NT-proBNP and exploratory biomakers 
 Corporation will prepare and submit a report of analysis results to the sponsor. 
 
13. Pharmacokinetics 
 Pharmacokinetic Measurements 
1） Variable to be measured 
Serum concentration of nemolizumab 
2） Collection of blood samples 
Blood samples will be collected on the day of study treatment initiation, at Week 1, 2, 4, 8, 12, 16, 20, 
24, and 36, Week 52 or on the day of visit for discontinuation, and on the day of follow up. On the 
days of study treatment, blood samples will be collected before administration of IP. 
The collected blood samples will be centrifuged to separate the serum, and the serum samples will be 
stored frozen until measured. The amount of blood collected, centrifugal conditions, and storage 
conditions are specified in a separate operating procedure. 
 
 Pharmacokinetic Outcome Measures 
1） Serum concentration of nemolizumab 
2） Pharmacokinetic parameters: Cmax、tmax、AUC0-28day、AUClast 
 
 Rationale for selection 
Parameters necessary and evaluable to examine pharmacokinetics of nemolizumab have been selected in 
reference to “Clinical pharmacokinetic studies on drugs (PFSB/ELD No.796 of June 1, 2001).” 
 
 Measurement Method and Reporting of Results 
1） Measurement method 
Serum concentration of nemolizumab will be measured using the ELISA method. The measurements 
will be performed by 
 Laboratories, Ltd. according to its assay protocol.  

62 
2） Report of measurement results 
 Laboratories, Ltd. will prepare and submit a report of analysis results to the 
sponsor. 
 
14. Immunogenicity 
 Immunogenicity Measurements 
1） Variable be measured 
Serum anti-nemolizumab antibody 
2） Collection of blood samples 
Blood samples will be collected on the day of study treatment initiation, at Week 24 and 36, Week 52 
or on the day of visit for discontinuation, and on the day of follow up. On the days of study treatment, 
blood samples will be collected before administration of IP.  
The collected blood samples will be centrifuged to separate the serum, and the serum samples will be 
stored frozen until measured. The amount of blood collected, centrifugal conditions, and storage 
conditions are specified in a separate operating procedure. 
 
 Immunogenicity Outcome Measures 
1） Serum anti-nemolizumab antibody 
2） Neutralizing antibody concentrations 
 
 Rationale for selection 
The variables have been selected to evaluate the effects of the development of anti-nemolizumab 
antibodies to efficacy and safety in participants. 
 
 Measurement Method and Reporting of Results 
1） Measurement method 
The serum anti-nemolizumab antibody will be measured using the ECL method. When anti-
nemolizumab antibodies are detected, their characteristics will be determined using the cell-based 
assay (CBA) method. The measurement will be performed by 
 Corporation according 
to its assay protocol. 
 
2） Report of measurement results 
 Corporation will prepare and submit a report of analysis results to the sponsor. 
 
15. Comprehensive Measurement of Autoantibodies 
Comprehensive measurement of autoantibodies will be performed to determine the disease state of SSc 
and explore the patient-group for whom nemolizumab is effective. 
 
 Measurement Method and Reporting of Results 
1） Collection of blood samples 
Blood samples will be collected on the day of study treatment initiation, at Week 24, and Week 52 or 
on the day of visit for discontinuation. On the days of study treatment, blood samples will be collected 
before administration of IP. 
The collected blood samples will be centrifuged to separate the serum, and the serum samples will be 
stored frozen until measured. The amount of blood collected, centrifugal conditions, and storage 

63 
conditions are specified in a separate operating procedure. 
 
2） Measurement method 
Autoantibodies will be measured comprehensively using HuPEX™ protein array. The measurement 
will be performed by 
 Corporation according to its assay protocol. 
 
3） Report of measurement results 
 Corporation will prepare and submit a report of analysis results to the sponsor. 
Measurement results will not be included in the clinical study report and will be summarized in a 
separate report. 
 
16. CyTOF measurement 
CyTOF measurement will be performed to explore the mechanism of action of nemolizumab in SSc. 
 
 Measurement Method and Reporting of Results 
1） Collection of blood samples 
Blood samples will be collected on the day of study treatment initiation, at Week 24, and Week 52 or 
on the day of visit for discontinuation. On the days of study treatment, blood samples will be collected 
before administration of IP.  
PBMC preparation of collected blood samples will be performed by the day following sample 
collection. The amount of blood to be collected and storage conditions are specified in a separate 
operating procedure. 
 
2） Measurement method 
Measurement will be performed by 
, Inc. according 
to its assay protocol. 
 
3） Report of measurement results 
, Inc. will prepare and submit a report of analysis 
results to the sponsor. Measurement results will not be included in the clinical study report and will be 
summarized in a separate report. 
 
17. Statistical Analysis 
The major plans for statistical analyses are presented below. The details are provided in the Statistical 
Analysis Plan. This plan will be fixed prior to database lock on through discussions on data review etc.  
 
 Analysis Sets 
17.1.1  Efficacy Analysis Set (Full Analysis Set: FAS) 
The efficacy analysis set includes all participants assigned to treatment except for those who meet any of the 
following criteria: 
1） Participants who are found not to have SSc 
2） Participants who have received no dose of nemolizumab at all after assigned to treatment   
3） Participants with no efficacy data at all after assigned to treatment   
 

64 
17.1.2  Safety Analysis Set 
The safety analysis set includes all participants assigned to treatment except for those who meet any of the 
following criteria: 
a） Participants who have received no dose of nemolizumab at all after assigned to treatment 
2） Participants with no safety data at all after assigned to treatment 
 
17.1.3  Pharmacokinetics Analysis Set 
The pharmacokinetics analysis set includes all participants assigned to treatment except for those who meet 
any of the following criteria: 
1) Participants who have received no dose of nemolizumab at all after assigned to treatment 
2) Participants with no pharmacokinetic data at all after assigned to treatment 
 
17.1.4  Biomarker Analysis Set 
The biomarker analysis set includes all participants assigned to treatment except for those who meet any of 
the following criteria: 
1) Participants who have received no dose of nemolizumab at all after assigned to treatment 
2) Participants with no biomarker data at all after assigned to treatment 
 
 Data Handling 
17.2.1  Common Rules 
a） Handling of missing values 
The missing values will not be imputed. 
 
2） Handling of data on the day of visit for discontinuation 
The data measured or evaluated on the day of visit for discontinuation will be handled as the data of 
the relevant evaluation period if the visit is within the allowance of any visit for evaluation period. 
However, such data will not be included in the analysis if another data has been obtained in the 
relevant evaluation period. 
 
17.2.2  Data Handling on Pharmacokinetics 
1) Handling of values below the lower limit of quantification (BLQ) and missing values for serum drug 
concentration data 
Values BLQ will be handled as follows and missing values will not be imputed. 
a) 
Tabulation: They will be reported as BLQ. 
b) Changes over time and profiles and summary statistics: They will be replaced by 0. However, 
if the number of participants with BLQ values exceeds half number of participants in 
pharmacokinetic analysis set, the summary statistics of serum drug concentrations at that time 
point will not be calculated and reported as N.C. (not calculated).  
 
2) Handling of pharmacokinetic parameters not calculable 
Parameters not calculable should be handled as follows: 
a) 
Tabulation: They will be reported as N.C. 
b) Summary statistic: They will be left missing. However, if the number of unevaluable 
participants for a pharmacokinetic parameter exceeds half of participants to be evaluated, the 
summary statistic of the parameter will not be calculated and reported as N.C. 
 

66 
 
𝛥𝛥mRSS: mRSS change 
𝛥𝛥FVC%: Percent FVC change 
𝛥𝛥pt−glob, 𝛥𝛥MD−glob :  Patient’s / Physician’s Global assessment change (cm) 
𝛥𝛥HAQ−DI: HAQ-DI Score change 
 
The score of participants occurring any of the following events is 0: 
 Onset of scleroderma renal crisis 
 Decline in FVC% ≥15% (requiring reevaluation within 1 month), and %FVC of 80% or less 
 Onset of left ventricular failure requiring treatment (defined as left ventricular ejection fraction ≤45%) 
* 
 Onset of pulmonary arterial hypertension requiring right heart catheterization * 
*Caused by SSc 
 
17.3.3  Safety Analysis 
The following variables will be summarized on the safety analysis set: 
1） Adverse events 
The following data will be collected and tabulated for AEs and separately for the treatment-related AEs. 
a） The number of participants included in the safety analysis set, and the number of participants 
with, and the number of occurrences of AEs, AEs by severity (mild, moderate, and severe), 
SAEs (total, fatal, and non-fatal), and AESIs will be calculated. 
b） The number of participants with AEs will be calculated by SOC and PT using MedDRA/J. 
c） For AESIs, the number of participants with AESIs, the number of participants with AESIs by 
PT will be calculated by the category. 
 
2） Laboratory test values 
a） Laboratory test values throughout the treatment period 
For the continuous variables, summary statistics will be calculated by laboratory parameter and 
time point. For the categorical variables, the number of participants will be calculated by category. 
The percentage of participants will be calculated using the number of observed participants at 
each time point. 
b） Changes in individual participants during the treatment period 
A spaghetti plot will be created for each participant using individual test values by laboratory 
parameter of continuous variables. 
 
3） Vital signs, physical findings, and other assessments related to safety 
a） Vital signs, electrocardiogram and echocardiography throughout the study period 
For the continuous variables, summary statistics will be calculated by vital sign, electrocardiogram 
parameter, and echocardiography parameter. For the categorical variables, the number and 
percentage of participants will be calculated by category. The percentage of participants will be 
calculated using the number of observed participants at each time point. 
 
17.3.4  Analyses of Drug Concentrations and Pharmacokinetic Parameters 
The following variables will be summarized on the pharmacokinetic analysis set. 
1） Serum concentrations of nemolizumab 

67 
a） Summary statistics including coefficient of variation and geometric mean of serum 
nemolizumab concentrations will be calculated by time point. 
b） The serum nemolizumab concentration-time profile will be created using mean serum drug 
concentrations and their standard deviations. 
c） The serum nemolizumab concentration-time profile will be created by participant. 
d） The serum nemolizumab concentration-time profile will be created by participant where 
participants who tested positive for the first time after study treatment (in blue), those who had 
tested positive since before treatment (in red), and those who tested negative at all time points 
(in black) for anti-nemolizumab antibodies in serum in the confirmatory test will be identified 
by color. 
2） Pharmacokinetic parameters (Cmax, tmax, AUC0-28Day, and AUClast) 
Summary statistics including coefficient of variation and geometric mean of parameters will be 
calculated. 
 
17.3.5  Analysis of Immunogenicity 
The following variables will be tabulated from the pharmacokinetics analysis set. 
1） Serum anti-nemolizumab antibody 
a） The percentage of participants with positive serum anti-nemolizumab antibodies will be 
calculated by test (Screening, Confirmatory, and Neutralizing) and time point. The positive rate 
in the Confirmatory test and the Neutralizing test is based on the number of participants having 
undergone the screening test. 
b） The number of and the percentage of participants who tested positive for anti-nemolizumab 
antibodies will be determined in this study. According to Shankar's definition,24) among 
participants who tested positive for anti-nemolizumab antibodies for the first time after study 
treatment or both before and after study treatment, a positive participant is defined as a 
participant with a ≥ 4-fold increase in difference in antibody titer. 
 
17.3.6  Analysis of Biomarker 
Details will be described in the Statistical Analysis Plan. 
 
 Determination of Sample Size 
17.4.1  Target Sample Size 
The target sample size for this study is 8 participants.  
 
17.4.2  Rationale for Sample Size 
The number of participants required to determine the efficacy of this drug for SSc was set at 8. Since no 
statistical evaluation is planned, the number is not based on the level of significance and power. 
 
 Data Review 
Data review will be performed before data fixation. In the data review, the appropriateness of data handling 
and analysis methods, etc., will be examined, and analysis sets, data handling, and an analysis plan will be 
determined. If a change in the statistical analysis plan is required after data review, the statistical analysis 
plan will be revised and documented. 

68 
18. Agreement on the Protocol and Protocol Deviation/Amendment 
 Agreement of and Compliance with the Protocol 
The investigator will, before the sponsor requests to conduct the study at the study site, agree in writing with 
the sponsor on the contents of the protocol and conducting the study in compliance with the protocol. The 
investigator will do the same when the protocol is revised through discussion with the sponsor or according 
to the instructions of the head of the study site on the basis of the opinion of the institutional review board 
(IRB). 
 
 Protocol Deviation/Amendment 
1） The investigator or subinvestigator should not deviate from or amend the protocol without prior written 
agreement with the sponsor and without written approval based on a prior review by the IRB. However, 
the investigator or subinvestigator may deviate from or amend the protocol without prior agreement with 
the sponsor or without prior approval from the IRB in the following cases where: 
a） it is medically unavoidable to avoid immediate danger to a participant 
b） it is on administrative matters of the study (e.g., change of the name of study site, change of the 
address or phone number of study site, and change of job title of the investigator) 
 
2） The investigator or subinvestigator will record all deviations from the protocol. The investigator will 
prepare a document only for deviations from the protocol to avoid immediate danger to the participant 
with the reason for deviation or for other medically unavoidable reasons and immediately submit it to 
the sponsor and the head of the study site. The investigator will also submit the document to the IRB via 
the head of the study site, obtain approval from the IRB, and obtain in writing approval of the head of 
the study site and agreement of the sponsor. 
 
3） If the protocol amendment is appropriate when the investigator is unable to comply with the protocol to 
avoid any immediate hazard to participants or due to other unavoidable medical reasons, the investigator 
will submit a draft amendment to the protocol to the sponsor as soon as possible to obtain written 
approval of the sponsor. Furthermore, the investigator will submit a draft amendment to the protocol to 
the head of the study site, obtain approval from the IRB and the head of the study site. 

69 
19. Case Report Form 
The EDC system (Table 19-1) will be used in this study. The original CRFs will be those generated in the 
EDC system. The validated EDC system will be used in this study. 
The data and audit trails entered in EDC system by the investigator, subinvestigator involved in CRF 
preparation, and CRCs are stored in the EDC server. 
 
Table 19-1 EDC system 
Name of EDC system 
 
Name of EDC system development Company 
. 
Input method 
Data entry via the web 
Input terminal 
Personal computer available at study sites 
 
 Data to be collected in CRF 
The data to be collected in the CRFs is shown below. 
 
19.1.1  Participants assigned to treatment 
1） Date of written informed consent 
2） Visit dates 
3） Participant demographics 
4） Major therapies received for SSc in the past  
5） Inclusion and exclusion criteria 
6） Complications 
7） Concomitant Medications/Concomitant Therapies 
8） Patient-reported Outcomes 
9） Global improvement rating  
10） mRSS 
11） The number of digital ulcers 
12） Respiratory function test 
13） Electrocardiogram 
14） Echocardiography 
15） HRCT 
16） Severity of pulmonary lesions 
17） ACR-CRISS 
18） Vital signs 
19） Body weight 
20） Laboratory tests 
21） Biomarkers 
22） Serum nemolizumab levels  
23） Immunogenicity measurement 
24） Comprehensive measurements of autoantibodies 
25） CyTOF measurement 
26） Dosing status of IP  
27） Adverse events 
Information on outcome of an adverse event is to be collected until the follow-up visit. 
28） The details of adverse events of atopic dermatitis and skin symptoms with edematous erythema or 

70 
scaling as well as the basis for determining the causal relationship with the IP 
29） Malfunction of DCS 
30） Status of study entry after screening, enrollment, completion/discontinuation of the study 
completion status of study entry after screening, completion status of enrollment, study completion 
status, date of completion, date and reason for discontinuation if discontinued, and impact of COVID-
19 
31） Follow-up visit 
Whether there was a follow-up visit or not, date of follow-up visit, date of determination and reason 
if no follow-up visit, and impact of COVID-19 
32） Others 
a） Comment on each assessment 
b） Unscheduled visits 
 
19.1.2  Participants Who Discontinue the Study before study entry after screening and those Who 
Discontinue the Study before enrollment 
The following data will be collected and documented in the CRF for respective participants: 
1) to 6) for participants having discontinued the study before study entry after screening 
1) to 6) and 7) to 16) for participants having discontinued the study before enrollment 
1） Date of written informed consent 
2） Visit dates 
3） Participant demographics 
4） Inclusion and exclusion criteria 
5） Adverse events 
6） Date of and reason for discontinuation 
7） mRSS 
8） The number of digital ulcers 
9） Respiratory function test 
10） Vital signs 
11） Body weight 
12） Severity of pulmonary lesions 
13） HRCT 
14） Echocardiography 
15） Electrocardiograms 
16） Laboratory tests 
 
 Source Data for Information Entered in Case Report Form 
Source data for information entered in the case report forms are as follows: 
1） Medical records 
2） Laboratory test slips 
3） Serious Adverse Event Report (copy) 
4） Serious Adverse Event and Device Malfunction Report (copy) 
5） Informed consent forms 
6） Participant screening logs 
7） IP accountability records 
8） ECG measurement results 

71 
9） Respiratory function test 
10） Patient QOL questionnaire (paper) 
 
 Information in the Case Report Forms Treated as Source Data  
Any information of the following items described only in the CRF will be treated as the original data. 
1） Presence or absence of data for each item 
2） Indication of drug/therapy 
3） Seriousness and severity of adverse event, causality of adverse event to IP, and presence or absence of 
abnormal laboratory changes 
4） Date of and reason for study discontinuation 
5） All comments 
 
 Guidelines for Preparation of Case Report Form 
The investigator, subinvestigator involved in CRF preparation, and CRCs will have to receive training before 
preparing CRFs. The sponsor will create an account management table to specify the authority given to each 
person in the place of a list of signatures/seals. 
1） The investigator or subinvestigator will accurately prepare CRFs based on the source documents of 
enrolled participants according to the “Guidance for CRF Preparation.” 
2） The investigator or subinvestigator will promptly prepare the CRF once the evaluation of the 
participant at each visit is completed. 
3） CRCs may fill out or transcript and correct CRFs on the basis of the source documents. The 
investigator will review the entries, transcriptions, and corrections made by CRCs and electronically 
sign the CRFs. 
4） The investigator will review the CRFs prepared at the study site and electronically sign the CRFs. 
5） The investigator will submit the CRFs to the sponsor. In addition, the investigator will obtain a copy 
of the CRFs from the sponsor at the end of the study and retain them electronically. 
6） If data in the CRF shows a discrepancy with the source document, the investigator will prepare a 
document explaining the discrepancy and submit it to the sponsor. The investigator will also retain a 
copy of the record. 
 
 Modification and Amendment to Case Report Forms 
1） The investigator, subinvestigator, or CRCs will amend the CRFs according to the “Guidance for CRF 
Preparation” provided by the sponsor. 
2） The investigator will review the modifications or amendments made by the subinvestigator or, CRCs 
and electronically sign the CRF. 
 
20. Follow-up report of adverse events of special interest 
For adverse events of interest falling under those specified in Section 11.6 1) which are “not recovered/not 
resolved” at the time of physical examination on the day of follow-up visit, the investigator will report their 
following information from after the physical examination of the follow-up visit to the time of obtaining the 
final outcome in the format separately specified by the sponsor. 
1） Outcome and date of outcome/date of outcome obtained 
2） Drugs used for the adverse event 
3） Therapies performed for the adverse event 
 

72 
21. Direct Access to Source Documents 
The investigator, subinvestigator, and the head of the study site will allow study monitoring, the sponsor’s 
audit, and inspections by the IRB and regulatory authorities, and their direct access to all study-related 
documents, including the source documents. 
When regulations on direct access are stipulated at the study site, they will be followed. 
 
22. Quality Control and Quality Assurance 
Risk management of this study will be performed based on the risk management plan prepared according to 
the standard operating procedures of 
. 
 
1） Monitoring 
The CRA will request the investigator and subinvestigator, etc. to comply with the GCP, related 
regulatory notifications, and study protocol throughout the study period, and will then assess their 
compliance. If any deviation from the GCP, related regulatory notifications, and the study protocol is 
found by monitoring, the CRA will inform the investigator immediately and the head of the study site 
as necessary and take appropriate measures to prevent the recurrence of the deviation. Furthermore, 
on the basis of direct access to the source documents, the CRA will verify whether the CRFs are 
completed accurately and are consistent with the source documents. 
 
2） Quality control 
a） Standardization of assessments 
Prior to the start of the study, the sponsor will explain the standards of the assessment and the 
protocol to the investigator and subinvestigator, etc. 
 
3） Quality control of CRF data 
The quality control of CRF data will be performed according to the SOPs of Maruho Co., Ltd. When 
necessary, a case review meeting may be held by the medical expert and the sponsor to determine the 
handling of individual cases. 
 
4） Audit 
The auditor will assess whether the study is being conducted in accordance with GCP, the protocol, 
and relevant operating procedures separately and independently from the monitoring and quality 
control activities performed by the clinical study department. The auditor will also assess whether the 
study is being conducted properly and that the reliability of the study data is being maintained by direct 
access to study-related documents and records or other methods. 
 
23. Completion, Discontinuation, or Interruption of the Study 
 Completion of the Study 
Upon the completion of the study, the investigator will report the completion and a summary of study results 
in writing to the head of the study site. Once receiving the report of study completion from the investigator, 
the head of the study site will notify the IRB and the sponsor of the fact the summary of study results. 
 
 Discontinuation or Interruption of the Study 
The investigator will, when interrupting or discontinuing the study at his/her own discretion, promptly report 
it and the reason in writing to the head of the study site. Once receiving the report of study discontinuation 

73 
or interruption from the investigator, the head of the study site will promptly notify the IRB and the sponsor 
of the fact and the reason in writing. 
The sponsor will, when deciding the discontinuation or interruption of the study or the termination of 
development of the IP, promptly notify the head of the study site of the fact and the reason in writing. Once 
receiving a notification of interruption or discontinuation of the study or the termination of development from 
the sponsor, the head of the study site will promptly notify the investigator and the IRB of the fact and the 
reason in writing. 
 
24. Archiving of Records 
1） Study site 
The head of the study site should retain the documents and records related to this study to be archived 
at the study site (hereinafter, the study-related records) until the elapse of 15 years after either the date 
of the marketing approval of the investigational drug or the date of decision of discontinuation of the 
development of the investigational drug. 
For archiving the study-related records, the head of the study site will assign a storage manager. The 
head of the study site and the storage manager must take necessary measures so that these records are 
not lost or disposed of during the retention period and that they can be presented at the request of the 
sponsor, regulatory authorities, etc. 
When the retention period of records to be archived at the study site expires, the sponsor will promptly 
notify the head of the study site of the fact. 
2） Sponsor 
The sponsor should retain the study-related records to be archived at the sponsor site until the elapse 
of 15 years after either the date of the marketing approval of the investigational drug or the date of the 
decision of discontinuation of the development of the investigational drug. 
 
25. Publication Policy 
1） The study site may not disclose or divulge data on the study provided by the sponsor or information 
such as study results to any third party without prior permission of the sponsor. If intending to publish 
the information obtained from the study to external parties such as academic conferences, the study 
site must obtain prior permission from the sponsor. 
2） The founder of the IRB shall accept the sponsor’s request (if any) for prior checking of a summary of 
the meeting minutes specified in Article 28, Paragraph 2-6 of the GCP to ensure the summary does not 
include the description infringing on the sponsor’s intellectual property rights. When necessary, the 
founder may publish the summary after taking appropriate measures such as data masking. 
3） The sponsor may freely use information obtained from this study for application for marketing 
approval for the test drug, product summary, promotional materials, publications, presentations at 
academic societies, and other materials to be submitted to the Ministry of Health, Labour, and Welfare. 
4） When publishing information, sufficient attention must be paid to participant privacy. 
 
26. Use of study-related data 
1） The sponsor may use information obtained from this study (the study-related data) for application for 
marketing approval for the test drug, product summary, promotional materials, publications, 
presentations at academic societies, and other materials to be submitted to the Ministry of Health, 
Labor, and Welfare.  
2） The sponsor may use the study-related data for the research and development of other than the test 

74 
drug and otherwise academic research when considered necessary. 
 
27. Ethics 
 Institutional Review Board 
Prior to the execution of the clinical study agreement, the IRB will review the contents of the protocol, 
informed consent form, and other explanatory documents, as well as the appropriateness of conducting the 
study. After the execution of the clinical study agreement, the IRB will continuously review the 
appropriateness of continuing the study. 
 
 Ethical Conduct of the Study 
This study shall be conducted in compliance with the Ministerial Ordinance on Good Clinical Practice for 
Drugs and related notifications, the ethical principles based on the Declaration of Helsinki, and the protocol. 
 
 Protection of Participants’ Confidentiality 
To protect the participants’ confidentiality, the investigator or subinvestigator will use participant 
identification codes instead of names to identify participants when completing CRFs and reporting adverse 
events and other study-related data to the sponsor. The sponsor’s CRA and auditors will similarly protect any 
confidential participant information obtained during the course of the study in accordance with the provisions 
of Article 80-2, Paragraph 10 of the Act on Securing Quality, Efficacy, and Safety of Products Including 
Pharmaceuticals”. 
 
 Participant Selection and Informed Consent 
27.4.1  Participant Selection 
During the selection of participants, the investigator or subinvestigator should carefully consider the 
advisability of asking for a patient to participate in the study taking into consideration the health condition, 
symptoms, age, sex, ability to consent, dependency on the investigator or subinvestigator, and status of 
participation in other clinical studies from the viewpoints of human rights protection and based on the 
protocol-specified inclusion and exclusion criteria. If a patient who is visiting another hospital is enrolled in 
the study, the investigator or subinvestigator will consider eligibility for study participation after examining 
the details of the medical treatment. 
 
27.4.2  Informed Consent 
1） Prior to the assessment for study participation, the investigator or subinvestigator will fully explain 
the study to each participant by using the informed consent form and other explanatory documents 
that describe the items provided in “27.4.3 Explanations to Participants.” After this explanation, 
written voluntary consent to participate in the study will be obtained from the participant personally. 
2） In cooperation with the sponsor, the investigator will prepare the informed consent and other 
explanatory documents that will be used to obtain the participants’ consent to participate in the study 
and revise them as needed. The prepared or revised informed consent form and other explanatory 
documents should be approved by the IRB before use. 
3） The investigator will comply with the ethical principles when preparing or revising the informed 
consent form and other explanatory documents. 
4） The investigator or subinvestigator who provided the explanation, and the participant will each sign 
and date on the informed consent form. If a CRC makes a supplemental explanation, the CRC will 
also sign and date on the form. 
5） The investigator or subinvestigator will provide the participant with the signed and dated informed 

75 
consent form (copy), and other explanatory documents before the participant participates in the study.  
6） The investigator, subinvestigator, and CRC should not put pressure or unjustified influence on the 
participants to participate or continue participating in the study.  
7） The informed consent form and other explanatory documents for the participants or information 
provided orally when explaining the study must not contain any words or suggestions that cause the 
participants to relinquish their rights. Furthermore, the consent materials and explanation must not 
contain any words or suggestions that absolve the investigator, subinvestigator, CRC, study site, or 
sponsor of their legal responsibilities. 
8） Nontechnical vocabulary that the participants can understand should be used as much as possible 
during the verbal explanation and in written explanation and the informed consent form. 
9） The investigator or subinvestigator will provide the participant with the opportunity to ask questions 
and sufficient time to decide whether to participate in the study before obtaining the participant’s 
consent. The investigator, subinvestigator, or CRC (as someone providing additional explanation) 
must answer all questions to the satisfaction of the participant. 
10） If information is obtained that could potentially affect the participants’ willingness to continue 
participating the study, the investigator or subinvestigator must promptly give the information to the 
participants and ask whether the participants are willing to continue participating the study. In such 
cases, the fact that this information has been given to the participants will be recorded in the source 
documents. 
11） If significant new information that may be related to the participants’ consent is obtained, the 
investigator should promptly revise the informed consent form and other explanatory documents for 
the participants on the basis of this information. 
12） When the informed consent form and other explanatory documents for participants are revised, the 
investigator or subinvestigator will promptly give the information which the amendment is based on 
to participants and ask whether the participants are willing to continue participation in the study. 
Furthermore, the investigator or subinvestigator will again explain the study using the revised 
informed consent form and other explanatory documents for participants and obtain voluntary written 
informed consent to continue participation in the study from each participant. The investigator or 
subinvestigator will provide the participants with the newly signed and dated revised informed 
consent form (copy) and the other explanatory documents.  
 
27.4.3  Explanations to Participants 
1） This study is being conducted for the purpose of investigation (i.e., this study involves research). 
2） Study objective 
3） Name, job title, and contact information of the investigator. 
4） The study method (including the investigative aspect of the study, the participant inclusion criteria, 
and the probability of being assigned to each treatment) 
5） The expected benefits to the participant’s physical and mental health and the expected disadvantages 
to the participant of the IP 
6） The presence or absence of other treatments available to the participant and the expected important 
benefits and risks of the treatments 
7） The participant’s scheduled duration of participation in the study 
8） Participation in the study is voluntary, and the participant can refuse or withdraw consent to participate 
in the study at any time. 
9） The participant will not undergo any disadvantages as a result of refusing or withdrawing consent to 

76 
participate in the study, and the participant will not lose any benefits that the participant should receive 
if he or she does not participate in the study. 
10） The CRAs, auditors, and the IRB which deliberated the protocol, and regulatory authorities will have 
direct access to medical records and similar documents on the condition that the participant’s 
confidentiality will be protected. At such times, the participant’s confidentiality will be protected. The 
participant allows direct access to such materials by signing the informed consent form. 
11） The participant’s confidentiality will be protected if the study results are published. 
12） The consultation service to the study site where the participant should make inquiries or should 
contact if the participant desires further information regarding the study or participant’s rights or if 
study-related injury occurs. 
13） The compensation and treatment available to the participant in the event of study-related injury. 
14） The types of IRBs that review the appropriateness of the study, the matters reviewed by each IRB, 
and other matters related to the IRBs involved in this study. 
15） Matters to be communicated to participants on this study 
 
The planned number of participants in the study 
 
If information is obtained that could potentially affect the participant’s willingness to continue 
participating the study, that information will be promptly reported to the participant. 
 
The conditions or reasons to withdraw participants from the study 
 
Information for the financial responsibility of the participant in the study 
 
Information related to payments to the participant 
 
Instructions to be followed by the participant 
 
Study staff will obtain medical information from other physicians with the consent of the 
participant. 
 
28. Payments 
Measures taken to reduce the participant’s financial burden resulting from participation in the study (if any) 
should be stipulated in writing after a discussion with the study site. Provisions for other necessary expenses 
will also be stipulated in writing after another discussion with each study site. 
 
29. Compensation for Injuries 
If a participant suffers from an injury attributable to the study and seeks compensation from the study site, 
the sponsor shall be fully responsible for the compensation unless the injury is due to an intentional error or 
a medical error by the study site. Prior to conducting the study, the sponsor will purchase product liability 
insurance for the IP as a measure to compensate for injuries. 
 
30. Responses to COVID-19 
Definitions of confirmed COVID-19 patients (including asymptomatic pathogen carriers), suspected 
COVID-19 patients, and persons in close contact with such patient follow the latest edition of the Treatment 
Guidelines for New Coronavirus Infections (COVID-19). 
 
 COVID-19-related instructions to participants 
The investigator or subinvestigator will instruct the participants in this study to promptly contact the study 
site if they are found to have confirmed COVID-19 (including asymptomatic pathogen carriers) or suspected 
COVID-19, or found to have been in close contact with a confirmed or suspected COVID-19 patient. 
 

78 
 
30.2.2  When staff at the study site who may have close contact with participants have confirmed 
COVID-19 (including asymptomatic pathogen carriers) or suspected COVID-19. 
(1) The investigator or subinvestigator will inform the participants in the study that staff at the study site 
who may have close contact with them are (or may be) infected with COVID-19, ask the safety of 
the subjects by telephone or other contact means, and document the result in the source documents. 
The investigator or subinvestigator will also provide response and instruction to the participants 
according to the instructions of the study site. 
(2) The investigator or subinvestigator will promptly inform the sponsor that staff at the study site who 
may have close contact with participants are (or may be) infected with COVID-19. 
 
 Discontinuation of the study due to the influence of COVID-19 
If the study has been discontinued due to the influence of COVID-19, the investigator or subinvestigator will 
record in the source document and the CRF that the study was discontinued due to COVID-19. 
 
 Deviations from the protocol due to the influence of COVID-19 
If a protocol deviation has occurred due to the influence of COVID-19, the investigator or subinvestigator 
will keep a record in the source document so as to make it clear that the deviation occurred due to the 
influence of COVID-19. 
 
31. Study Period 
December 2021 to October 2023 
 
32. Administrative Structure 
 Sponsor 
, Representative Director, President & CEO, Maruho Co., Ltd. 
 Osaka 
 
 
 Sponsor Organization 
1） Head of Clinical Trial 
, General Manager, Clinical Development Department, Maruho Co., Ltd 
 
Major roles: 
a） 
 
b）
 
c） 
 
 
2） Clinical Trial Supervisor 
 Clinical Development Department, Maruho Co., Ltd. 
 
Major roles: 
 
 
3） Medical Safety Officer 
 MD, PhD, Senior Medical Director, Maruho Co., Ltd. 

79 
 
Major roles: 
a） 
 
b）
 
 
 
4） Clinical Research Associate Leader 
, Clinical Development Department, Maruho Co., Ltd. 
 
Major roles: 
. 
 
 Study Sites and Investigators 
Study Center：The University of 
 Tokyo 
 
Investigator：
 
 
 Medical Expert 
Shinichi Sato 
Professor, Department of Dermatology, 
, The 
University of 
 
 
 Contract Research Organization 
1）  Clinical Testing Laboratory 
Corporation, 
 Tokyo 
 
 
 
2） Biomarker Measurement Institution 
Corporation, 
Tokyo 
 
 
 
 
3） Anti-Drug Antibody Measurement Institution 
Corporation, 
, Tokyo 
 
 
 
 
4） Drug Concentration Measurement Institution 
 Laboratories, Ltd., 
 Tokyo 
 
 
 
5） Autoantibody Measurement Institution 
 Corporation, 
, Tokyo 
 
 
 
6） CyTOF Measurement Institution 
, Inc., 
, Tokyo 
 
 

80 
 
33. Contact Information 
 Contact Information 
, Clinical Development Department, Maruho Co., Ltd. 
 Kyoto 
 
TEL 
 (dial in) 
FAX 
 
 
 Emergency Contact (Saturdays and Sundays, National Holidays, Nights) 
, Clinical Development Department, Maruho Co., Ltd. TEL 
 
, Clinical Development Department, Maruho Co., Ltd. TEL
 
 
 
 

81 
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