Conditions: Chronic Kidney Disease Associated Moderate to Severe Pruritus
Keywords: Chronic Kidney Disease Moderate to Severe Pruritus Nemolizumab CD14152
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 258
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy of nemolizumab compared to placebo at reducing the intensity of pruritus after a 12-week treatment period in adult hemodialysis participants with moderate to severe pruritus.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: Nemolizumab intervention 2: Nemolizumab intervention 3: Placebo
Intervention descriptions: intervention 1: Participants received a loading dose of 60 mg nemolizumab at Baseline followed by 2 Subcutaneous (SC) injections for a total dose of 30 mg nemolizumab once every 4 weeks i.e. at Week 4 and Week 8. intervention 2: Participants received 2 SC injections of 30 mg nemolizumab once every 4 weeks i.e. at Week 4 and Week 8. intervention 3: Participants received 2 SC injections of 30 mg placebo-matched to nemolizumab once every 4 weeks i.e. at Week 4 and Week 8.

Protocol document:
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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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5
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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.
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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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20
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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21
REFERENCES
Arai I, Tsuji M, Takeda H, Akiyama N, Saito S. A single dose of interleukin-31 (IL-31) 
causes continuous itch-associated scratching behavior in mice. Exp Dermatol 2013;22:669–
71.
Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. Edition Number 9. Little, Brown & 
Co; Boston, Mass: 1994. pp. 253–6.
Desai N, Poindexter G, Monthrope Y, Bendeck S, Swerlick R, Chen Suephy. A pilot quality-
of-life instrument for pruritus. J Am Acad Dermatol. 2008 Aug;59(2):234-44.
Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, et 
al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat 
Immunol 2004;5:752-60.
Fishbane S, Mathur V, Germain M, Shirazian S, Bhaduri S, Munera C, et al. Randomized 
controlled trial of difelikefalin for chronic pruritus in hemodialysis patients. Kidney Int Rep. 
2020 Jan 28;5(5):600-610.
Kfoury LW, Jurdi MA. Uremic pruritus. J Nephrol 2012;25(5):644-52.
Kimata N, Fuller DS, Saito A, Akizawa T, Fukuhara S, Pisoni RL, et al. Pruritus in 
hemodialysis patients: Results from the Japanese Dialysis Outcomes and Practice Patterns 
Study (JDOPPS). Hemodial Int 2014;18:657-67.
Kinugasa E, Igawa K, Shimada H, Kondo M, Funakoshi S, Imada N et al. Anti-pruritic effect 
of nemolizumab in hemodialysis patients with uremic pruritus: a phase II, randomized, 
double-blind, placebo-controlled clinical study. Clin Exp Nephrol 2021 Mar 22. 
Ko MJ, Peng YS, Chen HY, Hsu SP, Pai MF, Yang JY, et al. Interleukin-31 is associated 
with uremic pruritus in patients receiving hemodialysis. J Am Acad Dermatol 2014;71:
1151-9.
Kumagai H, Ebata T, Takamori K, Miyasato K, Muramastu T, Nakamoto H, et al. Efficacy 
and safety of a novel kappa-agonist for managing intractable pruritus in dialysis patients. Am 
J Nephrol 2012;36:175-83.
Mathur V, Lindberg J, Germain M, Block G, Tumlin J, Smith M, et al. A longitudinal study 
of uremic pruritis in hemodialysis patients. Clin J Am Soc Nephrol. 2010 Aug;5(8):1410-9.
Narita I, Alchi B, Omori K, Sato F, Ajiro J, Saga D, et al. Etiology and prognostic 
significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int 
2006;69:1626-32.
Nemoto O, Furue M, Nakagawa H, et al. The first trial of CIM331, a humanized antihuman 
interleukin-31 receptor A antibody, in healthy volunteers and patients with atopic dermatitis 
to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomized, double-
blind, placebo-controlled study. Br J Dermatol. 2016;174(2):296-304.
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Omori K, Aoike I, Aoyagi H, Aoyagi R, Imai K, Iwafuch Y, et al. Risk factors for uremic 
pruritus in long-term hemodialysis patients. J Jpn Soc Dial Ther 2001;34:1469-77.
Pisoni RL, Wikström B, Elder SJ, Akizawa T, Asano Y, Keen ML, et al. Pruritus in 
haemodialysis patients: international results from the Dialysis Outcomes and Practice 
Patterns Study (DOPPS). Nephrol Dial Transplant 2006;21:3495-505.
Polgar G, Weng TR. The functional development of the respiratory system from the period of 
gestation to adulthood. Am Rev Respir Dis. 1979;120(3):625-695.
Quanjer PH, Tammeling GJ, Cotes JE, et al. Lung volumes and forced ventilatory flows. Eur 
Respir J. 1993;6 Suppl 16:5-40.
Rayner H , Larkina M, Wang M, Graham-Brown M, van der Veer S, Ecder T, et al. 
International comparisons of prevalence, awareness, and treatment of pruritus in people on 
hemodialysis. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2000-2007. 
Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto H, Kemeny L, et al. IL-31: A new link 
between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol 
2006;117:411-17.
Yamada S, Sakurai H, Kasuga H, Kawahara H. Investigation of the status of uremic pruritus 
in hemodialysis patients and the efficacy of nalfurafine hydrochloride – Questionnaire 
administered to 1,936 patients from 17 clinics in Tokai area of Japan- J Jpn Soc Dial Ther 
2012;45:1133-40.
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 
1983;67(6):361-370.
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bothered                                                                     bothered
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SAP_001.pdf: 
Galderma S.A. 
RD.06.SPR.204358
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
19FEB2024
Final Statistical Analysis Plan
Version 1.0
Prepared by: PPD
PPD


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Galderma Approval and Acknowledgement Signatures
Galderma Study Biostatistician (for approval and acknowledgement) 
PPD
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Final Statistical Analysis Plan, Version 1.0
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Document History - Changes compared to previous versions of SAP
 
CCI


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Table of Contents
Galderma Approval and Acknowledgement Signatures
2 
 
Document History - Changes compared to previous versions of SAP 
3 
List of Abbreviations 
8 
1 
Introduction
11 
2 
Objectives
11 
3 
Investigational Plan 
12 
3.1 
Overall Study Design and Plan 
12 
3.2 
Study Endpoints 
14 
3.2.1 
Primary Efficacy Endpoint 
14 
3.2.2 
Secondary Efficacy Endpoints 
14 
 
 
 
 
 
 
3.2.5 
Safety Endpoints 
15 
3.2.6 
Other Safety Measurements
15 
3.3 
Treatments
16 
4 
General Statistical Considerations
16 
4.1 
Date Imputations
18 
4.2 
Sample Size
20 
4.3 
Randomization, Stratification, and Blinding 
20 
4.4 
Multiplicity Adjustment for Primary and Key Secondary Efficacy 
Endpoints 
20 
4.5 
Analysis Centers
21 
4.6 
Adjustments for Covariates 
22 
4.7 
Handling of Missing Data 
22 
4.8 
Use of an Efficacy Subset of Subjects 
24 
4.9 
Examination of Subgroups 
24 
4.10 
Analysis Visit Windows
25 
4.11 
Analysis Sets
27 
4.11.1 
Intent-to-treat (ITT) Set
27 
4.11.2 
Modified Intent-to-Treat (mITT) Set
27 
4.11.3 
Per Protocol (PP) Set
28 
PPD
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4.11.4 
Safety Set
28 
 
 
5 
Estimands
28 
6 
Subject Disposition
32 
6.1 
Disposition
32 
6.2 
Protocol Deviations 
33 
7 
Demographics and Baseline Characteristics
34 
7.1 
Demographics 
34 
7.2 
Baseline Disease Characteristics
34 
7.3 
Alcohol and Tobacco Usage 
35 
7.4 
Childbearing Potential Status, Methods of Contraception and Reproductive 
Status
35 
7.5 
Medical History
35 
8 
Treatments and Medications
36 
8.1 
Prior and Concomitant Medications 
36 
8.2 
Prior and Concomitant Medical and Surgical Procedures
36 
8.3 
Rescue Therapies
37 
8.4 
Study Treatments 
38 
8.4.1 
Extent of Exposure 
38 
8.4.2 
Treatment Compliance and Modifications
39 
9 
Efficacy Analysis 
39 
9.1 
Analysis of Primary Efficacy Endpoint 
40 
9.1.1 
Primary Analysis of the Primary Efficacy Endpoint (Estimand 1) 
40 
9.1.2 
Sensitivity and Supplementary Analyses of the Primary Efficacy Endpoint 
(Estimand 1) 
41 
9.1.3 
Impact of COVID-19 on the Primary Efficacy Endpoint (Estimand 1) 
42 
9.1.4 
Subgroup Analysis for Primary Efficacy Endpoint (Estimand 1) 
43 
9.2 
Analysis of the Key Secondary Efficacy Endpoints 
43 
9.2.1 
Main Analysis of Key Secondary Efficacy Endpoints 
 
43 
9.2.2 
Sensitivity Analysis of Key Secondary Efficacy Endpoints 
43 
9.2.3 
Impact of COVID-19 on the Key Secondary Efficacy Endpoints 
 
 
44 
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9.2.4 
Subgroup Analysis of the Key Secondary Efficacy Endpoints 
 
44 
 
 
 
 
 
 
 
 
11 
Immunogenicity Analyses 
48 
12 
Safety Analysis 
48 
12.1 
Adverse Events
48 
12.1.1 
Incidence of Adverse Events
49 
12.1.2 
Relationship of Adverse Events to Study Drug and/or Study Procedures 51 
12.1.3 
Severity of Adverse Event 
52 
12.2 
Clinical Laboratory Evaluations 
52 
12.3 
Pregnancy Testing 
54 
12.4 
Virology 
55 
12.5 
Tuberculosis (TB) Testing 
55 
12.6 
Vital Sign Measurements
55 
12.7 
Physical Examination
55 
12.8 
Electrocardiogram
56 
12.9 
Respiratory Assessments
56 
13 
Independent Data Monitoring Committee
57 
14 
Interim Analysis
57 
15 
Dose Selection
57 
16 
Changes from the Protocol Analysis Plan 
58 
17 
General Features of Tables, Listings and Figures
58 
18 
References
59 
19 
Appendices
60 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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19.6 
Appendix F: List of Tables, Figures and Listings 
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List of Abbreviations 
ACT
Asthma control test
AD
Atopic dermatitis
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic chemical
 
AVF
Arteriovenous fistula
AVG
Arteriovenous graft
CI
Confidence interval
CKD
Chronic kidney disease
CKD-aP
Chronic kidney disease with associated pruritus
Cl/F
Apparent total body clearance
CMH
Cochran-Mantel-Haenszel test
COVID-19
Coronavirus disease 2019
CPK
Creatinine phosphokinase
EASI
Eczema Area and Severity Index
ECG
Electrocardiogram
ECLIA
Electro-chemi-luminescence immunoassay
eCRF
Electronic Case Report Form
eDISH
Evaluation of drug-induced serious hepatotoxicity
ESKD
End-stage kidney disease
HBcAb
Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
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HDL
High-density lipoprotein
HIV
Human immunodeficiency virus
IAC
Independent adjudication committee
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
IDMC
Independent data monitoring committee
IGA 
Investigator’s global assessment
IRT
Interactive response technology
ITT
Intent-to-treat
IUG
Independent Unblinded Group
 
 
LDL
Low-density lipoprotein
LS
Least-Squares
MAR
Missing at random
MCMC
Markov Chain Monte Carlo
MedDRA
Medical dictionary for regulatory activities
MI
Multiple imputation
mITT
Modified intent-to-treat
MNAR
Missing not at random
NRS
Numeric rating scale
OC
Observed cases
PCR
Polymerase chain reaction
PEF 
Peak expiratory flow
PN
Prurigo nodularis
PP
Per Protocol
PT
Preferred term
PTAE
Pre-treatment adverse events
Q1
First quartile
Q3
Third quartile
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QoL
Quality of life
RA
Receptor A
RSE
Relative standard error
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SD
Standard deviation
SD NRS
Sleep disturbance numeric rating scale
SOC
System organ class
SOP
Standard operating procedure
TB
Tuberculosis
TCS
Topical corticosteroid
TEAE
Treatment-emergent adverse events
TLFs
Tables, Listings and Figures
WI NRS
Worst itch numeric rating scale
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1
Introduction
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 
disturbance1. Recently, an international comparison on the prevalence of pruritus in 
hemodialysis patients found that 68% of survey respondents reported they were at least 
somewhat bothered by itchy skin. Of the patients that were very much or extremely 
bothered by itchy skin, 84% were also bothered by dry skin and 60% had sleep 
restlessness2. Despite a prevalence rate and a clear association with poorer psychological 
and medical outcomes including higher mortality risk3, this condition is often 
underreported by patients and overlooked by health care providers2. 
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.
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. 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 topical 
corticosteroid (TCS). 
The purpose of this Statistical Analysis Plan (SAP) is to describe the analyses and data 
presentations used in determining the efficacy and safety of nemolizumab in the 
treatment of moderate to severe pruritus in adult CKD subjects undergoing hemodialysis.
This SAP outlines the types of analyses that will address the study objectives and 
explains in detail how the data will be handled and analyzed. It contains the definitions 
of analysis sets and statistical methods for the analysis of endpoints.  
This statistical analysis plan was written in accordance with ICH E9, ICH E9 (R1) and 
 (SOPs) and 
using the study protocol version 6.0 dated 21st September 2023. 
2
Objectives
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.
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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.
3
Investigational Plan 
3.1
Overall Study Design and Plan
This is a randomized, double-blind, placebo-controlled, multicenter, parallel-group study 
to evaluate the efficacy and safety of nemolizumab in adult subjects with moderate to 
severe 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 the last study drug injection). The 
screening period will evaluate subject eligibility. At the baseline visit, subjects will 
receive an initial dose of nemolizumab 60 mg or placebo by two subcutaneous (SC) 
injections (30 mg + 30 mg, or placebo + placebo). 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) at Week 4 and Week 8 after completion of hemodialysis treatment 
(within four hours).
 are to be taken before hemodialysis. Figure 1 below 
presents the study design:  
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3.2
Study Endpoints
3.2.1
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects with an improvement of 
Worst Itch Numeric Rating Scale (WI NRS)
without use 
of rescue therapies and without treatment discontinuation due to lack of efficacy or 
AE/death related to study drug. Subjects who took rescue therapies or discontinued 
treatment due to lack of efficacy or AE/death related to study drug will be considered 
treatment failures (see Table 6 for full details of the primary estimand). Note that this 
combines the outcome with intercurrent events by defining a binary composite response.
3.2.2
Secondary Efficacy Endpoints
The key secondary efficacy endpoints are defined as follows: 
1.
12.
2.
4.
3. Proportion of subjects with an improvement of Sleep Disturbance Numeric Rating 
Scale (SD NRS) 
4.
4.
5.
4.
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3.2.6
Other Safety Measurements
Other safety measurements are as follows:
1. Physical examination and vital signs. 
2. Clinical laboratory tests.
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3. Electrocardiogram (ECG) results.
4. Respiratory examination and assessments. 
3.3
Treatments
This study has three treatment arms at a ratio of 1:1:1. 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 Week 4 and at 
Week 8. All the study drug treatment should be performed following the completion of 
the hemodialysis treatment (within four hours). Table 1 below summarizes the study drug 
dosing during the treatment period of the study. 
Table 1 
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.
4
General Statistical Considerations
All summaries and results in Tables, Listings and Figures (TLFs) should be presented 
for the following groups:  
Table 2 
Treatment Group Labels in TLFs
Treatment Groups
Label in TLFs
60 mg loading dose of nemolizumab by two SC injections of 30 mg at 
Baseline, followed by one SC injection of 30 mg of nemolizumab + one 
SC injection of placebo at Week 4 and at Week 8
Nemolizumab 30 mg
Two SC injections of 30 mg of Nemolizumab at Baseline, at Week 4 and 
at Week 8
Nemolizumab 60 mg
Two SC injections of placebo at Baseline, at Week 4 and at Week 8
Placebo
Nemolizumab 30 mg, Nemolizumab 60 mg, and Placebo treatment groups 
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The reference date for the calculation of study days will be the date of the first treatment 
injection on Day 1/Baseline for subjects randomized and treated or the date of 
randomization for subjects randomized but not treated (if any). 
For events/assessments on or after the reference date, the study day of events/assessments
is calculated as the date of event minus the reference date + 1. For events/assessments 
before the reference date, the study day of the events/assessments is calculated as the 
date of assessment minus the reference date. 
Baseline is defined as the last non-missing measurement prior to the first treatment 
injection at Day 1/Baseline for subjects randomized and treated or prior to the 
randomization for subjects randomized but not treated (if any). Change from baseline 
and percent change from baseline are defined as follows:
Change from Baseline = PostBaseline
Baseline
Percent Change from Baseline = Baseline
0
100 PostBaseline
Baseline
Baseline
Baseline = 0
Missing                                          
All by-visit summaries and analyses will use the analysis visit (see section 4.10). 
Continuous data will be summarized using the following descriptive statistics: number 
of subjects (n), mean, standard deviation (SD), median, first and third quartiles (Q1 and 
Q3), minimum and maximum. Categorical data will be summarized using the frequency 
count (n) and percentage (%) of subjects for each category. For the summary statistics of 
all numerical variables unless otherwise specified, minimum and maximum will be 
displayed to the same level of precision as reported. Mean, median, Q1 and Q3 will be 
displayed to one level of precision greater than the data collected. Standard deviation will 
be displayed to two levels of precision greater than the data collected.  
P-values will be displayed in the following format, 0.9999. Any p-value less than 0.0001
will be displayed as <0.0001. Any p-value greater than 0.9999 will be displayed as 
>0.9999. 
The following flagging conventions will be applied for the p-values of all statistical 
testing:
0.01  p-values < 0.025 will be flagged with one asterisk (e.g. “0.0249 *”). 
0.001  p-value < 0.01 will be flagged with two asterisks (e.g. “0.0099 **”). 
0.0001  p-value < 0.001 will be flagged with three asterisks (e.g. “0.0009 ***”). 
p-value < 0.0001 will be flagged with four asterisks (e.g. “<0.0001 ****”). 
When count data are presented, the percentage will be suppressed when the count is zero 
in order to draw attention to the non-zero counts. The denominator for all percentages 
will be the number of subjects in that treatment within the analysis set of interest, unless 
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All proportions will be presented as percentages (not as fraction of unit). 
Any imputed data will be used in analysis tables and figures (as applicable) and the 
original collected data will be used in summary tables and figures and displayed in 
listings. 
Unless specified otherwise, all the summary tables will be presented overall and by 
treatment, and all the collected data will be presented in the listings. Data displayed in 
the listings will be sorted by treatment and subject identifier.  
All analyses will be conducted using SAS Version 9.4 or higher. 
4.1
Date Imputations
For the purpose of inclusion in prior and/or concomitant medication/procedure and AE 
tables, incomplete AEs and medications/procedures start and end dates will be imputed 
as follows: 
Start Date Imputation of Adverse Events: 
Imputation of adverse event end date has to be done before imputation of event 
start date.
Completely missing: For subjects treated, impute to the date of first treatment 
injection. For subject randomized but not treated, impute to the date of 
randomization. For subjects not randomized, impute to the date of informed 
consent. 
Missing day and month: For subjects treated, impute to January 1st, unless year is 
the same as year of first treatment injection then impute to the date of first 
treatment injection. For subject randomized but not treated, impute to January 1st,
unless year is the same as year of randomization then impute to the date of 
randomization. For subjects not randomized, impute to January 1st, unless year is 
the same as year of informed consent then impute to the informed consent date. 
Missing day: For subjects treated, impute to the 1st of the month, unless month 
and year are the same as month and year of first treatment injection then impute 
to the date of first treatment injection. For subject randomized but not treated, 
impute to the 1st of the month, unless month and year are the same as month and 
year of randomization then impute to the date of randomization. For subjects not 
randomized, impute to the 1st of the month, unless month and year are the same 
as month and year of informed consent then impute to the informed consent date.
If event end date (imputed or not) is not missing and imputed event start date is 
after event end date (imputed or not), set the event start date to the event end date
(imputed or not). 
Start Date Imputation of Prior/Concomitant Therapies and Medical/Surgical 
Procedures:
Imputation of therapy/procedure end date has to be done before imputation of 
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Completely missing: For subjects treated, impute to the date of first treatment 
injection. For subject randomized but not treated, impute to the date of 
randomization. For subjects not randomized, impute to the date of informed 
consent. 
Missing day and month: For subjects treated, impute to January 1st, unless year is 
the same as year of first treatment injection then impute to the date of first 
treatment injection. For subject randomized but not treated, impute to January 1st,
unless year is the same as year of randomization then impute to the date of 
randomization. For subjects not randomized, impute to January 1st, unless year is 
the same as year of informed consent then impute to the informed consent date. 
Missing day: For subjects treated, impute to the 1st of the month, unless month 
and year are the same as month and year of first treatment injection then impute 
to the date of first treatment injection. For subject randomized but not treated, 
impute to the 1st of the month, unless month and year are the same as month and 
year of randomization then impute to the date of randomization. For subjects not 
randomized, impute to the 1st of the month, unless month and year are the same 
as month and year of informed consent then impute to the informed consent date.
If therapy/procedure end date (imputed or not) is not missing and imputed 
therapy/procedure start date is after therapy/procedure end date (imputed or not), 
set the therapy/procedure start date to the therapy/procedure end date (imputed or 
not). 
Stop Date Imputation of Adverse Events, Prior/Concomitant Therapies and 
Medical/Surgical Procedures:
Completely missing and with outcome ‘Not Recovered/Not Resolved’ or 
‘Unknown’ (Adverse Events): Leave it missing.
Completely missing and flagged as being ongoing (Prior/Concomitant Therapies 
and Medical/Surgical Procedures): Leave it missing.
Completely missing and with an outcome different from ‘Not Recovered/Not 
Resolved’ and ‘Unknown’ (Adverse Events): Impute to the date of end of 
participation.
Completely missing and not flagged as being ongoing (Prior/Concomitant 
Therapies and Medical/Surgical Procedures, Medical History Diseases): Impute 
to the date of end of participation. 
Missing day and month: Impute to December 31st, unless year is the same as date 
of end of participation then impute to the date of end of participation. 
Missing day: Impute to the last day of the month, unless year and month are the 
same as year and month of date of end of participation then impute to the date 
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4.2
Sample Size
The sample size calculation is planned to enroll 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.  
Eighty-four (84) 
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. 
4.3
Randomization, Stratification, and Blinding 
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.  
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; 
Group 3: Placebo Q4W. 
Randomization will be stratified by clinical site.
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.
4.4
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: 


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:
=
 
:
where 
Nemolizumab is the proportion of subjects in nemolizumab group with an 
Placebo is the proportion of 
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 Set 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.
12.
2.
4.
3.
4 from baseline at Week 
12.
4.
4.
5. Proportion of 
4.
4.5
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 Set, and same pooling will be repeated for
the mITT Set and the PP Set.
A small center is defined as a center which randomizes less than 15 subjects. First, centers 
will be sorted by geographic region, country, 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 country with the smallest center 
within the same country (if applicable) or within the same geographic region. If there is 
a further need to combine data (the size of the pooled centers includes less than 15


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subjects), the next smallest center will be combined with the next largest of the small 
centers, until the criterion of a minimum of 15 subjects is met. The process will continue 
until all pooled centers have a minimum of 15 subjects within the same geographic 
region. Any remaining small centers of a country/geographic region will be pooled with 
the last pooled center within the same country/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 15 subjects in the ITT Set 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 Study Report.
4.6
Adjustments for Covariates
4.7
Handling of Missing Data
Missing data of the following dichotomous efficacy endpoints: 
Proportion of subjects with an improvement of WI NRS
4 from baseline at Week 
12
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
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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
Proportion of subjects with an improvement of WI NRS 
4 from baseline at Week 
1
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 (i.e., weekly averages of WI NRS and SD NRS, as 
applicable). 
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 (see Appendix C for details about Multiple Imputation and Tipping Point 
analysis).
Multiple imputation will be based on data collected up to Week 12. A further sensitivity 
analysis based on MI using all data collected up to Week 20 may be performed. 
Similarly, sensitivity analyses will be performed by imputing missing data using a CR 
approach under MNAR assumption and as “Non-responder” for the key secondary 
efficacy endpoints based on WI NRS and SD NRS. 
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 in the endpoints 
defined for Estimands 1 to 6 (see section 5). The values of the variable of interest 
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. 
Missing data of the following dichotomous efficacy endpoint: 
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will be imputed using MI under MAR assumption for the main analysis; changes and 
percent changes from baseline will be calculated from the imputed variables (i.e. 
questionnaires’ scores and weekly averages of WI NRS and 
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. The values of the variable of interest 
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 prior to 
conducting the MI. See Appendix C for details of the multiple imputation process.
4.8
Use of an Efficacy Subset of Subjects
The classification of the protocol deviations and the exclusion of subjects from the Per 
Protocol (PP) Set will be determined prior to breaking the study blind (see section 6.2).
The analysis on the PP Set will allow evaluating the impact of major protocol deviations 
on the estimation of the treatment effect.
4.9
Examination of Subgroups 
Descriptive summaries and analyses 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 group (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)
Subjects with or without prior or concomitant systemic anti-pruritus treatment
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Clinical laboratory tests: the latest assessment will be used for the summaries and 
analyses. 
Analysis visits of ePRO data will be defined depending on the data collection as below. 
For the evening assessments of WI NRS, the daily data collected up to Week 20 will be 
classified into analysis visits considering the data during the 7 days immediately 
preceding the target study day of analysis visit. Similarly, for the morning assessment of 
WI NRS (if the WI NRS assessment in the evening is missed, the subjects are allowed to 
complete the assessment the following morning) and SD NRS, the 7 days data up to the 
target study day will be classified into analysis visit. Details of the analysis visit window
of ePRO data are in the table below. 
Table 4 
Analysis Visit Windows for calculation of Weekly Average of WI NRS 
and SD NRS
Analysis
Visit
Target
Study
Day
Analysis Windows for 
WI NRS Evening 
Assessments
Analysis Windows for 
WI NRS Following 
Morning Assessments *
Analysis Windows for 
SD NRS Morning 
Assessments
Baseline a
1 
-7 to -1 
-6 to 1 before dosing
-6 to 1 before dosing
Week 1
8 
1 to 7
2 to 8
2 to 8
Week 2
15
8 to 14
9 to 15
9 to 15
Week 3
22
15 to 21
16 to 22
16 to 22
Week 4
29
22 to 28
23 to 29
23 to 29
Week 5
36
29 to 35
30 to 36
30 to 36
Week 6
43
36 to 42
37 to 43
37 to 43
Week 7
50
43 to 49
44 to 50
44 to 50
Week 8
57
50 to 56
51 to 57
51 to 57
Week 9
64
57 to 63
58 to 64
58 to 64
Week 10
71
64 to 70
65 to 71
65 to 71
Week 11
78
71 to 77
72 to 78
72 to 78
Week 12 b
85
78 to 84
79 to 85
79 to 85
Week 13
92
85 to 91
86 to 92
86 to 92
Week 14
99
92 to 98
93 to 99
93 to 99
Week 15
106
99 to 105
100 to 106
100 to 106
Week 16
113
106 to 112
107 to 113
107 to 113
Week 17
120
113 to 119
114 to 120
114 to 120
Week 18
127
120 to 126
121 to 127
121 to 127
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Analysis
Visit
Target
Study
Day
Analysis Windows for 
WI NRS Evening 
Assessments
Analysis Windows for 
WI NRS Following 
Morning Assessments *
Analysis Windows for 
SD NRS Morning 
Assessments
Week 19
134
127 to 133
128 to 134
128 to 134
Week 20
141
134 to 140
135 to 141
135 to 141
*: If the WI NRS assessment in the evening is missed, the subjects are allowed to complete the assessment 
the following morning. 
a: 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.
b: 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.
4.11 Analysis Sets 
A summary of the analysis sets including the number and percentage of subjects for the 
following categories: subjects in the ITT Set, subjects in the mITT Set, subjects in the 
PP Set, subjects in the Safety Set, and subjects in the 
will be presented. All 
percentages will be based on the number of subjects randomized. A corresponding listing 
will be displayed. 
4.11.1 Intent-to-treat (ITT) Set
The Intent-to-treat (ITT) Set consist of all randomized subjects. The ITT Set will be the 
primary set for all efficacy analysis. Subjects will be summarized and analyzed according 
to their randomized treatment group. 
4.11.2 Modified Intent-to-Treat (mITT) Set
The Modified Intent-to-treat (mITT) Set 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. The mITT Set will be used for the supplementary analysis of the primary 
endpoint. Subjects will be summarized and analyzed according to their randomized 
treatment group. 
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4.11.3 Per Protocol (PP) Set
The Per Protocol (PP) Set 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. The PP Set will be used for the 
supplementary analysis of the primary endpoint. Subjects will be summarized and 
analyzed according to their randomized treatment group. 
4.11.4 Safety Set
The Safety Set includes all randomized subjects who receive at least one dose of study 
drug. All safety data will be summarized based on the Safety Set. Subjects will be
summarized according to their actual treatment group.
5
Estimands
The estimands for primary and key secondary endpoints provide precise descriptions of 
the treatment effect reflecting the clinical questions posed by the trial objectives. They 
summarize at a population level what the outcomes would be in the same patients under 
different treatment conditions being compared. 
The intercurrent events are events occurring after treatment initiation that affect either 
the interpretation or the existence of the measurements associated with the clinical 
question of interest. It is necessary to address intercurrent events when describing the 
clinical question of interest in order to precisely define the treatment effect that is to be 
estimated.
The intercurrent events identified for this study and the estimands for primary and key 
secondary endpoints are defined in the following tables. 
Table 5 
List of Intercurrent Events
Intercurrent Event
Strategy to Deal With 
Intercurrent Event 
Within Analysis
Assessment of Subjects 
Rescue therapy
Composite strategy
Subjects will be considered as treatment 
failures. The values of the variable of 
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randomized subjects 
treated subjects
subjects who completed the treatment
subjects who terminated treatment early
subjects who terminated treatment early due to COVID-19 
subjects who completed the treatment period 
subjects who terminated treatment period early
subjects who terminated treatment period early due to COVID-19 
subjects who completed the study 
subjects who terminated study early 
subjects who terminated study early due to COVID-19 
The reasons for screen failure, early treatment termination and early study termination
will be summarized. Subjects affected by COVID-19 related study disruptions, COVID-
19 related study disruptions impacting efficacy and COVID-19 related study disruptions 
impacting safety will be summarized. The percentages of screen failure and subjects 
randomized will be calculated based on number of subjects screened and other 
percentages will be based on the number of subjects in the ITT Set.
The reasons for study and treatment discontinuation will also be summarized in the 
aforementioned table.  
Subject disposition data will be presented in a listing. A corresponding listing will be 
provided for screen failures, subjects with early treatment termination and for subjects 
with early study termination. Subjects affected by COVID-19 related study disruptions 
will be presented in a listing. A summary of inclusion/exclusion criteria not met will be 
presented for all screened subjects. Details of inclusion/exclusion criteria not met will be 
provided in a listing for the screened set.
6.2
Protocol Deviations 
All deviations will be identified, evaluated, and closed prior to database lock. Deviations 
from the protocol will be assessed as “Major” (or equivalently “Significant”) and 
“Minor” (or equivalently “Not Significant”) in cooperation with the sponsor. A case-by-
case decision regarding exclusions of subjects from the PP Set will be made in a blind 
data review meeting which will take place prior to database lock and study unblinding. 
All major protocol deviations will be summarized by category and by treatment in a table 
for the ITT Set. The major deviations which lead to exclusion from the PP Set will be 
summarized in a separate table. All protocol deviations (major and minor) will be listed 
with major protocol deviations which would lead to exclusion from the PP Set being 
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category and all COVID-19 related protocol deviations will be flagged in the 
corresponding listing. 
7
Demographics and Baseline Characteristics
7.1
Demographics
The demographics will be summarized by treatment group in the ITT Set, Safety Set and 
 The following variables will be included: 
Age (Years)  
Age group (18 to 45; >45 to 65; >65 to 80; >80) 
Sex (Male, Female)
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown or Not reported) 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Other, Multiple or Not reported) 
Race group (White, Black, Asian, Other)  
Region (US; Excl-US) 
Pre-dialysis weight (kg), Height (cm) at baseline  
Status of habitual tobacco use (Never, Former, Current), status of habitual alcohol use 
(Never, Former, Current), and history of tuberculosis in the past will also be summarized 
by treatment in the same table as Demographics.
Subject demographics will be presented in a listing. 
7.2
Baseline Disease Characteristics
The following baseline disease characteristics will be summarized by treatment group in 
the ITT Set, Safety Set and 
: 
Duration of end-stage kidney disease (ESKD) (months) 
Duration of hemodialysis (months)  
Duration of hemodialysis ( 1 year; >1 year to 3 years; >3 years) 
Hemodialysis access location (AVF/AVG/Catheter)
Kt/V result 
Duration of pruritus (months) 
Duration of pruritus ( 3 months; >3 to 12 months; >12 months) 
With or without prior or concomitant systemic anti-pruritus treatment
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Cause 
of 
chronic 
kidney 
disease 
(CKD) 
(Hypertension, 
Diabetes, 
Glomerulonephritis, Cystic disease, Urologic, Congenital/hereditary, Other) 
Investigator’s global assessment (IGA) of CKD-aP skin status 
Weekly Average of WI NRS score  
Severity of pruritus/WI NRS group (5 to 7; >7 to 10) 
Weekly Average of SD NRS score 
 
 
 
Baseline disease characteristics will be also presented in a listing.
7.3
Alcohol and Tobacco Usage  
Smoking status and alcohol consumption status will be summarized together with 
demographics characteristics (see section 7.1).
7.4
Childbearing Potential Status, Methods of Contraception and Reproductive 
Status
Childbearing Potential Status, Methods of Contraception and Reproductive Status will 
be listed and summarized. 
7.5
Medical History
The number and percentage of subjects with any medical history will be summarized by 
treatment and for each body system by system organ class (SOC) and preferred term 
(PT). SOC will be sorted in decreasing order of frequency based on the total number of 
subjects of all treatment groups and within each SOC, PT will be presented in decreasing 
order of frequency. Percentages will be calculated based on number of subjects in the 
ITT Set.  
Subject medical history data including specific details will be presented in a listing. Body 
systems will be included as recorded on the CRF. 
Medical Dictionary for Regulatory Authorities (MedDRA) dictionary Version 24.1 or 
higher will be used for reporting and will be described in the relevant table and listing 
footnotes. 
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8
Treatments and Medications
8.1
Prior and Concomitant Medications 
All medications used within 3 months prior to the date of screening through to the end 
of study will be collected on the CRF. All medications will be coded according to the 
World Health Organization drug dictionary Global B3 September 2021 or higher. The 
medication names will be coded according to the Anatomical Therapeutic Chemical 
(ATC) class level 4, and preferred terms provided in the dictionary.  
A prior medication is defined as any medication that is taken within 3 months prior to 
the date of the first treatment injection, that is stopped prior to the date of the first 
treatment injection. A concomitant medication is defined as any existing therapy ongoing 
at the time of the first treatment injection, or any changes to existing therapies during the 
course of the study, or any new therapies the subject received since the date of the first 
treatment injection. 
For missing start or end dates, the rules stated in section 4.1 will be followed. Though 
note that, for treated subjects, if the start date is completely missing and end date is not 
prior to the first treatment injection, then the medication will be classified as 
concomitant. If the end date is missing, then the medication will be classified as ongoing. 
Medications for which the start and end dates are missing will be classified as 
concomitant. All medications of not treated subjects will be classified as prior.
Prior medications will be summarized by providing the number and percentage of 
subjects by ATC class level 2, ATC class level 4 and preferred term overall and for each 
treatment. ATC class level 2 and ATC class level 4 will be sorted in decreasing order of 
frequency based on the total number of subjects who take each medication in the total 
column. In the same way, preferred terms within each drug class will be presented in 
decreasing order of frequency based on the total of all treatment groups. In addition, the 
total number of prior medications and the number and percentage of subjects receiving 
at least one prior medication will also be presented in this table. If a subject has multiple 
medications for a given preferred term the subject will only be counted once. A similar 
table will be presented for concomitant medications.
All summaries will be performed using the ITT Set. Prior and concomitant medications 
will be presented in a listing for the ITT Set. 
8.2
Prior and Concomitant Medical and Surgical Procedures
All relevant medical and surgical procedures done within 3 months prior to the date of 
screening through to the end of study will be collected on the CRF. Medical and surgical 
procedures will be coded according to MedDRA version 24.1 or higher. 
For analysis purpose, a prior medical or surgical procedure is defined as any medical or 
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injection. A concomitant medical or surgical procedure is defined as any medical or 
surgical procedure started or changed since the first treatment injection.
For missing start or end dates, the rules stated in section 4.1 will be followed. Though 
note that, for treated subjects, if the start date is completely missing and end date is not 
prior to the first treatment injection, then the medical or surgical procedure will be 
classified as concomitant. If the end date is missing, then the medical or surgical
procedure will be classified as ongoing. Medical or surgical procedures for which the 
start and end dates are missing will be classified as concomitant. All medical/surgical 
procedures of not treated subjects will be classified as prior. 
Prior medical or surgical procedures will be summarized by providing the number and 
percentage of subjects by system organ class (SOC) and preferred term (PT) overall and 
for each treatment group. In addition, the total number of prior medical or surgical 
procedures and the number and percentage of subjects undergoing at least one prior 
medical or surgical procedures will also be presented in this table. A similar table will be 
presented for concomitant medical and surgical procedures. 
All summaries will be performed using the ITT Set. Prior and concomitant medical or 
surgical procedures will be presented in a listing for the ITT Set. 
8.3
Rescue Therapies
Rescue therapies are defined as below and include the following treatments: 
Antihistamines (new or increased dose): For those given as needed (“PRN”), at 
baseline, 
total weekly dose relative to the dose during the last week of screening 
Gabapentin (new or increased dose) 
Selected Opioids: Nalbuphine or kappa opioid agonists (e.g., difelikefalin, 
nalfurafine), one or more doses. 
Ultraviolet radiation therapy: one or more treatments.
For the purpose of efficacy analyses (including sensitivity and supplementary analyses), 
that are not based on Observed Case (OC), subjects receiving any rescue therapies will 
be considered as treatment failures. Efficacy data collected after the use of rescue 
therapies will be set to the worst possible value for continuous variables and subject’s
binary response will be imputed as “Non-responder” prior to conducting the MI and 
Tipping Point analysis. 
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 
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Rescue medications will be summarized for the ITT Set, by rescue therapy type (topical, 
systemic) and, within each rescue type, by ATC class level 2, ATC class level 4 and 
preferred term overall and for each therapy. ATC class level 2 and ATC class level 4 will 
be sorted in decreasing order of frequency based on the total number of subjects of all 
treatment groups and within each drug class, preferred terms will be presented in 
decreasing order of frequency.  
Rescue procedures will be summarized for the ITT Set, by rescue therapy type 
(phototherapy) and by SOC and PT overall and for each therapy. SOC will be sorted in 
decreasing order of frequency based on the total number of subjects of all treatment 
groups and within each SOC, PT will be presented in decreasing order of frequency. 
Rescue therapies data including specific details will be presented in a listing.
The time to first rescue therapy will be analyzed using Kaplan-Meier survival functions 
that will be compared between treatment groups by using the log-rank test. The number 
and proportion of events and censoring, point estimates of the median, Q1 and Q3 with 
the corresponding 97.5% CI will be presented and Kaplan-Meier curves will also be 
provided. Subjects who do not use any rescue therapy during the study will be censored 
and date of end of participation will be used as censoring date. 
8.4
Study Treatments
8.4.1
Extent of Exposure 
The duration of treatment (in days), the duration of treatment period (in days), the 
duration of study (in days), the total dose administered (in mg), the number of injections 
per subject, the number of missed injections per subject, the number of missed injections 
per subject due to COVID-19, the proportion of subjects who missed at least one 
injection, the proportion of subjects who missed at least one injection due to COVID-19 
will be summarized by treatment group for the Safety Set.
The duration of treatment (in days) is defined as the number of days from the date of first 
treatment injection through the date of the last treatment injection, inclusive, adding 1 
day (i.e. date of last treatment injection – date of first treatment injection + 1).
The duration of treatment period (in days) is defined as the number of days from the date 
of first treatment injection through the date of the end of treatment period as collected in 
the CRF, inclusive, adding 1 day (i.e. date of end of treatment period – date of first 
treatment injection + 1).
The duration of study (in days) is defined as the number of days from the date of signature 
of first informed consent (across all screening occurrences) through the date of the end 
of participation (across all screening occurrences), inclusive, adding 1 day (i.e. date of 
end of participation – date of signature of first informed consent + 1). 


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8.4.2
Treatment Compliance and Modifications
Dosage modifications of the study drug will not be permitted during the clinical study. 
Any inadvertent dose modifications should be reported to the sponsor/Contract Research 
Organization (CRO). 
Treatment compliance will be assessed through the treatment record and drug 
dispensation logs. Dosing frequency is scheduled for every 4 weeks, based on the 
baseline/Day 1 visit date. If a study visit occurs outside the visit window, 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 overall compliance in percent will be calculated as the ratio of the total number of 
actual injections during the treatment period divided by the total number of expected 
injections during the treatment period multiplied by 100.  
Dose compliance will be documented in the CRF, with the total volume (mL) of the study 
drug that was properly administered. Total volume injected in mL is converted into total 
dose administered in mg following the correspondence below:  
Volume injected (mL)
Dose administered (mg)
0.49 mL
30 mg dual-chamber, single-use syringe (DCS)
Injected volume is assumed to be proportional to the dose administered. 
Subjects are considered as compliant when their compliance is 
.
The overall compliance until Week 8, the compliance by visit and the number of 
injections received and missed per subject will be presented in a table by treatment for 
the Safety Set. The number of missing injections will be based on the full treatment 
period (six injections) and will not be adjusted for subjects that terminate treatment early 
(i.e. a subject that received 2 injections at baseline and then discontinued before Week 4 
will be counted as missing 4 injections). A corresponding listing will be provided for 
exposure and compliance. Details of study drug administration at each visit will also be 
listed.
9
Efficacy Analysis 
Efficacy assessments will be conducted for all subjects at the screening visit (upon 
signing of the ICF) and at every subsequent visit as described in schedule of assessments 
in Appendix A. All efficacy assessments will be listed in by-subject listing.
All efficacy analyses will be performed in the ITT Set. The primary efficacy analysis 
will be repeated in the mITT Set and PP Set as supportive evidence and to assess 
robustness of efficacy findings.  
Subjects will be summarized and analyzed according to their randomized treatment 
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Summaries based on observed case (OC) will be provided for all primary, secondary, 
and exploratory efficacy endpoints without imputation of any missing data. For the OC
summaries, if any rescue therapy 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. 
P
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.
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.  
9.1
Analysis of Primary Efficacy Endpoint 
An overview of the analyses for primary efficacy is given in Appendix B.
9.1.1
Primary Analysis of the Primary Efficacy Endpoint (Estimand 1)
A summary will be provided for the primary efficacy endpoint without any imputation 
of missing data. Note that subjects who took rescue therapies at any point up to and 
including Week 12 are considered as treatment failures in this endpoint. 


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In the main statistical analysis described below, missing WI NRS weekly average values 
will be imputed for the ITT set using multiple imputations (MI) under missing at random 
(MAR) assumption. Worst values are assumed after use of rescue therapy or treatment 
discontinuation due to lack of efficacy or AE/death related to study drug prior to 
imputation. Dichotomous endpoints will be calculated from the underlying imputed 
variable. See Appendix C for details about Multiple Imputation. 
The proportion of subjects with an improvement at Week 12
baseline without use of rescue therapies and without treatment discontinuation due to 
lack of efficacy or AE/death related to study drug will be analyzed in the ITT Set for 
each multiply imputed dataset, using the Cochran-Mantel-Haenszel (CMH) test stratified 
by analysis center; strata-adjusted difference in proportions between treatment groups
(Nemolizumab – Placebo) and the 97.5% confidence interval (CI) of the difference will 
be based on the large sample approximation method for binary data using Mantel-
Haenszel strata weights8 and the Sato variance estimator9. This analysis will be 
performed for both dosing schedules compared to placebo using the “Commonriskdiff” 
and “CL=MH” options in SAS PROC FREQ. Proportions and strata-adjusted difference 
in proportions will be pooled using Rubin’s method. Results from the CMH analysis will 
be combined using the Wilson-Hilferty transformation as described in the Bohdana 
Ratitch, et al. paper10 to produce a pooled CMH test p-value. 
9.1.2
Sensitivity and Supplementary Analyses of the Primary Efficacy Endpoint
(Estimand 1)
The following sensitivity analyses will be conducted for the robustness of the primary 
analysis of the primary efficacy endpoint: 
Sensitivity Analysis 1: MI using a copy reference (CR) approach under MNAR 
assumption (dichotomous endpoints will be calculated from the underlying imputed 
variable); 
Sensitivity Analysis 2: “Non-responder” analysis; 
Sensitivity Analysis 3: Tipping Point analysis; 
Sensitivity Analysis 4: the primary analysis at Week 12 as per section 9.1.1 will be 
repeated in the ITT Set using weekly averages of WI NRS obtained by averaging at 
least 3 daily scores over 7-day periods. No period extension at baseline and week 12 
applies for these weekly averages. MI under MAR will be repeated using the weekly 
averages obtained by averaging at least 3 daily scores over 7-day periods;  
Sensitivity Analysis 5: the primary analysis at Week 12 as per section 9.1.1 will be 
repeated in the ITT Set using weekly averages of WI NRS obtained by averaging at 
least 2 daily scores over 7-day periods. No period extension at baseline and week 12 
applies for these weekly averages. MI under MAR will be repeated using the weekly 
averages obtained by averaging at least 2 daily scores over 7-day periods; 
Sensitivity Analysis 6: the primary analysis at Week 12 as per section 9.1.1 will be 
repeated in the ITT Set using weekly averages of WI NRS obtained by averaging at 


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least 1 daily score over 7-day periods. No period extension at baseline and week 12 
applies for these weekly averages. MI under MAR will be repeated using the weekly 
averages obtained by averaging at least 1 daily scores over 7-day periods.  
See Appendix C for details about Multiple Imputation and Tipping Point analysis. 
The primary analysis imputes all missing data using MI under MAR assumption. The 
sensitivity analyses and tipping point will investigate the robustness of results to 
assumptions made for missing data.  
In all these sensitivity analyses, subjects who took rescue therapies or discontinued 
treatment due to lack of efficacy or AE/death related to study drug are considered as 
treatment failure as defined for this estimand (i.e., the values of the variable of interest 
collected after the intake 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”). 
In addition, the following supplementary analyses will be conducted: 
Supplementary Analysis 1: the primary analysis at Week 12 as per section 9.1.1 will 
be repeated in the mITT Set; subjects who took rescue therapies or discontinued 
treatment due to lack of efficacy or AE/death related to study drug are considered as 
treatment failure as defined for this estimand; MI will not be repeated on the mITT 
Set and missing values will be imputed using the values of MI under MAR 
assumption on the ITT Set (dichotomous endpoints will be calculated from the 
underlying imputed variable); 
Supplementary Analysis 2: the primary analysis at Week 12 as per section 9.1.1 will 
be repeated in the PP Set; subjects who took rescue therapies are considered as 
treatment failure as defined for this estimand; subjects who discontinued treatment 
for any reason will not be included in the PP set; subjects with missing data at 
Baseline or Week 12 will not be included in the PP set and thus no imputation of 
missing data is needed; 
Supplementary Analysis 3 (Treatment Policy Adaptation): the primary analysis at 
Week 12 as per section 9.1.1 will be repeated in the ITT Set using observed cases 
only, without any imputation of missing data and without considering either rescue 
therapies or treatment discontinuation.
9.1.3
Impact of COVID-19 on the Primary Efficacy Endpoint (Estimand 1)
To assess the impact of COVID-19 related study disruptions (e.g. treatment 
discontinuation, missing assessments, etc.), the primary efficacy endpoint will also be 
analyzed on the ITT Set excluding subjects affected by COVID-19 related study 
disruptions. Missing values will be imputed using MI under MAR assumption 
(dichotomous endpoints will be calculated from the underlying imputed variable). 
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9.1.4
Subgroup Analysis for Primary Efficacy Endpoint (Estimand 1)
A summary based on the primary efficacy endpoint (without imputation of missing data) 
will be repeated in the subgroups defined in section 4.9.
The primary analysis for the primary efficacy endpoint will be repeated in the subgroups 
defined in section 4.9. The strata-adjusted difference in proportions of responders with 
97.5% CI, pooled CMH test p-value will be derived as described in section 9.1.1.
MI will not be repeated on each subgroup and missing values will be imputed using the 
values of MI under MAR assumption on the ITT Set (dichotomous endpoints will be 
calculated from the underlying imputed variable). 
A Forest plot with the result of primary analysis and all subgroup analysis of primary 
efficacy endpoint will be presented.
9.2
Analysis of the Key Secondary Efficacy Endpoints  
An overview of the analyses for key secondary efficacy is given in Appendix B.
9.2.1
Main Analysis of Key Secondary Efficacy Endpoints
 
A summary will be provided for the key secondary efficacy endpoints without any 
imputation of missing data.
Analysis will be as for the main estimation of Estimand 1 with missing values imputed 
using MI under MAR assumption. Worst values are assumed after use of rescue therapy 
or treatment discontinuation due to lack of efficacy or AE/death related to study drug 
prior to imputation. Dichotomous endpoints will be calculated from the underlying 
imputed variable. The strata-adjusted difference in proportions of responders with 97.5% 
CI, pooled CMH test p-value will be derived as described in section 9.1.1. 
The same MI output dataset as used for the primary endpoint will be used to derive the 
other dichotomous endpoints from WI NRS (Estimand 2, 3, and 5). 
 
 
 
9.2.2
Sensitivity Analysis of Key Secondary Efficacy Endpoints
 
The following sensitivity analyses will be conducted for the robustness of the main 
analysis of the key secondary efficacy endpoints:
Sensitivity Analysis 1: MI using a copy reference (CR) approach under MNAR 
assumption (dichotomous endpoints will be calculated from the underlying imputed 
variable); the same MI output dataset for WI NRS using a copy reference (CR) 
approach under MNAR assumption will be used to derive the other dichotomous 
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endpoints 
. Similarly, the same CR output dataset for SD NRS 
will feed into all dichotomous endpoints derived from that 
 
Sensitivity Analysis 2: “Non-responder” analysis.
See Appendix C for details about Multiple Imputation.
9.2.3
Impact of COVID-19 on the Key Secondary Efficacy Endpoints 
 
 
To assess the impact of COVID-19 related study disruptions (e.g. treatment 
discontinuation, missing assessments, etc.), the key secondary efficacy endpoints will 
also be analyzed on the ITT Set excluding subjects affected by COVID-19 related study 
disruptions. Missing values will be imputed using MI under MAR assumption 
(dichotomous endpoints will be calculated from the underlying imputed variable). 
Subjects affected by COVID-19 related study disruptions will not be included in the MI.
9.2.4
Subgroup Analysis of the Key Secondary Efficacy Endpoints 
 
Summaries for the key secondary endpoints (without imputation of missing data) will be 
repeated in the subgroups defined in section 4.9.
The main analysis for the key secondary efficacy endpoint will be repeated in the 
subgroups defined in section 4.9. The strata-adjusted difference in proportions of 
responders with 97.5% CI, pooled CMH test p-value will be derived as described in 
section 9.1.1.
MI will not be repeated on each subgroup and missing values will be imputed using the 
values of MI under MAR assumption on the ITT Set (dichotomous endpoints will be 
calculated from the underlying imputed variable).
Forest plots with the result of primary analysis and all subgroup analysis of the key 
secondary efficacy endpoints will be presented.
 
 
 
 
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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, and all scores 
after the intake of rescue therapies or treatment discontinuation due to lack of efficacy or 
AE/death related to study drug will be assigned the worst possible value. 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. 
These continuous endpoints will be analyzed using an ANCOVA with treatment group 
and analysis center as factors and baseline score as covariate. Missing data will be 
imputed using MI under MAR assumption (see Appendix C for details about Multiple 
Imputation).
 
 
 
Time to onset of effect on pruritus from baseline (defined as the day when the weekly 
analyzed using Kaplan-
Meier survival functions that will be compared between treatment groups by using the 
log-rank test. The number and proportion of events and censoring, point estimates of the 
median, Q1 and Q3 with the corresponding 97.5% CI will be presented and Kaplan-
Meier curves will also be provided. 
The following censoring rules will be applied: 
Subjects who took rescue therapy before achieving onset of effect on pruritus from 
baseline will be censored and the date of decision to put subject under rescue 
therapies will be used as censoring date.  
Subjects who discontinued treatment due to lack of efficacy or AE/death related to 
study drug before achieving onset of effect on pruritus from baseline will be censored 
and the date of treatment discontinuation will be used as censoring date.  
Subjects who discontinued treatment for any other reason, did not take rescue 
therapies and did not achieve onset of effect on pruritus from baseline during the 
study will be censored and date of end of participation will be used as censoring date.
Subjects who did not take rescue therapies, did not discontinue treatment and did not 
achieve onset of effect on pruritus from baseline during the study will be censored 
and date of end of participation will be used as censoring date. 
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In case of occurrence of both intake of rescue therapy and treatment discontinuation due 
to lack of efficacy or AE/death related to study drug, the earlier date will be used for 
censoring purposes. 
The following rules will be applied: 
1st Intercurrent Event
2nd Intercurrent Event
Censoring Rule
Intake of rescue therapies
Treatment discontinuation due to 
lack of efficacy or AE/death 
related to study drug
Subjects will be censored and 
the date of decision to put 
subject under rescue therapies 
will be used as censoring date
Intake of rescue therapies
Treatment discontinuation for 
any other reason
Subjects will be censored and 
the date of decision to put 
subject under rescue therapies 
will be used as censoring date
Treatment discontinuation due to 
lack of efficacy or AE/death 
related to study drug
Intake of rescue therapies
Subjects will be censored and 
the date of treatment 
discontinuation will be used as 
censoring date
Treatment discontinuation for 
any other reason
Intake of rescue therapies
Subjects will be censored and 
the date of decision to put 
subject under rescue therapies 
will be used as censoring date
In order to investigate the impact of rescue medication intake and treatment 
discontinuation, cumulative incidence functions for competing-risks data will be 
presented and compared between treatment groups by using Gray’s test. 
Proportion of subjects with an improvement
will 
be analyzed in the ITT Set, using the Cochran-Mantel-Haenszel (CMH) test stratified by 
analysis center. The strata-adjusted difference in proportions of responders with 97.5% 
CI, pooled CMH test p-value will be derived as described in section 9.1.1. Subjects who 
took rescue therapies will be considered as treatment failures, efficacy data collected 
after the use of rescue therapies will be set to the worst possible value and subject’s 
binary response will be imputed as “Non-responder”. Treatment discontinuation due to 
lack of efficacy, AE/death related to study drug or any other reason is not a factor at this 
early timepoint since the second administration is not due until Week 4. Missing subject’s 
binary response will be imputed using MI under MAR assumption (dichotomous 
endpoints will be calculated from the underlying imputed variable). See Appendix C for 
details about Multiple Imputation.
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11
Immunogenicity Analyses 
The immunogenicity endpoint is nemolizumab immunogenicity in adult hemodialysis 
subjects with moderate to severe pruritus.
Anti-drug antibodies assessments using a validated electro-chemiluminescence 
immunoassay (ECLIA) (screening, confirmatory, titer, Nab) and incidence of positive 
ADA results (absolute occurrence, percent of subject, and treatment-related ADA) will 
be summarized by visit and by treatment group. A treatment-related ADA is defined 
when at baseline, the screening or confirmatory ADA result is negative, and the post-
baseline confirmatory ADA result is positive. A corresponding listing will be provided. 
Summaries will be based on the Safety Set. Subjects will be summarized according to 
their actual treatment group.
12
Safety Analysis 
Safety assessments/measurements will be conducted for all subjects at the screening visit 
(upon signing of the ICF) and at every subsequent visit as described in schedule of 
assessments in Appendix A. All safety assessments/measurements will be listed in by-
subject listing.
Subjects will be summarized according to their actual treatment group.
TEAEs will be summarized descriptively overall and by treatment and other safety 
information will be summarized descriptively by treatment.  
All safety analyses will be based on the Safety Set.
12.1 Adverse Events
A TEAE is defined as any AE with a start date/time on or after the date/time of the first 
injection (Baseline/Day 1) through the last study visit (follow-up visit), whether or not it 
is considered causally related to the study drug. 
Treatment Emergent/Non-Treatment Emergent: 
Complete Missing Dates:
If both the start date and the end date are totally missing, then the AE is assumed 
to be treatment emergent. 
Partial Missing Dates:
If the start date is missing and the non-missing end date is prior to first injection 
(Baseline/Day 1) date, then the AE is not considered treatment emergent. 


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If the start date is missing and the partial end date can be assumed to be prior to 
first injection (Baseline/Day 1) date (month and/or year before infusion date), 
then the AE is not considered treatment emergent.
If the start date is missing and the end date is after the first injection (Baseline/Day 
1) date or the partial end date cannot be assumed to be prior to the first injection 
(Baseline/Day 1) date (based on month and/or year), then the AE is assumed to 
be treatment emergent.
If the start date is partial and can be assumed to be prior to the first injection 
(Baseline/Day 1) date (based on the month and/or year) and the non-missing end 
date is prior to the injection date, then the AE is not considered treatment 
emergent. 
If the partial start date cannot be assumed to be prior to the first injection 
(Baseline/Day 1) date, then the AE is assumed to be treatment emergent.
Complete Dates:
If the start date is prior to the first injection (Baseline/Day 1) date, then the AE is 
not considered treatment emergent. 
If the start date is equal to the first injection (Baseline/Day 1) date and the start 
time is missing, then the AE is considered treatment emergent.
If the start date is equal to the first injection (Baseline/Day 1) date and the start 
time is prior to the first injection time, then the AE is not considered treatment 
emergent.
If the start date is equal to the first injection (Baseline/Day 1) date and the start 
time is on or after the first injection time, then the AE is considered treatment 
emergent.
If the start date is after the first injection (Baseline/Day 1) date, then the AE is 
considered treatment emergent.
For the imputation of missing start or end dates, the rules stated in Section 4.1 will be 
followed. 
All AEs will be coded according to MedDRA 24.1 or higher. 
12.1.1 Incidence of Adverse Events
An overall summary table with count and percentage of subjects with TEAEs and count 
of events will include: 
TEAEs
TEAEs by greatest severity
TEAEs by closest relationship to study drug 
TEAEs by closest relationship to study procedures 


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TEAEs leading to treatment discontinuation 
TEAEs leading to study discontinuation 
TEAEs of special interest
TEAEs of special interest by greatest severity
TEAEs due to COVID-19
Asthma-related TEAEs adjudicated by IAC
Asthma-related TEAEs adjudicated by IAC by greatest severity
Asthma-related TEAEs adjudicated by IAC by closest relationship to study drug 
Serious TEAEs (both fatal and non-fatal)
Non-fatal serious TEAEs 
TEAEs leading to death 
Serious TEAEs by closest relationship to study drug 
Serious TEAEs by closest relationship to study procedures 
Serious TEAEs leading to treatment discontinuation 
Serious TEAEs leading to study discontinuation 
The incidence of AEs will be summarized in tables with count and percentage of subjects 
with AEs and count of events by system organ class (SOC) and preferred term (PT). 
Unless otherwise specified, at each level of SOC or preferred term, a subject with 
multiple events will only be counted once per SOC or preferred term. AEs will be 
displayed by treatment for the Safety Set.  
The following categories of AE will be summarized by SOC and PT: 
TEAEs
TEAEs by greatest severity
TEAEs related to study drug 
TEAEs related to study procedures 
TEAEs leading to treatment discontinuation 
TEAEs leading to study discontinuation 
TEAEs of special interest
TEAEs of special interest by greatest severity
TEAEs due to COVID-19
Asthma-related TEAEs adjudicated by IAC


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Asthma-related TEAEs related to study drug adjudicated by IAC
Asthma-related TEAEs reported by Investigator with adjudication outcome by IAC 
Asthma-related TEAEs related to study drug reported by Investigator with 
adjudication outcome by IAC 
Asthma-related TEAEs adjudicated by IAC by greatest severity
Asthma-related TEAEs related to study drug adjudicated by IAC by greatest severity
Serious TEAEs (both fatal and non-fatal)
Non-fatal serious TEAEs
TEAEs leading to death 
Serious TEAEs related to study drug 
Serious TEAEs related to study procedures 
Serious TEAEs leading to treatment discontinuation 
Serious TEAEs leading to study discontinuation 
At each level of SOC or PT, if a subject experiences more than 1 occurrence of the same 
AE, the occurrence with the greatest severity, the closest relationship with the study drug
and the closest relationship with the study procedures will be used in the corresponding
summary tables. All AEs will be presented in tables in descending order from the SOC 
with the highest total incidence (across all treatment groups) to the SOC with the lowest 
total incidence. Within each SOC, AEs will be sorted in descending order of PT based 
on the total of all treatment groups. 
TEAEs, TEAEs leading to death, serious TEAEs, non-fatal serious TEAEs, severe 
TEAEs, TEAEs of special interest, TEAEs leading to treatment discontinuation, TEAEs 
leading to study discontinuation and TEAEs due to COVID-19 will be listed separately.
Pre-treatment AEs (PTAEs) will be listed separately.
12.1.2 Relationship of Adverse Events to Study Drug and/or Study Procedures
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 procedures (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 relationship assessment for an AE is to be completed using the following definitions 
for all AEs occurring during this clinical study: 


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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 between the study drug and the AE, and/or 
between the clinical study protocol procedures (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 
procedures and the AE. 
If the relationship to study drug information is missing, then the corresponding AE is 
assumed to be related with reasonable possibility to the study drug. If a subject 
experiences more than 1 occurrence of the same AE, the occurrence with the closest
relationship to study drug will be used in summary tables. 
12.1.3 Severity of Adverse Event
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. 
If the severity is missing, then the AE is assumed to be severe. If a subject experiences 
more than 1 occurrence of the same AE, the occurrence with the greatest severity will be 
used in summary tables. 
12.2 Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed according to the schedule of 
assessments in Appendix A.
The safety laboratory assessments include the following parameters:  
Hematology: 
Hemoglobin (g/L) 
Hematocrit (L/L) 
White blood cell count (with differential including eosinophils) (10^9/L)
Red blood cell count (10^12/L)
Platelet count (10^9/L)
Erythrocytes Mean Corpuscular Volume (fL)


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Urinalysis:
pH 
Bacteria
Glucose 
Casts
Crystals
Epithelial Cells
Erythrocytes 
Ketones 
Occult Blood  
Protein  
Leukocytes  
Leukocytes Esterase
Mucous Threads 
Nitrites 
Bilirubin 
Urobilinogen  
Specific gravity 
Yeast Cells
Serum chemistry:
Creatinine (umol/L) 
Aspartate Amino Transferase (AST) (U/L)
Alanine Amino Transferase (ALT) (U/L)
Gamma glutamyltransferase (U/L)
Alkaline Phosphatase (U/L) 
Lactate Dehydrogenase (U/L)
Total Bilirubin (umol/L) 
Direct Bilirubin (umol/L)
Albumin (g/L) 
Total Protein (g/L)
Urate (mmol/L) 
Sodium (mmol/L) 
Potassium (mmol/L)
Calcium (mmol/L) 
Chloride (mmol/L)
Glucose (mmol/L)
Urea Nitrogen (mmol/L)
Total Cholesterol (mmol/L) 
Triglycerides (mmol/L) 
Low-density lipoprotein (LDL) Cholesterol (mmol/L) 


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High-density lipoprotein (HDL) Cholesterol (mmol/L) 
Creatine Kinase (CK) (U/L)
Summary statistics of the observed values and change from baseline for all laboratory 
parameters will be provided by visits and treatment groups.  
For quantitative parameter, results will be presented for each parameter by treatment in 
a shift table, using above, below, within normal range, between baseline and visits at 
Week 4, Week 8, Week 12 and Week 20. Results will be presented for each parameter 
by treatment group in a shift table, using normal, abnormal not clinically significant and 
abnormal clinically significant categorization based on the current version of Central Lab 
Manual and Alert Report Specification, between baseline and visits at Week 4, Week 8, 
Week 12 and Week 20. 
Last post-baseline and worst post-baseline results (derived using both scheduled and 
unscheduled measurements) will also be included in summaries and shift tables. For each 
parameter, worst post-baseline value will be defined as the highest or lowest value 
relative to the reference range.
All post-baseline (both scheduled and unscheduled) measurements will be used for 
Potentially Clinically Significant Values (PCSV) determination (criteria are available in
Appendix D).
Number and proportions of subjects with Potentially Clinically Significant Values will 
be summarized by visits and treatment groups. 
All laboratory data will also be presented in listings for each parameter with abnormal
values, clinically significant values and potentially clinically significant values (PCSV) 
flagged. Moreover, abnormal values and potentially clinically significant values will be 
presented in separate listings.
For statistical or graphical summaries of the laboratory tests, values above or below the 
limit of detection will be substituted with the lower limit of detection minus 1%, or the 
upper limit of detection plus 1% (e.g. ‘<3’ is substituted by 2.97). In the data listings, the 
values are shown including the ‘<’ or ‘>’ sign. 
Boxplots presenting the distribution of AST, ALT, ALP, Total Bilirubin and CPK over 
the visits will be displayed by treatment. An additional boxplot will be presented on the 
figure considering the maximum post-baseline value. Additionally, individual plots 
presenting the distribution of AST, ALT, ALP, Total Bilirubin and CPK, for subjects 
with abnormal values, over the visits will be displayed by treatment. An evaluation of 
drug-induced serious hepatotoxicity (eDISH) plot will be displayed in addition.  
12.3 Pregnancy Testing
Pregnancy tests will be performed on female subjects of child-bearing potential. Serum 
pregnancy tests will be performed at all visits according to the schedule of assessments 
summarized in Appendix A. Pregnancy test results will be presented in a listing. 


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12.4 Virology 
Virology including Hepatitis B Surface Antigen (HBsAg), Hepatitis B Core Antibody 
(HBcAb), Hepatitis C Virus (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. Polymerase Chain Reaction (PCR) test). These
data will be presented in a listing.
12.5 Tuberculosis (TB) 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. The 
data will be presented in a listing.
12.6 Vital Sign Measurements
Vital signs including pulse rate (beats/min), systolic and diastolic blood pressure 
(mmHg), body temperature (C), pre-dialysis weight (kg) and post-dialysis weight (kg)
will be assessed over time during the study according to the schedule of assessments in 
Appendix A. Descriptive statistics of observed values and change from baseline will be 
summarized by visit and by treatment. 
Results from overall interpretation of vital signs assessments will be summarized by visit 
and treatment group and will be presented by treatment group in a shift table, using 
normal, abnormal not clinically significant and abnormal clinically significant 
categorization, between baseline and visits at Week 4, Week 8, Week 12 and Week 20. 
All post-baseline (both scheduled and unscheduled) measurements will be used for 
Potentially Clinically Significant Values (PCSV) determination (criteria are available in 
Appendix E).
Number and proportions of subjects with Potentially Clinically Significant Values will 
be summarized by visits and treatment groups.
A corresponding listing with potentially clinically significant values (PCSV) flagged will 
also be provided. 
12.7 Physical Examination 
A complete physical examination including assessments of the head, ears, eyes, nose, 
throat, neck (including thyroid), skin/integumentary system, cardiovascular system, 
respiratory system, gastrointestinal system, musculoskeletal system, lymph nodes, 
nervous system, and extremities will be performed at screening, baseline/Day 1, and


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subsequent scheduled visits. All physical examinations will be summarized in a table by 
visit and by treatment group. Results of physical examinations are categorized into 
normal, abnormal, and not done. If abnormal, results will be categorized with or without 
clinical significance. A corresponding listing will be provided with abnormal values 
flagged. 
12.8 Electrocardiogram
A 12-lead ECG will be performed at specific visits according to the schedule of 
assessments in Appendix A. Electrocardiogram results are categorized into normal, and 
abnormal. If abnormal, results will be categorized with or without clinical significance. 
Results will be summarized by visit and treatment group and will be presented by 
treatment group in a shift table, using normal, abnormal not clinically significant and 
abnormal clinically significant categorization, between baseline and visit at Week 12. 
Heart rate (beats/min) and PR, QRS, RR, QT, QTcB and QTcF intervals (msec) and their 
changes from baseline will be summarized by visit and treatment group. A corresponding 
listing will be provided with abnormal values flagged.  
12.9 Respiratory Assessments
PEF and ACT will be performed according to subjects’ asthma history as follows:  
1) If subjects have no asthma history, PEF will be performed at Screening and Baseline.
2) If subjects have asthma history, PEF and ACT will be performed at all visits 
according to the schedule of assessments in Appendix A.
3) If subjects have a new (de novo) diagnosis of asthma PEF and ACT will be performed 
at all subsequent visits (considering that some subjects will have performed some 
PEF testing at prior visits as per point 1). 
ACT and PEF (observed values and changes from baseline) will be summarized by visit
and treatment group. A corresponding listing will be also provided for both assessments.
For ACT, the numbers and percentages of subjects with an ACT score <=19 will be 
summarized by visit and treatment group. 
For PEF, the numbers and percentages of subjects with PEF<80% of the predicted value 
will be presented by visit and treatment group and percent change from baseline will be 
classified as follows
<= -20% 
<= -15% and > -20% 
<= -10% and > -15% 
< 0% and > -10% 
>= 0% and < 10% 


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>= 10% and < 15% 
>= 15% and < 20% 
>= 20%
and will be presented by visit and treatment group. 
All PEF summaries will be presented for subjects with/without asthma history.
Additionally, individual plots presenting the distribution of ACT and PEF for subjects 
with abnormal values, over the visits will be displayed by treatment. 
A listing with all known asthma triggers will be provided. 
13
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (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. 
14
Interim Analysis
No interim analysis is planned for this study. 
15
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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Changes from the Protocol Analysis Plan 
Any change from the protocol will be justified and fully documented. 
If the blind review suggests changes to the principal features stated in the protocol, these 
have to be documented in a protocol amendment. Otherwise, it will suffice to update the 
statistical analysis plan with the considerations suggested from the blind review.
No changes have been made to the intent of protocol text. 
The following clarification has been made:
Addition of Appendix C for details about Multiple Imputation and Tipping Point 
analysis. Note that this clarifies that the tipping point approach is using the delta-
adjustment multiple imputation framework under Missing Not at Random (MNAR) 
assumption. 
17
General Features of Tables, Listings and Figures
TLF have to be printed in A4 page size with landscape orientation and with the following 
margins: 
Top: 
2.0 cm (i.e. headers at 2.0 cm from page edge) 
Bottom: 
2.0 cm (i.e. footers at 2.0 cm from page edge) 
Left: 
0.8 cm
Right: 
0.8 cm
Courier New, 8-point font will be used for TLF contents (excluding column headers) and 
TLF footnotes. 
Courier New, 8-point, bold font will be used for page headers and footers, TLF title, TLF 
headers, column headers and figures' axis labels.
A clear, accurate and complete programming code will be developed to generate the 
statistical analyses, summary tables, figures and listings to be integrated in the Clinical 
Study Report. The use of precise titles and footnotes will be made to improve the 
understanding of summaries and document any assumption. Details of analysis 
specifications including but not limited to the SAS code will be documented on the shells.
The final list of TLF is available in Appendix F. The final mock TLF shells for the 
reporting of this study will be available in a separate document that will be developed 
and will be finalized before database lock.


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References
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uremicpruritus in long-term hemodialysis patients. J Jpn Soc Dial Ther 
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2. Rayner H , Larkina M, Wang M, Graham-Brown M, van der Veer S, Ecder T, et al. 
International comparisons of prevalence, awareness, and treatment of pruritus in 
people on hemodialysis. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2000-2007. 
3. Pisoni RL, Wikström B, Elder SJ, Akizawa T, Asano Y, Keen ML, et al. Pruritus in 
haemodialysis patients: international results from the Dialysis Outcomes and Practice 
Patterns Study (DOPPS). Nephrol Dial Transplant 2006;21:3495-505. 
4. Fishbane S, Mathur V, Germain M, Shirazian S, Bhaduri S, Munera C, et al. 
Randomized controlled trial of difelikefalin for chronic pruritus in hemodialysis 
patients. Kidney Int Rep. 2020 Jan 28;5(5):600-610. 
5. Mathur V, Lindberg J, Germain M, Block G, Tumlin J, Smith M, et al. A longitudinal 
study of uremic pruritis in hemodialysis patients. Clin J Am Soc Nephrol. 2010
Aug;5(8):1410-9. 
6. Desai N, Poindexter G, Monthrope Y, Bendeck S, Swerlick R, Chen Suephy. A pilot 
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7. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr 
Scand. 1983;67(6):361-370. 
8. Mantel, N., and Haenszel, W. (1959). "Statistical Aspects of Analysis of Data from 
Retrospective Studies of Disease". Journal of the National Cancer Institute 22:719–
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9. Sato, T. (1989). "On the Variance Estimator of the Mantel-Haenszel Risk 
Difference". Biometrics 45:1323–1324. Letter to the editor 
10. Bohdana Ratitch, et al. "Combining Analysis Results from Multiply Imputed 
Categorical Data", 2013, PharmaSUG Proceedings, Paper SP-03 
11. Victoria Liublinska and Donald B. Rubin, "Sensitivity analysis for a partially missing 
binary outcome in a two-arm randomized clinical trial", 2014, Stat Med. 








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