A Multicenter, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Efficacy and Safety of Nemolizumab in Subjects With Chronic Kidney Disease With Associated Moderate to Severe Pruritus
Phase: PHASE2
Conditions: Chronic Kidney Disease Associated Moderate to Severe Pruritus
Sponsor: Galderma R&D

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1
CLINICAL STUDY PROTOCOL
Protocol Title:
A Multicenter, Double-blind, Randomized, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of Nemolizumab in 
Subjects with Chronic Kidney Disease with Associated 
Moderate to Severe Pruritus
Protocol Number:
RD.06.SPR.204358
IND Number:
117122
EudraCT Number:
2021-004766-35
Investigational Product:
Nemolizumab (CD14152)
Phase of Development:
2/3
Indication:
Chronic Kidney Disease Associated Moderate to Severe 
Pruritus
Sponsor:
Galderma SA
Zählerweg 10
CH-6300 Zug
Switzerland
Galderma Research & Development, LLC
2001 Ross Avenue
Suite 1600
Dallas, TX 75201
United States
Protocol Version:
6.0
Protocol Date:
21SEPT23
This document and its contents are the property of and confidential to 
Galderma SA/Galderma R&D, LLC. Any unauthorized copying or use of this 
document is prohibited.
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3
INVESTIGATOR SIGNATURE PAGE
Protocol Title:
A Multicenter, Double-blind, Randomized, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of Nemolizumab in 
Subjects with Chronic Kidney Disease with Associated 
Moderate to Severe Pruritus
Protocol Number:
RD.06.SPR.204358
Confidentiality and Current GCP/E6 (R2) Compliance Statement 

I, the undersigned, have reviewed this protocol, including appendices, and I will 
conduct the study as described in compliance with this protocol (and amendments), 
GCP, and relevant ICH guidelines.

I am thoroughly familiar with the appropriate use of the study drug, as described in 
this protocol and any other information provided by Galderma SA including, but not 
limited to, the current Investigator’s Brochure (IB).

Once the protocol has been approved by the Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB), I will not modify this protocol without 
obtaining prior approval of Galderma SA and of the IEC/IRB. I will submit the 
protocol amendments and/or any ICF modifications to Galderma SA and the 
IEC/IRB, and approval will be obtained before any amendments are implemented.

I ensure that all persons or party assisting me with the study are adequately qualified 
and informed about the Galderma SA study drug and of their delegated study-related 
duties and functions as described in the protocol.

I ensure that source documents and trial records that include all pertinent observations 
on each of the site’s trial subjects will be attributable, legible, contemporaneous, 
original, accurate, and complete.

I understand that all information obtained during the conduct of the study with regard 
to the subjects’ state of health will be regarded as confidential. No subjects’ names 
will be disclosed. All subjects will be identified by assigned numbers on all case 
report forms, laboratory samples, or source documents forwarded to the sponsor. 
Clinical information may be reviewed by the sponsor or its agents or regulatory 
agencies. Agreement must be obtained from the subject before disclosure of subject 
information to a third party.

Information developed in this clinical study may be disclosed by Galderma SA to 
other clinical investigators, regulatory agencies, or other health authority or 
government agencies as required.
___________________________________________________________________________
Name, Title
Investigator Signature
___________________________________________________________________________
Institution
Date (DD-Mmm-YYYY)
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STUDY PERSONNEL
 
 
 
 
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SYNOPSIS
Title of Study:
A Multicenter, Double-blind, Randomized, Placebo-controlled Study to Evaluate the 
Efficacy and Safety of Nemolizumab in Subjects with Chronic Kidney Disease with 
Associated Moderate to Severe Pruritus
Protocol Number:
RD.06.SPR.204358
Investigators/Study 
Sites:
Approximately 70 study sites are planned in North America and Europe
Phase of 
Development:
Phase 2/3
Objectives:
Primary objective: The primary objective is to evaluate the efficacy of nemolizumab 
compared to placebo at reducing the intensity of pruritus after a 12-week treatment 
period in adult hemodialysis subjects with moderate to severe pruritus.
Secondary objectives: The secondary objectives are to evaluate the safety of 
nemolizumab compared to placebo, and to assess the 
 and 
optimal dose in adult hemodialysis subjects with moderate to severe pruritus.
Study Design:
This is a randomized, double-blind, placebo-controlled, multicenter, parallel-group, 
phase 2/3 study to evaluate the efficacy and safety of nemolizumab in adult subjects 
with CKD-aP.
Subjects will be randomized in one of the three arms/groups (two different doses of 
nemolizumab and a placebo) in a 1:1:1 ratio: 

Group 1: 30 mg nemolizumab Q4W with a 60 mg loading dose at baseline;

Group 2: 60 mg nemolizumab Q4W without loading dose at baseline;

Group 3: placebo Q4W. 
Approximately 84 subjects will be randomized in each nemolizumab group and in the 
placebo group for a total sample size of approximately 252 subjects.
In order to maintain the blind, all subjects will receive 2 injections at each 
administration (30 mg + 30 mg or 30 mg + placebo or placebo + placebo). 
The study consists of a screening period (up to 4 weeks), a 12-week treatment period, 
and an 8-week follow up period (12 weeks after their last study drug injection).
The screening period will evaluate subject eligibility. The subjects’ other (non-pruritus) 
complications of end-stage kidney disease (ESKD) are to be managed according to 
local standard of care. The use of moisturizers is encouraged to keep the skin hydrated.
At the baseline visit, subjects will receive an initial dose of nemolizumab 60 mg or 
placebo by two subcutaneous (SC) injections. Study drug treatment with either 
nemolizumab or placebo should start after completion of the hemodialysis treatment 
(within four hours). Then study drug (i.e., nemolizumab 30 mg, nemolizumab 
60 mg, or placebo) will be administered via two SC injections (30 mg + placebo or 30 
mg + 30 mg or placebo + placebo) every four weeks (Q4W) at Week 4 and 8 after 
completion of the hemodialysis treatment (within four hours). 
 are to be 
taken before hemodialysis. Refer to the figure below.
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An independent data monitoring committee (IDMC) will review and monitor subject 
safety throughout the study. The study team will remain blinded until the end of the 
study.
An independent adjudication committee (IAC) will review and adjudicate all asthma-
related AEs.
Selection of 
Subjects:
Main Inclusion Criteria:
1.
Subjects aged  18 years at the screening visit.
2.
Has end-stage kidney disease (ESKD) and have been on hemodialysis three times 
per week for at least three months prior to the start of screening.
Note 1: Subjects who require an occasional additional hemodialysis treatment to 
manage fluid overload may be enrolled as long as it is anticipated that no more 
than one such treatment will be required in any given week.
Note 2: Subjects having received in-home hemodialysis may participate as long as 
they have switched to in-center hemodialysis at least two weeks prior to screening 
and plan to remain on in-center hemodialysis for the duration of the study.
3.
Hemodialysis subjects meeting the Kidney Outcome Quality Initiative Guidelines 
of hemodialysis adequacy within 60 days of screening, two:

Single-pool Kt/V measurements of at least 1.2.
4.
Pruritus for ≥ three months (documented pruritus with no etiology identified other 
than CKD by medical record, previous physician’s letter/statement, or  written 
documentation by site investigators based on the medical history obtained from the 
subject). 
5.
WI NRS score ≥ 5.0 at the screening and baseline visit. Screening WI NRS score 
will be determined by a single WI NRS assessment (score ranging from 0 to 10) 
for the 24-hour period immediately preceding the screening visit. Baseline WI 
NRS score will be determined based on the weekly average of daily WI NRS 
scores (score ranging from 0 to 10) during the seven days immediately preceding 
W -4
W 20
Screening
Treatment Period
W 4*
W 8*
Follow-Up
W 12
R = Randomization; * = Visits with study drug administration
Note: All subjects in each arm will receive 2 injections at each administration
(either 30 mg + 30 mg, or 30 mg + placebo, or placebo + placebo) in order to mantain the blind
BL*
Group 1: 30 mg nemolizumab Q4W
with a 60 mg loading dose at baseline
Group 2: 60 mg nemolizumab Q4W
without loading dose at baseline
Group 3: placebo Q4W
R
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baseline (rounding is not permitted). A minimum of four daily scores out of the 
seven days immediately preceding baseline is required for this calculation.
6.
Women of childbearing potential (WOCBP) (i.e., fertile, following menarche and 
until becoming post-menopausal unless permanently sterile) must agree either to 
commit to true abstinence throughout the study and for 12 weeks after the last 
study drug injection, when this is in line with the preferred and usual lifestyle of 
the subject, or to use an adequate and approved method of contraception 
throughout the study and for 12 weeks after the last study injection.
Adequate and approved methods of contraception applicable for the subject and/or 
her partner are defined below:

Progestogen-only oral hormonal contraception.

Combination of male condom with cap, diaphragm, or sponge with spermicide 
(double-barrier methods).
Note: “Double barrier methods” refers to simultaneous use of a physical barrier by 
each partner. Use of a single barrier method (e.g., condom) together with a 
spermicide is not acceptable.

Combined (estrogen- and progestogen-containing) oral, intravaginal, or 
transdermal hormonal contraception.

Injectable or implanted hormonal contraception.

Intrauterine devices or intrauterine hormone releasing system.

Bilateral tubal ligation or tube insert (such as the Essure system) at least three 
months before the study.

Bilateral vasectomy of partner at least three months before the study.
7.
Women are considered to be of non-childbearing potential if they meet one of the 
following criteria:

Absence of menstrual bleeding for one year prior to screening without any 
other medical reason, confirmed with follicle stimulating hormone (FSH) 
level in the postmenopausal range.

Documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy 
at least three months before screening.
Note: Bilateral tubal ligation is not accepted as reason for non-childbearing 
potential.
8.
Subject willing and able to comply with all time commitments and procedural 
requirements of the clinical study protocol.
9.
Understands and signs an informed consent form (ICF) before any investigational 
procedure(s) are performed.
Main Exclusion Criteria:
1.
Body weight < 30 kg.
2.
Pruritus caused by a concomitant condition unrelated to ESKD (e.g., dermatologic 
or systemic disorders such as, but not limited to atopic dermatitis (AD), psoriasis, 
prurigo nodularis (PN), Chronic T- cell Lymphoma, Leukemia or cholestatic liver 
disease).
3.
Localized itch of only the palms of the hands and/or soles of the feet.
4.
Pruritus present only during hemodialysis session.
5.
History of or anticipated non-compliance with hemodialysis (i.e., such that it 
would adversely affect the conduct of the study or significantly change dialysis 
adequacy during the study) in the opinion of the investigator.
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6.
New York Heart Association Class IV symptoms (see Appendix 11)or myocardial 
infarction within three months prior to screening.
7.
History of stroke or transient ischemic attack within six months prior to screening.
8.
Subjects meeting one or more of the following criteria at screening or baseline:
a.
Had an exacerbation of asthma requiring hospitalization in the preceding 12 
months.
b.
Reporting asthma that has not been well-controlled (i.e. symptoms occurring 
on > two days per week, nighttime awakenings two or more times per week, 
or some interference with normal activities) during the preceding three 
months.
c.
Asthma Control Test (ACT) ≤ 19 (only for subjects with a history of asthma).
9.
Cutaneous infection within one week before the baseline visit, any infection 
requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics or 
antifungals within two weeks before the baseline visit.
Note: Subjects with chronic, stable use of prophylactic treatment for recurrent 
herpes viral infection can be included in this clinical study.
10. Any confirmed or suspected coronavirus disease (COVID-19) infection within two 
weeks before the screening or baseline visit. Subjects may be rescreened after the 
infection has resolved. Resolution of COVID-19 infection can be confirmed by 
recovery assessment methods, as described in the protocol.
11. Positive serology results (hepatitis B surface antigen [HbsAg] or hepatitis B core 
antibody [HbcAb], hepatitis C [HCV] antibody with positive confirmatory test for 
hepatitis C virus [HCV] (e.g., HCV polymerase chain reaction [PRC]), or human 
immunodeficiency virus [HIV] antibody) at the screening visit.
Note: Subjects with a positive HbcAb and a negative HbsAg can be included in 
this clinical study if hepatitis B surface antibody is positive (considered immune 
after a natural infection or vaccination). Subjects who are positive for HCV 
antibody and negative for HCV RNA may be enrolled.
In the event of rescreening, the serology tests results (e.g., HBV, HCV, HIV) from 
the previous screening can be used by the investigator to assess the eligibility of 
rescreened subjects if those tests were performed within six weeks prior to the 
baseline visit.
12. Known active or untreated latent tuberculosis (TB) infection or history of either 
untreated or inadequately treated active or latent TB according to the local 
applicable guidelines.
Note: Subjects who have a documented history of completion of an appropriate TB 
treatment regimen for latent or active TB with no history of re-exposure to TB 
since their treatment was completed are eligible to participate in the study.
13. Known or suspected immunosuppression beyond that expected due to end-stage 
kidney disease and its comorbidities or unusually frequent, recurrent, severe, or 
prolonged infections as per investigator judgment.
14. History of lymphoproliferative disease or history of malignancy of any organ 
system within the last five years, except for (1) basal cell carcinoma, squamous 
cell carcinoma in situ (Bowen’s disease), or carcinomas in situ of the cervix that 
have been treated and have no evidence of recurrence in the last 12 weeks before 
the baseline visit, or (2) actinic keratoses that have been treated.
15. Pregnant women (positive serum pregnancy test result at any visits), breastfeeding 
women, or women planning a pregnancy during the clinical study.
16. In the opinion of the investigator the subject has any medical or psychological 
condition that could pose undue risk to the subject, prevent study completion, or 
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adversely affect the validity or interpretability of the study measurements or 
interfered with study assessments. 
17. Any clinically relevant laboratory abnormalities, such as but not limited to 
elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (> 3 
× upper limit of normal [ULN]) in combination with elevated bilirubin 
(> 2 × ULN), during the screening period that may put the subject at significant 
risk according to the investigator’s judgment, if he/she participates in the clinical 
study.
18. Planned or expected major surgical procedure during the clinical study, including a 
scheduled kidney transplant during the study. Subjects on a kidney transplant 
waiting list with no scheduled transplant date are not excluded.
19. Has not adhered to the restrictions in the selected medications and dialysis 
procedures prior to screening or is not expected to be compliant with restrictions 
during the study as listed in the following table.
Timeframe
Treatment(s)
Before Screening 
Screening Period
and
Day 1 – Week 20
Systemic corticosteroids  (i.e., administered by the 
intravenous, oral, or intramuscular route). 
Note: Low dose prednisone (up to 10 mg per day [or 
equivalent other corticosteroid]) is permitted if the 
dose has been stable for 2 weeks prior to Screening 
Note: Use of steroids given by other routes (inhaled, 
topical for indications other than itching, ophthalmic, 
intra-articular, etc. are permitted). 
Not allowed for 4 weeks, 
other than stable low dose 
prednisone or equivalent 
Prohibited, other 
than stable low dose 
prednisone or 
equivalent
Topical corticosteroids
Not allowed for 2 weeks
Prohibited
Topical PDE-4 inhibitor
Not allowed for 2 weeks 
Prohibited
TCIs 
Not allowed for 2 weeks 
Prohibited
Biologics and their biosimilars (e.g. etanercept, 
adalimumab, infliximab, omalizumab, etc.)
Not allowed for 8 weeks or 
5 half-lives 
(whichever is longer) 
Prohibited
Dupilumab
Not allowed for 10 weeks 
Prohibited
Cannabinoids
Not allowed for 2 weeks 
Prohibited
Immunosuppressive or immunomodulatory drugs 
(e.g. cyclosporine A, oral tacrolimus, 
cyclophosphamide, azathioprine, methotrexate, 
mycophenolate mofetil, JAK inhibitors)
Not allowed for 4 weeks or 
5 half-lives 
(whichever is longer) 
Prohibited
Systemic and topical antihistamines (excluding for 
ophthalmic use)
Stable dose for 2 weeks
Stable dose
Local anesthetics such as pramoxine, seed oil, 
capsaicin, topical ketamine, CBD oil, various lotions 
with anti-pruritic effects, etc.
Not allowed for 1 week
Prohibited
Gabapentin and pregabalin
Stable dose for 2 weeks
Stable dose
Phototherapy or tanning beds
Not allowed for 4 weeks
Prohibited
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Selected Opioids
Nalbuphine or kappa opioid agonists (e.g., 
difelikefalin, nalfurafine)
Not allowed for 4 weeks 
Prohibited
All other opioids (e.g. codeine, tramadol, oxycodone, 
hydrocodone, methadone, buprenorphine)
Stable dose for 2 weeks 
Stable dose
Change in hemodialysis treatment  (i.e., number of 
hemodialysis sessions per week, change in dialyzer 
or switch between hemodialysis and 
hemodiafiltration). Also see inclusion criterion #2
Not allowed for 8 weeks 
Prohibited
Live attenuated vaccine and non-live vaccine 
(Seasonal vaccine (e.g., influenza), emergency 
vaccine (e.g., rabies or tetanus) and COVID vaccines 
as noted in Section 12.5.2 are permitted)
Not allowed for 4 weeks 
Prohibited
Abbreviations: PDE-4 = phosphodiesterase-4; TCI = topical calcineurin inhibitor; 
TCS = topical corticosteroid.
For medications given as needed (“PRN”), stable dose during the study is defined as that without 
an increase or decrease by ≥75% in the total weekly dose relative to the dose during the last 
week of screening. For example, if the total weekly dose of 100 mg of diphenhydramine during 
the last week of the screening period increased to 175 mg in a given week during the study, this 
would be considered not a stable dose. During the Screening Period, a “stable dose” is one that 
has not changed (increase or decrease) by ≥ 75% during the period of required stability.
Note: Subjects should not interrupt ongoing treatment with medications important for the 
subject’s health for the sole purpose of participating in this study.
20. Requiring rescue therapy for pruritus during the screening period or expected to 
require rescue therapy within 4 weeks following the baseline visit. See 
Section 12.5.1.2.
21. Previous treatment with nemolizumab.
22. History of hypersensitivity (including anaphylaxis) to an immunoglobulin product 
(plasma-derived or recombinant, e.g. monoclonal antibody) or to any of the study 
drug excipients.
23. Currently participating or participated in any other study of an investigational drug 
or device, within the past four weeks (or five half-lives of the investigational 
medication, whichever is longer) before the screening visit.
24. History of alcohol or substance abuse within six months of the screening visit.
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Study Endpoints:
Data of both nemolizumab groups (30 mg and 60 mg) and placebo group and 
comparisons versus placebo group of both nemolizumab groups will be presented. 
Primary Efficacy 
Estimand Description
Estimand Attributes
Treatment Conditions: initial dose of nemolizumab 
(60 mg) or placebo at baseline, then nemolizumab (30 mg 
or 60 mg) or placebo Q4W at Weeks 4 and 8 via 
subcutaneous injection. 
Population: adult hemodialysis patients with chronic 
kidney disease and associated moderate to severe pruritus 
(will be estimated in the Intent-to-Treat analysis set).
Variable: a binary composite response where:
Responder is defined as an improvement ≥ 4 in WI NRS 
from baseline at Week 12 without use of rescue therapies 
and without treatment discontinuation due to lack of 
efficacy or AE/death related to study drug.
Non-responder is defined as an improvement < 4 in WI 
NRS from baseline at Week 12 or use of rescue therapies 
or treatment discontinuation due to lack of efficacy or 
AE/death related to study drug.
Strategies for Intercurrent Events: A composite strategy 
was chosen for the use of rescue therapies and treatment 
discontinuation due to lack of efficacy or AE/death related 
to study drug; in case of use of rescue therapies or 
treatment discontinuation due to lack of efficacy or 
AE/death related to study drug, subjects will be considered 
as treatment failures in the binary composite response. In 
the case of treatment discontinuation for any other reason, 
a treatment policy strategy will be used and observed after 
discontinuation data (if available) will be used.
In adult hemodialysis 
patients with chronic 
kidney disease and 
associated moderate to 
severe pruritus, 2 
nemolizumab dosing 
schedules[1] compared 
to placebo by the 
difference in 
proportions of 
responders where 
response is defined as 
an improvement from 
baseline of WI NRS ≥ 
4 at Week 12 without 
use of rescue therapies 
and without treatment 
discontinuation due to 
lack of efficacy or 
AE/death related to 
study drug
Summary measure: treatment difference of nemolizumab 
from placebo in proportions of responders
[1] Dosing schedules compared to placebo Q4W are an initial SC dose of nemolizumab 
(60 mg) at baseline then either 30 mg or 60 mg Q4W at Week 4 and Week 8.
Abbreviation(s): WI NRS = Worst Itch Numeric Rating Scale; Q4W = Every 4 Weeks
Key Secondary Efficacy Endpoints:
1.
Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at 
Week 12.
2.
Proportion of subjects with an improvement of WI NRS ≥ 4 from baseline at 
Week 4.
3.
Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at 
Week 12.
4.
Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at 
Week 4.
5.
Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at 
Week 4.
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Therapies:
Investigational therapy
Nemolizumab 30 mg or placebo will be provided as lyophilized powder for solution for 
injection for SC use only after reconstitution in a dual-chamber, single-use syringe 
(DCS). Subjects will receive a loading dose of nemolizumab (60 mg) or placebo by 
two SC injections at baseline (30 mg + 30 mg, placebo + placebo) and a 30 mg or 60 
mg dose of nemolizumab or placebo by two SC injections (30 mg + placebo, 30 mg + 
30 mg, placebo + placebo) at Weeks 4 and 8. All the study drug treatment should be 
performed following the completion of the hemodialysis treatment (within four hours).
Rescue Therapies
If deemed to be medically necessary by the investigator (e.g. to control intolerable 
pruritus), rescue therapies can be prescribed to the subjects at any time during the study 
except during the screening period. Subjects receiving rescue therapies during the 
screening period are not eligible to participate in the study.
As a general guideline and per individual investigator judgment, rescue therapy should 
not be prescribed within the first four weeks after baseline to allow a minimum time for 
study drug potential effect in the presence of background therapy. 
Investigator assessments of efficacy should be performed before initiating rescue 
therapy. Subjects requiring rescue therapy between scheduled visits should return to 
the clinic (unscheduled visit) for investigator assessment of efficacy before starting 
rescue therapy. The Investigator must contact the Medical Monitor prior to initiating 
rescue therapy.
As judged appropriate by the investigator and following discussion with the Medical 
Monitor, rescue therapies are defined as below and include the following treatments:
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
Antihistamines (new or increased dose):  For those given as needed (“PRN”) 
at baseline, rescue of antihistamine is defined as that with an increase by 
≥75% in the total weekly dose relative to the dose during the last week of 
screening administered for ≥ 1 week.  

Gabapentin (new or increased dose) administered for ≥ 1 week.

Selected Opioids: Nalbuphine or kappa opioid agonists (e.g., difelikefalin, 
nalfurafine), one or more doses.

Ultraviolet (UV) radiation therapy: one or more treatments.
Note: all new concomitant medication or increase of frequency or increase of dose 
will be recorded 
Treatment 
Duration:
The expected duration of each subject’s participation in the study is up to 24 weeks, 
including an up to 4-week screening period, a 12-week treatment period, and an 
8-week follow-up period (12-weeks after the last study medication injection).
Efficacy:
The following efficacy assessments are planned according to the schedule of 
assessments:

WI NRS

SD NRS 
 
 
 
 
 
Statistical Methods 
and Planned 
Analyses:
Analysis Populations
Statistical analyses will be performed on the following subject populations.

Intent-to-Treat Population: The intent-to-treat (ITT) population will consist 
of all randomized subjects. 

Modified Intent-to-Treat Population: The modified intent-to-treat (mITT) 
population will consist of all ITT subjects who receive at least one dose of 
study drug and have at least one post baseline assessment of primary efficacy 
variable.
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
Per Protocol Population: The per protocol (PP) population will include all 
randomized subjects who receive all scheduled doses of study drug and have 
Baseline and Week 12 assessments of WI NRS and with no major deviation 
that could impact efficacy.

Safety Population: The safety population will include all randomized 
subjects who receive at least one dose of study drug.

 
The ITT population will be the primary population for all efficacy analyses. The mITT 
and PP populations will be used for the supplementary analysis of the primary 
endpoint. 
 
Efficacy Analysis
A summary based on observed case (OC) will be provided for all primary, secondary, 
and exploratory efficacy endpoints. At this case, no data will be imputed. For this 
summary, if any rescue medication is received or treatment is discontinued, and data 
are collected post-rescue receipt or treatment discontinuation, then the data post-rescue 
or post-discontinuation will be summarized as observed.
Proportion of subjects with WI NRS/SD NRS ≥ 4 and WI NRS ≥ 3, changes and 
percent changes from baseline of WI NRS/SD NRS at each week (from week 1 
through week 20) will be calculated on the basis of the weekly average, obtained by 
averaging at least 4 daily WI NRS/SD NRS scores over 7-day periods. If fewer than 4 
daily WI NRS/SD NRS scores for the 7-day period (for baseline and week 12 wider 
periods apply) are available, weekly average WI NRS/SD NRS will be considered 
missing for that period. For the aim of sensitivity analyses, weekly averages of WI 
NRS obtained by averaging at least 3, 2 and 1 daily scores over 7-day periods will be 
calculated (no period extension at baseline and week 12 applies for these weekly 
averages). For detailed rules, refer to section 19.3.
Data of both nemolizumab groups (30 mg and 60 mg) and placebo group and 
comparisons versus placebo group of both nemolizumab groups will be presented.
Analysis of Primary Efficacy Endpoint
The proportion of subjects with an improvement of WI NRS ≥ 4 from baseline will be 
analyzed using the Cochran-Mantel-Haenszel (CMH) test stratified by analysis center; 
strata-adjusted difference in proportions between treatment groups and the 97.5% 
confidence interval (CI) of the difference will be based on the large sample 
approximation method for binary data.
Analysis of Key Secondary Efficacy Endpoints
The following key secondary efficacy endpoints will be analyzed using the Cochran-
Mantel-Haenszel (CMH) test stratified by analysis center; strata-adjusted difference in 
proportions between treatment groups and the 97.5% confidence interval of the 
difference will be based on the large sample approximation method for binary data.

Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at 
Week 12.

Proportion of subjects with an improvement of WI NRS ≥ 4 from baseline at 
Week 4.

Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at 
Week 12.

Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at 
Week 4.

Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at 
Week 4.
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Multiplicity Adjustment for Primary and Key Secondary Efficacy Endpoints
In order to maintain the overall two-sided alpha of 0.05, a two-sided alpha of 0.025 
will be spent for the comparison of each Nemolizumab dose group versus placebo 
group. A predefined hierarchal testing procedure will be implemented to test the 
primary and key secondary endpoints of each nemolizumab dose group versus placebo 
group.
Analysis Centers
Prior to database lock, a review of the blinded data will be performed to determine the 
size of each center. If there are centers with a small number of randomized subjects 
(i.e., centers with less than 12 randomized subjects), then these centers will be pooled 
in order for analyses to be carried out. The process of combining centers will be based 
on the ITT population, and same pooling will be repeated for mITT population and PP 
population.
Handling of Missing Data
Missing data for dichotomous efficacy endpoints will be imputed using multiple 
imputations (MI) under missing at random (MAR) assumption for the primary/main 
analyses. Dichotomous endpoints will be calculated from the underlying imputed 
variable.
For the sensitivity analyses of the primary endpoint, missing data will be imputed using 
a copy reference (CR) approach under missing not at random (MNAR) assumption 
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(dichotomous endpoints will be calculated from the underlying imputed variable) and 
as “Non-responder”; moreover a Tipping Point analysis under MNAR assumption will 
be carried out.
For the sensitivity analyses of the key secondary efficacy endpoints, missing data will 
be imputed using a CR approach under MNAR assumption (dichotomous endpoints 
will be calculated from the underlying imputed variable) and as “Non-responder.”
Missing data for continuous efficacy endpoints and Quality-of-life/Health Outcome 
endpoints will be imputed using MI under MAR assumption.
For the multiple imputation, the MI procedure of the SAS system will be used to 
generate sets of data with missing values imputed from observed data. It is expected 
that the pattern of missing data will be monotonic, with slight deviations being 
corrected by the Markov Chain Monte Carlo (MCMC) method of the MI procedure. A 
predictive mean matching method will be used for the continuous data with the 
following covariates included in the imputation model: non-missing data from earlier 
time points. Separate imputations by treatment group will be carried out. Changes and 
percent changes from baseline and dichotomous endpoints will be calculated from the 
imputed data.
Subjects who took rescue therapies or discontinued treatment due to lack of efficacy or 
AE/death related to study drug will be considered as treatment failures, efficacy data 
collected after the use of rescue therapies or treatment discontinuation due to lack of 
efficacy or AE/death related to study drug will be set to the worst possible value and 
subject’s binary response will be imputed as “Non-responder” prior to conducting the 
MI and Tipping Point analysis.
Sensitivity and Supplementary Analysis for Primary and Key Secondary Efficacy 
Endpoints
For the sensitivity analyses of the primary endpoint, missing data will be imputed using 
a copy reference (CR) approach under missing not at random (MNAR) assumption 
(dichotomous endpoints will be calculated from the underlying imputed variable) and 
as “Non-responder”; moreover a Tipping Point analysis under MNAR assumption will 
be carried out. Furthermore, the analysis of the primary efficacy endpoint will be 
repeated using weekly averages of WI NRS with at least 3 daily scores over 7-day 
periods, at least 2 daily scores over 7-day periods and at least 1 daily scores over 7-day 
periods (no period extension at baseline and week 12 applies for these averages).
A mITT analysis, a PP analysis and an observed case analysis will be performed too as 
supplementary analyses for the primary efficacy endpoint.
Sensitivity analyses will be performed by imputing missing data using a CR approach 
under MNAR assumption (dichotomous endpoints will be calculated from the 
underlying imputed variable) and as “Non-responder” for the following key secondary 
efficacy endpoints:

Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at 
Week 12.

Proportion of subjects with an improvement of WI NRS ≥ 4 from baseline at 
Week 4.

Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at 
Week 12.

Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at 
Week 4.

Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at 
Week 4.
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Subjects who took rescue therapies or discontinued treatment due to lack of efficacy or 
AE/death related to study drug will be considered as treatment failures, efficacy data 
collected after the use of rescue therapies or treatment discontinuation due to lack of 
efficacy or AE/death related to study drug will be set to the worst possible value and 
subject’s binary response will be imputed as “Non-responder” prior to conducting the 
MI and Tipping Point analysis.
Impact of COVID-19
To assess the impact of COVID-19 related study disruptions (e.g. treatment 
discontinuation, missing assessments, etc.), the primary and key secondary efficacy 
endpoints will also be analyzed using multiple imputations (MI) under missing at 
random (MAR) assumption on the ITT population excluding subjects affected by 
COVID-19 related study disruptions.
Subgroup Analysis
Descriptive summary and analysis for primary and key secondary efficacy endpoints 
will be produced for the following subgroups: 

Age group (18 to 45; >45 to 65; >65 to 80; >80) 

Sex (Male, Female)

Race (White, Black, Asian, Other)

Region (US; Excl-US)

Severity of pruritus at baseline (5 to 7; >7 to 10)

Duration of pruritus at baseline (≤3 months; >3 to 12 months; >12 months)

Duration of hemodialysis at baseline (≤1 year; >1 year to 3 years; >3 years)

With or without prior or concomitant systemic anti-pruritus treatment
Safety Analysis
The duration of exposure and the number of administrations per subject will be 
summarized by treatment group.
TEAEs, AESIs, and SAEs will be summarized using frequency tables by System 
Organ Class (SOC) and Preferred Term (PT) based on the Medical Dictionary for 
Regulatory Activities (MedDRA version 23.0 or later).
Physical examination, vital signs (including weight), clinical laboratory tests, ECG and 
respiratory examination and assessments will be summarized by visit using descriptive 
statistics/frequency tables as applicable. Shift tables from baseline by reference ranges 
will be presented for clinical laboratory tests.
Dose selection
Dose selection will be based on the final analysis by evaluating the optimal risk-benefit 
and considering the potential impact of body weight.
 
 
 
 
 
Safety assessment
The IDMC will review and monitor subject safety throughout the study. 
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6
TABLE OF CONTENTS
1
CLINICAL STUDY PROTOCOL...................................................................................1
2
PROTOCOL APPROVAL SIGNATURES.....................................................................2
3
INVESTIGATOR SIGNATURE PAGE..........................................................................3
4
STUDY PERSONNEL.....................................................................................................4
5
SYNOPSIS .......................................................................................................................5
6
TABLE OF CONTENTS ...............................................................................................18
LIST OF TABLES ...................................................................................................................24
7
LIST OF ABBREVIATIONS ........................................................................................25
8
INTRODUCTION..........................................................................................................28
8.1
Background on Chronic Kidney Disease with associated Pruritus............................28
8.2
Background on Nemolizumab ...................................................................................29
8.3
Clinical Studies with Nemolizumab ..........................................................................29
8.3.1
Phase 2a Study in Subjects with CKD-aP.............................................................30
8.4
Risk/Benefit Assessment ...........................................................................................31
8.5
Drug Profile ...............................................................................................................33
8.6
Study and Dose Selection Rationale..........................................................................33
9
STUDY OBJECTIVES AND ENDPOINTS .................................................................35
9.1
Study Objectives ........................................................................................................35
9.1.1
Primary Objective .................................................................................................35
9.1.2
Secondary Objectives............................................................................................35
9.2
Study Endpoints.........................................................................................................35
9.2.1
Primary Efficacy Endpoint....................................................................................35
9.2.2
Secondary Efficacy Endpoints ..............................................................................36
10
INVESTIGATIONAL PLAN.........................................................................................38
10.1
Description of Overall Study Design and Plan..........................................................38
10.1.1
Study Visit Schema ...............................................................................................39
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10.2
Discussion of Study Design.......................................................................................39
10.3
End of Study ..............................................................................................................41
11
SELECTION OF STUDY POPULATION....................................................................42
11.1
Number of Planned Subjects......................................................................................42
11.2
Inclusion Criteria .......................................................................................................42
11.3
Exclusion Criteria ......................................................................................................44
11.4
Rescreening................................................................................................................48
11.5
Removal of Subjects from Therapy or Assessments .................................................48
11.5.1
Pregnancy..............................................................................................................50
11.5.2
Coronavirus Disease 2019.....................................................................................51
12
TREATMENTS..............................................................................................................52
12.1
Details of Study Medication ......................................................................................52
12.1.1
Investigational Products Administered .................................................................52
12.1.2
Identity of Investigational Products ......................................................................52
12.1.3
Preparation ............................................................................................................52
12.1.4
Study Drug Injection .............................................................................................53
12.1.5
Packaging and Labeling ........................................................................................53
12.1.6
Study Drug Management ......................................................................................54
12.2
Measures to Minimize Bias: Study Treatment Assignment.......................................54
12.2.1
Allocation Concealment and Method of Study Treatment Assignment ...............54
12.2.2
Blinding.................................................................................................................55
12.3
Dosage Modifications ................................................................................................56
12.4
Treatment Accountability and Compliance ...............................................................56
12.4.1
Dispensing and Return of Study Drug ..................................................................57
12.4.2
Compliance............................................................................................................57
12.5
Prior and Concomitant Therapy.................................................................................57
12.5.1
Permitted Concomitant Therapy ...........................................................................58
12.5.2
Prohibited and Restricted Medication/Therapy.....................................................59
12.6
Product Technical Complaints...................................................................................62
13
STUDY PROCEDURES................................................................................................63
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13.1
Schedule of Assessments ...........................................................................................63
13.2
Duration of Subject Participation...............................................................................68
13.2.1
Early Termination Visit.........................................................................................68
13.2.2
Unscheduled Visit .................................................................................................68
14
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .......................................69
14.1
Medical History .........................................................................................................69
14.2
Height and Weight .....................................................................................................69
14.3
Baseline Characteristics.............................................................................................69
15
EFFICACY ASSESSMENTS........................................................................................70
15.1
Worst Itch Numeric Rating Scale ..............................................................................70
15.2
Sleep Disturbance Numeric Rating Scale..................................................................71
16
SAFETY ASSESSMENTS ............................................................................................74
16.1
Vital Signs..................................................................................................................74
16.2
Physical Examination.................................................................................................74
16.3
Electrocardiogram......................................................................................................74
16.4
Clinical Laboratory Evaluation..................................................................................75
16.4.1
Hematology ...........................................................................................................76
16.4.2
Biochemistry .........................................................................................................76
16.4.3
Urinalysis ..............................................................................................................76
16.5
Pregnancy Testing......................................................................................................76
16.6
Virology .....................................................................................................................76
16.7
Tuberculosis Testing..................................................................................................76
16.7.1
Definitions.............................................................................................................77
16.7.2
Tuberculosis Screening .........................................................................................77
16.8
Respiratory Assessments ...........................................................................................77
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16.8.1
Asthma Control Test .............................................................................................78
16.8.2
Respiratory Examination.......................................................................................78
16.8.3
Peak Expiratory Flow............................................................................................78
16.8.4
Respiratory Referrals.............................................................................................79
16.9
Adverse Events ..........................................................................................................79
16.9.1
Assessment of Severity .........................................................................................80
16.9.2
Assessment of Causality........................................................................................80
16.9.3
Action Taken.........................................................................................................81
16.9.4
Follow-up of Adverse Event .................................................................................81
16.9.5
Documenting and Reporting of Adverse Events...................................................81
16.10
Adverse Events of Special Interest ............................................................................82
16.11
Serious Adverse Events .............................................................................................83
16.12
Reporting Procedures.................................................................................................84
16.12.1
Adverse Events of Special Interest Reporting.......................................................84
16.12.2
Serious Adverse Event Reporting .........................................................................85
16.12.3
Suspected Unexpected Serious Adverse Reactions ..............................................86
16.12.4
Pregnancy Reporting.............................................................................................87
16.12.5
Overdose Reporting...............................................................................................87
18
OTHER ASSESSMENTS..............................................................................................89
18.1
Immunogenicity: Anti-drug Antibodies.....................................................................89
18.2
Independent Data Monitoring Committee .................................................................89
18.3
Independent Adjudication Committee .......................................................................89
19
STATISTICAL ANALYSIS..........................................................................................90
19.1
Determination of Sample Size ...................................................................................90
19.2
Analysis Populations..................................................................................................90
19.3
Efficacy Analysis.......................................................................................................91
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19.3.1
Analysis of Primary Efficacy Endpoint ................................................................92
19.3.2
Analysis of Secondary Efficacy Endpoints...........................................................92
19.3.3
Analysis of Exploratory Efficacy Endpoint ..........................................................93
19.3.4
Multiplicity Adjustment for Primary and Key Secondary Efficacy 
Endpoints...............................................................................................................94
19.4
Safety Analysis ..........................................................................................................94
19.4.1
Extent of Exposure................................................................................................94
19.4.2
Adverse Events......................................................................................................95
19.4.3
Clinical Laboratory ...............................................................................................95
19.4.4
Vital Signs.............................................................................................................95
19.4.5
12-Lead Electrocardiogram...................................................................................95
19.4.6
Physical Examination............................................................................................95
19.4.7
Respiratory Assessments.......................................................................................96
19.4.8
Prior and Concomitant Medications......................................................................96
19.5
Pharmacokinetic and Anti-drug Antibody Analysis..................................................96
19.6
Dose selection ............................................................................................................96
19.7
Handling of Missing Data..........................................................................................97
19.8
Analysis Centers ........................................................................................................97
19.9
Sensitivity and Supplementary Analysis for Primary and Key Secondary 
Efficacy Endpoints.....................................................................................................98
19.10
Impact of COVID-19 .................................................................................................99
19.11
Subgroup Analysis.....................................................................................................99
20
STUDY MANAGEMENT...........................................................................................100
20.1
Approval and Consent..............................................................................................100
20.1.1
Regulatory Guidelines.........................................................................................100
20.1.2
Institutional Review Board/Independent Ethics Committee...............................100
20.1.3
Informed Consent................................................................................................100
20.2
Data Management ....................................................................................................100
20.3
Source Documents ...................................................................................................101
20.4
Record Retention .....................................................................................................101
20.5
Monitoring ...............................................................................................................101
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20.6
Quality Control and Quality Assurance...................................................................102
20.7
Protocol Amendment and Protocol Deviation .........................................................102
20.7.1
Protocol Amendment...........................................................................................102
20.7.2
Protocol Deviations.............................................................................................102
20.8
Ethical Considerations .............................................................................................103
20.9
Financing and Insurance ..........................................................................................103
20.10
Publication Policy/Disclosure of Data.....................................................................103
20.11
Subject Confidentiality ............................................................................................103
21
REFERENCES.............................................................................................................105
22
APPENDICES..............................................................................................................107
 
Appendix 3
Worst Itch Numeric Rating Scale...................................................................113
Appendix 4
Sleep Disturbance Numeric Rating ................................................................114
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LIST OF TABLES
Table 1
Prior Treatments and Procedures ..........................................................................46
Table 2
Description and Usage of Investigational Products ..............................................52
Table 3
Treatment Period Dosing by Treatment Group.....................................................54
Table 4
Prohibited and Restricted Medication/Therapy.....................................................60
Table 5
Schedule of Assessments ......................................................................................64
 
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7
LIST OF ABBREVIATIONS
Abbreviation
Definition
ACT
Asthma Control Test
AD
Atopic dermatitis
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AR
Adverse reaction
AST
Aspartate aminotransferase
AVF
Arteriovenous Fistula
AVG
Arteriovenous Graft
BCG
Bacillus Calmette-Guérin
BL
Baseline
CDC
Center for Disease Control and Prevention
CDER
Center for Drug Evaluation and Research 
CFR
Code of Federal Regulations
CI
Confidence interval
CKD
Chronic kidney disease
CKD-aP
Chronic kidney disease with associated pruritis
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus disease 2019
CP
Conditional power
CPK
Creatine phosphokinase
CR
Copy reference
CRO
Contract research organization
CS
Clinically significant
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
CYP450
Cytochrome P450
DCS
Dual-chamber, single-use syringe
EASI
Eczema Area and Severity Index
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
electronic data capture
ELISA
Enzyme-linked immunosorbent assay
EMEA
Europe, Middle East, and Africa
ESKD
End-stage kidney disease
EQ-5D-5L
EuroQoL 5-dimension 5-level
ET
Early termination
FSH
Follicle-stimulating hormone
GCP
Good Clinical practice
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Abbreviation
Definition
HbcAb
Hepatitis B core antibody
HbsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
IAC
Independent adjudication committee
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IGA
Investigator’s Global Assessment
IL
Interleukin
IRB
Institutional Review Board
IRR
Injection-related reaction
IRT
Interactive response technology
ITT
Intent-to-treat
IUG
Independent Unblinded Group
JAK
Janus kinase
Kt/V
Volume of plasma cleared of urea (Kt) relative to volume of distribution of urea (V)
LCL
Lower Confidence Limit
LSM
Least squares mean
MAR
Missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MNAR
Missing not at random
MCMC
Markov-Chain-Monte-Carlo
MI
Multiple imputation
mITT
Modified intent-to-treat
N
Number of subjects or sample size
NA
North America
NCS
Not clinically significant
NRS
Numeric rating scale
OC
Observed case
PCR
Polymerase chain reaction
PD
Pharmacodynamics
PDE
Phosphodiesterase
PE
Point Estimate
PEF
Peak expiratory flow
PN
Prurigo nodularis
popPK
Population pharmacokinetics
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Abbreviation
Definition
PP
Per protocol
PRN
Pro re nata (when necessary or as needed)
PT
Preferred Term
PTC
Product technical complaint
Q4W
Every four weeks
QoL
Quality of life
RA
Receptor A
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous 
SD NRS
Sleep Disturbance Numeric Rating Scale
SHPT
Secondary hyperparathyroidism
SIN
Subject identification number
SOC
System Organ Class
SRO
Subject-reported outcome
SUSAR
Suspected unexpected serious adverse reaction
TB
Tuberculosis
TCI
Topical calcineurin inhibitor
TCS
Topical corticosteroid
TEAE
Treatment-emergent adverse event
TMF
Trial Master File
UCL
Upper Confidence Limit
ULN
Upper limit of normal
US
United States
UV
Ultraviolet
VAS
Visual analogue scale
WI NRS
Worst Itch Numeric Rating Scale
WOCBP
Women of childbearing potential
WHO
World Health Organization
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8
INTRODUCTION
8.1
Background on Chronic Kidney Disease with associated Pruritus
Chronic kidney disease with associated pruritus (CKD-aP) is a common, troubling and, in 
some cases, debilitating problem for patients with chronic kidney disease (CKD) and 
end-stage kidney disease (ESKD). It’s characterized by systemic and intractable itching and 
is one of the diseases that troubles dialysis patients on a daily basis including adverse medical 
outcomes and poor quality of life (QoL).
A survey conducted in Japan in 2000 revealed that 72.8% of hemodialysis patients have 
experienced pruritus and that around half of these individuals have suffered from sleep 
disturbance (Omori 2001). Furthermore, the extent of sleeplessness among patients with 
CKD-aP reportedly increased as the itching became more severe (Narita 2006, Kimata 2014). 
The Dialysis Outcomes and Practice Patterns Study conducted in 12 countries found that 
approximately 41.7% of tracked patients had at least moderate pruritus and reduced sleep 
quality (Pisoni 2006). Severe pruritus is also a purported risk factor for poor prognosis among 
dialysis patients (Narita 2006).
More recently (i.e., 2012-2015), an international comparison on the prevalence of pruritis in 
hemodialysis patients found that 68% of survey respondents reported they were at least 
somewhat bothered by itchy skin (31% somewhat; 19% moderately; 11% very much; 
7% extremely). Of the patients that were very much or extremely bothered by itchy skin, 
84% were also bothered by dry skin, and 60% had sleep restlessness. Similar findings were 
reported in country specific regions such as the US and throughout Europe (Rayner 2017).
Despite a prevalence rate and a clear association with poorer psychosocial and medical 
outcomes including higher mortality risk (Pisoni 2006), this condition is often underreported 
by patients and overlooked by health care providers. In one survey, the rate of pruritis in 
hemodialysis patients was underestimated by medical directors by 69% (Rayner 2017). This 
is likely due, in part, to uncertainty regarding its pathogenesis and treatment. Conventional 
treatments include changing the dialysis conditions or using highly biocompatible dialysis 
membranes, regulating calcium and phosphorus concentrations, treating the secondary 
hyperparathyroidism (SHPT), topical application of moisturizers or steroid preparations, drug 
therapy with antihistamines or anti-allergic agents, and ultraviolet (UV) phototherapy. 
Nevertheless, these treatments often prove ineffective (Kfoury 2012).
The cause of CKD-aP has been attributed to various factors including accumulation of uremic 
substances, elevated serum calcium and phosphorus concentrations, SHPT, dialysis 
membrane-induced complement activation or heparin, induction of endogenous itch 
mediators (e.g., histamines, serotonin, substance P), immune system abnormalities, and 
endogenous opioid abnormalities. However, the precise mechanism of onset is still unclear.
In Japan, nalfurafine hydrochloride was launched in 2009 for the indication of improvement 
of pruritus in hemodialysis patients when response to conventional treatments is inadequate. 
However, the degree of improvement in pruritus after taking nalfurafine hydrochloride has 
varied among patients (Yamada 2012), and 19.4% of clinical trial subjects experienced 
insomnia (sleep disturbance) as an adverse reaction (AR) to the drug (Kumagai 2012). On 
23 AUG 2021, the US Food and Drug Administration granted NDA approval through priority 
review for difelikefalin for the treatment of moderate to severe pruritus in hemodialysis 
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patients (Fishbane 2020), thus highlighting the need for further investigations into treatment 
options that possesses both adequate efficacy and a high level of safety for this population.
A 2014 study by Ko et al. investigated the relationship between CKD-aP and serum 
interleukin (IL-31) concentrations in 178 patients undergoing hemodialysis (Ko 2014). The 
study found that serum IL-31 concentrations were higher in patients with pruritus than in 
those without pruritus and that some of the patients with pruritus had serum IL-31 
concentrations that exceeded 100 pg/mL. The study also found a correlation between serum 
IL-31 concentration and the Visual Analog Scale (VAS) score of pruritus intensity in patients 
whose serum IL-31 concentrations exceeded a certain level. This finding implies that IL-31 is 
involved in itching in CKD-aP and suggests that inhibition of IL-31 may have a therapeutic 
effect.
8.2
Background on Nemolizumab
Nemolizumab is a humanized anti-human IL-31 receptor A (RA) monoclonal antibody that 
inhibits the binding of IL-31 to IL-31RA and subsequent signal transduction. The 
T-cell-derived cytokine IL-31 has been suggested to be a key player in the development of 
pruritus, inducing severe pruritus and dermatitis in mouse models (Dillon 2004, Arai 2013). 
IL-31 binds to a heterodimeric receptor at TRPV1 (+)/TRPA1 (+)-Cfibres, keratinocytes, 
macrophages and eosinophils, and thus may be involved in transmission of pruritus and 
promotion of inflammation. Not limited to the skin, the densest area of this receptor seems to 
be at the dorsal horn of spinal cord where the cell bodies of cutaneous sensory neurons reside 
(Sonkoly 2006). Therefore, IL-31 may be a link between the immune and the neural system.
Nemolizumab, with its novel mechanism of action of blocking the IL-31 pathway, is 
expected to have a therapeutic effect in patients with CKD-aP, atopic dermatitis (AD), and 
prurigo nodularis (PN) not adequately controlled by existing treatments.
Nemolizumab was initially developed by Chugai Pharmaceutical Co., Ltd., a Japanese based 
pharmaceutical company; it was subsequently licensed to Galderma (sponsor) in 2016 
worldwide except in Japan and Taiwan. Nemolizumab is an investigational agent under 
clinical development, and its safety and efficacy have not been fully evaluated by any 
regulatory authority.
8.3
Clinical Studies with Nemolizumab
The Investigator’s Brochure (IB) contains detailed information on clinical and non-clinical 
studies. Summaries of completed and ongoing clinical studies of nemolizumab in CKD-aP, 
AD, and PN are included in the IB. The CKD-ap phase 2a study is outlined below.
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8.3.1
Phase 2a Study in Subjects with CKD-aP
Study CIM106JP was a Phase 2a study conducted in adult hemodialysis subjects with uremic 
pruritus (Kinugasa 2021). The study was a randomized, double-blind, 
placebo-controlled, parallel four arm study with three doses of blinded study drug (CIM331; 
Chugai’s internal code for nemolizumab) or placebo, and an open-label reference product 
arm (nalfurafine hydrochloride group). Study duration was 12 weeks. The population 
consisted of hemodialysis subjects with pruritus for which existing treatment, other than 
nalfurafine hydrochloride, was ineffective. 
The primary endpoint was to analyse the absolute change in pruritus VAS score from 
baseline to four weeks. It was the pairwise comparison of each nemolizumab treatment group 
against placebo. Secondary endpoints included Pruritus VAS score, and the Shiratori severity 
score. (The Shiratori severity score is a Japanese itch severity questionnaire, which includes 
separate set of questions for both daytime and nighttime. Each set of questions consists of 
5 grades from 0 to 4, with 4 being the worst and 0 being absent. Grade 3 or higher on each 
scale was considered moderate to severe pruritus). 5-D itch scale score and mean in absolute 
change from baseline at each evaluation time point up to week 12, and 
 
), safety. A total of 69 subjects were enrolled:15 subjects in the nemolizumab 0.125 
mg/kg group, 14 subjects in the placebo and nemolizumab 2.0 mg/kg groups, and 13 subjects 
in the nemolizumab 0.5 mg/kg and nalfurafine hydrochloride groups). There were not 
statistically significant differences between the placebo group and each nemolizumab group 
in the absolute changes in pruritus VAS at Week 4 the primary efficacy endpoint. The LSM 
absolute changes in pruritus VAS (95% CI) at Week 4, the primary efficacy parameter, were 
−32.09 mm (−44.40 mm, −19.78 mm) in the placebo group, and −34.50 mm (−46.73 mm, 
−22.28 mm), −40.82 mm (−53.61 mm, −28.04 mm), and −31.74 mm (−43.97 mm, 
−19.51 mm) in the CIM331 0.125, 0.5, and 2.0 mg/kg groups, respectively.
In all groups including the placebo group, remarkable improvements in pruritus VAS were 
observed by Week 4. 
In all groups including the placebo group, improvements in the secondary efficacy 
parameters, pruritus VAS, Shiratori severity score, and 5-D itch score, were observed by 
Week 4, and there was no clear difference between the placebo group and each nemolizumab 
group. 
However, post hoc analyses conducted in the proportion of subjects achieving a pruritus VAS 
score of less than 30 mm (corresponding to “no or mild pruritus”) showed approximately 
two-fold higher proportion in the 0.5 mg/kg group compared to that in the placebo group at 
Week 4. 
The proportion of subjects with decrease in VAS ≥ 30 or ≥ 40 mm, proportion of subjects 
with VAS ≤ 2 or with VAS 0 -1 from baseline in all dose groups of nemolizumab were higher 
than that in the placebo group at week 4. Again, the 0.5 mg/kg dose provide the best efficacy 
profile compared to the two other tested doses.
The placebo effect of this study has been higher than expected. This could be explained by 
the bias of subjects expecting similar or superior effect of the blinded treatment including the 
blinded placebo, compared to open-label nalfurafine, the treatment subjects has received prior 
to randomization into the study. Therefore, the placebo effect might have been biased by 
expectation of higher treatment effect of the blinded treatments compared to the effect 
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subjects had experienced with nalfurafine before entering the study. Consistent with the 
explanation, open-label nalfurafine performed inferior to placebo.
 
 
 
Overall, no clinically significant (CS) safety findings were reported in the nemolizumab 
groups.
8.4
Risk/Benefit Assessment
Results of previous clinical studies in adults demonstrated that treatment with nemolizumab 
had a marked effect on AD and PN, pruritus, and pruritus-related sleep loss. Nemolizumab 
was also well tolerated overall when used as monotherapy or concomitantly with a TCS.
Based on the currently available information on nemolizumab and the risks associated with 
biologic agents in general, the potential risks of nemolizumab treatment include local or 
systemic IRRs, newly diagnosed asthma or worsening of asthma, and skin or non-skin 
infections. Refer to the IB for the most current risk/benefits.
The following specific risk-minimization and safety follow-up measures have been planned 
in this clinical study: 
a.
In a phase 2b study for Atopic dermatitis indication (SPR.114322), a dose-dependent 
increase of asthma flares (1 [1.8%], 2 [3.6%], 7 [12.3%], and 10 [17.5%] in placebo, 
10 mg, 30 mg, and 90 mg treatment arms, respectively) in subjects with pre-existing 
asthma was observed. Events were mostly mild or moderate (one severe event with 
highest dose), manageable, and reversible under treatment with study drug. This 
protocol (SPR. 204358) will exclude subjects with asthma exacerbation requiring 
hospitalization in the preceding 12 months before screening, subjects whose asthma 
has not been well controlled (i.e., symptoms > 2 days per week, nighttime awakenings 
two or more times per week, or some interference with normal activities) during the 
last three months before the screening visit, and Asthma Control Test (ACT) score ≤ 
19. At all visits, all subjects will be asked about respiratory changes and a respiratory 
examination will be performed. At screening and baseline conduct PEF for all 
subjects and ACT for subjects with medical history of asthma. After baseline ACT 
and PEF are only required for subjects with a medical history of asthma. Subjects 
diagnosed with de novo asthma will perform PEF and ACT assessments at all visits 
starting with the visit in which the diagnosis was confirmed. Subjects with a medical 
history of asthma will be referred to the physician managing their asthma if ACT ≤ 
19,  with signs and symptoms suggestive of asthma, and/or unexpected worsening of 
asthma is observed or reported, PEF value is used as supplemental information. 
Subjects without a medical history of asthma will be referred to a respiratory 
specialist if respiratory changes suggestive of asthma are observed or reported. An 
independent adjudication committee (IAC) will review and adjudicate all asthma AEs 
reported during the course of the study. PEF value is used as supplemental 
information as well.
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b. The exclusion criteria of this clinical study (i.e., restricting entry of subjects with 
recent/current infections or known/suspected immunosuppression or unusually 
frequent, recurrent, severe, or prolonged infections) will prevent non-eligible subjects 
at potentially higher risk of infection from receiving nemolizumab. As no data are 
available in pregnant or breastfeeding women, these subjects are not eligible for this 
study. Subjects who have recently received live vaccines may be considered for 
enrollment after an appropriate time has elapsed before baseline/Day 1. 
Administration of live attenuated vaccines and non-live vaccine is prohibited during 
the study. 
c.
A slight trend of dose-dependent increase of peripheral edema was reported in the 
nemolizumab study CIM003JG. Most events were mild (11 of 21), no case was 
serious, and none resulted in premature treatment discontinuation; no case was 
associated with renal or cardiac AEs. The EASI values and thymus and activation 
regulated chemokine levels were relatively higher in subjects with peripheral edema 
indicating that peripheral edema might be related to more severe AD. There were a 
few subjects reporting peripheral edema in study SPR.114322 (2 [3.6%], 2 [3.6%], 
4 [7%], and 2 [3.5%] in placebo, 10 mg, 30 mg, and 90 mg groups, respectively). 
Peripheral edema will be followed as an AE of special interest (AESI) in this study. 
Recognizing that peripheral edema occurs commonly in dialysis patients related to 
their overall volume status, dialysis treatment, and other factors, peripheral edema is 
only to be reported as an AESI if assessed by the investigator as having a reasonable 
possibility for a relationship to study drug.
d. An independent data monitoring committee (IDMC) will monitor the safety data 
regularly throughout the study, including AESIs, which were defined based on the 
currently available safety information on nemolizumab and the risks associated with 
biologic agents in general. AESIs for this study are: 
o
IRRs
-
Anaphylactic reactions
-
Acute allergic reactions requiring treatment
-
Severe injection site reactions with a duration greater than 24 hours
o
Newly diagnosed asthma or worsening of asthma
o
Infections
-
Any severe infection or any infection requiring treatment with 
parenteral antibiotics or with oral antibiotics/antivirals/antifungals for 
> 2 weeks
-
Any confirmed or suspected coronavirus disease (COVID-19) 
infection
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o
Peripheral edema: limbs, if assessed by the investigator as having a reasonable 
possibility for a relationship to study drug. Peripheral edema is only to be 
reported as an AESI if assessed by the investigator as having a reasonable 
possibility for a relationship to study drug.
o
Facial edema
o
Elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
(> 3 × upper limit of normal [ULN]) in combination with elevated bilirubin
(> 2 × ULN). Note: This abnormal lab findings may indicate potential severe 
liver injury (possible Hy's Law) and should be reported as an SAE (see 
Section 16.10 AESI and  Section 16.12.2 Procedure for reporting a serious 
adverse event). 
In conclusion, when taking into consideration the currently available data of nemolizumab 
and the risk-minimization approaches to be implemented, the benefit/risk ratio of 
nemolizumab is considered to be favorable in this study.
8.5
Drug Profile
Nemolizumab is a humanized monoclonal modified immunoglobulin G2 (IgG2) antibody 
comprising a structure of 2 H-chains (445 amino acid residues) and 2 L-chains (214 amino 
acid residues) connected by 16 disulfide bonds. The investigational product will be supplied 
as a lyophilized powder for solution for SC injection only after reconstitution in a pre-filled, 
dual-chamber, single-use syringe (DCS). The lyophilized nemolizumab powder (39 mg) and 
solution for reconstitution (0.595 mL) are stored in separate syringe chambers, with each 
DCS designed to deliver a 30 mg dose of nemolizumab. The concentration of nemolizumab 
in the DCS will be 61.5 mg/mL once reconstituted, with an injection volume of 0.49 mL (for 
the loading dose, two injections of 0.49 mL).
The placebo will be supplied as a lyophilized powder, reconstituted and administered in the 
same manner as the investigational product.
8.6
Study and Dose Selection Rationale
Based on data suggesting the role of IL-31 in the pathophysiology of CKD-aP (Ko 2014), 
Chugai conducted a Phase 2a study (study CIM106JP) to assess the efficacy and safety of 
ascending nemolizumab single doses (0.1 mg/kg, 0.5 mg/kg and 2.0 mg/kg) in subjects with 
CKD-aP undergoing hemodialysis. The data from this study were reviewed during an 
advisory board meeting held in October 2020 with experts in the field of Nephrology and 
Dermatology. Based on the secondary endpoints on efficacy trends, safety, and individual 
data analyses and post hoc analysis, the results indicated that nemolizumab was well tolerated 
and nemolizumab 0.5 mg/kg single dose was associated with the higher magnitude of effect 
on pruritus VAS. Consensual recommendation initially from the experts was to move forward 
with nemolizumab in subjects suffering from CKD-aP focusing first on subjects with severe 
pruritus as assessed by WI NRS of at least 7.0 and undergoing hemodialysis, therefore that 
was the approach in the original protocol.
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From recently evolved data we believe that the treatment effect is unlikely driven by the 
severity of pruritus among the moderate and severe patients, based on the following findings: 
1) Treatment effect including placebo effect observed from Difelifekalin pivotal studies are 
similar between severe vs. moderate plus severe pruritus HD pts and 2) Further review of the 
Chugai HD CKD phase 2a study (CIM106JP) 0.5mg/kg group (nemolizumab n= 12; placebo 
n=12), there was no different treatment pattern that could be identified between the group 
with VAS > 70 mm and VAS <70 mm at baseline. Thus, the protocol is amended (version 4, 
08JUN22) to include Hemodialysis patients with both moderate to severe pruritus as assessed 
by WI NRS of at least 5.
Of note, it is acknowledged that patient population of CKD-aP is a new population and there 
is limited data available from the completed Phase 2a dose ranging trial to definitely conclude 
that there is a lack of effect of body weight on efficacy. Therefore, an additional 60 mg flat 
dose (without loading dose) will be assessed in this study and will provide data to decide on 
the need for weight-based dosing in subjects with higher body weight. 
At the end of this study, dose selection will be based on the final analysis by evaluating the 
optimal risk-benefit and considering the potential impact of body weight.
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9
STUDY OBJECTIVES AND ENDPOINTS
9.1
Study Objectives
9.1.1
Primary Objective
The primary objective is to evaluate the efficacy of nemolizumab compared to placebo at 
reducing the intensity of pruritus after a 12-week treatment period in adult hemodialysis 
subjects with moderate to severe pruritus.
 
.
9.2
Study Endpoints
Data of both nemolizumab groups (30 mg and 60 mg) and placebo group and comparisons 
versus placebo group of both nemolizumab groups will be presented. 
9.2.1
Primary Efficacy Endpoint
Primary Efficacy 
Estimand Description
Estimand Attributes
Treatment Conditions: initial dose of nemolizumab (60 mg) or placebo at 
baseline, then nemolizumab (30 mg or 60 mg) or placebo Q4W at Weeks 4 and 8 
via subcutaneous injection. 
Population: adult hemodialysis patients with chronic kidney disease and associated 
moderate to severe pruritus (will be estimated in the Intent-to-Treat analysis set).
Variable: a binary composite response where:
Responder is defined as an improvement ≥ 4 in WI NRS from baseline at Week 12 
without use of rescue therapies and without treatment discontinuation due to lack of 
efficacy or AE/death related to study drug.
Non-responder is defined as an improvement < 4 in WI NRS from baseline at 
Week 12 or use of rescue therapies or treatment discontinuation due to lack of 
efficacy or AE/death related to study drug.
Strategies for Intercurrent Events: A composite strategy was chosen for the use 
of rescue therapies and treatment discontinuation due to lack of efficacy or 
AE/death related to study drug; in case of use of rescue therapies or treatment 
discontinuation due to lack of efficacy or AE/death related to study drug, subjects 
will be considered as treatment failures in the binary composite response. In the 
case of treatment discontinuation for any other reason, a treatment policy strategy 
will be used and observed after discontinuation data (if available) will be used.
In adult hemodialysis 
patients with chronic 
kidney disease and 
associated moderate to 
severe pruritus, 2 
nemolizumab dosing 
schedules[1] compared 
to placebo by the 
difference in 
proportions of 
responders where 
response is defined as 
an improvement from 
baseline of WI NRS ≥ 4 
at Week 12 without use 
of rescue therapies and 
without treatment 
discontinuation due to 
lack of efficacy or 
AE/death related to 
study drug
Summary measure: treatment difference of nemolizumab from placebo in 
proportions of responders
[1] Dosing schedules compared to placebo Q4W are an initial SC dose of nemolizumab (60 mg) at baseline then 
either 30 mg or 60 mg Q4W at Week 4 and Week 8.
Abbreviation(s): WI NRS = Worst Itch Numeric Rating Scale; Q4W = Every 4 Weeks
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9.2.2
Secondary Efficacy Endpoints
9.2.2.1
Key Secondary Efficacy Endpoints
1. Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at Week 12.
2. Proportion of subjects with an improvement of WI NRS ≥ 4 from baseline at Week 4.
3. Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at Week 12.
4. Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at Week 4.
5. Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at Week 4.
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10
INVESTIGATIONAL PLAN
10.1
Description of Overall Study Design and Plan
This is a randomized, double-blind, placebo-controlled, multicenter, parallel-group, phase 2/3 
study to evaluate the efficacy and safety of nemolizumab in adult subjects with CKD-aP.  
Subjects will be randomized in one of the following three arms/groups (two different doses of 
nemolizumab and a placebo) in a 1:1:1 ratio: 

Group 1: 30 mg nemolizumab Q4W with a 60 mg loading dose at baseline;

Group 2: 60 mg nemolizumab Q4W without loading dose at baseline;

Group 3: placebo Q4W. 
Approximately 84 subjects will be randomized in each nemolizumab group and in the 
placebo group for a total sample size of approximately 252 subjects.
In order to maintain the blind, all subjects will receive 2 injections at each administration 
(30 mg + 30 mg or 30 mg + placebo or placebo + placebo). 
The study consists of a screening period (up to 4 weeks), a 12-week treatment period, and an 
8-week follow up period (12 weeks after their last study drug injection).
The screening period will evaluate subject eligibility. In exceptional circumstances, e.g. 
health reason or hemodialysis rescheduling, up to 72 hours deviation from screening window 
may be permitted after consultation with the Medical Monitor. The subjects’ other (non-
pruritus) complications of end-stage kidney disease (ESKD) are to be managed according to 
local standard of care. The use of moisturizers is encouraged to keep the skin hydrated.
At the baseline visit, subjects will receive an initial dose of nemolizumab 60 mg or placebo 
by two SC injections. Study drug treatment with either nemolizumab or placebo should start 
after completion of the hemodialysis treatment (within four hours). Then study drug (i.e., 
nemolizumab 30 mg, nemolizumab 60 mg or placebo) will be administered via two SC 
injections (30 mg + placebo, 30 mg + 30 mg, or placebo + placebo) Q4W at Week 4 and 
Week 8 after completion of hemodialysis treatment (within four hours). PK samples to be 
taken before hemodialysis. Refer to Section 13.1.
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An IDMC will review and monitor subject safety throughout the study. The study team to 
remain blinded until the end of the study.
An independent adjudication committee (IAC) will review and adjudicate all asthma-related 
AEs. 
10.1.1
Study Visit Schema
10.2
Discussion of Study Design
This study will evaluate the efficacy and safety of nemolizumab in adult subjects with 
CKD-aP undergoing hemodialysis. The rationale for the study is based on the prior Phase 2a 
study (study CIM106JP) conducted by the sponsor’s licensing partner, and the 
recommendation from experts in the field of Nephrology and Dermatology to further 
investigate nemolizumab in subjects with CKD-aP. The rationale for the nemolizumab 
dose/dose regimen is provided in Section 8.6.
W -4
W 20
Screening
Treatment Period
W 4*
W 8*
Follow-Up
W 12
R = Randomization; * = Visits with study drug administration
Note: All subjects in each arm will receive 2 injections at each administration
(either 30 mg + 30 mg, or 30 mg + placebo, or placebo + placebo) in order to mantain the blind
BL*
Group 1: 30 mg nemolizumab Q4W
with a 60 mg loading dose at baseline
Group 2: 60 mg nemolizumab Q4W
without loading dose at baseline
Group 3: placebo Q4W
R
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The subject population is selected based on the current unmet need in the management of 
CKD-aP, the mode of action of nemolizumab, and the need to better understand the efficacy 
and safety profile of nemolizumab in this indication. The study will enroll adult subjects with 
ESKD that have been on hemodialysis three times per week for at least three months prior to 
the start of screening. Other main inclusion criteria include hemodialysis adequacy (i.e., 
single-pool Kt/V measurements of at least 1.2), pruritis for ≥ 3 months (documented pruritus 
with no etiology identified other than CKD by medical record, previous physician’s 
letter/statement, or  written documentation by site investigators based on the medical history 
obtained from the subject), and a WI NRS score of ≥ 5.0 at the screening and baseline visit.
Following the screening period, qualified subjects will receive a loading dose of 
nemolizumab 60 mg or placebo by two SC injections at baseline (30 mg + 30 mg, placebo + 
placebo), and a 30 mg or 60 mg dose of nemolizumab or placebo by two SC injections 
(30 mg + placebo, 30 mg + 30 mg, placebo + placebo) at Weeks 4 and 8. All study drug 
treatments should be performed following the completion of the hemodialysis (within four 
hours). Subsequent visits will occur at Week 12 and Week 20 (end of study). A 12-week 
treatment period is considered adequate to evaluate the safety and efficacy of nemolizumab 
on pruritus based on the results of Phase 2a study and finding from other nemolizumab 
indications. The efficacy assessments are performed using validated scales that are commonly 
employed in pruritus clinical trials to capture subject-reported outcomes. 
The primary endpoint is the proportion of subject with an improvement of WI NRS ≥ 4 from 
baseline at Week 12. The selected endpoints for assessing the 
and safety of nemolizumab 
are in accordance with current standards, as are the safety endpoints of the study. 
Differences may be detectable during the study drug reconstitution process between active 
study drug and placebo but appear similar after reconstitution is complete (approximately 
10 minutes). Throughout the study, a pharmacist (or other qualified personnel) will prepare 
study medication for injection, including confirmation of complete reconstitution, prior to 
delivery of study medication for injection. The pharmacist (or other qualified personnel) 
preparing study medication should not be involved with any study assessments and should 
not discuss any aspects of study drug reconstitution with the subject/caregiver or study staff 
involved in subject interviews or study assessments.
If deemed to be medically necessary by the investigator (e.g. to control intolerable pruritus) 
and after discussion with the Medical Monitor, rescue therapies can be prescribed to the 
subjects at any time during the study except during the screening period. Subjects receiving 
rescue therapies during the screening period are not eligible to participate in the study.
As a general guideline and per individual investigator judgment, rescue therapy should not be 
prescribed within the first four weeks after baseline to allow a minimum time for study drug 
potential effect in the presence of background therapy.
Investigator assessments of efficacy should be performed before initiating rescue therapy. 
Subjects requiring rescue therapy between scheduled visits should return to the clinic 
(unscheduled visit) for investigator assessment of efficacy before starting rescue therapy. The 
Investigator must contact the Medical Monitor prior to initiating rescue therapy.
As judged appropriate by the investigator and following discussion with the Medical 
Monitor, rescue therapies include the following treatments:
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
Antihistamines (new or increased dose):  For those given as needed (“PRN”) at baseline, 
rescue of antihistamine is defined as that with an increase by ≥75% in the total weekly 
dose relative to the dose during the last week of screening administered for ≥ 1 week.   

Gabapentin (new or increased dose) administered for ≥ 1 week.

Selected Opioids: Nalbuphine or kappa opioid agonists (e.g., difelikefalin, nalfurafine), 
one or more doses

Ultraviolet (UV) radiation therapy: one or more treatments
Note: all new concomitant medication or increase of frequency or increase of dose will be 
recoded
Blinding subjects and the designated study team to the treatment assignment(s) ensures 
objectivity and minimizes bias. Randomization through the interactive response technology 
(IRT) guards against selection bias. To avoid bias and to ensure the integrity of the blind, 
personnel directly involved with the ongoing conduct of the study from the sponsor, CRO, or 
other investigational study centers will not have access to any information that may lead to 
unblinding.
10.3
End of Study
A subject will have fulfilled the requirements for study completion if/when the subject has 
completed all study periods, including the follow-up visit at Week 20 or the last scheduled 
visit as indicated in the Schedule of Assessments (Table 5).
The end of the study will be the last subject’s last visit as indicated in the Schedule of 
Assessments (Table 5).
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11
SELECTION OF STUDY POPULATION
The study is to evaluate the efficacy and safety of nemolizumab in adult subjects with chronic 
kidney disease (CKD) undergoing hemodialysis with moderate to severe CKD-associated 
pruritus. 
The subjects’ other (non-pruritus) complications of End-stage kidney disease (ESKD) are to 
be managed according to local standard of care. The use of moisturizers is also encouraged to 
keep their skin hydrated. 
The study allows for stable background use of the most common medications prescribed for 
patients with this condition (antihistamines and gabapentin) but disallows use of other 
treatments as well as significant changes to the hemodialysis prescription within 8 weeks 
prior to screening (see exclusion criterion 19). The study population consist of patients with 
moderate to severe CKD-associated pruritus (WI NRS ≥ 5.0 ).
Section 10.1 provides information regarding the number of subjects planned to be 
randomized.
Refer to Section 19.1 for the statistical considerations on which the sample size is based.
11.1
Number of Planned Subjects
Approximately 84 subjects will be randomized in each nemolizumab group and in the 
placebo group for a total sample size of approximately 252 subjects. Refer to Section 19.1 for 
the statistical considerations on which the sample size is based.
11.2
Inclusion Criteria
Individuals must meet all of the following criteria to be included in the study:
1. Subjects aged ≥ 18 years at the screening visit.
2. Has end-stage kidney disease (ESKD) and have been on hemodialysis three times per 
week for at least three months prior to the start of screening.
Note 1: Subjects who require an occasional additional hemodialysis treatment to manage 
fluid overload may be enrolled as long as it is anticipated that no more than one such 
treatment will be required in any given week.
Note 2: Subjects having received in-home hemodialysis may participate as long as they 
have switched to in-center hemodialysis at least two weeks prior to screening and plan to 
remain on in-center hemodialysis for the duration of the study. 
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3. Hemodialysis subjects meeting the Kidney Outcome Quality Initiative Guidelines of 
hemodialysis adequacy within 60 days of screening, two:

Single-pool Kt/V measurements of at least 1.2.
4. Pruritus for ≥ three months (documented pruritus with no etiology identified other than 
CKD by medical record, previous physician’s letter/statement, or a written documentation 
by of site investigators based on the medical history obtained from the subject). 
5. WI NRS score ≥ 5.0 at the screening and baseline visit. Screening WI NRS score will be 
determined by a single WI NRS assessment (score ranging from 0 to 10) for the 24-hour 
period immediately preceding the screening visit. Baseline WI NRS score will be 
determined based on the weekly average of daily WI NRS scores (score ranging from 0 to 
10) during the seven days immediately preceding baseline (rounding is not permitted). A 
minimum of four daily scores out of the seven days immediately preceding baseline is 
required for this calculation.
6. Women of childbearing potential (WOCBP) (i.e., fertile, following menarche and until 
becoming post-menopausal unless permanently sterile) must agree either to commit to 
true abstinence throughout the study and for 12 weeks after the last study drug injection, 
when this is in line with the preferred and usual lifestyle of the subject, or to use an 
adequate and approved method of contraception throughout the study and for 12 weeks 
after the last study injection.
Adequate and approved methods of contraception applicable for the subject and/or her 
partner are defined below:

Progestogen-only oral hormonal contraception.

Combination of male condom with cap, diaphragm, or sponge with spermicide 
(double-barrier methods).
Note: “Double barrier methods” refers to simultaneous use of a physical barrier by 
each partner. Use of a single barrier method (e.g., condom) together with a spermicide 
is not acceptable.

Combined (estrogen- and progestogen-containing) oral, intravaginal, or transdermal 
hormonal contraception.

Injectable or implanted hormonal contraception.

Intrauterine devices or intrauterine hormone releasing system.

Bilateral tubal ligation or tube insert (such as the Essure system) at least three months 
before the study.

Bilateral vasectomy of partner at least three months before the study.
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7. Women are considered to be of non-childbearing potential if they meet one of the 
following criteria:

Absence of menstrual bleeding for one year prior to screening without any other 
medical reason, confirmed with follicle stimulating hormone (FSH) level in the 
postmenopausal range.

Documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy at least 
three months before screening.
Note: Bilateral tubal ligation is not accepted as reason for non-childbearing potential.
8. Subject willing and able to comply with all time commitments and procedural 
requirements of the clinical study protocol.
9. Understand and sign an informed consent form (ICF) before any investigational 
procedure(s) are performed.
11.3
Exclusion Criteria
Individuals meeting any of the following criteria at screening or baseline are ineligible to 
participate in this study:
1. Body weight < 30 kg. 
2. Pruritus caused by a concomitant condition unrelated to ESKD (e.g., dermatologic or 
systemic disorders such as, but not limited to AD, psoriasis, PN, Chronic T- cell 
Lymphoma, Leukemia or cholestatic liver disease).
3. Localized itch of only the palms of the hands and/or soles of the feet.
4. Pruritus present only during hemodialysis session.
5. History of or anticipated non-compliance with hemodialysis (i.e, such that it would 
adversely affect the conduct of the study or significantly change dialysis adequacy during 
the study) in the opinion of the investigator.
6. New York Heart Association Class IV symptoms (see Appendix 11) or myocardial 
infarction within three months prior to screening.
7. History of stroke or transient ischemic attack within six months prior to screening.
8. Subjects meeting one or more of the following criteria at screening or baseline:
a. Had an exacerbation of asthma requiring hospitalization in the preceding 12 months.
b. Reporting asthma that has not been well-controlled (i.e. symptoms occurring on 
> two days per week, nighttime awakenings two or more times per week, or some 
interference with normal activities) during the preceding three months.
c. ACT ≤ 19 (only for subjects with a history of asthma).
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9. Cutaneous infection within one week before the baseline visit, any infection requiring 
treatment with oral or parenteral antibiotics, antivirals, antiparasitics or antifungals within 
two weeks before the baseline visit.
Note: Subjects with chronic, stable use of prophylactic treatment for recurrent herpes 
viral infection can be included in this clinical study.
10. Any confirmed or suspected COVID-19 infection within two weeks before the screening 
or baseline visit. Subjects may be rescreened after the infection has resolved. Resolution 
of COVID-19 infection can be confirmed by recovery assessment methods, as described 
in Section 11.5.2.
11. Positive serology results (hepatitis B surface antigen [HbsAg] or hepatitis B core antibody 
[HbcAb], hepatitis C [HCV] antibody with positive confirmatory test for hepatitis C virus 
[HCV] (e.g. HCV polymerase chain reaction [PRC]), or human immunodeficiency virus 
[HIV] antibody) at the screening visit. 
Note: Subjects with a positive HbcAb and a negative HbsAg can be included in this 
clinical study if hepatitis B surface antibody is positive (considered immune after a 
natural infection or vaccination). Subjects who are positive for HCV antibody and 
negative for HCV RNA may be enrolled. 
In the event of rescreening, the serology tests results (e.g., HBV, HCV, HIV) from the 
previous screening can be used by the investigator to assess the eligibility of rescreened 
subjects if those tests were performed within six weeks prior to the baseline visit.
12. Known active or untreated latent tuberculosis (TB) infection or history of either untreated 
or inadequately treated active or latent TB according to the local applicable guidelines.
Note: Subjects who have a documented history of completion of an appropriate TB 
treatment regimen for latent or active TB with no history of re-exposure to TB since their 
treatment was completed are eligible to participate in the study.
13. Known or suspected immunosuppression beyond that expected due to end-stage kidney 
disease and its comorbidities or unusually frequent, recurrent, severe, or prolonged 
infections as per investigator judgment.
14. History of lymphoproliferative disease or history of malignancy of any organ system 
within the last five years, except for (1) basal cell carcinoma, squamous cell carcinoma in 
situ (Bowen’s disease), or carcinomas in situ of the cervix that have been treated and have 
no evidence of recurrence in the last 12 weeks before the baseline visit, or (2) actinic 
keratoses that have been treated.
15. Pregnant women (positive serum pregnancy test result at all visits), breastfeeding women, 
or women planning a pregnancy during the clinical study.
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16. In the opinion of the investigator the subject has any medical or psychological condition 
that could pose undue risk to the subject, prevent study completion, or adversely affect 
the validity or interpretability of the study measurements or interfered with study 
assessments.  
17. Any clinically relevant laboratory abnormalities, such as but not limited to elevated ALT 
or AST (> 3 × ULN) in combination with elevated bilirubin (> 2 × ULN), during the 
screening period that may put the subject at significant risk according to the investigator’s 
judgment, if he/she participates in the clinical study.
18. Planned or expected major surgical procedure during the clinical study, including a 
scheduled kidney transplant during the study. Subjects on a kidney transplant waiting list 
with no scheduled transplant date are not excluded. 
19. Has not adhered to the restrictions in the selected medications and dialysis procedures 
prior to screening or is not expected to be compliant with restrictions during the study as 
list in the following table:
Table 1
Prior Treatments and Procedures
Timeframe
Treatment(s)
Before Screening 
Screening Period
and
Day 1 – Week 20
Systemic corticosteroids  (i.e., administered by the 
intravenous, oral, or intramuscular route at a dose). 
Note: Low dose prednisone (up to 10 mg per day [or 
equivalent other corticosteroid]) is permitted if the 
dose has been stable for 2 weeks prior to Screening 
Note: Use of steroids given by other routes (inhaled, 
topical for indications other than itching, ophthalmic, 
intra-articular, etc. are permitted). 
Not allowed for 4 weeks, 
other than stable low dose 
prednisone or equivalent 
Prohibited, other than 
stable low dose 
prednisone or 
equivalent
Topical corticosteroids
Not allowed for 2 weeks
Prohibited
Topical PDE-4 inhibitor
Not allowed for 2 weeks 
Prohibited
TCIs 
Not allowed for 2 weeks 
Prohibited
Biologics and their biosimilars (e.g. etanercept, 
adalimumab, infliximab, omalizumab, etc.)
Not allowed for 8 weeks or 
5 half-lives 
(whichever is longer) 
Prohibited
Dupilumab
Not allowed for 10 weeks 
Prohibited
Cannabinoids
Not allowed for 2 weeks 
Prohibited
Immunosuppressive or immunomodulatory drugs 
(e.g. cyclosporine A, oral tacrolimus, 
cyclophosphamide, azathioprine, methotrexate, 
mycophenolate mofetil, JAK inhibitors)
Not allowed for 4 weeks or 
5 half-lives 
(whichever is longer) 
Prohibited
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Timeframe
Treatment(s)
Before Screening 
Screening Period
and
Day 1 – Week 20
Systemic and topical antihistamines (excluding for 
ophthalmic use)
Stable dose for 2 weeks
Stable dose
Local anesthetics such as pramoxine, seed oil, 
capsaicin, topical ketamine, CBD oil, various lotions 
with anti-pruritic effects, etc. 
Not allowed for 1 week
Prohibited
Gabapentin and pregabalin
Stable dose for 2 weeks
Stable dose
Phototherapy or tanning beds
Not allowed for 4 weeks
Prohibited
Selected Opioids
Nalbuphine or kappa opioid agonists (e.g., 
difelikefalin, nalfurafine)
Not allowed for 4 weeks 
Prohibited
All other opioids (e.g. codeine, tramadol, oxycodone, 
hydrocodone, methadone, buprenorphine)
Stable dose for 2 weeks 
Stable dose
Change in hemodialysis treatment  (i.e., number of 
hemodialysis sessions per week, change in dialyzer 
or switch between hemodialysis and 
hemodiafiltration). Also see in inclusion # 2
Not allowed for 8 weeks 
Prohibited
Live attenuated vaccine and non-live vaccine 
(Seasonal vaccine (e.g., influenza), emergency 
vaccine (e.g., rabies or tetanus) and COVID vaccines  
as noted in Section 12.5.2 are permitted)
Not allowed for 4 weeks 
Prohibited
Abbreviations: PDE-4 = phosphodiesterase-4; TCI = topical calcineurin inhibitor; TCS = topical corticosteroid.
For medications given as needed (“PRN”), stable dose during the study is defined as that 
without an increase or decrease by ≥75% in the total weekly dose relative to the dose during 
the last week of screening. For example, if the total weekly dose of 100 mg of diphenhydramine 
during the last week of the screening period increased to 175 mg in a given week during the 
study, this would be considered not a stable dose. During the screening period, a “stable dose” 
is one that has not changed (increase or decrease) by ≥ 75% during the period of required 
stability.
Note: Subjects should not interrupt ongoing treatment with medications important for the 
subject’s health for the sole purpose of participating in this study.
20. Requiring rescue therapy for pruritus during the screening period or expected to require 
rescue therapy within 4 weeks following the baseline visit. Section 12.5.1.2.
21. Previous treatment with nemolizumab.
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22. History of hypersensitivity (including anaphylaxis) to an immunoglobulin product 
(plasma-derived or recombinant, e.g. monoclonal antibody) or to any of the study drug 
excipients.
23. Currently participating or participated in any other study of an investigational drug or 
device, within the past four weeks (or five half-lives of the investigational medication, 
whichever is longer) before the screening visit.
24. History of alcohol or substance abuse within six months of the screening visit.
11.4
Rescreening
Screen failures may be allowed to rescreen up to two times. Subjects who screen fail due to 
disease severity inclusion criteria WI NRS will not be allowed to rescreen (note: subjects 
screen failed prior to protocol amendment three (version 4.0 dated 08JUN22), are allowed to 
rescreen if their WI NRS is ≥ 5.0). 
Subjects who are rescreened must sign a new ICF and be assigned a new subject 
identification number (SIN). The SIN of previous screening must be documented in the 
eCRF.
In the event of rescreening, the serology and TB tests results from the previous screening can 
be used by the investigator to assess the eligibility of rescreened subjects if those tests were 
performed within six weeks prior to the baseline visit.
11.5
Removal of Subjects from Therapy or Assessments 
Although the importance of completing the entire clinical study will be explained to the 
subjects, any subject is free to discontinue his/her participation in the study at any time and 
for whatever reason, specified or unspecified, and without any prejudice. No constraints are 
to be imposed on the subject, and when appropriate, a subject may be treated with other 
conventional therapy when clinically indicated once the subject is no longer in the study. 
Investigators or the sponsor can also withdraw subjects from the clinical study if deemed to 
be necessary.
Unless medically urgent, investigators are required to contact the Medical Monitor to discuss 
patients that are being considered for withdrawal from study drug treatment or from the 
study.
A subject may be withdrawn from the study treatment at any time for the following reasons:

At the discretion of the investigator or the sponsor for safety, behavioral, compliance, 
or administrative reasons.

Occurrence of AEs, including laboratory abnormalities, not compatible with the 
continuation of subject participation in the study, in the investigator’s opinion, or 
unacceptable to the subject to continue, including but not limited to the following:
o
Serious immediate-type allergic manifestations including anaphylactic reaction;
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o
Serious new or worsening of asthma, or newly diagnosed asthma considered 
related to study drug administration;
o
Diagnosis of a malignancy (except curatively treated in situ cervical carcinoma, 
squamous cell carcinoma [Bowen’s disease] or basal cell carcinoma);
o
Opportunistic infections such as but not limited to active TB and other infections 
whose nature or course suggest an immune-compromised or immune-suppressed 
status;
o
Any serious infection or any severe infection requiring treatment with parenteral 
antibiotics or oral antibiotics/antivirals/antifungals for > 2 weeks considered 
related to study drug administration; or
o
Confirmed COVID-19 infection (at least a temporary discontinuation is required,  
while suspected COVID-19 may be acceptable see Section 11.5.2).
o
ALT or AST > 3 x ULN and TBL > 2 x ULN or INR > 1.5

Pregnancy, for which discontinuation of study drug is mandated.

Use of non-permitted systemic concurrent therapy (discussed and agreed upon with 
the investigator and medical monitor).

Use of systemic rescue therapy, as specified in Table 4 of Section 12.5.2 and Section 
12.5.1.2. (discussed and agreed upon with the investigator and medical monitor).
The main reason for withdrawal will be documented in the electronic case report form 
(eCRF). Subjects who have been randomized and treated will not be replaced by another 
subject.
Subjects who prematurely discontinue study drug and/or take rescue medication(s) will be 
encouraged to complete the scheduled study visits.
When a subject discontinues study drug, he/she will be fully assessed whenever possible, and 
followed according to guidelines presented in Section 13.2.1.
Reasonable efforts will be made to contact subjects who are lost to follow-up. These efforts 
must be documented in the subject’s file.
The sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the investigational product or the company itself occur, making 
further treatment of subjects impossible. In this event, the investigator(s) will be informed of 
the reason for study termination.
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11.5.1
Pregnancy
The safety of nemolizumab in pregnant or lactating women has not been established.
Subjects will be instructed that known or suspected pregnancy occurring during the study 
should be confirmed and reported to the investigator. If a subject becomes pregnant, the 
investigator must withdraw the subject from the study without delay. The subject must not 
receive any further injection(s) of the study drug.
The investigator must:

Follow the procedures for reporting/follow-up of a pregnancy within 24 hours (see 
Section 16.12.4) of receipt of the information.

Complete as fully as possible the applicable Pregnancy Surveillance Form(s) (see 
Section 16.12.4).

Monitor and record the progress of the pregnancy until its outcome. Contact the 
subject’s regular physician (general practitioner or gynecologist) or hospital staff to 
obtain further details and ask for regular follow-up information.

Provide tri-monthly updates until the final outcome of the pregnancy. If the subject 
can no longer be reached (lost to follow-up), documentation of the non-response/ 
contact with two phone calls and a letter (certified with return receipt) is required.

If the pregnancy leads to an abortion (i.e., voluntary abortion, spontaneous abortion, 
or therapeutic abortion), in utero death, or congenital anomaly, follow the procedure 
for declaration of/reporting an SAE (Section 16.12.2).
The investigator and sponsor should also be notified of pregnancy occurring during the study 
(and within 12 weeks [± 5 days] after the last dose of study drug) but confirmed after 
completion of the study. In the event that a subject is subsequently found to be pregnant after 
inclusion in the study, any pregnancy will be followed to term, and the status of mother and 
child will be reported to the sponsor after delivery.
Full details will be recorded on the withdrawal page (exit form), or an SAE report will be 
completed if the subject has completed the study. Pregnancy is not to be considered as an AE; 
however, it must be monitored and reported as described in Section 16.12.4.
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11.5.2
Coronavirus Disease 2019 
Study drug administration will be discontinued in a subject in whom COVID-19 is confirmed 
or suspected. COVID-19 must be specified as the reason for study drug discontinuation.
Study drug administration may resume in subjects with confirmed or suspected COVID-19 
based on investigator judgment after discussion with the medical monitor or Sponsor and 
only if the following minimum conditions are met:

For symptomatic subjects: At least 14 days have passed since recovery, defined as 
resolution of fever without the use of fever-reducing medications and improvement in 
respiratory symptoms (e.g., cough, shortness of breath).

For asymptomatic subjects: At least 21 days have passed since the positive PCR test 
and no symptoms.
Note: The above should be considered minimum criteria. Where the local guidelines are more 
stringent for infection resolution criteria, those must be applied.
See Appendix 1 for additional guidance for management of subjects and study conduct 
during the COVID-19 pandemic.
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12
TREATMENTS
12.1
Details of Study Medication
12.1.1
Investigational Products Administered
“Study drug” or “study medication” refers to nemolizumab or placebo drug product for 
purposes of this double-blind study. The list of excipients is detailed in the IB.
The Sponsor has developed a lyophilized powder in a DCS which holds the lyophilized 
nemolizumab or placebo, and the sterile water for injection separately.
Subjects will receive a loading dose of nemolizumab (60 mg) or placebo by two SC 
injections at baseline (30 mg + 30 mg, placebo + placebo), and a 30 mg or 60 mg dose of 
nemolizumab or placebo by two SC injections (30 mg + placebo, 30 mg + 30 mg, placebo + 
placebo) at Weeks 4 and 8. All the study drug treatment should be performed within four 
hours following the completion of the hemodialysis .
12.1.2
Identity of Investigational Products
Table 2
Description and Usage of Investigational Products
Investigational Product
Placebo
Name (internal code)
Nemolizumab (CD14152)
CD14152 placebo (N/A)
Pharmaceutical form
Lyophilized powder for solution for 
injection in a DCS
Lyophilized powder for solution for 
injection in a DCS
Dosage
30 mg (with a loading dose of 60 mg 
at baseline) or 60 mg
N/A
Dose regimen
Q4W
Q4W
Route a
SC use by subjects or clinic staff after 
reconstitution
SC use by subjects or clinic staff after 
reconstitution
Duration of 
treatment
12 weeks: baseline to Week 12
12 weeks: baseline to Week 12
Abbreviations: DCS = dual-chamber, single-use syringe; N/A = not applicable; Q4W = every four weeks.
a All injections are performed at the study center. Injections by subjects are performed under supervision 
by clinic staff, after appropriate training.
12.1.3
Preparation
A pharmacist (or other qualified personnel) will prepare study medication for injection 
according to instructions provided in the current version of the pharmacy manual and the 
Instructions for Use. Study medication preparation should be conducted in a secured and 
clean area with limited access to only designated personnel at the time of the preparation. 
Good hygiene practices and clean techniques must be applied at all times.
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Differences may be detectable during the study drug reconstitution, however active and 
placebo appear similar after reconstitution is complete (approximately 10 minutes). 
Throughout the study, a pharmacist (or other qualified personnel) will prepare study 
medication for injection, including confirmation of complete reconstitution, prior to delivery 
of study medication for injection. The pharmacist (or other qualified personnel) preparing 
study medication should not be involved with any study assessments and should not discuss 
any aspects of study drug reconstitution with the subject or study staff involved in subject 
interviews or study assessments to maintain the blind of the study.
The study drug does not contain preservatives. From a microbiological point of view, the 
preparation of the study drug has to be done as close to subject administration as possible, 
and the study drug should be used immediately (less than one hour) after reconstitution. If not 
used immediately, the study drug has to be used within four hours maximum after 
reconstitution stored at room temperature (below 30 °C) but only if the preparation has taken 
place applying strictly good hygiene practices and clean techniques to ensure controlled 
aseptic conditions.
12.1.4
Study Drug Injection
All study drug injections will occur at the study center, following instructions provided in the 
current versions of the pharmacy manual and Instruction for Use. After confirming that the 
study drug is fully reconstituted, the pharmacist (or other qualified personnel) will deliver the 
DCS to the investigator or other qualified personnel, for SC injection in the subject’s 
abdomen or alternative injection site. A different injection site should be selected for each 
injection. Refer to the current versions of the Instructions for Use for further details. The site 
of injection should be recorded in the subject’s treatment record as well as the eCRF at each 
time point.
For subjects willing and able to self-inject study medication and preferring to do self-inject, 
study center staff will provide training on study medication injections. Subjects will be 
allowed to inject medication at subsequent visits under supervision by study center clinic 
staff (with DCS preparation including reconstitution performed by the pharmacist or other 
qualified personnel and delivered for injection after reconstitution is complete). Study 
center/clinic staff can perform all injections if the subject is unwilling or unable to perform 
injections. The eCRF must record who performed study drug injection at each visit.
After study drug administration, subjects will be monitored closely for any signs or 
symptoms of hypersensitivity reaction before being discharged. For the first two visits where 
study drug is administered, subjects should remain at the study center for at least 30 minutes 
after study drug administration.
12.1.5
Packaging and Labeling
All IMP packaging and labeling operations will be performed according to Good 
Manufacturing Practice for Medicinal Products in the local language, national 
regulations/guidelines, and the relevant regulatory requirements, specifying that the drug is 
for use in a clinical study. Each DCS will be packaged in an individual carton, including a 
27G ½” needle and a plunger rod (not assembled). Local adaptation of the kit design may be 
required; specific details for each country are provided in the pharmacy manual.
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12.1.6
Study Drug Management
12.1.6.2
Dosing Schedule
Table 3 summarizes study drug dosing during the treatment period of the study.
Table 3
Treatment Period Dosing by Treatment Group
Group
Treatment
Dose at Day 1/Baseline
Dose at Week 4 
and Week 8
Route
Schedule
1
30 mg Nemolizumab 
(CD14152)
60 mg 
(two 30 mg injections)
30 mg
(30 mg injection +
placebo injection)
SC
Q4W
2
60 mg Nemolizumab 
(CD14152)
60 mg 
(two 30 mg injections)
60 mg 
(two 30 mg injections)
SC
Q4W
3
Placebo
Placebo 
(two placebo injections)
Placebo
(two placebo injections)
SC
Q4W
Abbreviation(s): Q4W = every four weeks; SC = subcutaneous.
12.2
Measures to Minimize Bias: Study Treatment Assignment
12.2.1
Allocation Concealment and Method of Study Treatment Assignment
Subjects will be centrally randomized using an Interactive Response Technology (IRT) 
system. Allocation concealment will be ensured, as the system will assign the randomization 
number only upon confirmation of eligibility for a given subject to participate in the study. 
Randomization will occur individually, the randomization number will be assigned to the 
unique Subject Identification Number (SIN) of each randomized subject, and the 
simultaneous randomization of groups of subjects will be prevented.
Subjects will be randomized in a 1:1:1 ratio to:

Group 1: 30 mg nemolizumab Q4W with 60 mg loading dose at baseline;

Group 2: 60 mg nemolizumab Q4W without loading dose at baseline; or

Group 3: placebo Q4W.
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Randomization will be stratified by clinical site. 
12.2.2
Blinding
All attempts will be made to keep the study center staff and subjects blinded throughout the 
study. Members of the study center staff, including those responsible for DCS preparation, 
will not have access to the randomized treatment assignment.
To ensure double-blind administration of study drug, the study center pharmacist(s) or other 
qualified personnel will prepare all nemolizumab or placebo treatments, according to the 
current versions of the pharmacy manual and the Instructions for Use, of the assigned DCS 
provided by the IRT system.
As there may be detectable differences between active and placebo during the reconstitution 
process, the DCS is delivered for injection after the reconstitution is complete. The 
pharmacist (or other qualified personnel) preparing study medication should not be involved 
with any study assessments and should not discuss any aspects of study drug reconstitution 
with the subject or study staff involved in subject interviews or study assessments.
Unblinding of a subject’s individual treatment code should occur only in case of a medical 
emergency or in the event of a serious medical condition that necessitates identification of the 
study drug for the welfare of that subject, as judged by the investigator. The emergency 
unblinding process utilizes IRT to allow the investigator to have unrestricted, immediate, and 
direct access to the subject’s individual study treatment. When possible (i.e., when the health 
of the subject is not immediately at risk), the investigator or sub-investigator is encouraged to 
consult with the medical monitor and the sponsor before breaking the blind.
If emergency unblinding is required:

Only the investigator will make the decision to unblind the treatment assignment.

Only the affected subject will be unblinded.

The IRT system will provide the treatment assignment to the investigator.
Refer to the IRT User Guide for information on the steps for breaking the blind.
When the blinding code is broken, the reason must be fully documented. If the code is broken 
by the investigator, the subject must be withdrawn from the study drug treatment and must 
also be appropriately followed for a minimum of 12 weeks after the last dose of study drug.
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The reporting requirements for unblinding are the same for reporting an SAE. See also 
Section 16.12.2.
The randomization code will remain blinded to all study sites and study team members until 
completion of the study and after the study database has been locked.
The IDMC will review data at periodic intervals throughout the study as defined in the IDMC 
charter. The IDMC charter will specify the procedures for unblinding to ensure that treatment 
assignment remains undisclosed to all individuals involved in the direct execution and 
management of the study until the final database is locked.
12.3
Dosage Modifications
Dosage modification of the study drug will not be permitted during the clinical study. Any 
inadvertent dose modification(s) should be reported to the sponsor/CRO.
In the event of a missed dose (i.e., temporary discontinuation of the study drug), it will be 
documented in the eCRF that the drug has not been administered at the study visit, together 
with the reason (e.g., for safety). Subjects will be asked to return to the study centers for all 
remaining visits and complete all study assessments and procedures as described in 
Section 13.1.
Dosing frequency is scheduled for Q4W, based on the baseline/Day 1 visit date. If a study 
visit occurs outside the visit window (see Table 5), study drug can be administered provided 
there is a minimum of three weeks since the last injection. Future visits should be scheduled 
within the required windows based on the baseline/Day 1 visit date, while maintaining the 
minimum 3-week interval between two injections.
The rationale for the nemolizumab dose/dose regimen is provided in Section 8.6.
12.4
Treatment Accountability and Compliance
Study drug will be provided to the investigational site, and site personnel will acknowledge 
receipt of the study drug using IRT to confirm the shipment condition and content as per the 
current version of the pharmacy manual. 
The designated personnel will also maintain accurate records of the study drug throughout the 
clinical study, including the inventory delivered to the study center, the use by each subject, 
the reconciliation of all delivered and received DCS units, and the return/destruction of 
unused study drug as specified in the current version of the pharmacy manual. No 
unauthorized use is permitted. Used DCS units will be properly documented in drug 
accountability records. Unless a product technical complaint (PTC) is detected or an event 
occurs before, during, or just after the injection, the used DCS can be disposed in an 
appropriate sharps container and according to waste regulation(s) in the country. A DCS 
involved in a malfunction or an investigator or subject complaint must be retained on site and 
designated personnel must proceed as defined in the current version of the pharmacy manual. 
Refer to Section 12.6 for PTCs.
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The study monitor may check the study supplies at each study center at any time during the 
study. It is the responsibility of the study monitor to ensure that the investigator (or designee) 
has correctly documented the amount of the study drug received, dispensed, and 
returned/destroyed on the dispensing log that will be provided. A full drug accountability log 
will be maintained at the study center at all times. The study monitor will arrange collection 
of any unused study drug. The study monitor will also perform an inventory of study drug at 
the close-out visit to the study center. All discrepancies must be accounted for and 
documented appropriately in conjunction with the supply chain manager.
12.4.1
Dispensing and Return of Study Drug
All drug preparation must be appropriately performed and documented by the designated 
personnel. Any error in the preparation of the dose must be reported to the study monitor 
promptly and be properly documented. At the end of the study, the reconciliation/ 
return/destruction process for all unused study drug will be conducted according to the 
pharmacy manual.
12.4.2
Compliance
Treatment compliance will be assessed through the treatment records. 
As study drug is administered in the clinic, treatment compliance will be overseen and 
documented by the investigator and study staff (using the treatment records and drug 
accountability records). At a minimum, date, time, dose, injector (subject or site staff), and 
site of injection should be accurately recorded to confirm that each dose of study treatment 
was properly administered.
12.5
Prior and Concomitant Therapy
Prior therapies are defined as therapies that have been stopped within the three months before 
the screening visit, unless relevant to the inclusion/exclusion criteria. Whenever possible, all 
prior therapies for CKD-aP should be documented.
Concomitant therapies/medications are defined as follows:

Any existing therapies ongoing at the time of the screening visit,

Any changes to existing therapies (such as changes in dose, formulation or application 
frequency) during the course of the study, or

Any new therapies received by the subject since the screening visit.
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The following two categories are to be considered for prior and concomitant therapies:

Drugs/Therapies include but are not limited to prescription, over-the-counter, birth 
control pills/patches/hormonal devices, vitamins, moisturizers, sunscreens, herbal 
medicines/supplements, vaccines (emergency or seasonal), and homeopathic 
preparations.

Medical and surgical procedures (e.g., phototherapy, exodontia). Procedures whose 
sole purpose is diagnosis (non-therapeutic) are not included.
Prior and concomitant therapies for drugs/therapies or for medical/surgical procedures are to 
be recorded in the appropriate eCRF.
Concomitant therapies are to be recorded, reviewed, and updated at each visit.
At each visit, investigators should also confirm concomitant therapies for contraception. 
Contraceptive counseling should occur at screening.
Any new concomitant therapy or modification of an existing therapy may be linked to an AE. 
In such cases, a corresponding AE form should be completed to account for the new therapy 
or change in therapy, except in some cases such as dose modification for a chronic condition 
(see Section 12.3), in which case the medication will be linked to an item in the subject’s 
medical history.
12.5.1
Permitted Concomitant Therapy
Unless specified as prohibited therapies (see Section 12.5.2), all therapies are authorized, 
including basic skin care (cleansing and bathing), moisturizers, bleach baths, stable 
antihistamines, and stable TCS. 
The formation of cytochrome P450 (CYP450) metabolic enzymes can be altered by increased 
levels of certain cytokines (e.g., IL-1, IL-6, IL-10) during chronic inflammation. Although 
there is no known evidence suggesting that IL-31 affects the level or activity of CYP450 
enzymes, the impact of nemolizumab on such enzymes has not been studied. Therefore, 
investigators should consider observing for clinical or laboratory signs that might indicate a 
potential effect of nemolizumab in subjects using concomitant therapies that are CYP450 
substrates, particularly those with a narrow therapeutic index. Typical examples of substrates 
with a narrow therapeutic range include warfarin, drugs that may cause torsade de pointes, 
almost all cytotoxic antineoplastic drugs, and aminoglycoside antibiotics. A list of 
representative CYP450 substrates with narrow therapeutic index can be found in Appendix 2.
12.5.1.1
Moisturizer
The subjects’ current moisturizer or a moisturizer recommended by the investigator may be 
used. Whenever possible, subjects should use the same moisturizer throughout the study.
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12.5.1.2
Rescue Therapy
If deemed to be medically necessary by the investigator (e.g. to control intolerable pruritus), 
rescue therapies can be prescribed to the subjects at any time during the study except during 
the screening period. Subjects receiving treatments defined as rescue therapies during the 
screening period are not eligible to participate in the study (see exclusion criterion 20 in 
Section 11.3). 
As a general guideline and per individual investigator judgment, rescue therapy should not be 
prescribed within the first four weeks after baseline to allow a minimum time for study drug 
exposure in the presence of background therapy. 
Investigator assessments of efficacy should be performed before initiating rescue therapy. 
Subjects requiring rescue therapy between scheduled visits should return to the clinic 
(unscheduled visit) for investigator assessment of efficacy before starting rescue therapy. The 
Investigator must contact the Medical Monitor prior to initiating rescue therapy.
As judged appropriate by the investigator, and following discussion with the Medical 
Monitor, rescue therapies are defined as below and  include the following treatments: 

Antihistamines (new or increased dose): For those given as needed (“PRN”), at 
baseline, rescue of antihistamine is defined as that with an increase by ≥75% in the 
total weekly dose relative to the dose during the last week of screening administered 
for ≥ 1 week.  

Gabapentin (new or increased dose) administered for ≥ 1 week.   

Selected Opioids: Nalbuphine or kappa opioid agonists (e.g., difelikefalin, 
nalfurafine), one or more doses

Ultraviolet radiation therapy: one or more treatments
Note: all new concomitant medication or increase of frequency or increase of dose will be 
recorded.
Whenever possible, investigators should first use topical medications as rescue therapy before 
escalating to systemic therapies. If subjects receive topical treatments or phototherapy as 
rescue therapy, study drug administration should be continued unless there is a safety concern 
according to the investigator’s judgment. If subjects receive systemic rescue therapy, the 
study drug administration can be discontinued if the subject is at risk (discussed and agreed 
upon with investigator and medical monitor).
Further, the use of any rescue therapies should be documented in the eCRF.
12.5.2
Prohibited and Restricted Medication/Therapy
Treatment with the following concomitant medications/therapies is prohibited during the 
study unless otherwise specified in Table 4. Pro re nata (PRN) use of TCS or TCI is not 
permitted.
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Table 4
Prohibited and Restricted Medication/Therapy
Timeframe
Treatment(s)
Before Screening 
Screening Period
and
Day 1 – Week 20
Systemic corticosteroids  (i.e., administered by the 
intravenous, oral, or intramuscular route at a dose). 
Note: Low dose prednisone (up to 10 mg per day [or 
equivalent other corticosteroid]) is permitted if the 
dose has been stable for 2 weeks prior to Screening. 
Note: Use of steroids given by other routes (inhaled, 
topical for indications other than itching, ophthalmic, 
intra-articular, etc. are permitted). 
Not allowed for 4 weeks, 
other than stable low dose 
prednisone or equivalent 
Prohibited, other than 
stable low dose 
prednisone or 
equivalent
Topical corticosteroids
Not allowed for 2 weeks
Prohibited
Topical PDE-4 inhibitor
Not allowed for 2 weeks 
Prohibited
TCIs 
Not allowed for 2 weeks 
Prohibited
Biologics and their biosimilars (e.g. etanercept, 
adalimumab, infliximab, omalizumab, etc.)
Not allowed for 8 weeks or 
5 half-lives 
(whichever is longer) 
Prohibited
Dupilumab
Not allowed for 10 weeks 
Prohibited
Cannabinoids
Not allowed for 2 weeks 
Prohibited
Immunosuppressive or immunomodulatory drugs 
(e.g. cyclosporine A, oral tacrolimus, 
cyclophosphamide, azathioprine, methotrexate, 
mycophenolate mofetil, JAK inhibitors)
Not allowed for 4 weeks or 
5 half-lives 
(whichever is longer) 
Prohibited
Systemic and topical antihistamines (excluding for 
ophthalmic use)
Stable dose for 2 weeks
Stable dose
Local anesthetics such as pramoxine, seed oil, 
capsaicin, topical ketamine, CBD oil, various lotions 
with anti-pruritic effects, etc.
Not allowed for 1 week
Prohibited
Gabapentin and pregabalin
Stable dose for 2 weeks
Stable dose
Phototherapy or tanning beds
Not allowed for 4 weeks
Prohibited
Selected Opioids
Nalbuphine or kappa opioid agonists (e.g., 
difelikefalin, nalfurafine)
Not allowed for 4 weeks 
Prohibited
All other opioids (e.g. codeine, tramadol, oxycodone, 
hydrocodone, methadone, buprenorphine)
Stable dose for 2 weeks 
Stable dose
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Timeframe
Treatment(s)
Before Screening 
Screening Period
and
Day 1 – Week 20
Change in hemodialysis treatment  (i.e., number of 
hemodialysis sessions per week, change in dialyzer 
or switch between hemodialysis and 
hemodiafiltration) Also see inclusion #2
Not allowed for 8 weeks 
Prohibited
Live attenuated vaccine and non-live vaccine 
(Seasonal vaccine (e.g., influenza), emergency 
vaccine (e.g., rabies or tetanus) and COVID as noted 
in Section 12.5.2 are permitted)
Not allowed for 4 weeks 
Prohibited
Note: Subjects should not interrupt ongoing treatment with medications important for the subject’s health for the sole purpose 
of participating in this study.
Abbreviations: PDE-4 = phosphodiesterase-4; TCI = topical calcineurin inhibitor; TCS = topical corticosteroid.
For medications given as needed (“PRN”), stable dose during the study is defined as that 
without an increase or decrease by ≥75% in the total weekly dose relative to the dose during 
the last week of screening. For example, if the total weekly dose of 100 mg of 
diphenhydramine during the last week of the Screening Period increased to 175 mg in a given 
week during the study, this would be considered not a stable dose. During the Screening 
Period, a “stable dose” is one that has not changed (increase or decrease) by ≥ 75% during the 
period of required stability.
Note: Subjects should not interrupt ongoing treatment with medications important for the 
subject’s health for the sole purpose of participating in this study.
If a prohibited therapy becomes necessary for the safety of the subject, the investigator 
should notify the medical monitor and discuss possible alternatives. If a subject receives a 
prohibited therapy during the clinical study (e.g., inadvertent short-term use), the investigator 
should also notify the medical monitor and discuss whether or not it is acceptable for the 
subject to continue receiving the study drug.
If the use of systemic corticosteroids more than prednisone 10 mg per day or equivalent 
becomes necessary for the safety of the subject to treat conditions other than CKD-aP, the 
study drug should be temporarily discontinued for the duration of treatment with systemic 
corticosteroids plus five half-lives.
 It is recommended that all subjects should be up to date with respect to standard of care 
vaccinations as defined by the local guidance. For subjects who have vaccination planned 
during the study, other than allowed vaccinations below, it will be determined after 
consultation with the treating physician, whether the administration of vaccine can be 
postponed until after the end of study, or preponed to before the start of the study, without 
compromising the health of the subject.
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Vaccinations during the study including the screening and follow-up periods are not 
permitted, except for use of the following non-live vaccines:

Seasonal vaccinations (e.g., influenza)

Emergency vaccinations (e.g., rabies or tetanus)

COVID-19 vaccinations
Wherever possible, it is recommended to avoid administration of seasonal and COVID-19 
vaccinations +/- one week from study drug dosing. A different anatomical location should be 
used for study drug administration and vaccine administration.
In the event of emergency vaccination (e.g., rabies or tetanus) during the study, the study 
drug administration should be discontinued until the immune response to vaccination is 
verified. It is recommended to discuss with the medical monitor before discontinuing the 
study drug. 
12.6
Product Technical Complaints
All DCS units must be inspected prior to preparation/injection by the persons performing the 
preparation/injection to ensure absence of visual defects that could lead to a DCS PTC. This 
also includes the needle and plunger rod. In case of doubt, the DCS should not be used, and 
the deficiency must be reported as defined in the pharmacy manual.
All PTCs should be reported to the sponsor/designee by filing the relevant form available in 
the Investigator Site File and the pharmacy manual and as required by local regulations. A 
PTC is any written, electronic, or oral communication that alleges deficiencies related to the 
identity, quality, reliability, safety, durability, effectiveness, or performance of a drug or 
delivery system. Examples may include but are not limited to appearance issues, 
discoloration, odor, broken/cracked syringe, missing parts, damaged stoppers, and foreign 
matter in lyophilized powder or diluent. These complaints may or may not represent a 
potential risk to the subject. For these types of events, a form must be completed as per the 
specific instruction by the site personnel, pictures of the defective DCS must be attached, and 
forwarded to the sponsor/ designee at the latest on the next working day. Reporting to health 
authorities will be in accordance with local regulations. The defective DCS/items must be 
kept in case of investigation need as defined in the pharmacy manual and may be requested to 
be sent to the sponsor/designee in accordance with regulations.
Refer to the current version of the pharmacy manual for further details.
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13
STUDY PROCEDURES
A written, signed ICF, assent form, and Health Insurance Portability and Accountability Act 
(HIPAA) authorization is required before any study-related procedures are performed.
Upon provision of the signed ICF/assent form, each subject will be assigned a unique SIN. 
For the duration of the entire clinical study, the subject will be identified using the SIN in all 
documentations and discussion.
The planned study assessments are in Section 13.1. At each visit, assessments/procedures 
should be performed in the following order:
Pre-Dialysis
1. Sample collections for safety laboratory assessments
3. Vital signs and pre-dialysis weight
Recommended During Dialysis 
1. Subject-reported efficacy and safety measurements (during the first hour of dialysis 
treatment, whenever possible)
2. Investigator assessments (including efficacy and safety);
Post-Dialysis
1. 12-lead ECG. See Section 16.3.
2. PEF and respiratory examination (may also be done during the last hour of dialysis)
3. Post-dialysis weight. 
4. Administration of study drug injections
If for logistical reasons, it is preferable for the ECG to be performed prior to dialysis, then all 
ECGs for that subject should be performed prior to dialysis.
Assessment on Non-Dialysis Days
Subjects will complete the WI NRS and SD NRS daily at home at approximately the same time 
each day on the ePRO device provided. See Sections 15.1 and 15.2. The form is to be dated, 
timed, and signed by the subject. Subjects will be instructed to complete the assessment on 
their own without consulting others. The forms will be returned to the site when the subject 
next returns for a dialysis treatment.
13.1
Schedule of Assessments
Table 5 outlines the timing of procedures and assessments to be performed throughout the 
study.
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Table 5
Schedule of Assessments
Study period
Screening 
perioda
Treatment period
Follow-up 
Unscheduled visitc
Visit
V1
V2
V3
V4
 V5
V6
Week
W-4
Baseline
W4
W8
W12/ETb
W20
Day
Day 29
Day 57
Day 85
Day 141
Visit window
Day 1
± 3 days
± 3 days
± 5 days
±5 days
(if applicable)
Informed consent form
X
Inclusion/exclusion criteria
X
X
Demographics
X
Baseline characteristics d
X
X
Medical history, previous therapies 
and procedures, smoking status
X
SUBJECT-REPORTED OUTCOME (SRO) ASSESSMENTS
(eDiary) Daily WI NRS/SD NRS e,f
X ------------------------------------------------------------------------------------------------------X
(X)
INVESTIGATOR ASSESSMENT
IGA of CKD-aP skin status h
X
X
X
X
X
X
(X)
SAFETY ASSESSMENTS
ACT g,i
X
X
X
X
X
X
(X)
PEF testing i,j,k
X
X
X 
X
X 
X
(X)
Respiratory exam k,l
X
X
X
X
X
X
(X)
Full physical examination 
X
X
X
X
X
X
(X)
Height
X
(X)
Pre-Dialysis and Post-Dialysis Weight
X
X
X
(X)
 
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Study period
Screening 
perioda
Treatment period
Follow-up 
Unscheduled visitc
Visit
V1
V2
V3
V4
 V5
V6
Week
W-4
Baseline
W4
W8
W12/ETb
W20
Day
Day 29
Day 57
Day 85
Day 141
Visit window
Day 1
± 3 days
± 3 days
± 5 days
±5 days
(if applicable)
12-lead ECG k,m
X
X
(X)
Vital signs n
X 
X
X
X
X
X
(X)
Contraceptive counseling 
X
(X)
Adverse Events 
X
X
X
X
X
X
(X)
Concomitant therapies and 
procedures 
X
X
X
X
X
X
(X)
LABORATORY ASSESSMENTS
Blood sample for virology (HIV, 
Hepatitis B, and C test) 
X
(X)
Blood samples for TB test 
X
(X)
Blood samples for hematology and 
biochemistry o
X
X
X
X
X
X
(X)
Urinalysis p
X
X
X
X
X
X
(X)
Pregnancy test q
X
X
X
X
X
X
(X)
FSH r
X
RANDOMIZATION and STUDY DRUG ADMINISTRATION
Randomization
X
Study drug injection and training t,u,v
X
X
X
(X)
 
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13.2
Duration of Subject Participation
The expected duration of each subject’s participation in the study is up to 24 weeks, including 
an up to 4-week screening period, a 12-week treatment period, and an 8-week follow-up 
period (12-weeks after the last study medication injection).
13.2.1
Early Termination Visit
Subjects who prematurely discontinue from the study should complete an early termination 
(ET) visit at the time of discontinuation. A follow-up/final visit is required 12 weeks after the 
last study drug administration.
Subjects who prematurely discontinue the study treatment will be asked to continue 
participation in the study and return for all remaining visits and assessments.
Participation will continue until the subject completes the final study visit or otherwise 
discontinues study participation.
13.2.2
Unscheduled Visit
The subject should be reminded to adhere to the study schedule. Unscheduled visits are 
defined as visits to repeat testing for abnormal laboratory results, for follow-up of AEs, or to 
conduct efficacy assessments for subjects requiring rescue medication between regularly 
scheduled study visits. Visits occurring outside of the visit window are not considered 
unscheduled visits.
 
 
 
 
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14
DEMOGRAPHIC AND BASELINE CHARACTERISTICS
14.1
Medical History
Medical history will be recorded at screening. Investigators should document the subject’s 
pre-existing conditions, including all prior relevant (e.g., allergic conditions such as asthma) 
and significant illnesses, before screening. Medical history will include alcohol consumption, 
if applicable and smoking history. Medical history will be coded using the most recent 
version of Medical Dictionary for Regulatory Activities (MedDRA).
Additionally, demographic data will be collected for all subjects and include but are not 
limited to age, sex, race, etc., according to applicable regulations.
14.2
Height and Weight
Height and weight will be measured, according to Section 13.1.
Subject weight must be more than 30 kg at both screening and baseline visits in order to be 
enrolled into this clinical study.
14.3
Baseline Characteristics
The following baseline characteristics will be collected for all subjects:

Duration of ESKD (months) at baseline

Duration of hemodialysis (months) at baseline

Hemodialysis access (AVF/AVG/Catheter)

Kt/V at baseline

Cause of CKD

Hypertension

Diabetes

Glomerulonephritis

Cystic disease

Urologic

Congenital/Hereditary

Other

Duration of pruritus (months) at baseline
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15
EFFICACY ASSESSMENTS
The Schedule of Assessments (Table 5) outlines the efficacy assessments to be performed 
throughout the study and their timing.
Efficacy measurements should be conducted by subjects (for subject-reported efficacy 
measurements) according to Sections 15.1 - 15.5.
Whenever possible, the same evaluator should make the investigator global assessment (IGA) 
throughout the study. Refer to Section 9.2 for efficacy endpoints.
15.1
Worst Itch Numeric Rating Scale
The WI NRS is a scale to be used by the subjects to report the intensity of their worst pruritus 
(itch) during the last 24 hours (see Appendix 3). The WI NRS is a validated measurement tool 
and has been used to assess subject-reported severity of itch in CKD-aP clinical trials 
(Fishbane 2020). 
Subjects will be asked the following question:

For worst itch intensity: “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being the 
‘worst itch imaginable’, how would you rate your itch at the worst moment during the 
previous 24 hours?”
The screening WI NRS score will be determined by a single WI NRS assessment (score 
ranging from 0 to 10) for the 24-hour period immediately preceding the screening visit. The 
baseline WI NRS score will be determined based on the weekly average of daily WI NRS 
scores (score ranging from 0 to 10) during the seven days immediately preceding baseline 
(rounding is not permitted). A minimum of four daily scores out of the seven days 
immediately preceding baseline is required for this calculation.
Subjects will record their 24-hour worst itching assessment scores on all days. Subjects will 
receive instructions on how to record their WI NRS scores and will complete the assessment 
once daily in the evening throughout the clinical study (including the screening and the 
follow-up period) in an eDiary. If they cannot record it in the evening, then record it in the 
following morning is acceptable.
If a subject does not complete the WI NRS assessments in the evening, the subject will be 
allowed to complete the assessments the following morning. 
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15.2
Sleep Disturbance Numeric Rating Scale
The SD NRS is a scale to be used by the subjects to report the degree of their sleep loss 
related to CKD-aP (see Appendix 4). Subjects will receive instructions on how to record their 
SD NRS scores and will complete the assessment once daily in the morning throughout the 
clinical study during the screening and treatment periods.
Subjects will be asked the following question:

“On a scale of 0 to 10, with 0 being ‘no sleep loss related to the symptoms of pruritus 
and 10 being ‘I did not sleep at all due to the symptoms of pruritus, how would you 
rate your sleep last night?”
If a subject does not complete the SD NRS assessment the morning of a scheduled visit, the 
subject will be allowed to complete the assessment at the clinic visit.
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16
SAFETY ASSESSMENTS
Safety assessments will be conducted for all subjects at the screening visit (upon signing of 
the ICF) and at every subsequent visit.
16.1
Vital Signs
Vital signs will be evaluated at the screening visit and at each subsequent visit according to 
Section 13.1. Vital signs will include pulse rate, systolic and diastolic blood pressure (after 
the subject has been sitting for at least five minutes), and body temperature. All abnormal 
values at the screening visit identified as CS by the investigator will be recorded in the 
medical history form. Any CS changes from the screening visit will be recorded as an AE.
16.2
Physical Examination
Complete physical examination should be performed at the screening, baseline, and 
subsequent scheduled visits, according to Section 13.1. A complete physical examination will 
include assessments of the head, ears, eyes, nose, throat, neck (including thyroid), 
skin/integumentary system, cardiovascular system, respiratory system (for additional 
respiratory assessments, see Section 16.8), gastrointestinal system, musculoskeletal system, 
lymph nodes, nervous system, and extremities. 
The investigator should assess all abnormal findings for clinical significance. All CS 
abnormal findings at the screening visit will be recorded in the medical history form. Any CS 
changes from the screening visit will be recorded as an AE.
16.3
Electrocardiogram
A 12-lead ECG will be performed and read locally according to visits specified in 
Section 13.1. ECGs will be performed in the supine position at the time points described in 
the Schedule of Assessments, Table 5. Subjects should be monitored for potentially CS ECG 
results (refer to the current version of the central laboratory manual). Tests with abnormal 
results that are deemed CS should be repeated to ensure reproducibility of the abnormality. 
ECG abnormalities present at screening should be recorded in the medical history form. Any 
abnormalities considered by the investigator to be CS after the screening visit are to be 
recorded as AEs and discussed with the medical monitor, as needed.
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16.4
Clinical Laboratory Evaluation
The hematology laboratory analyses, biochemistry laboratory analyses, and urinalyses will be 
performed at a central laboratory. Reference ranges will be supplied by the central laboratory 
and used by the investigator to assess the laboratory data for clinical significance and 
pathological changes.
The investigator or medically qualified sub-investigator must review and evaluate laboratory 
values for each subject in a timely manner. Study centers should refer to the current version 
of the laboratory manual for laboratory values outside of normal limits. For each out-of-range 
laboratory result, the investigator or designee will evaluate whether he/she considers it to be 
CS, defined as meeting at least 1 of the following conditions:

The abnormality suggests a disease and/or organ toxicity, or

The abnormality is of a degree that requires additional active management (e.g., 
discontinuation of the drug, close observation, more frequent follow-up assessments, 
or further diagnostic investigation).
If the investigator observes a CS laboratory result that meets the criteria for an adverse event 
or at the investigator’s discretion, the test will be repeated as soon as possible, and the subject 
will be monitored until the value returns to normal and/or an adequate explanation for the 
abnormality is found.
Investigators will also be allowed to repeat specific laboratory test(s) or procedure(s) where 
the investigator suspects an inaccuracy or false result and that may impact the safety of the 
subject or the interpretation of the trial results; only after discussion with medical monitor.
All CS out-of-range laboratory values at the screening visit will be recorded in the medical 
history form (report a diagnosis rather than the laboratory value whenever possible). All CS 
out-of-range laboratory values after the screening visit are to be reported as an AE if this 
abnormality was not present at the screening visit or is assessed as having worsened since the 
screening visit (i.e., changed by a clinically significantly extent from the screening visit). 
Whenever possible, the investigator should provide a diagnosis of an AE when reporting the 
abnormal laboratory value.
Subjects should fast for at least 8 hours before the visits when blood chemistry testing is 
planned, except for the screening visit, if possible. The screening visit laboratory values must 
be available before the baseline visit. Laboratory testing conducted in a nonfasting state will 
not be a protocol deviation.
Total blood volumes to be drawn at each visit are provided in the clinical laboratory manual. 
Additional samples may be required if medically indicated (e.g., at unscheduled visits for 
safety reasons, when an abnormal laboratory value is observed and requires a re-test).
See Section 16.5, Section 16.6, and Section 16.7 for details regarding pregnancy testing, 
virology, and TB testing samples, respectively (See Section 17.1 for details regarding
 
 and Section 18.1 for ADA sampling).
The following laboratory safety tests will be performed as specified in Section 13.1.
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16.4.1
Hematology
Hemoglobin, hematocrit, white blood cell count (with differential including eosinophils), red 
blood cell count, platelet count, and mean cell volume.
16.4.2
Biochemistry
Creatinine, AST, ALT, gamma glutamyltransferase, alkaline phosphatase, lactate 
dehydrogenase, total bilirubin, direct bilirubin, albumin, total protein, uric acid, sodium, 
potassium, calcium, chloride, glucose, urea, total cholesterol, triglycerides, low-density 
lipoprotein, high-density lipoprotein (HDL), CPK. CPK isoenzyme test will be performed 
only if CPK is elevated to > 2.5 × ULN. The investigator should also contact the medical 
monitor in such situations.
For postmenopausal subjects (i.e., no menses for 12 consecutive months), postmenopausal 
status will be confirmed with a high follicle-stimulating hormone (FSH) level in the 
postmenopausal range.
16.4.3
Urinalysis
Only applies to subjects who are able to produce urine. pH, glucose, ketones, blood, protein, 
leukocytes, nitrites, bilirubin, urobilinogen, and specific gravity.
16.5
Pregnancy Testing
All WOCBP will have a serum pregnancy test performed at all visits. Pregnancy test 
results must be available prior to the administration of the study drug.
Subjects with a positive serum pregnancy test result at screening must not be enrolled.
Subjects with a positive serum pregnancy test result during the trial must discontinue 
treatment and but remain in the study for follow-up.
16.6
Virology
Virology including HBsAg, HBcAb, HCV, HIV-1, and HIV-2 antibody will be assessed at 
the screening visit. Subjects with a positive HBcAb and a negative HBsAg will also be 
assessed for hepatitis B surface antibody. Subjects with positive HCV antibodies will have a 
confirmatory test for HCV (e.g., PCR).
16.7
Tuberculosis Testing
Immunosuppressant biologic treatments have been shown to increase the risk of TB infection 
or to cause conversion from latent to active TB in some circumstances. Because of this, 
subjects will be screened for active or latent TB before entry into this study. TB blood testing 
(using an interferon gamma release assay) may be performed at the central laboratory or at a 
local laboratory based on the investigator’s preference. 
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16.7.1
Definitions
Active TB is a disease caused by Mycobacterium TB in any part of the body and that is in an 
active state as determined by either a smear or culture taken from any source in the person's 
body which tests positive for TB or by radiographic evidence. Individuals with active TB are 
symptomatic, depending upon the location of the disease (most commonly in the lungs but 
also possibly in the brain, kidneys, spine, or elsewhere), and can spread the infection to 
others.
Latent TB is said to exist when an individual is infected with Mycobacterium TB, as 
evidenced by a positive Interferon Gamma Release Assay, 40 such as QuantiFERON-TB 
Gold, but is asymptomatic and has no evidence of active infection on screening pathology or 
radiographic tests. Such individuals do not pass the disease to others and should commence a 
course of prophylactic antimycobacterial treatment to eliminate the infection and commit to 
completing the course of treatment.
16.7.2
Tuberculosis Screening
As part of the medical history, the subject should be asked if they have presented with active 
or latent TB in the past and whether they have received a bacillus Calmette- Guérin (BCG) 
vaccination. They should also be asked if they have been in contact with any individuals 
known to have active TB or been placed in any circumstances that may have exposed them to 
an increased risk of TB infection, such as travel to TB endemic regions, close contact with 
persons with active TB, or workplace risk (e.g., prison, hospitals).
A subject who tests positive for latent TB (with a positive QuantiFERON-TB Gold test) 
should be referred to the subject's treating physician for appropriate follow-up, unless the 
subject has a documented history of completion of an appropriate TB treatment regimen with 
no history of re-exposure to TB since her/his treatment was completed. If the result is 
indeterminate, the test may be repeated once. If confirmed indeterminate, the subject should 
then be managed as though he/she has a positive test result.
16.8
Respiratory Assessments
At screening, the investigator should specifically question all subjects about any medical 
history of asthma and their respiratory health (e.g., wheezing, coughing, allergies, infections). 
Subjects with a history of asthma will be questioned about the seasonality of their asthma and 
known triggers, such as allergens. Newly diagnosed asthma or worsening of asthma during 
the study will be reported as an AESI.
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16.8.1
Asthma Control Test
Subjects with a medical history of asthma will take the ACT at visits according to 
Section 13.1 before questioning and physical examination by the investigator. Subjects with a 
new (de novo) diagnosis of asthma will take the ACT beginning at the visit the diagnosis was 
first confirmed and at all subsequent study visits thereafter. Subjects with an ACT score ≤ 19 
will be referred to the physician managing their asthma.
The ACT is an assessment to determine if a subject's asthma symptoms are well controlled. 
The ACT is designed for adults and adolescents 12 years or older and is composed of five 
questions. For each question, the subject will choose the best answer out of five possible 
answers. The test provides a numerical score ranging from five to 25 to assess asthma 
control; a higher score indicates better asthma control while a score of 19 or less indicates the 
subject's asthma may not be under control. The ACT will also aid the investigator's 
questioning of subjects with a medical history of asthma. See Appendix 10.
16.8.2
Respiratory Examination
A respiratory examination will be required to be performed for all subjects at all scheduled 
visits, according to Section 13.1. After the screening visit, all subjects will be asked 
non-leading questions about any respiratory changes. The investigator or designee will then 
perform a respiratory examination of all subjects at all visits.
Subjects with a medical history of asthma will be referred to the physician managing their 
asthma if unexpected worsening of asthma is observed or reported. Subjects without a 
medical history of asthma who experience respiratory changes (examination findings or 
newly reported signs and/or symptoms suggestive of asthma) will be referred to a respiratory 
specialist.
16.8.3
Peak Expiratory Flow
All subjects will undergo PEF testing at screening, baseline, and specified visits according to 
Section 13.1. For subjects reporting a medical history of asthma, PEF testing will be 
conducted at all visits.
Subjects with a new (de novo) diagnosis of asthma will undergo PEF testing at all visits after 
the diagnosis is first made according to Section 13.1.
PEF testing during the clinical study will be performed under the supervision of qualified 
study personnel. PEF measurements should consist of three good efforts, with the best result 
documented. It is preferable that the PEF measurement be performed post-dialysis or during 
the last 1 hour of dialysis when most/all excess fluid has been removed. Obtained PEF values 
will be compared to predicted values based on the subject's age, sex, and height 
(Quanjer 1993, Polgar 1979). 
Subjects with a medical history of asthma should be asked to withhold asthma medication, if 
applicable, on study visit days until after PEF testing is complete, to the extent it does not 
pose an undue risk to the subject, to avoid interference with PEF measurements.
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16.8.4
Respiratory Referrals
Subjects with a medical history of asthma will be referred to the physician who manages their 
asthma when:

ACT score ≤ 19 (an ACT score ≤ 19 conveys asthma that may not be adequately 
controlled).

Unexpected worsening of asthma is observed or reported at any time during the study.

At any study visit, subjects without a medical history of asthma will be referred to an 
appropriate specialist physician whenever:
o Signs and/or symptoms suggestive of asthma are newly observed or reported.
o Respiratory assessments (e.g., examination, ) suggest a worsening in the 
subject's respiratory health.

PEF value is only supplemental to the clinical evaluation of respiratory signs and 
symptoms suggestive of asthma (de novo or worsening in patients with history of 
asthma) at investigators judgement. 
16.9
Adverse Events
An AE is defined as any untoward medical occurrence in a clinical study subject 
administered a medicinal product which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not it is related to the medicinal 
(investigational) product. This includes an exacerbation of pre-existing conditions or events, 
intercurrent illnesses, drug interaction, or the significant worsening of the indication under 
investigation that is not recorded elsewhere in the eCRF under specific efficacy assessments.
Note(s):

Any new sign or symptom reported by the subject that appears after accidental or 
intentional overdose or misuse of study drug should be reported as an AE.

Whenever possible, a diagnosis should be reported on the AE form, instead of signs, 
symptoms, or abnormal laboratory values.

Pregnancy is not to be considered an AE; however, it must be monitored and reported 
as described in Section 16.12.4.

Each worsening of a chronic disease from the screening visit should be reported as a 
new AE.
The investigator or designee will report all AEs that occur from the time the ICF is signed 
until the end of the study. The sponsor/CRO should be informed if the investigator becomes 
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aware of any safety information that appears to be drug-related, even after the subject has 
completed the clinical study.
At each post enrollment visit, the investigator (or sub-investigator) will question the subject 
about AEs using an open nonpersuasive question to elicit reporting of AEs (for example, 
“Have you noticed any change in your health since the last visit?”). Directed questioning and 
examination will then be performed as appropriate.
Any AE occurring during the AE reporting period, whether it is related to the study drug(s) or 
not, will be recorded immediately in the source document and described on the Adverse 
Event Form (“AE Form”) along with the date of onset, severity, relationship to the study 
drug(s), and outcome, without omitting any requested and known information. Additional 
information will be requested under certain circumstances.
AEs assessed as related to the treatment or study procedure will be monitored until they have 
resolved or reached a stable condition. Other AEs will be monitored until the last visit if they 
have not resolved or reached a stable condition.
The investigator will obtain and maintain in the subject's files all pertinent medical records, 
information and medical judgment from colleagues who assisted in the treatment and 
follow-up of the subject. If necessary, the investigator will contact the subject's personal 
physician or hospital staff to obtain further details.
16.9.1
Assessment of Severity
Each AE will be assigned a category by the investigator as follows:

Mild:An AE that is easily tolerated by the subject, causes minimal discomfort, and 
does not interfere with everyday activities.

Moderate: An AE that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed.

Severe: An AE that prevents normal everyday activities; treatment or other 
intervention usually needed.
16.9.2
Assessment of Causality
The investigator is to determine whether there is a reasonable causal relationship between the 
occurrence of the AE and exposure to the study drug (i.e., nemolizumab or placebo) and/or 
study procedure (e.g., injection, topical background therapy, blood sample collection). 
Medical judgment should be used to determine the relationship, considering all relevant 
factors including the pattern of the reaction, temporal relationships, relevant medical history, 
and confounding factors such as co-medication or concurrent diseases.
The expression “reasonable causal relationship” is meant to convey in general that there are 
facts or arguments to suggest a causal relationship (ICH E2A, Section IIIA 1).
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The relationship assessment for an AE is to be completed using the following definitions as a 
guideline for all AEs occurring during this clinical study:

Reasonable Possibility: According to the reporting investigator, there is a reasonable 
possibility (i.e., suggestive evidence or arguments) that there is a causal relationship 
irrespective of the dose administered:
o Between the study drug and the AE, and/or
o Between the clinical study protocol procedure (e.g., injection, topical 
background therapy, blood sample collection) and the AE.

No Reasonable Possibility: No suggestive evidence or arguments can be identified 
regarding a causal relationship between the study drug or the clinical study protocol 
procedure and the AE.
16.9.3
Action Taken
The investigator will describe the action taken with the study drug for the AE in the 
appropriate section of the eCRF. 
16.9.4
Follow-up of Adverse Event
All investigators should follow-up with subjects with AEs until the event is resolved or until, 
in the opinion of the investigator, the event is stabilized or determined to be chronic. Details 
of AE resolution must be documented in the eCRF.
Subjects should be followed up for 12 weeks (± 5 days) after receiving the last dose of study 
drug, and any AEs that occur during this time should be reported according to the procedures 
outlined above.
16.9.5
Documenting and Reporting of Adverse Events
AEs should be reported and documented in accordance with the procedures outlined below. 
All AEs occurring during the study must be documented on the relevant eCRF pages. The 
following data should be documented for each AE:

Description of the symptom event

Classification of “serious” or “not serious”

Severity

Date of first occurrence and date of resolution (if applicable)

Action taken with study drug

Other action taken (e.g., concomitant medication, other intervention)

Causal relationship
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
Outcome of event (unknown, recovered, not yet recovered, recovered with sequelae, 
death [with date and cause reported])
16.10
Adverse Events of Special Interest
An AESI is a noteworthy treatment-emergent event for the study drug that should be 
monitored closely and reported promptly. See Section 16.12.1 for reporting procedure. An 
AESI can be either serious or non-serious.
Based on the potential risks of nemolizumab and the risks associated with biologics (and their 
biosimilar equivalents) in general (i.e., class effects), the following AEs will be considered 
AESIs:

IRRs
o Anaphylactic reactions
o Acute allergic reactions requiring treatment
o Severe injection site reactions with a duration greater than 24 hours 

Newly diagnosed asthma or worsening of asthma
o More specifically, subjects with a medical history of asthma will be referred to 
the physician who manages their asthma when:
-
ACT score ≤ 19: An ACT score ≤ 19 conveys asthma that may not be 
adequately controlled. An AESI is reported based on the investigator's 
clinical judgment, including consideration of the managing physician's 
report.
-
Unexpected worsening of asthma is observed or reported. An AESI is 
reported based on the investigator's clinical judgment.
o Subjects without a medical history of asthma will be referred to an appropriate 
respiratory physician/specialist when:
-
Signs and/or symptoms suggestive of asthma have been observed or 
reported. An AESI is reported based on the investigator's clinical 
judgment of the specialist's report.
-
Respiratory assessments (e.g., examination) suggest a worsening in the 
subject's respiratory health. An AESI is reported based on the 
investigator's clinical judgment of the specialist's report.
o
PEF value is only supplemental to the clinical evaluation of respiratory signs 
and symptoms suggestive of asthma (de novo or worsening in patients with 
history of asthma) at investigators judgement. 

Infections
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o Any severe infection or any infection requiring treatment with parenteral 
antibiotics or oral antibiotics/antivirals/antifungals for > 2 weeks
o Confirmed or suspected COVID-19

Peripheral edema: limbs, bilateral, if assessed by the investigator as having a 
reasonable possibility for a relationship to study drug. Peripheral edema is only to be 
reported as an AESI if assessed by the investigator as having a reasonable possibility 
for a relationship to study drug.

Facial edema

Elevated ALT or AST (> 3 × ULN) in combination with elevated bilirubin 
(> 2 × ULN). These abnormal lab findings may indicate potential severe liver injury 
(possible Hy's Law) and should be reported as an SAE (see Section 16.12.2, 
procedure for reporting a serious adverse event).
16.11
Serious Adverse Events
An SAE is any untoward medical occurrence or effect that, at any dose:

Results in death.

Is life-threatening (an AE is life-threatening if the subject was at immediate risk of 
death from the event as it occurred, i.e., it does not include a reaction that might have 
caused death if it had occurred in a more serious form).

Requires or prolongs inpatient hospitalization (Complications occurring during 
hospitalization are AEs and SAEs if they cause prolongation of the current 
hospitalization. Inpatient hospitalization is considered to have occurred if the subject 
has had to stay for a night at the hospital. The criterion for prolongation of 
hospitalization is also defined as an extra night at the hospital. Hospitalization may 
not constitute sufficient grounds to be considered as an SAE if it is solely for the 
purpose of diagnostic tests [even if related to an AE], elective hospitalization for an 
intervention that was already planned before subject enrollment in the clinical study, 
admission to a day care facility, social admission [e.g., if the subject has no place to 
sleep], or administrative admission [e.g., for a yearly examination]. The details of 
such hospitalizations must be recorded on the medical history or physical examination 
eCRF).

Results in persistent or significant disability/incapacity (An AE is incapacitating or 
disabling if it results in a substantial and/or permanent disruption of the subject's 
ability to carry out normal life functions).

Results in a congenital anomaly/birth defect.

An important medical event that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, the event may jeopardize the safety of the subject, and may require medical 
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or surgical intervention to prevent 1 of the outcomes listed above in this definition. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasia, or convulsions that do not result in 
hospitalization.
16.12
Reporting Procedures
16.12.1
Adverse Events of Special Interest Reporting
For any AESI occurring during the clinical study, regardless of whether or not related to the 
treatment, the investigator must:
1. Take prompt and appropriate medical action, if necessary. The safety of subjects is the 
first priority.
2. Ensure that the event is evaluated as an AESI. Notify (within three days of receipt of the 
event) the 
 of an AESI report by fax or phone: 
 
Note: AESI reporting is required by the investigator if it occurs during the clinical study 
following the first dose of study drug or within 12 weeks (± 5 days) of receiving the last 
dose of study drug, whether or not the event is considered to be related to the 
investigational product.
The demographics, medical history, drugs/therapies, and medical and surgical procedures 
forms must also be available for review in eCRF, at that time.
3. Send any relevant information or medical records (e.g., laboratory test results) to the 
 
 within three days of receipt of this relevant 
information.
4. Monitor and record the progress of the event until it resolves or reaches a stable 
condition, with or without sequelae. For all additional follow-up evaluations, update the 
AESI form within three days of receipt of the updated information.
5. Obtain and maintain in the files all pertinent medical records, information, and medical 
judgments from colleagues who participate in the treatment and follow-up of the subject. 
If necessary, contact the subject's personal physician or hospital staff to obtain further 
details.
6. When the outcome of the event is known, update the AESI form, if appropriate.
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16.12.2
Serious Adverse Event Reporting
For any SAE occurring during the clinical study, regardless of whether or not related to the 
study drug and/or procedure, the investigator must:
1. Take prompt and appropriate medical action, if necessary. The safety of the subject is the 
first priority.
2. Ensure that the event is evaluated as an SAE. Immediately notify (within 24 hours of 
receipt of the event) the
 of an SAE report by 
fax or phone:
 
Note: Immediate SAE reporting is required by the investigator if it occurs during the 
clinical study or within 12 weeks (± 5 days) of receiving the last dose of study drug, 
whether or not the event is considered to be related to the investigational product.
The demographics, medical history, drugs/therapies, and medical and surgical procedures 
forms must also be available for review in eCRF, at that time.
3. Send any relevant information or anonymized medical records (e.g., laboratory test 
results) to the
 (see contact details above), 
within 24 hours of receipt of this relevant information.
4. Monitor and record the progress of the event until it resolves or reaches a stable 
condition, with or without sequelae. For all additional follow-up evaluations, complete an 
updated SAE report within 24 hours of receipt of the updated information.
5. Obtain and maintain in the subject files all pertinent medical records, information, and 
medical judgments from colleagues who participate in the treatment and follow- up of the 
subject. If necessary, contact the subject's personal physician or hospital staff to obtain 
further details.
6. When the outcome of the event is known, complete an updated SAE report, if appropriate.
7. Prompt notification of SAEs by the investigator is essential so that legal obligations and 
ethical responsibilities toward the safety of subjects are met. The sponsor has a legal 
responsibility to notify both the local regulatory authority and other regulatory agencies 
about the safety of a product under clinical investigation. The sponsor or its delegate (i.e., 
the CRO) will comply with country-specific regulatory requirements relating to safety 
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reporting to regulatory authorities, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and investigators. Investigator safety reports are prepared for SUSARs 
according to local regulatory requirements and are forwarded to investigators as 
necessary.
An investigator who receives an investigator safety report describing an SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor or its 
delegate (i.e., the CRO) will file it accordingly (i.e., within the Trial Master File [TMF]), 
and will notify the IRB/IEC, if appropriate according to local requirements.
8. Comply with the applicable regulatory requirement(s) related to the reporting of SAEs to 
the IRB/IEC.
16.12.3
Suspected Unexpected Serious Adverse Reactions
AEs that meet all of the following criteria will be classified as SUSARs and reported to the 
appropriate regulatory authorities in accordance with applicable regulatory requirements for 
expedited reporting:

Serious.

Unexpected (i.e., the event is not consistent with the Reference Safety Information in 
the IB for nemolizumab).

There is at least a reasonable possibility that there is a causal relationship between the 
event and the study treatment.
The sponsor or its delegate will comply with country-specific regulatory requirements 
relating to safety reporting to regulatory authorities, IRB/IEC and investigators.
Investigator safety reports are prepared for SUSARs according to local regulatory 
requirements and sponsor policy and are forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SUSAR or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor or its delegate 
will file it accordingly (i.e., with the TMF), and will notify the IRB/IEC, if appropriate 
according to local requirements.
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16.12.4
Pregnancy Reporting
Any pregnancy occurring during clinical studies where the fetus could have been exposed to 
the study drug must be monitored until its outcome in order to ensure the complete collection 
of safety data. If a subject becomes pregnant, the investigator must:
1. Withdraw the subject from the clinical study. The subject must not receive any further 
injection of the study drug.
2. Complete as fully as possible the Pregnancy Surveillance Form - Part I: History and Start 
of Pregnancy. Send by fax along with the exit form within 24 hours of receipt of the 
information to the 
Note: Immediate pregnancy reporting is required by the investigator if it occurs during the 
clinical study or within 12 weeks (± 5 days) of receiving the last dose of study drug, 
whether or not the event is considered to be related to the investigational product.
3. Monitor and record the progress of the pregnancy until its outcome. Contact the subject's 
regular physician (general practitioner or gynecologist) or hospital staff to obtain further 
details and ask for regular follow-up information.
4. Provide tri-monthly updates until the final outcome of the pregnancy, by completing the 
Pregnancy Surveillance Form - Part II: Course and Outcome of Pregnancy. For all 
additional follow-up evaluations, send the form by fax to the 
 
 within 24 hours of receipt of the information. If the subject can 
no longer be reached (i.e., lost to follow-up), documentation of the non-response/contact 
with two phone calls and a letter (certified with return receipt) is required.
5. At the outcome of the pregnancy, complete as fully as possible the Pregnancy 
Surveillance Form - Part II: Course and Outcome of Pregnancy. Print and send the form 
by fax to the 
 within 24 hours of receipt of the 
information.
6. If the pregnancy leads to an abortion (i.e., voluntary abortion, spontaneous abortion, or 
therapeutic abortion), in utero death or congenital anomaly, follow the procedure for 
declaration of/reporting an SAE (see Section 16.12.2).
16.12.5
Overdose Reporting
Study drug overdose is the accidental or intentional use of the drug in an amount higher than 
the dose being studied. The investigator must immediately notify the sponsor of any 
occurrence of overdose with study drug.
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18
OTHER ASSESSMENTS
18.2
Independent Data Monitoring Committee
An IDMC will review and monitor subject safety throughout the study. The IDMC will 
provide recommendations on the safety of subjects. 
Details on the IDMC, including the plan of analysis for IDMC outputs, the composition of 
the IDMC, the procedures, roles, responsibilities, and their communications are provided in 
the IDMC charter.
18.3
Independent Adjudication Committee
An IAC will review all asthma-related AEs throughout the study. Details on the IAC, 
including the plan of analysis for IAC outputs, the composition of the IAC, the procedures, 
roles, responsibilities, and their communications are provided in the IAC charter.
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19
STATISTICAL ANALYSIS
A statistical analysis plan (SAP) will be prepared after the protocol is approved. This 
document will provide further details regarding the definition of analysis variables and 
analysis methodology to address all study objectives. The SAP will serve as a complement to 
the protocol and supersedes it in case of differences.
The statistical evaluation will be performed using SAS® software version 9.4 or higher (SAS 
Institute, Cary, NC). All data will be listed. All primary, secondary, and exploratory efficacy 
endpoints, and safety endpoints will be summarized. Summary statistics will be presented by 
treatment group. For continuous variables, data will be summarized with the number of 
subjects (n), mean, standard deviation, median, first quartile, third quartile, minimum, and 
maximum by treatment group. For categorical variables, data will be tabulated with the 
number and proportion of subjects for each category by treatment group.
19.1
Determination of Sample Size
The sample size calculation is based on providing enough subjects to enable the detection of 
treatment difference in the primary endpoint at Week 12. Approximately 84 subjects will be 
randomized in each nemolizumab group and in the placebo group for a total sample size of 
approximately 252 subjects. 84 subjects per treatment group will have power ≥ 90% to detect 
difference between placebo group (expected success proportion 20%) and nemolizumab 
group (30 mg or 60 mg, expected success proportion 50%) at the overall two-sided alpha of 
0.05. A two-sided alpha of 0.025 will be spent for the comparison of each nemolizumab dose 
group versus placebo group.
19.2
Analysis Populations
Statistical analyses will be performed on the following subject populations.

Intent-to-Treat Population: The intent-to-treat (ITT) population will consist of all 
randomized subjects. 

Modified Intent-to-Treat Population: The modified intent-to-treat (mITT) population 
will consist of all ITT subjects who receive at least one dose of study drug and have at 
least one post baseline assessment of primary efficacy variable.

Per Protocol Population: The per protocol (PP) population will include all randomized 
subjects who receive all scheduled doses of study drug and have Baseline and Week 12 
assessments of WI NRS and with no major deviation that could impact efficacy.

Safety Population: The safety population will include all randomized subjects who 
receive at least one dose of study drug.

 
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The ITT population will be the primary population for all efficacy analyses. The mITT and 
PP populations will be used for the supplementary analysis of the primary endpoint. 
 
 and all safety data will be summarized based 
on the safety population.
19.3
Efficacy Analysis
A summary based on observed case (OC) will be provided for all primary, secondary, and 
exploratory efficacy endpoints. At this case, no data will be imputed. For this summary, if 
any rescue medication is received or treatment is discontinued, and data are collected 
post-rescue receipt or treatment discontinuation, then the data post-rescue or post-
discontinuation will be summarized as observed.
Proportion of subjects with WI NRS/SD NRS ≥ 4 and WI NRS ≥ 3, changes and percent 
changes from baseline of WI NRS/SD NRS at each week (from week 1 through week 20) 
will be calculated on the basis of the weekly average, obtained by averaging at least 4 daily 
WI NRS/SD NRS scores over 7-day periods.
For baseline weekly average, if fewer than 4 daily WI NRS/SD NRS scores for the 7-day period 
are available, the interval lower bound will be extended up to 7 additional days, one day at a 
time, until 4 daily WI NRS/SD NRS scores are available. If after the interval extension fewer 
than 4 daily WI NRS/SD NRS scores are available, the baseline weekly average WI NRS/SD 
NRS will be considered missing. The interval extension for the baseline weekly average 
calculation applies to the statistical analysis only. For eligibility, 4 daily WI NRS/SD NRS 
scores for the 7-day period are required (see inclusion criterion 5).
For week 12 weekly average, if fewer than 4 daily WI NRS/SD NRS scores for the 7-day period 
are available, the interval upper bound will be extended for 5 additional days, one day at a time, 
until 4 daily WI NRS/SD NRS scores are available. If after extending the upper bound fewer 
than 4 daily WI NRS/SD NRS scores available, the interval lower bound will be extended for 
5 additional days, one day at a time, until 4 daily scores are available. If after the interval 
extension fewer than 4 daily WI NRS/SD NRS scores are available, the week 12 weekly 
average WI NRS/SD NRS will be considered missing.
For all the other weekly averages, if fewer than 4 daily WI NRS/SD NRS scores for the 7-day 
period are available, the weekly average WI NRS/SD NRS will be considered missing for that 
period.
For the aim of sensitivity analyses, weekly averages of WI NRS obtained by averaging at least 
3 daily scores over 7-day periods, at least 2 daily scores over 7-day periods and at least 1 daily 
score over 7-day periods will be calculated. No period extension at baseline and week 12 
applies for these weekly averages. If fewer than 3, 2 or 1 daily WI NRS scores for the 7-day 
period are available, the corresponding weekly average of WI NRS will be considered missing 
for that period.
Data of both nemolizumab groups (30 mg and 60 mg) and placebo group and comparisons 
versus placebo group of both nemolizumab groups will be presented.
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19.3.1
Analysis of Primary Efficacy Endpoint
Primary efficacy endpoint and related estimand are the following:
Primary Efficacy 
Estimand Description
Estimand Attributes
Treatment Conditions: initial dose of nemolizumab (60 mg) or placebo at 
baseline, then nemolizumab (30 mg or 60 mg) or placebo Q4W at Weeks 4 and 8 
via subcutaneous injection. 
Population: adult hemodialysis patients with chronic kidney disease and associated 
moderate to severe pruritus (will be estimated in the Intent-to-Treat analysis set).
Variable: a binary composite response where:
Responder is defined as an improvement ≥ 4 in WI NRS from baseline at Week 12 
without use of rescue therapies and without treatment discontinuation due to lack of 
efficacy or AE/death related to study drug.
Non-responder is defined as an improvement < 4 in WI NRS from baseline at 
Week 12 or use of rescue therapies or treatment discontinuation due to lack of 
efficacy or AE/death related to study drug.
Strategies for Intercurrent Events: A composite strategy was chosen for the use 
of rescue therapies and treatment discontinuation due to lack of efficacy or 
AE/death related to study drug; in case of use of rescue therapies or treatment 
discontinuation due to lack of efficacy or AE/death related to study drug, subjects 
will be considered as treatment failures in the binary composite response. In the 
case of treatment discontinuation for any other reason, a treatment policy strategy 
will be used and observed after discontinuation data (if available) will be used.
In adult hemodialysis 
patients with chronic 
kidney disease and 
associated moderate to 
severe pruritus, 2 
nemolizumab dosing 
schedules[1] compared 
to placebo by the 
difference in 
proportions of 
responders where 
response is defined as 
an improvement from 
baseline of WI NRS ≥ 4 
at Week 12 without use 
of rescue therapies and 
without treatment 
discontinuation due to 
lack of efficacy or 
AE/death related to 
study drug
Summary measure: treatment difference of nemolizumab from placebo in 
proportions of responders
[1] Dosing schedules compared to placebo Q4W are an initial SC dose of nemolizumab (60 mg) at baseline then 
either 30 mg or 60 mg Q4W at Week 4 and Week 8.
Abbreviation(s): WI NRS = Worst Itch Numeric Rating Scale; Q4W = Every 4 Weeks
The estimand for the primary endpoint will be analyzed using the Cochran-Mantel-Haenszel 
(CMH) test stratified by analysis center; strata-adjusted difference in proportions between 
treatment groups and the 97.5% confidence interval of the difference will be based on the 
large sample approximation method for binary data.
19.3.2
Analysis of Secondary Efficacy Endpoints
19.3.2.1
Analysis of Key Secondary Efficacy Endpoints
The following key secondary efficacy endpoints will be analyzed using the Cochran-Mantel-
Haenszel (CMH) test stratified by analysis center; strata-adjusted difference in proportions 
between treatment groups and the 97.5% confidence interval of the difference will be based 
on the large sample approximation method for binary data.

Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at Week 12.

Proportion of subjects with an improvement of WI NRS ≥ 4 from baseline at Week 4.

Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at Week 12.
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
Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at Week 4.

Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at Week 4.
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19.3.4
Multiplicity Adjustment for Primary and Key Secondary Efficacy Endpoints
In order to maintain the overall two-sided alpha of 0.05, a two-sided alpha of 0.025 will be 
spent for the comparison of each Nemolizumab dose group versus placebo group. A 
predefined hierarchal testing procedure will be implemented to test the primary and key 
secondary endpoints of each nemolizumab dose group versus placebo group.
The following hypothesis test will be evaluated for the primary endpoint at the two-sided 
alpha of 0.025:
𝐻0:𝜋𝑁𝑒𝑚𝑜𝑙𝑖𝑧𝑢𝑚𝑎𝑏= 𝜋𝑃𝑙𝑎𝑐𝑒𝑏𝑜 
𝐻𝑎:𝜋𝑁𝑒𝑚𝑜𝑙𝑖𝑧𝑢𝑚𝑎𝑏≠𝜋𝑃𝑙𝑎𝑐𝑒𝑏𝑜
where pNemolizumab is the proportion of subjects in nemolizumab group with an improvement of 
WI NRS ≥ 4 from baseline at Week 12 and pPlacebo is the proportion of subjects in placebo 
group with an improvement of WI NRS ≥ 4 from baseline at Week 12.
The hypothesis tests for the key secondary efficacy endpoints are conditional on the success 
of the primary endpoint. The hypothesis tests for the key secondary efficacy endpoints will be 
evaluated on the ITT population according to the following predefined order, all at the same 
two-sided alpha of 0.025, moving to the next hypothesis test only after a success on the 
previous hypothesis test. This approach does not inflate the type I error rate as long as the 
hypothesis tests for the key secondary efficacy endpoints are conditional on the success of the 
primary, there is a prospective specification of the testing sequence and no further testing is 
performed once the sequence breaks, that is, further testing stops as soon as there is a failure 
of a hypothesis test in the sequence to show significance at the predefined alpha level.
Key Secondary Efficacy Endpoints:
1. Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at Week 12.
2. Proportion of subjects with an improvement of WI NRS ≥ 4 from baseline at Week 4.
3. Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at Week 12.
4. Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at Week 4.
5. Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at Week 4.
19.4
Safety Analysis
19.4.1
Extent of Exposure
The duration of exposure and the number of administrations per subject will be summarized 
by treatment group.
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19.4.2
Adverse Events
All reported AEs will be coded according to the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA). TEAEs, defined as those AEs occurring or 
worsening after the first administration of study treatment until last visit be tabulated in 
frequency tables by system organ class and preferred term. Additional summary tables will be 
provided for SAEs, AEs related to the study drug(s) (reasonable possibility, no reasonable 
possibility), AEs related to the study procedure, AESIs, and AEs leading to treatment 
discontinuation and study withdrawal. For a given AE, a subject will be counted once even if 
he/she has experienced multiple episodes of that particular AE.
Pre-treatment AEs will be listed separately.
19.4.3
Clinical Laboratory
Laboratory data (absolute values and change from baseline) will be summarized by visit and 
treatment group. In addition, the number and percentage of subjects below, within, and above 
the laboratory reference ranges and/or pre-defined threshold according to the Common 
Terminology Criteria for Adverse Events (CTCAE) and the number and percentage of 
subjects who met criteria of potential clinically significant value will be summarized by 
treatment group. Shift tables will be generated using the reference ranges. Reference ranges 
will be provided in the laboratory manual. Details of any potential clinically significant 
ranges will be provided in the SAP. 
19.4.4
Vital Signs
All vital signs and weight data (absolute values and change from baseline) will be 
summarized by visit and treatment group. In addition, the number and percent of subjects 
with clinically significant abnormal values (of clinical concern as identified by the 
investigator) will be summarized by treatment group.
19.4.5
12-Lead Electrocardiogram
The number and percentage of subjects who have ECGs that are normal, abnormal NCS and 
abnormal CS will be summarized by visit and treatment group. Heart Rate and PR, QRS, RR, 
QT, QTcB and QTcF intervals and their changes from baseline will be summarized by visit 
and treatment group.
19.4.6
Physical Examination
The number and percentage of subjects who are normal, abnormal CS, and abnormal not 
clinically significant (NCS) will be displayed by treatment at each visit.
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19.4.7
Respiratory Assessments
The results (absolute values and change from baseline) from PEF testing and respiratory 
exam will be summarized by visit and treatment group. ACT for subjects with a medical 
history of asthma will be listed.
19.4.8
Prior and Concomitant Medications
Prior and concomitant medications will be coded according to the most recent version of the 
World Health Organization (WHO) Drug Dictionary Enhanced for Concomitant Medication 
and summarized. Summary and analysis of rescue medications will be described in the SAP.
19.5
Pharmacokinetic and Anti-drug Antibody Analysis
Descriptive statistics (arithmetic and geometric mean, standard deviation [SD], coefficient of 
variation [CV%], median, first quartile, third quartile, minimum [min.], maximum [max.]) 
will be used to summarize the observed nemolizumab Ctrough in serum.
In addition, individual and mean serum concentration versus time curves will be presented for 
both linear and semi-log scales. Treatment related positive ADA subjects and positive ADA 
subject will be identified in the graphs.
Descriptive statistics (n, arithmetic mean, standard deviation, Coefficient of Variation (CV)%, 
geometric mean, minimum, median, maximum) will be calculated for all individual
 
derived parameters.
Incidence of positive ADA results will be summarized (absolute occurrence, percent of 
subjects, and treatment-related ADA). The ADA results presentation will be detailed in the 
SAP. 
19.6
Dose selection
Dose selection will be based on the final analysis by evaluating the optimal risk-benefit and 
considering the potential impact of body weight.
Safety assessment:
The IDMC will review and monitor subject safety throughout the study.  
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19.7
Handling of Missing Data
Missing data for dichotomous efficacy endpoints will be imputed using multiple imputations 
(MI) under missing at random (MAR) assumption for the primary/main analysis. 
Dichotomous endpoints will be calculated from the underlying imputed variable.
For the sensitivity analyses of the primary endpoint, missing data will be imputed using a 
copy reference (CR) approach under missing not at random (MNAR) assumption 
(dichotomous endpoints will be calculated from the underlying imputed variable) and as 
“Non-responder”; moreover a Tipping Point analysis under MNAR assumption will be 
carried out.
For the sensitivity analyses of the key secondary efficacy endpoints, missing data will be 
imputed using a CR approach under MNAR assumption (dichotomous endpoints will be 
calculated from the underlying imputed variable) and as “Non-responder”.
Missing data of continuous efficacy endpoints and QoL/Health Outcome endpoints will be 
imputed using MI under MAR assumption.
For the multiple imputation, the MI procedure of the SAS system will be used to generate sets 
of data with missing values imputed from observed data. It is expected that the pattern of 
missing data will be monotonic, with slight deviations being corrected by the Markov Chain 
Monte Carlo (MCMC) method of the MI procedure. A predictive mean matching method will 
be used for the continuous data with the following covariates included in the imputation 
model: non-missing data from earlier time points. Separate imputations by treatment group 
will be carried out. Changes and percent changes from baseline and dichotomous endpoints 
will be calculated from the imputed data.
Subjects who took rescue therapies as defined in Section 12.5.1.2 or discontinued treatment 
due to lack of efficacy or AE/death related to study drug will be considered as treatment 
failures, efficacy data collected after the use of rescue therapies or treatment discontinuation 
due to lack of efficacy or AE/death related to study drug will be set to the worst possible 
value and subject’s binary response will be imputed as ”Non-responder” prior to conducting 
the MI and Tipping Point analysis.
Further details will be provided in the SAP.
19.8
Analysis Centers
Prior to database lock, a review of the blinded data will be performed to determine the size of 
each center. If there are centers with a small number of randomized subjects, then these 
centers will be pooled in order for analyses to be carried out. The process of combining 
centers will be based on the ITT population, and same pooling will be repeated for mITT 
population and PP population.
A small center is defined as a center which randomizes less than 12 subjects. First, centers 
will be sorted by geographic region, number of randomized subjects (descending order) and 
center number (ascending order). Pooling will start with combining the largest of the set of 
small centers of a geographic region with the smallest center within the same geographic 
region. If there is a further need to combine data (the size of the pooled centers includes less 
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than 12 subjects), the next smallest center will be combined with the next largest of the small 
centers, until the criterion of a minimum of 12 subjects is met. The process will continue until 
all pooled centers have a minimum of 12 subjects within the same geographic region. Any 
remaining small centers of a geographic region will be pooled with the last pooled center 
within the same geographic region. The pooled centers and the remaining original unpooled 
clinical centers will be referred to as 'analysis centers' and will be used as stratification factor 
in the statistical analyses.
If at the start of pooling any geographic region has less than 12 subjects in the ITT population 
in total, then centers will be added to the list of small centers in another geographic region 
and then combined as above. This decision will be documented in clinical report.
19.9
Sensitivity and Supplementary Analysis for Primary and Key Secondary 
Efficacy Endpoints
For the sensitivity analyses of the primary endpoint, missing data will be imputed using a 
copy reference (CR) approach under missing not at random (MNAR) assumption 
(dichotomous endpoints will be calculated from the underlying imputed variable) and as 
“Non-responder”; moreover a Tipping Point analysis under MNAR assumption will be 
carried out. Furthermore, the analysis of the primary efficacy endpoint will be repeated using 
weekly averages of WI NRS with at least 3 daily scores over 7-day periods, at least 2 daily 
scores over 7-day periods and at least 1 daily scores over 7-day periods (no period extension 
at baseline and week 12 applies for these averages).
A mITT analysis, a PP analysis and an observed case analysis will be performed too as 
supplementary analyses for the primary efficacy endpoint. 
Sensitivity analyses will be performed by imputing missing data using a CR approach under 
MNAR assumption (dichotomous endpoints will be calculated from the underlying imputed 
variable) and as “Non-responder” for the following dichotomous secondary endpoints:

Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at Week 12.

Proportion of subjects with an improvement of WI NRS ≥ 4 from baseline at Week 4.

Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at Week 12.

Proportion of subjects with an improvement of WI NRS ≥ 3 from baseline at Week 4.

Proportion of subjects with an improvement of SD NRS ≥ 4 from baseline at Week 4.
Subjects who took rescue therapies as defined in Section 12.5.1.2 or discontinued treatment 
due to lack of efficacy or AE/death related to study drug will be considered as treatment 
failures, efficacy data collected after the use of rescue therapies or treatment discontinuation 
due to lack of efficacy or AE/death related to study drug will be set to the worst possible 
value and subject’s binary response will be imputed as “Non-responder” prior to conducting 
the MI and Tipping Point analysis.
Further details will be provided in the SAP.
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19.10
Impact of COVID-19
To assess the impact of COVID-19 related study disruptions (e.g. treatment discontinuation, 
missing assessments, etc.), the primary and key secondary efficacy endpoints will also be 
analyzed using multiple imputations (MI) under missing at random (MAR) assumption on the 
ITT population excluding subjects affected by COVID-19 related study disruptions.
Further details will be provided in the SAP.
19.11
Subgroup Analysis
Descriptive summary and analysis for primary and key secondary efficacy endpoints will be 
produced for the following subgroups: 

Age group (18 to 45; >45 to 65; >65 to 80; >80) 

Sex (Male, Female)

Race (White, Black, Asian, Other)

Region (US; Excl-US)

Severity of pruritus at baseline (5 to 7; >7 to 10)

Duration of pruritus at baseline (≤3 months; >3 to 12 months; >12 months)

Duration of hemodialysis at baseline (≤1 year; >1 year to 3 years; >3 years)

With or without prior or concomitant systemic anti-pruritus treatment
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STUDY MANAGEMENT
20.1
Approval and Consent
20.1.1
Regulatory Guidelines
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 
21 of the United States (US) Code of Federal Regulations (CFR), in compliance with 
International Council for Harmonisation (ICH) and Good Clinical Practice (GCP) guidelines, 
and according to the appropriate regulatory requirements in the countries where the study was 
conducted.
20.1.2
Institutional Review Board/Independent Ethics Committee
Conduct of the study must be approved by an appropriately constituted IRB/IEC. Approval is 
required for the study protocol, protocol amendments (if applicable), IB, ICFs, recruitment 
material and subject information sheets and other subject-facing material.
20.1.3
Informed Consent
For each study subject, written informed consent will be obtained before any protocol- related 
activities. As part of this procedure, the principal investigator or designee must explain orally 
and in writing the nature of the study, its purpose, procedures, expected duration, alternative 
therapy available, and the benefits and risks involved in study participation. The subject 
should be informed that he/she may withdraw from the study at any time, and the subject will 
receive all information that is required by local regulations and guidelines for ICH. The 
principal investigator will provide the sponsor or its representative with a copy of the 
IRB/IEC approved ICF before the start of the study.
20.2
Data Management
The designated CRO will be responsible for activities associated with the data management 
of this study. This will include, but is not limited to, setting up a relevant database and data 
transfer mechanisms, along with appropriate validation of data and resolution of queries. All 
data management activities will be detailed in the data management plan.
Study centers will enter data directly into an electronic data capture (EDC) system by 
completing the eCRF via a secure internet connection. Data entered into the eCRF must be 
verifiable against source documents at the study center. Data to be recorded directly on the 
eCRF will be identified and the eCRF will be considered the source document. Any changes 
to the data entered into the EDC system will be recorded in the audit trail.
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20.3
Source Documents
Source documents are considered to be all information in original records and certified copies 
of original records of clinical findings, observations, data, or other activities in a clinical 
study necessary for the reconstruction and evaluation of the study. The investigator will 
provide direct access to source documents and/or source data in the facilitation of trial-related 
monitoring, audits, review by IECs/IRBs, and regulatory inspections.
The investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial subjects.
Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, not obscure the original entry, and be 
explained if necessary.
Sponsor monitors, auditors, and regulatory inspectors should have direct access to source 
data.
20.4
Record Retention
Study records and source documents must be preserved for at least 25 years after the 
completion or discontinuation of/withdrawal from the study, at least two years after the drug 
being studied has received its last approval for sale, or at least two years after the drug 
development has stopped, and in accordance with the applicable local privacy laws, 
whichever is the longer period.
20.5
Monitoring
The study will be monitored according to the monitoring plan to ensure that it is conducted 
and documented properly according to the protocol, GCP, and all applicable regulatory 
requirements.
Monitoring visits and contacts will be made at appropriate times during the study. The 
principal investigator will assure he/she and adequate site personnel are available throughout 
the study to collaborate with clinical monitors. Clinical monitors must have direct access to 
source documentation in order to check the completeness, clarity, and consistency of the data 
recorded in the eCRFs for each subject.
The investigator will make available to the clinical monitor all source documents and medical 
records necessary to review protocol adherence and eCRFs. In addition, the investigator will 
work closely with the clinical monitor and, as needed, provide them appropriate evidence that 
the study is being conducted in accordance with the protocol, applicable regulations, and 
GCP guidelines.
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20.6
Quality Control and Quality Assurance
The sponsor or its designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, security, and reliability of 
the study data presented to the sponsor lies with the investigator generating the data.
The sponsor will arrange audits as part of the implementation of quality assurance to ensure 
that the study is being conducted in compliance with the protocol, standard operating 
procedures, GCP, and all applicable regulatory requirements. Audits will be independent of 
and separate from the routine monitoring and quality control functions. Quality assurance 
procedures will be performed at study sites and during data management to assure that safety 
and efficacy data are adequate and well documented.
20.7
Protocol Amendment and Protocol Deviation
20.7.1
Protocol Amendment
Amendments to the protocol that entail corrections of typographical errors, clarifications of 
confusing wording, changes in study personnel, and minor modifications that have no effect 
on the safety of subjects or the conduct of the study will be classed as administrative 
amendments and will be submitted to the IEC/IRB for information only. The sponsor will 
ensure that acknowledgment is received and filed. Amendments that are classed as substantial 
amendments must be submitted to the appropriate regulatory authorities and the IECs/IRBs 
for approval and will not be implemented at sites until such approvals are received other than 
in the case of an urgent safety measure.
20.7.2
Protocol Deviations
Should a protocol deviation occur, the sponsor must be informed as soon as possible. 
Protocol deviations and/or violations and the reasons they occurred will be included in the 
clinical study report. Protocol deviations will be reported to the IRB/IEC and in accordance 
with applicable regulatory authority mandates.
Changes that involve only logistical or administrative changes to the clinical study protocol 
are authorized. The investigator should document and explain any deviation from the clinical 
study protocol. Major deviations are categorized into the following categories:

Eligibility deviations (inclusion/exclusion criteria).

Improper reconstitution and administration of study medication.

Non-compliance with study medication per the investigator’s discretion.

Non-compliance with study procedures if the consequence of non-compliance would 
compromise either the subject’s safety and/or the study integrity, primary endpoint, 
and/or is not in line with GCP/ICH guidelines.

Use of prohibited concomitant therapies.
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All protocol deviations will be identified, evaluated, and closed before the respective 
database lock and will be described in the clinical study report. Protocol deviations incurred 
as a direct result of the COVID-19 pandemic should be specifically recorded as a COVID-19 
deviation. Further details of protocol deviations will be provided in the Protocol Deviation 
and Non-Compliance Management Plan.
20.8
Ethical Considerations
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 
312, Subpart D, of Title 21 of the CFR; EU 536/2014, Annex 1, D, 17 (a); and in compliance 
with GCP guidelines.
IECs/IRBs will review and approve this protocol and the ICF. All subjects are required to 
give written informed consent before participation in the study.
20.9
Financing and Insurance
Before the study commences, the sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This agreement 
will be documented in a financial agreement that will be signed by the investigator (or the 
institution signatory) and the sponsor (or its designee).
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice. The sponsor will provide no-exclusion insurance coverage for the clinical 
study as required by national regulations.
20.10
Publication Policy/Disclosure of Data
Both the use of data and the publication policy are detailed within the clinical study 
agreement. Intellectual property rights (and related matters) generated by the investigator and 
others performing the clinical study will be subject to the terms of a clinical study agreement 
that will be agreed between the institution and the sponsor or their designee.
With respect to such rights, the sponsor or its designee will solely own all rights and interests 
in any materials, data, and intellectual property rights developed by investigators and others 
performing the clinical study described in this protocol, subject to the terms of any such 
agreement. In order to facilitate such ownership, investigators will be required to assign all 
such inventions either to their institution or directly to the sponsor or its designee, as will be 
set forth in the clinical study agreement.
20.11
Subject Confidentiality
Monitors, auditors, and other authorized agents of the sponsor and/or its designee, the IEC(s) 
approving this research, as well as that of any other applicable agency(ies), will be granted 
direct access to the study subjects’ original medical records for verification of clinical study 
procedures and/or data, without violating the confidentiality of the subjects to the extent 
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permitted by the law and regulations. In any presentations of the results of this study or in 
publications, the subjects’ identities will remain confidential.
All personal data collected and processed for the purposes of this study should be managed 
by the investigator and his/her staff with adequate precautions to ensure confidentiality of 
those data, and in accordance with the applicable national and/or local laws and regulations 
on personal data protection.
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bothered                                                                     bothered
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