Conditions: Prurigo Nodularis
Keywords: Prurigo Neurodermatitis Pruritus Skin diseases
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 274
Healthy volunteers: no

Brief summary:
The primary objective was to assess the efficacy of nemolizumab (CD14152) compared to placebo in participants greater than or equal to (\>=) 18 years of age with prurigo nodularis (PN) after a 16-week treatment period.

Detailed description:

Arms:
arm 1: Participants weighing less than (\<) 90 kilogram (kg) received two subcutaneous (SC) injections of 30 milligrams (mg) nemolizumab (60 mg loading dose) at baseline then one SC injection once for every 4 weeks (Q4W). Participants weighing greater than or equal to (\>=) 90 kg received two SC injections of 30 mg nemolizumab (60 mg total) at baseline (no loading dose) and two SC injections Q4W throughout the treatment period of 16 weeks. arm 2: Participants weighing \< 90 kg received two SC injections of matching placebo at baseline, then one SC injection Q4W. Participants weighing \>= 90 kg received two SC injections of matching placebo at baseline, then two SC injections Q4W throughout the treatment period of 16 weeks.

Interventions: intervention 1: Nemolizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants received either 30 mg or 60 mg dose of nemolizumab as SC injection. intervention 2: Participants received matching placebo as SC injection.

Protocol document:
Prot_000.pdf: 
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1
CLINICAL STUDY PROTOCOL
Galderma S.A.
Galderma Research & Development, LLC
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Study to Assess the 
Efficacy and Safety of Nemolizumab (CD14152) in Subjects with Prurigo Nodularis
Protocol Number: RD.06.SPR.203065
Short Title: A study to assess the efficacy and safety of nemolizumab (CD14152) in 
subjects with prurigo nodularis (PN)
IND Number:
117122
EudraCT Number:
2019-004789-17
Name of Investigational Product 
Nemolizumab (CD14152)
Phase of Development:
3
Indication:
Prurigo Nodularis
Sponsor:
Galderma S.A.
Avenue Gratta-Paille 2
1018 Lausanne
Switzerland
Galderma Research & Development, LLC
14501 North Freeway
Fort Worth, Texas 76177
United States
Protocol Version: 
5.0 
Protocol Date:
19 November 2021
-CONFIDENTIAL-
This document and its contents are the property of and confidential to Galderma 
S.A./Galderma R&D, LLC. Any unauthorized copying or use of this document is
prohibited.


Galdenna S.A./Galdenna R&D, LLC 
Nemolizumab (CD 14152) 
PROTOCOL APPROVAL SIGNATURES 
RD.06.SPR.203065 
Version 5.0 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Assess 
the Efficacy and Safety of Nemolizumab (CD 14152) in Subjects 
with Prurigo Nodularis 
Protocol Number: 
RD.06.SPR.203065 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation guidelines for current Good 
Clinical Practice and applicable regulatory requirements. 
Sponsor Signatory 
Zarif Jabbar-Lopez, MBBS, MPH 
Medical Expert 
Galderma S.A. 
Signature 
2 2.- Nov-'to2 I
Date (DD-Mmm-YYYY) 
CONFIDENTIAL 
Page 2 of185 


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INVESTIGATOR SIGNATURE PAGE
Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Efficacy and Safety of Nemolizumab (CD14152) in 
Subjects with Prurigo Nodularis
Protocol Number:
RD.06.SPR.203065
Confidentiality and Current Good Clinical Practice (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 International Council for Harmonisation 
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 S.A./Galderma 
R&D, LLC including, but not limited to, the current investigator’s brochure

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 S.A./Galderma R&D, LLC and of the 
IEC/IRB. I will submit the protocol amendments and/or any informed consent 
form modifications to Galderma S.A./Galderma R&D, LLC 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 S.A./Galderma R&D, LLC 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 subject’s state of health will be regarded as confidential. No 


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subject’s name 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 
S.A./Galderma R&D, LLC to other clinical investigators, regulatory agencies, or 
other health authority or government agencies as required.
Investigator Signature
Date (DD-Mmm-YYYY)
Printed Name and Title
Institution


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2
SYNOPSIS
Title of Study:
A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy 
and Safety of Nemolizumab (CD14152) in Subjects with Prurigo Nodularis
Protocol Number:
RD.06.SPR.203065
Investigators/Study 
Sites/Centers:
Approximately 70 sites in Europe, North America, and Asia Pacific
Phase of 
Development:
Phase 3
Objectives:
The primary objective is to assess the efficacy of nemolizumab (CD14152) 
compared to placebo in subjects ≥18 years of age with prurigo nodularis (PN)
after a 16-week treatment period.
The secondary objectives are to assess the safety, pharmacokinetics, and 
immunogenicity of nemolizumab (CD14152) compared to placebo.
Study Endpoints:
Primary endpoints: 

Proportion of subjects with an improvement of ≥ 4 from baseline in 
Peak Pruritus Numeric Rating Scale (PP NRS) at Week 16

Proportion of subjects with an Investigator Global Assessment (IGA) 
success (defined as an IGA of 0 [Clear] or 1 [Almost clear] and a ≥ 2-
point improvement from baseline) at Week 16
Key secondary endpoints: 

Proportion of subjects with an improvement of ≥ 4 from baseline in PP 
NRS at Week 4

Proportion of subjects with PP NRS < 2 at Week 16

Proportion of subjects with an improvement of ≥ 4 from baseline in SD 
NRS at Week 16

Proportion of subjects with an improvement of ≥ 4 from baseline in SD 
NRS at Week 4

Proportion of subjects with PP NRS < 2 at Week 4


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Secondary efficacy endpoints:

IGA success rate at each visit through Week 16

Percentage of pruriginous lesions with excoriations/crusts (Prurigo 
Activity Score [PAS] item 5a) at each visit through Week 16

Percentage of healed prurigo lesions (PAS item 5b) at each visit 
through Week 16

Change from baseline in number of lesions in representative area (PAS 
item 4) at each visit through Week 16

Proportion of subjects with an improvement of ≥ 4 from baseline in PP 
NRS through Week 16

Proportion of subjects with PP NRS < 2 from baseline through Week 
16

Proportion of subjects with PP NRS < 3 from baseline through Week 
16

Absolute change from baseline in PP NRS through Week 16

Percent change from baseline in PP NRS through Week 16

Proportion of subjects with an improvement of ≥ 4 from baseline in 
Average Pruritus (AP) NRS through Week 16

Proportion of subjects with PP NRS improvement ≥ 4 from baseline 
and IGA success at Week 16

Proportion of subjects with AP NRS < 2 from baseline through Week 
16

Absolute change from baseline in AP NRS through Week 16

Percent change from baseline in AP NRS through Week 16

Proportion of subjects with an improvement of ≥ 4 from baseline in SD
NRS through Week 16

Absolute change from baseline in SD NRS through Week 16

Percent change from baseline in SD NRS through Week 16

Change from baseline in sleep diary endpoints (sleep onset latency, 
wakefulness after sleep onset [WASO], total awake time, total sleep 


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time, sleep efficiency, WASO related to PN, number of WASO related 
to PN) based on recordings from subject sleep diary through Week 16

Change from baseline in PN-associated pain frequency through Week 
16

Change from baseline in PN-associated pain intensity through Week 16

Proportion of subjects reporting low disease activity (clear, almost 
clear, or mild) based on Patient Global Assessment of Disease (PGAD) 
at Week 16

Proportion of subjects satisfied with study treatment (good, very good, 
or excellent) based on Patient Global Assessment of Treatment (PGAT) 
at Week 16

Proportion of subjects with an improvement of ≥ 4 in Dermatology Life 
Quality Index (DLQI) through Week 16

Change from baseline in DLQI through Week 16Change from baseline 
in Hospital Anxiety and Depression Scale (HADS) for each subscale 
(ie, depression and anxiety) at Week 16

Change from baseline in EuroQoL 5-Dimension (EQ-5D) at Week 16
Safety endpoints:

Incidence and severity of adverse events (AEs), including treatment-
emergent AEs (TEAEs), AEs of special interest (AESIs), and serious 
AEs (SAEs).
Pharmacokinetic endpoints:

Nemolizumab (CD14152) serum concentrations
Immunogenicity endpoints:

ADA assay (screening, confirmatory, titer, NAb)
Study Design:
This phase 3, multicenter, double-blind, placebo-controlled, randomized, 
parallel-group study is designed to evaluate the efficacy and safety of 
nemolizumab in subjects with PN. 
Approximately 270 subjects with PN will be randomized 2:1 to receive either 
nemolizumab (CD14152) or placebo, stratified by study center and body weight 
(< 90 kg vs ≥90 kg). Subjects weighing < 90 kg at baseline will receive either 
30 mg nemolizumab (with 60 mg loading dose at baseline) or placebo every 4 


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weeks (Q4W). Subjects weighing ≥90 kg at baseline will receive either 60 mg 
nemolizumab or placebo Q4W (no loading dose at baseline).
Subjects’ participation in the study will be up to 28 weeks. The study consists of 
a screening period (up to 4 weeks), a 16-week treatment period, and an 8-week 
follow up period (12 weeks after their last study drug injection). Refer to 
Figure 1 for an overview of study design.
Following provision of written informed consent, subjects with PN will be 
screened for enrolment in the study. Eligible subjects will return for a baseline 
visit where, following randomization, they will be administered either a dose of 
60 mg nemolizumab or placebo via 2 subcutaneous (SC) injections. Thereafter, 
study drug will be administered Q4W at Week 4, 8, and 12 by either a single SC
injection of either nemolizumab 30 mg or placebo for subjects weighing < 90 kg
at baseline or by two SC injections of either nemolizumab 30 mg or placebo for 
subjects weighing ≥90 kg at baseline. Refer to Table 1 for an overview of the 
study therapy. Efficacy and safety assessments will be performed at visits 
throughout the screening and treatment period, as outlined in the Schedule of 
Assessments (Table 5).
At the end of the 16-week treatment period, consenting subjects may be eligible 
to enter an active treatment/long-term extension (LTE) study 
(RD.06.SPR.202699). Subjects who participate in the LTE are not required to 
complete the follow-up visit. Subjects who do not participate in the LTE will 
return for a follow-up visit at Week 24 (12 weeks after the last study drug
injection). 
Subjects who prematurely discontinue the study drug will be asked to continue 
participation in the study and return for all remaining visits and assessments 
(including daily assessments of pruritus and sleep disturbance). Subjects who 
discontinue study drug due to required rescue therapy may be eligible to 
participate in the LTE study following completion of study visits through Week 
16. Subjects who discontinue the study prematurely should complete an early 
termination (ET) visit and a follow-up visit 12 weeks after the last study drug 
injection.
An independent data monitoring committee (IDMC) will review and monitor 
subject safety throughout the study, and an independent adjudication committee 
(IAC) will review all asthma-related events throughout the study. The IDMC 
and IAC charters provide details on the IDMC and IAC, including the plan of 


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analysis for outputs; the composition of the committees; and the procedures, 
roles, responsibilities and communications.
Figure 1.
Study Schema
Abbreviations: BL, baseline; W, week.


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Selection of 
Subjects:
Inclusion Criteria:
Individuals must meet all of the following criteria to be included in the study:
1.
Male or female and aged ≥18 years at the time of screening
2.
Clinical diagnosis of PN for at least 6 months with:
a.
Pruriginous nodular lesions on upper limbs, trunk, and/or 
lower limbs
b.
At least 20 nodules on the entire body with a bilateral 
distribution
c.
IGA score ≥ 3 (based on the IGA scale ranging from 0 to 4, in 
which 3 is moderate and 4 is severe) at both the screening and 
baseline visits
3.
Severe pruritus defined as follows on the PP NRS:

At the screening visit (Visit 1): PP NRS score is ≥ 7.0 for the 
24-hour period immediately preceding the screening visit

At the baseline visit (Visit 2): Mean of the daily intensity of 
the PP NRS score is ≥ 7.0 over the previous week;
Note: PP NRS score should be measured on at least 4 days 
during the week preceding the baseline visit. Rounding of the 
mean NRS score is not permitted.
4.
Female subjects of childbearing potential (ie, fertile, following 
menarche and until becoming post-menopausal unless permanently 
sterile) must agree to use at least 1 adequate and approved method of 
contraception throughout the study and for 12 weeks after the last study 
drug injection. 
Adequate and approved methods of contraception applicable for the 
subject and/or her partner are defined below:

True abstinence, when in line with the preferred and usual lifestyle 
of the subject. See Appendix 1 for details. Periodic abstinence (eg, 
calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception 

Progestogen-only oral hormonal contraception


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
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 
(eg, 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 3 months before the study

Bilateral vasectomy of male partner at least 3 months before the 
study
5.
Female subjects of non-childbearing potential must meet 1 of the 
following criteria:

Absence of menstrual bleeding for 1 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 3 months before the study
6.
Subject is willing and able to comply with all of the time commitments 
and procedural requirements of the clinical study protocol, including 
daily diary recordings by the subject using an electronic handheld 
device provided for this study
7.
Read, understood and signed an informed consent form (ICF) before 
any investigational procedure(s) are performed
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


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2.
Chronic pruritus resulting from another active condition other than PN, 
such as but not limited to scabies, lichen simplex chronicus, psoriasis, 
atopic dermatitis, contact dermatitis, acne, folliculitis, lichen planus, 
habitual picking/excoriation disorder, sporotrichosis, bullous 
autoimmune disease, end-stage renal disease, cholestatic liver disease 
(eg, primary biliary cirrhosis), or diabetes mellitus or thyroid disease 
that is not adequately treated, as per standard of care
3.
Unilateral lesions of prurigo (eg, only one arm affected)
4.
History of or current confounding skin condition (eg, Netherton 
syndrome, cutaneous T-cell lymphoma [mycosis fungoides or Sezary 
syndrome], chronic actinic dermatitis, dermatitis herpetiformis)
5.
Subjects meeting 1 or more of the following criteria at screening or 
baseline:
5a. Had an exacerbation of asthma requiring hospitalization in the 
preceding 12 months
5b. Reporting asthma that has not been well-controlled (ie, 
symptoms occurring on > 2 days per week, nighttime 
awakenings 2 or more times per week, or some interference 
with normal activities) during the preceding 3 months
5c. Asthma Control Test (ACT) ≤ 19 (only for subjects with a 
history of asthma)
5d. Peak expiratory flow (PEF) < 80% of the predicted value
Note: In the event that PEF is < 80% of the predicted value at 
the screening visit in subjects without any history of asthma or 
in subjects with history of asthma but with the ACT score >
19, PEF testing can be repeated once within 48 hours.
6.
Subjects with a current medical history of chronic obstructive 
pulmonary disease and/or chronic bronchitis
7.
Cutaneous infection within 1 week before the baseline visit, any 
infection requiring treatment with oral or parenteral antibiotics, 
antivirals, antiparasitics, or antifungals within 2 weeks before the 
baseline visit, or any confirmed or suspected coronavirus disease 
(COVID)-19 infection within 2 weeks before the screening or baseline 


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visit. Subjects may be rescreened once the infection has resolved. 
Resolution of COVID-19 infection can be confirmed by recovery 
assessment methods, as described in Section 8.4.2.
8.
Positive serology results (hepatitis B surface antigen [HBsAg] or 
hepatitis B core antibody [HBcAb], hepatitis C [HCV] antibody with 
positive confirmatory test for HCV [eg, polymerase chain reaction 
(PCR)], or human immunodeficiency virus 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). Subjects with negative 
confirmatory test for HCV can be included in this clinical study.
In the event of rescreening, the serology tests results (eg, HBV, HCV, 
HIV) from the first screening can be used by the investigator to assess 
the eligibility of rescreened subjects if those tests were performed 
within 6 weeks prior to the baseline visit.
9.
Requiring rescue therapy for PN during the screening period or 
expected to require rescue therapy within 4 weeks following the 
baseline visit
10. Subjects with active atopic dermatitis (signs and symptoms other than 
dry skin) in the last 3 months
Note: Subjects with atopic diathesis, as diagnosed by the medical 
history and/or laboratory analysis (ie, specific immunoglobulin E), are 
eligible for the study.
11. Neuropathic and psychogenic pruritus such as but not limited to 
notalgia paresthetica, brachioradial pruritus, small fiber neuropathy, 
skin picking syndrome, or delusional parasitosis
12. Having received any of the following treatments in the table below 
within the specified timeframe before the baseline visit:


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Treatments
Timeframe
Topical calcineurin inhibitors (tacrolimus, 
pimecrolimus), and topical corticosteroids
2 weeks
Topical vitamin D analogs
2 weeks
Topical or systemic PDE-4 inhibitors
2 weeks
Any other topical treatment other than moisturizer 
(eg, capsaicin, cryotherapy for treatment of PN)
2 weeks
Emollients or moisturizers with menthol, polidocanol 
or other having “anti-itch” claim
1 week
Systemic or intralesional corticosteroids 
(corticosteroid inhalers are permitted)
4 weeks 
Oral antihistamines (unless these treatments were 
taken at a stable dose for 3 months prior to screening 
or for a seasonal allergy)
1 week
Drugs with sedative effect such as benzodiazepines, 
imidazopyridines, barbiturates, sedative anti-
depressants (eg, amitriptyline), SSRIs (eg, 
paroxetine), or SNRIs, except if these treatments 
were taken at a stable dose for at least 3 months 
before screening
1 week
Phototherapy or tanning beds
4 weeks
Immunosuppressive or immunomodulatory drugs 
(eg, cyclosporine, methotrexate, thalidomide, oral 
tacrolimus, cyclophosphamide, azathioprine, 
mycophenolate mofetil, JAK inhibitors)
8 weeks or 5 half-lives 
(whichever is longer)
Biologics and their biosimilars (eg, etanercept, 
adalimumab, infliximab, omalizumab)
8 weeks or 5 half-lives 
(whichever is longer)
Dupilumab
10 weeks


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Treatments
Timeframe
Systemic retinoids
8 weeks or 5 half-lives 
(whichever is longer)
Systemic roxithromycin, erythromycin
1 week
Opioid antagonists (eg, naltrexone, naloxone), opioid 
partial/mixed agonists (eg, nalbuphine, butorphanol),
or opioid agonists (except when used for short 
term/acute pain); NK1 receptor antagonists (eg, 
aprepitant, serlopitant)
4 weeks or 5 half-lives 
(whichever is longer)
Gabapentinoids, unless used at a stable dose for at 
least 6 months or used for non-prurigo conditions
4 weeks
Cannabinoids (eg, dronabinol)
2 weeks
Alternative medicine for PN (eg, traditional Chinese 
medicine)
2 weeks
Live vaccines
12 weeks
Non-live vaccines
4 weeks
Abbreviations: JAK, Janus kinase; NK1, neurokinin; PDE-4, 
phosphodiesterase-4; PN, prurigo nodularis; SNRI, serotonin-norepinephrine 
reuptake inhibitor SSRI, selective serotonin reuptake inhibitor.
Note: Subjects should not interrupt ongoing treatment with medications 
important for the subject’s health for the sole purpose of participating in this 
study.
13. Previous participation in a clinical study with nemolizumab
14. Pregnant women (positive serum pregnancy test result at the screening 
visit or positive urine pregnancy test at the baseline visit), breastfeeding 
women, or women planning a pregnancy during the clinical study
15. History of lymphoproliferative disease or history of malignancy of any 
organ system within the last 5 years, except for:
o
Basal cell carcinoma, squamous cell carcinoma in situ 
(Bowen’s disease), or carcinomas in situ of the cervix that 


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have been treated and have no evidence of recurrence in the 
last 12 weeks before the screening visit, or;
o
Actinic keratoses that have been treated
16. History of hypersensitivity (including anaphylaxis) to an 
immunoglobulin product (plasma-derived or recombinant, eg, 
monoclonal antibody) or to any of the study drug excipients
17. Current active or 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.
In the event of rescreening, the TB tests result from the first screening 
can be used by the investigator to assess the eligibility of rescreened 
subjects if the test was performed within 6 weeks prior to the baseline 
visit.
18. Known or suspected immunosuppression or unusually frequent, 
recurrent, severe, or prolonged infections as per investigator judgment
19. Any medical or psychological condition or 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, or may interfere with study 
assessments (eg, poor venous access or needle-phobia)
20. History of alcohol or substance abuse within 6 months of the screening 
visit
21. Planned or expected major surgical procedure during the clinical study
22. Subject is unwilling to refrain from using prohibited medications 
during the clinical study (see Section 9.10.3)


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23. Currently participating or participated in any other study of an 
investigational drug or device, within the past 8 weeks (or 5 half-lives 
of the investigational drug, whichever is longer) before the screening 
visit, or is in an exclusion period (if verifiable) from a previous study
For subjects accepting optional biopsy sampling (by signing an additional 
consent), the following exclusion criteria also apply. If any of the below criteria 
are met, biopsy samples must not be collected: 
24. History of coagulation disorders 
25. Known sensitivity to local anesthetics 
26. Using platelet aggregation inhibitors, or anticoagulants (sporadic intake 
or continuous low-dose intake of aspirin or other non-steroidal anti-
inflammatory drugs is allowed) 
27. History or physical evidence of keloids or hypertrophic scarring 
resulting from skin trauma. The clinical examination will include the 
observation of scars.
Planned Sample 
Size:
Approximately 270 subjects are planned to be randomized in this study
Therapy:
Nemolizumab (CD14152) or placebo will be provided as lyophilized powder for 
solution for subcutaneous injection only after reconstitution in a single-use, pre-
filled, dual-chamber syringe (DCS).
During the treatment period, eligible subjects will be randomized to receive 
either nemolizumab (CD14152) or placebo, administered Q4W for 16 weeks 
(last injection at Week 12). Subjects weighing < 90 kg at baseline will receive
either nemolizumab 30 mg or placebo via a single SC injection (with a loading 
dose of 60 mg on Day 1/baseline); subjects weighing ≥90 kg at baseline will 
receive either nemolizumab 60 mg or placebo via two SC injections at all visits 
(no loading dose).
Subjects will have the option to self-inject study drug while at the study center 
under staff supervision. Subjects will be trained on injecting the study drug and 
will be allowed to inject study drug at all subsequent visits, while at the study 
center, under staff supervision. If the subject does not wish to perform the 
injections, study staff can administer study drug at each visit.


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Table 1.
Investigational therapy
Investigational product
Placebo
Name
Nemolizumab
Nemolizumab placebo
Internal code
CD14152
NA
Pharmaceutical 
form
Lyophilized powder in a 
DCS for solution for 
injection 
Lyophilized powder in a 
DCS for solution for 
injection 
Packaging
DCS
DCS
Storage 
conditions
Stored between 2°C to 
8°C (36°F to 46°F),
protected from light, 
protected from freezing
Stored between 2°C to 
8°C (36°F to 46°F),
protected from light, 
protected from freezing
Dosage
Subjects weighing < 90 kg 
at baseline: 30 mg, with a 
loading dose of 60 mg at 
baseline;
Subjects weighing ≥90 kg 
at baseline: 60 mg
Not applicable
Route
SC use by subjects or 
clinic staff after 
reconstitution
SC use by subjects or 
clinic staff after 
reconstitution
Dose regimen
Subjects weighing < 90 kg 
at baseline: 2 injections at 
baseline, then 1 injection 
Q4W;
Subjects weighing ≥90 kg 
at baseline: 2 injections at 
baseline, then 2 injections
Q4W
Subjects weighing < 90 kg 
at baseline: 2 injections at 
baseline, then 1 injection 
Q4W;
Subjects weighing ≥90 kg at 
baseline: 2 injections at 
baseline, then 2 injections
Q4W
Treatment 
duration
16 weeks with last 
injection at Week 12
16 weeks with last 
injection at Week 12
Abbreviations: DCS, dual chamber syringe; Q4W, every 4 weeks; SC, 
subcutaneous.
Rescue therapies
If deemed to be medically necessary by the investigator (eg, to control 
intolerable signs/symptoms of PN), rescue therapies can be prescribed to the 
subjects at any time during the study except during the screening period. 


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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 4 weeks after baseline to allow a 
minimum time for study drug exposure.
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.
Whenever possible, investigators should first use topical medication or oral 
antihistamines as rescue therapy before escalating to other systemic therapies. If 
subjects receive topical treatments, oral antihistamines, or ultraviolet B (UVB) 
phototherapy as rescue therapy, study drug administration should be continued 
unless there is a concern according to the investigator’s judgment. If subjects 
receive systemic rescue therapy (other than oral antihistamines), intralesional 
corticosteroids, or oral psoralen + ultraviolet A (PUVA) treatment, the study 
drug administration must be permanently discontinued. See Section 9.10.2 for a 
complete list of allowed rescue therapies.
Subjects requiring rescue medication (with or without study drug
discontinuation) may be eligible for LTE participation. These subjects must 
continue with study visits through Week 16 to be considered for LTE 
participation. 
Treatment 
Duration:
The expected duration of each subject’s participation in the study is up to 28
weeks, including a screening period (up to 4 weeks), a 16-week treatment 
period, and an 8-week follow-up period (12-weeks after the last study drug
injection).
Subjects who rollover into the LTE are not required to complete the follow-up 
visit.
Efficacy:
The following efficacy assessments are planned according to the Schedule of 
Assessments (Table 5):

IGA

Peak and Average Pruritus NRS

PAS 

SD NRS

Subject Sleep Diary

PN-associated pain intensity and frequency

PGAD and PGAT


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
Clinical photographs (optional and subject to a specific, separate ICF at 
selected sites)
The following quality of life assessments are planned according to the Schedule 
of Assessments (Table 5):

DLQI

HADS

EQ-5D
Additional Patient-Reported Outcomes assessments are planned according to the 
Schedule of Assessments (Table 5), as follows: 

Patient Global Impression of Severity-Pruritus 

Patient Global Impression of Change-Pruritus 

Patient Global Impression of Severity-Sleep Disturbance 

Patient Global Impression of Change-Sleep Disturbance
Safety:
The following safety assessments are planned according to the Schedule of 
Assessments (Table 5):

AEs, including TEAEs, AESIs, and SAEs

Physical examination and vital signs 

Clinical laboratory tests 

Electrocardiogram (ECG) 

Respiratory examination and assessments
Pharmacokinetics, 
Immunogenicity, 
Pharmacodynamics, 
and
Pharmacogenomics:
The following assessments are planned according to the Schedule of 
Assessments (Table 5):

Serum nemolizumab concentrations

Anti-drug antibody (ADA) assessments (screening, confirmatory, titer, 
and neutralizing antibody (NAb)

Biomarkers (eg, interleukin-31 and/or other biomarkers) from blood,
stratum corneum (D-Squames), and optional skin biopsies (subject to 
specific, separate ICF) (select centers only)

Pharmacogenomic testing (optional and subject to a specific, separate 
ICF)
Statistical Methods 
and Planned 
Analyses:
The intent-to-treat (ITT) population will consist of all randomized subjects. The 
safety population will include all randomized subjects who receive at least 1 
dose of study drug. The Per-Protocol (PP) population will consist of all subjects 
in the ITT population who have no major protocol deviations that would have a 


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significant effect on the efficacy of the study treatment. The ITT population will 
be the primary population for all efficacy analyses, and all safety data will be 
summarized based on the safety population. The PP population will be used as 
the population for sensitivity analyses of the primary and key secondary efficacy 
endpoints. 
Primary Efficacy Endpoints:
There are 2 primary efficacy endpoints
-
The proportion of subjects with at least 4 points of improvement in PP
NRS at Week 16.
-
The proportion of subjects reporting success on the IGA at Week 16, 
defined as an IGA response of 0 [Clear] or 1 [Almost clear] and a ≥2-
point reduction from baseline. 
Both primary endpoints will be analyzed using a Cochran-Mantel-Haenszel 
(CMH) test adjusted for randomized stratification variable analysis center and 
baseline body weight (< 90 kg and ≥90 kg). The estimate of the treatment 
difference (nemolizumab minus placebo), p-value and 2-sided 95% confidence 
interval will be presented. Missing data at Week 16, and any data for subjects in 
receipt of rescue medication up to Week 16, will be regarded as a non-responder 
for the primary analysis of the endpoint.
A number of sensitivity analyses are included for the primary endpoints, as per 
Section 15.4.3.
Key Secondary Endpoints:
All binary key secondary efficacy endpoints will be analyzed as per the primary 
endpoint. 
Additionally, sensitivity analyses using multiple-imputation assuming missing at 
random (MAR) and observed case (OC) analysis will be performed for key 
secondary endpoints as outlined in Section 15.4.4.
Secondary Efficacy Endpoints:
Binary secondary endpoints will be analyzed in the same manner as the primary 
endpoint; missing values will be imputed as non-responder. 
Continuous secondary endpoints (except EQ-5D, HADS) will be analyzed using 
multiple-imputation assuming MAR and using mixed effect model for repeated 
measure (MMRM) approach, including analysis center as factor and baseline as 


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covariate where applicable. The estimated treatment difference for each 
endpoint at each visit will be displayed in the summary of statistical analysis 
together with the 95% CI and associated p-value. EQ-5D and HADS endpoints 
will be analyzed using analysis of covariance (ANCOVA) including analysis 
center as factor and baseline as covariate. All secondary endpoints will be 
presented descriptively using OC. 
Further details will be provided in the Statistical Analysis Plan.
Multiplicity:
To control the type I error at 5%, a fixed sequential testing approach will be 
implemented. For testing purposes both primary endpoints will be tested first in 
a predefined order (as listed in Section 15.4.1) at 5% significance level, and 
testing of key secondary endpoints will start only if both primary endpoints are 
successful at 5% level of significance. Key secondary endpoints will be tested in 
an order listed in section 15.4.4, stopping when a non-significant result (p> 0.05) 
is found.
Safety Analyses:
The incidence of TEAEs, vital signs, laboratory values and ECG will be 
summarized by treatment groups. 
Pharmacokinetics (PK):
Summary statistics will be used to describe the PK profile of nemolizumab. 
Individual and mean serum concentration versus time curves will be presented 
for both linear and semi-log scales. Descriptive statistics of the serum 
concentrations versus time will be presented as well as for the PK parameters. 
Sample size:
In order to achieve at least 90% power for both primary endpoint at 5%
significance level, 270 (180 nemolizumab, 90 placebo) subjects will be required 
to detect the following difference in both primary endpoints between treatment 
groups with 2:1 randomization, assuming 15% dropout rate during treatment 
period. 
NRS responders (≥4 point reduction from baseline): Based on phase 2a data, it is 
expected that the NRS response at Week 16 would be 50% in Nemolizumab 
group and 20% in placebo.
IGA response (0/1): It is expected that the IGA response at Week 16 would be 
30% in Nemolizumab group and 10% in placebo.  


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3
TABLE OF CONTENTS
1
CLINICAL STUDY PROTOCOL..............................................................................1
PROTOCOL APPROVAL SIGNATURES ........................................................................2
INVESTIGATOR SIGNATURE PAGE.................................................................................3
2
SYNOPSIS ..................................................................................................................5
3
TABLE OF CONTENTS ..........................................................................................23
LIST OF IN-TEXT TABLES .......................................................................30
LIST OF IN-TEXT FIGURES......................................................................30
4
LIST OF ABBREVIATIONS ...................................................................................31
5
INTRODUCTION.....................................................................................................35
BACKGROUND ON PRURIGO NODULARIS.........................................35
BACKGROUND ON NEMOLIZUMAB.....................................................37
Nonclinical Studies ......................................................................................37
Clinical Pharmacokinetic Profile and Immunogenicity...............................37
Clinical Studies ............................................................................................38
Phase 2a Safety and Efficacy Study: Prurigo Nodularis..............................39
Phase 2b Dose-Ranging Study: Atopic Dermatitis......................................40
CLINICAL RISKS/BENEFITS OF NEMOLIZUMAB...............................42
DOSE SELECTION RATIONALE .............................................................44
6
STUDY OBJECTIVES AND ENDPOINTS ............................................................47
STUDY OBJECTIVES.................................................................................47
Primary Objective ........................................................................................47
Secondary Objectives...................................................................................47
STUDY ENDPOINTS..................................................................................47
Primary Endpoints........................................................................................47
Secondary Endpoints....................................................................................47


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6.2.2.1
Key Secondary Efficacy Endpoints........................................................47
6.2.2.2
Secondary Efficacy Endpoints ...............................................................48
6.2.2.3
Safety Endpoints ....................................................................................49
6.2.2.4
Pharmacokinetic Endpoints....................................................................49
6.2.2.5
Immunogenicity Endpoints ....................................................................50
7
INVESTIGATIONAL PLAN ...................................................................................51
DESCRIPTION OF OVERALL STUDY DESIGN AND PLAN................51
DISCUSSION OF STUDY DESIGN...........................................................54
END OF STUDY..........................................................................................56
8
SELECTION OF STUDY POPULATION...............................................................57
INCLUSION CRITERIA..............................................................................57
EXCLUSION CRITERIA ............................................................................58
RESCREENING...........................................................................................64
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENTS .....64
Pregnancy.....................................................................................................66
COVID-19 Infection ....................................................................................68
9
STUDY TREATMENTS ..........................................................................................69
DETAILS OF STUDY DRUG.....................................................................69
PACKAGING AND LABELING ................................................................70
STUDY DRUG PREPARATION ................................................................71
STUDY DRUG INJECTION/ADMINISTRATION....................................71
STUDY DRUG MANAGEMENT...............................................................72
Storage of Study Drug..................................................................................72
Study Drug Accountability ..........................................................................72
Dispensing and Return of Study Drug .........................................................73
PRODUCT TECHNICAL COMPLAINTS..................................................74


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MEASURES TO MINIMIZE BIAS: STUDY TREATMENT 
ASSIGNMENT AND BLINDING...............................................................74
Method of Study Treatment Assignment.....................................................74
Study Blinding .............................................................................................75
DOSAGE MODIFICATION........................................................................76
TREATMENT COMPLIANCE ...................................................................77
PRIOR AND CONCOMITANT THERAPY ...............................................77
Permitted Concomitant Therapy ..................................................................78
Rescue Therapy............................................................................................79
Prohibited Therapy.......................................................................................80
10
STUDY PROCEDURES...........................................................................................84
INFORMED CONSENT ..............................................................................84
STUDY ASSESSMENTS AND PROCEDURES........................................84
Unscheduled Visit........................................................................................92
11
EFFICACY ASSESSMENTS...................................................................................93
INVESTIGATOR GLOBAL ASSESSMENT .............................................93
PRURIGO ACTIVITY SCORE ...................................................................93
NUMERIC RATING SCALES ....................................................................93
Itch/Pruritus Numeric Rating Scales............................................................93
Sleep Disturbance Numeric Rating Scale ....................................................94
SUBJECT SLEEP DIARY ...........................................................................94
PAIN FREQUENCY AND INTENSITY.....................................................95
PATIENT-REPORTED OUTCOMES ASSESSMENTS............................95
Patient Global Assessment of Disease.........................................................95
Patient Global Assessment of Treatment.....................................................95
Patient Global Impression of Severity - Pruritus .........................................96
Patient Global Impression of Change - Pruritus ..........................................96


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Patient Global Impression of Severity - Sleep Disturbance.........................96
Patient Global Impression of Change - Sleep Disturbance..........................97
QUALITY OF LIFE QUESTIONNAIRES..................................................97
Dermatology Life Quality Index..................................................................97
Hospital Anxiety and Depression Scale.......................................................97
EuroQoL 5 Dimension Instrument...............................................................97
CLINICAL PHOTOGRAPHS......................................................................98
12
SAFETY ASSESSMENTS .......................................................................................99
VITAL SIGNS..............................................................................................99
HEIGHT AND WEIGHT .............................................................................99
PHYSICAL EXAMINATION......................................................................99
12-LEAD ELECTROCARDIOGRAM ......................................................100
CLINICAL LABORATORY EVALUATION...........................................100
Hematology................................................................................................102
Clinical Chemistry .....................................................................................102
Urinalysis ...................................................................................................102
Pregnancy Testing......................................................................................102
Virology .....................................................................................................103
Tuberculosis Testing..................................................................................103
12.5.6.1
Tuberculosis Definitions ......................................................................103
12.5.6.2
Tuberculosis Screening ........................................................................104
RESPIRATORY ASSESSMENTS ............................................................104
Asthma Control Test ..................................................................................104
Respiratory Examination............................................................................105
Peak Expiratory Flow.................................................................................105
Respiratory Referrals .................................................................................106


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ADVERSE EVENTS..................................................................................107
Adverse Events ..........................................................................................107
Adverse Events of Special Interest ............................................................110
Serious Adverse Events .............................................................................112
Procedure for Reporting Serious Adverse Events......................................112
Procedure for Reporting Adverse Events of Special Interest ....................114
Suspected Unexpected Serious Adverse Reactions ...................................115
Procedures for Reporting Pregnancy .........................................................116
Overdose ....................................................................................................117
INDEPENDENT DATA MONITORING COMMITTEE .........................117
INDEPENDENT ADJUDICATION COMMITTEE .................................117
13
PHARMACOKINETICS ........................................................................................118
PHARMACOKINETIC SAMPLING ........................................................118
Blood Samples ...........................................................................................118
CD14152 Quantification in Biological Sampling......................................118
PK parameters, PopPK and PK/PD analyses .............................................118
14
OTHER ASSESSMENTS.......................................................................................120
PHARMACOGENOMICS.........................................................................120
IMMUNOGENICITY.................................................................................121
PHARMACODYNAMIC BIOMARKERS................................................121
Blood Samples for PD................................................................................122
Stratum Corneum (D-Squames) Samples for PD ......................................122
Skin biopsies for PD (optional)..................................................................122
15
STATISTICAL ANALYSIS ...................................................................................124
DATASETS OR STUDY POPULATIONS ANALYZED ........................125
SUBJECT DISPOSITION..........................................................................126
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ...126


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EFFICACY ANALYSIS ............................................................................126
Primary Efficacy Endpoints.......................................................................126
Analysis of Primary Efficacy Endpoints....................................................126
Sensitivity Analyses of the Primary Endpoint ...........................................127
Key Secondary Efficacy Endpoints ...........................................................129
Multiplicity/Multiple comparisons ............................................................130
Secondary Efficacy/QoL Endpoints...........................................................130
Handling of small study sites.....................................................................132
Subgroup Analysis .....................................................................................132
SAFETY ANALYSIS.................................................................................133
PHARMACOKINETIC ANALYSIS.........................................................133
OTHER ANALYSES .................................................................................134
Psychometric Validation Analyses ............................................................134
DETERMINATION OF SAMPLE SIZE...................................................134
PROTOCOL DEVIATIONS ......................................................................135
INTERIM ANALYSIS ...............................................................................136
16
STUDY MANAGEMENT......................................................................................137
APPROVAL AND CONSENT ..................................................................137
Regulatory Guidelines................................................................................137
Institutional Review Board/Independent Ethics Committee......................137
Informed Consent.......................................................................................137
DATA MANAGEMENT............................................................................137
SOURCE DOCUMENTS...........................................................................138
RECORD RETENTION.............................................................................138
MONITORING...........................................................................................139
QUALITY CONTROL AND QUALITY ASSURANCE..........................139
PROTOCOL AMENDMENT AND PROTOCOL DEVIATION..............140


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Protocol Amendment .................................................................................140
Protocol Deviations....................................................................................140
ETHICAL CONSIDERATIONS................................................................140
FINANCING AND INSURANCE.............................................................141
PUBLICATION POLICY/DISCLOSURE OF DATA ..............................141
17
REFERENCES........................................................................................................142
18
APPENDICES.........................................................................................................146
APPENDIX 1: CONTRACEPTION GUIDELINES....................................................146
APPENDIX 2: SPECIFIC GUIDANCE FOR STUDY CONDUCT AND SUBJECT 
SAFETY DURING THE COVID-19 PANDEMIC ...................................148
APPENDIX 3: CYP SUBSTRATES WITH NARROW THERAPEUTIC INDEX....158
APPENDIX 4: INVESTIGATOR GLOBAL ASSESSMENT (IGA)..........................159
APPENDIX 5: PRURIGO ACTIVITY SCORE (PAS) ...............................................160
APPENDIX 6: PRURITUS (PEAK AND AVERAGE) NUMERIC RATING SCALE 
(PP NRS and AP NRS)...............................................................................164
APPENDIX 7: SLEEP DISTURBANCE NUMERIC RATING SCALE (SD NRS) ..165
APPENDIX 8: MORNING SUBJECT SLEEP DIARY ..............................................166
APPENDIX 9: PAIN FREQUENCY AND INTENSITY............................................170
APPENDIX 10: PATIENT GLOBAL ASSESSMENT OF DISEASE (PGAD) .........171
APPENDIX 11: PATIENT GLOBAL ASSESSMENT OF TREATMENT (PGAT)..172
APPENDIX 12: PATIENT GLOBAL IMPRESSION OF SEVERITY – PRURITUS 
(PGIS-P)......................................................................................................173
APPENDIX 13: PATIENT GLOBAL IMPRESSION OF CHANGE – PRURITUS 
(PGIC-P) .....................................................................................................174
APPENDIX 14: PATIENT GLOBAL IMPRESSION OF SEVERITY – SLEEP 
DISTURBANCE (PGIS-SD)......................................................................175
APPENDIX 15: PATIENT GLOBAL IMPRESSION OF CHANGE – SLEEP 
DISTURBANCE (PGIC-SD) .....................................................................176
APPENDIX 16: DERMATOLOGY LIFE QUALITY INDEX (DLQI)......................177
APPENDIX 17: HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS) ......179


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APPENDIX 18: EUROQoL-5 DIMENSION (EQ-5D) ...............................................181
APPENDIX 19: ASTHMA CONTROL TEST (ACT).................................................182
APPENDIX 20: EUROQoL-5 DIMENSION (EQ-5D) REMOTE VERSION............183
LIST OF IN-TEXT TABLES
Table 1.
Investigational therapy......................................................................................18
Table 2.
Restricted Prior Treatments ..............................................................................61
Table 3.
Study Drugs.......................................................................................................70
Table 4.
Prohibited Therapy............................................................................................81
Table 5.
Schedule of Assessments ..................................................................................86
LIST OF IN-TEXT FIGURES
Figure 1. Study Schema......................................................................................................9
Figure 2. Study Design.....................................................................................................53


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4
LIST OF ABBREVIATIONS
Abbreviation
Definition
ACT
Asthma Control Test
AD
atopic dermatitis
ADA
anti-drug antibodies
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AP 
Average Pruritus 
AST
aspartate aminotransferase
BDRM
Blind Data Review Meeting
BSA
body surface area
CFR
Code of Federal Regulations
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
COVID-19
coronavirus disease-19
CPK
creatine phosphokinase
CRF
case report form
CRO
contract research organization
DBL
database lock
DCS
dual-chamber syringe
DLQI
Dermatology Life Quality Index
EASI
Eczema Area and Severity Index
eCRF
electronic case report form
ECG
electrocardiogram
EDC
electronic data capture
EQ-5D
EuroQoL 5-Dimension
ET
early termination
GCP
good clinical practice
HADS
Hospital Anxiety and Depression Scale


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Abbreviation
Definition
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIPAA
Health Insurance Portability Accountability Act
HIV
human immunodeficiency virus
IAC
independent adjudication committee
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
independent data monitoring committee
IEC
independent ethics committee
IGA
Investigator Global Assessment
IgE
immunoglobulin e
IgG
immunoglobulin g
IND
Investigational New Drug
IRB
institutional review board
IRR
injection-related reaction
IRT
interactive response technology
ITT
intent-to-treat
JAK
Janus kinase
LOCF
last observation carried forward
LTE
long-term extension
MAR
missing at random
MI
multiple imputation
MMRM
mixed-effect models for repeated measures
NAb
neutralizing antibodies
NKR1
Neurokinin receptor 1
NONMEM
Nonlinear Mixed Effect Modeling
NRS
numeric rating scale
OC
observed case
PAS
Prurigo Activity Score


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Abbreviation
Definition
PCR
polymerase chain reaction
PD
pharmacodynamic
PEF
peak expiratory flow
PGAD
Patient Global Assessment of Disease
PGAT
Patient Global Assessment of Treatment
PGIC-P
Patient Global Impression of Change - Pruritus
PGIC-SD
Patient Global Impression of Change – Sleep Disturbance
PGIS-P
Patient Global Impression of Severity - Pruritus
PGIS-SD
Patient Global Impression of Severity – Sleep Disturbance
PGx
pharmacogenomic
pH
potential of hydrogen
PI
principal investigator
PK
pharmacokinetic
PKAP
pharmacokinetic analysis population
PN
prurigo nodularis
PopPK
Population Pharmacokinetic
PP
per-protocol
PP NRS
Peak Pruritus Numeric Rating Scale
PRO
Patient-reported outcome
PT
preferred term
PTC
product technical complaint
Q4W
every 4 weeks
QoL
quality of life
RTSM
randomization and trial supply management
SAE
serious adverse event
SAF
safety population
SAP
statistical analysis plan
SC
subcutaneous
SD NRS
Sleep Disturbance Numeric Rating Scale
SIN
Subject identification number
SNRI
serotonin-norepinephrine reuptake inhibitor


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Abbreviation
Definition
SOC
system organ class
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
UP
uremic pruritus
UPT
urine pregnancy test
US
United States
VAS
visual analogue scale
WASO
wakefulness after sleep onset
WOCBP
women of childbearing potential


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5
INTRODUCTION
BACKGROUND ON PRURIGO NODULARIS
Prurigo nodularis (PN) is characterized by the presence of multiple (up to hundreds), 
symmetrically distributed, highly pruritic, hyperkeratotic, erosive or crusted nodules and 
papules.1 Chronic itching is believed to induce and maintain the characteristic PN skin 
lesions through an itch-scratch cycle.2 This leads to an impaired quality of life (QoL) and 
high burden due not only to the severe itch but also the chronic skin lesions and lack of 
treatment options.3
Limited data exist about the incidence and prevalence of PN in the general population, 
but it seems to be more frequent and intense in females and the elderly.4,5
The physiopathology of PN is still not fully understood; however, the interactions 
between cutaneous nerve fibers, neuropeptides and immune cells seem to play an 
important role in the onset of PN.6 The etiology of PN is associated with a subclinical 
small fiber neuropathy based on the observed reduction of intraepidermal nerve fiber 
density in patient biopsies and the epidemiological association of PN with various 
etiologies of peripheral neuropathies.7,8,9 Further supporting this theory is the observation 
of a positive response in some patients to gabapentin and pregabalin, commonly utilized 
treatments for pain and neuropathy.10 PN also has a neuroinflammatory component as 
changes in the morphology of skin nerve fibers and increased dermal neural hyperplasia 
are associated with concomitant inflammation caused by T lymphocytes, eosinophils, 
granulocytes and mast cells.6
As itch is the hallmark symptom of PN, a role for neural sensitization followed by lesion 
appearance and development of a chronic itch-scratch cycle has been suggested. 
A large spectrum of underlying conditions that induce chronic pruritus can be associated 
with PN, including dermatological (eg, atopic dermatitis), systemic (eg, chronic kidney 
failure), neurological (eg, brachioradial pruritus), and psychiatric or mixed origin 
disorders.11


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Only a few studies have described the incidence and the strength of association of 
different co-morbidities in a representative cohort of patients with PN.4 A large study of 
PN patients at a major academic center in the United States noted associations of PN with 
chronic kidney disease, Type II Diabetes, and HIV.12 Further, data from US claims 
databases confirmed these associations.5 A subset of patients with PN also have a 
concomitant atopic diathesis, occurring in nearly half of subjects with PN in a small 
European study in a predominantly Caucasian population. Atopic diathesis was also 
found to predict a significantly earlier age of onset (median age of 19 years) compared to 
non-atopic patients (median age of 48 years).13
Psychosocial disorders are also significantly associated with PN. Rowland Payne et al.,14
found that more than 50% of their PN patients had a history of depression or anxiety 
requiring medical intervention.
The goal of PN treatment is to break the itch-scratch cycle and allow the skin to heal. 
However, treatment of PN is notoriously challenging and frustrating for both 
dermatologists and patients, as the response to current therapy options is typically limited 
or associated with adverse events (AEs). There are no standardized or approved therapies
for PN to date and evidence from controlled studies is limited.10 The difficulty in treating 
this disease is reflected in the wide range of treatments proposed in the literature.
The current treatment recommendations for PN include identification and treatment of 
any underlying disease, moisturizers and antipruritics, topical therapies (corticosteroids, 
calcineurin inhibitors), and oral antihistamines as first-line agents.15 Phototherapy, oral or 
intra-lesional steroids, topical vitamin D3 (calcipotriol), capsaicin, cryotherapy and 
antidepressants (amitriptyline, selective serotonin re-uptake inhibitors) are used as 
second-line therapies with variable efficacy. In third-line, systemic treatments such as 
cyclosporine,16 antiepileptic drugs (gabapentin, pregabalin)17 and thalidomide18 showed 
moderate-to-good response in pruritus reduction after several months of administration, 
but their use is limited by their unfavorable safety profile. Other off-label therapeutic 
options proposed for pruritus based on limited evidence include opioid receptor agonists 
and antagonists (naltrexone),19 NKR1-antagonists (aprepitant),20 and antibiotics 
(roxithromycin, erythromicin).21


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The T-cell-derived cytokine interleukin-31 (IL-31) has been suggested to be a key player 
in the development of pruritus in PN. Skin biopsies from PN patients with an atopic 
background showed a 50-fold upregulation of IL-31 mRNA compared to skin from 
healthy individuals and a 4.5-fold upregulation compared to skin from atopic dermatitis 
(AD) patients.22 A significantly higher level of IL-31 mRNA was also observed in PN 
patients with unknown AD background compared to normal skin.23
IL-31 is preferentially produced by T helper 2 (Th2) cells, following induction by IL-4.24
The IL-31 receptor A (IL-31RA) has been found to be expressed in several tissues 
including the dorsal root spinal ganglia, where the cell bodies of cutaneous sensory 
neurons reside,22 as well as keratinocytes. IL-31 binds to IL-31RA, forming a 
heterodimer with Oncostatin M receptor (OSMR), which activates the down-stream 
JAK/STAT signaling pathway and transmits signals into the cell.25, 26
Taken together, IL-31 seems to be an important cytokine for the regulation of PN and a 
potential therapy target.
BACKGROUND ON NEMOLIZUMAB
Nemolizumab is a humanized anti-human IL-31 receptor A (RA) monoclonal modified 
immunoglobulin G (IgG) 2 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.
Nemolizumab inhibits the binding of IL-31 to IL-31RA and subsequent signal 
transduction.
Nonclinical Studies
Non-clinical studies in mice, cynomolgus monkeys, and dogs have demonstrated a role 
for IL-31 in pruritus models that were inhibited by administration of anti-IL-31 or anti-
IL-31RA monoclonal antibodies.27-31 The Investigator’s Brochure (IB) contains detailed 
information on nonclinical studies. 
Clinical Pharmacokinetic Profile and Immunogenicity
Nemolizumab PK profile was extensively assessed in subjects with AD in Phase 1, 2, and 
2b studies (Studies CIM001JP, CIM003JG, and RD.03.SPR.114322, respectively) and 


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after repeated doses and in subjects with PN (Phase 2 study, RD.03.SPR.115828). 
Similar nemolizumab systemic exposure was observed in subjects with AD and in 
subjects with PN when treated with the same dose (0.5 mg/kg). 
The similarity in nemolizumab exposure between the PN and AD subjects was also 
confirmed using popPK modelling.  Overall pharmacokinetic assessments after 
subcutaneous (SC) injections of weight-based (0.1 to 3 mg/kg) or flat (10 to 90 mg) doses 
showed a dose proportional increase of nemolizumab serum concentrations after a single 
(mg/kg) injection and a less than proportional increase after repeated (mg/kg and flat) 
administrations. The terminal elimination half-life of nemolizumab was around 2 weeks 
after single and repeated administrations. Steady state concentrations were achieved from 
week 16 of treatment following single SC injections and from Week 4 of treatment when 
a loading (flat 2x) dose was administered at the baseline injection. Limited systemic 
accumulation was observed after repeated administrations.
The IB contains additional detailed information on nemolizumab pharmacokinetics.
Immunogenicity results showed nemolizumab to have a very low potential of inducing 
ADA in subjects with AD or in subjects with PN. Only one treatment related ADA-
positive subjects was reported out of the 34 subjects with PN receiving the treatment. No 
subjects had positive ADA that included IgE and no subjects developed neutralizing 
antibodies (NAb).
Clinical Studies
One phase 2 study with nemolizumab has been completed in PN subjects. Additional 
studies have been completed in healthy subjects, subjects with AD, and subjects with 
uremic pruritus.  Results of phase 2 studies in PN and AD subjects are summarized 
below. The IB contains additional detailed information on clinical studies conducted with 
nemolizumab. 


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Phase 2a Safety and Efficacy Study: Prurigo Nodularis
The phase 2a study (RD.03.SPR.115828) was a randomized, placebo-controlled, double-
blind, parallel-group, multicenter study to evaluate the safety and efficacy of 
nemolizumab in subjects suffering from PN over a 12-week treatment period. 
A total of 70 subjects were randomized: 36 subjects were randomized to placebo and 34 
subjects were randomized to nemolizumab 0.5 mg/kg. Sixty subjects (85.7%) completed 
the study. Demographic characteristics were similar in both treatment groups. Disease 
characteristics at baseline were similar in both treatment groups, with the exception of the 
Prurigo Activity Score (PAS) at baseline, which was slightly higher in the placebo 
compared with the nemolizumab group, and more subjects in the nemolizumab group had 
a severe Investigator Global Assessment (IGA) score compared with the placebo group.
The primary efficacy endpoint was percent change from baseline in Peak Pruritus 
Numeric Rating Scale (PP NRS) to Week 4 (weekly average of the peak). Nemolizumab 
was clinically and statistically significantly superior to placebo in reducing the PP NRS 
scores at Week 4 (difference between treatment groups -38.0%; 95% confidence interval 
[CI] -51.0, -25.0; p<0.001). 
The proportion of subjects with IGA success, a secondary endpoint, was higher in the 
nemolizumab group compared with the placebo group at Week 12 and at a follow-up visit 
at Week 18, and the differences were statistically significant (Week 12: difference 17.2%; 
p=0.020; Week 18: difference 32.0%; p=0.001).
Secondary endpoints also included PP NRS scores at other time points, Average Pruritus 
(AP) NRS, PP and AP Verbal Rating Scale, Dynamic Pruritus Scale, and PAS. 
Improvements were statistically significantly greater in the nemolizumab group than in
the placebo group at all time points for pruritus endpoints and at or before Week 12 for 
PAS endpoints.
The most frequently reported treatment-emergent adverse event (TEAE) was 
nasopharyngitis, the incidence of which was similar in the nemolizumab group (5 
subjects, 14.7%) and the placebo group (4 subjects, 11.1%). The incidence of 
neurodermatitis was higher in the placebo group (5 subjects, 13.9%) compared with the 


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nemolizumab group (2 subjects, 5.9%). The incidence of atopic dermatitis was higher in 
the nemolizumab group (3 subjects, 8.8%) compared with the placebo group (0 subjects). 
The percentage of subjects with severe TEAEs was higher in the nemolizumab group (5 
subjects, 14.7%) compared with the placebo group (1 subject, 2.8%). The incidence of 
TEAEs leading to permanent discontinuation of the study drug was similar between the 
nemolizumab and placebo groups.
The incidence of treatment-emergent SAEs was similar between the nemolizumab group 
(4 subjects, 11.8%) and the placebo group (3 subjects, 8.3%). Neurodermatitis was the 
most frequently reported treatment-emergent SAE, for which all subjects were in the 
placebo group (3 subjects, 8.3%). One subject in the nemolizumab group had a treatment-
emergent SAE related to study drug (dermatitis psoriasiform). There were no deaths 
reported during the study.
Phase 2b Dose-Ranging Study: Atopic Dermatitis
The phase 2b study (RD.03.SPR.114322) was a randomized, placebo-controlled, double-
blind, parallel-group, dose-ranging study to evaluate the efficacy, safety, and 
pharmacokinetics of various doses of nemolizumab in moderate-to-severe AD subjects 
with severe pruritus (PP NRS ≥7).
A total of 226 adult subjects were randomized: 57 subjects were randomized to placebo 
and 169 subjects were randomized to nemolizumab arms (55 subjects to 10 mg, 57 
subjects to 30 mg, and 57 subjects to 90 mg). Overall, all demographic and baseline 
disease characteristics were similar in all treatment groups.
The primary efficacy endpoint was percent change from baseline in Eczema Area and 
Severity Index (EASI) to Week 24. At the Week 24 visit, a greater percent change 
reduction in EASI was observed with the nemolizumab 30-mg dose (least squares mean
difference versus placebo = 16.7%) and the difference was statistically significant (95%
CI = -30.2, -3.2; p = 0.016) compared to placebo. The nemolizumab 10-mg dose showed 
a marginally statistically significant difference versus placebo (least squares mean
difference = 13.6%; 95% CI = -27.3, 0.0; p = 0.051). However, the difference between
the nemolizumab 90-mg dose and placebo did not achieve statistical significance.


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The PP NRS responder (PP NRS improvement ≥4) rate was statistically significant (p <
0.05) for all nemolizumab doses at all timepoints from Week 2. 
All doses of nemolizumab were associated with a slightly higher incidence of TEAEs 
when compared to placebo. There was no increase in the incidence of skin infections in 
the nemolizumab compared to the placebo groups, although there was a higher incidence 
of non-skin infections with nemolizumab (mainly rhinopharyngitis and upper respiratory 
tract infections). There was 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, respectively) in 
subjects with pre-existing asthma. Events were mostly mild or moderate (1 severe event 
with the highest dose), manageable, and reversible under treatment with study drug. 
Local and systemic injection-related reactions (IRRs) occurred more frequently in the 
placebo group compared to the active treatment groups. Finally, there was a low 
incidence of peripheral edema, with no serious cases and no imbalance with the placebo 
arm. There was a comparable percentage of subjects discontinuing treatment due to 
TEAE in the placebo and active treatment arms.
There was 1 non-related AE with a fatal outcome (82-year-old subject treated with the
10-mg dose died due to non–study drug related aspiration pneumonia and
cardiopulmonary arrest). Three suspected unexpected serious adverse reactions
(SUSARs) were recorded in the study: exacerbation of AD (10-mg dose, withdrawal
from study), septic shock (90-mg dose, sepsis, Staphylococcus aureus–positive blood
culture, recovered/resolved without sequelae), and phlegmon/cellulitis of the right cheek
(30-mg dose, recovered/resolved without sequelae). All doses of nemolizumab were
associated with a slightly higher incidence of serious TEAEs (1 [1.8%], 3 [5.5%], 2 
[3.5%], and 2 [3.5%] in placebo, 10 mg, 30 mg, and 90 mg, respectively) but not severe 
TEAEs (6 [10.7%], 3 [5.5%], 5 [8.8%], and 2 [3.5%] in placebo, 10 mg, 30 mg, and 90 
mg, respectively) when compared to placebo. 
The safety and efficacy data generated in the phase 2b dose-finding study supported the
selection of the 30-mg dose as the treatment dose for the phase 3 studies in AD.


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CLINICAL RISKS/BENEFITS OF NEMOLIZUMAB
Pruritus is the cardinal symptom in PN, and is often difficult to treat with current 
therapies. Chronic itching is believed to induce and maintain the characteristic PN skin 
lesions through an itch-scratch cycle. Therefore, the goal of PN treatments target pruritus 
remission in order to allow skin healing and improvement in patients’ QoL.
Results from a previous clinical study with nemolizumab demonstrated a marked effect 
on PN and pruritus. The decrease in itching sensation was rapid, within the first week 
following the first injection and improved with subsequent administrations. This 
improvement in the signs and symptoms of PN was consistent with the observed 
improvement in QoL (evaluated using the Dermatology Life Quality Index [DLQI]).
Continuous treatment with nemolizumab also led to an improvement in the overall 
severity of PN, which was evaluated with various validated scales (ie, IGA, PP NRS, and 
PAS). Based on the results of the phase 2a study (RD.03.SPR.115828) nemolizumab was 
clinically and statistically significantly superior to placebo in reducing the weekly 
average of PP NRS scores at Week 4 (difference between treatment groups -38.0%; 95% 
CI -51.0, -25.0; p<0.001). Improvements in IGA success and PAS observed in the 
nemolizumab group were also statistically significantly greater than those observed in the 
placebo group.
According to the currently available information on nemolizumab and the risks 
associated with biologic agents in general, the important potential risks for nemolizumab 
include IRRs (including local injection site reaction as well as systemic injection 
reaction), newly-diagnosed or worsening of asthma, skin and non-skin infections, and 
exacerbation of AD. The following specific risk-minimization and safety follow-up 
measures have been planned in this clinical study:
a.
In the phase 2b dose-ranging study (RD.03.SPR.114322) in AD, a dose-dependent 
increase of asthma flares in subjects with pre-existing asthma was observed. The 
protocol will exclude subjects with asthma exacerbation requiring hospitalization in 
the preceding 12 months before screening, subjects whose asthma has not been well 
controlled (ie, symptoms > 2 days per week, nighttime awakenings 2 or more times 
per week, or some interference with normal activities) during the last 3 months before 


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the screening visit, Asthma Control Test (ACT) score ≤ 19, and subjects with peak 
expiratory flow (PEF) below 80% of the predicted value. At all visits, all subjects will 
be asked about respiratory changes and a respiratory examination will be performed. 
Peak expiratory flow measurements will be performed for all subjects at screening,
baseline, and at intervals throughout the study. For subjects with a history of asthma, 
PEF measurements and ACT will be administered at all visits. 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, PEF < 
80% of the predicted value, and/or unexpected worsening of asthma is observed or 
reported. 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 all asthma AEs 
reported during the course of the study. 
b. The exclusion criteria of this clinical study (ie, restricting entry of subjects with 
recent/current infections or known/suspected immunosuppression or unusually 
frequent, recurrent, severe, or prolonged infections) will prevent non-eligible patients 
from receiving nemolizumab. As no data are available in pregnant or breastfeeding 
women, these patients are not eligible for this study. Patients who have recently 
received live or non-live vaccines may be considered for enrollment after an 
appropriate time has elapsed before baseline/Day 1. Administration of live vaccines is 
prohibited during the study. Administration of non-live vaccines is prohibited with 
the exception of seasonal, emergency, and COVID-19 vaccinations.
c.
A slight trend of dose-dependent increase of peripheral edema was reported in the 
nemolizumab phase 2a study (CIM003JG) for AD. 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 the phase 2b 
(RD.03.SPR.114322) study (2 [3.6%], 2 [3.6%], 4 [7%], and 2 [3.5%] in placebo, 10-


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mg, 30-mg, and 90-mg groups, respectively). Peripheral edema will be followed as an 
AE of special interest (AESI) in this study.
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:

IRRs
o
Anaphylactic reactions
o
Acute allergic reactions requiring treatment
o
Severe injection site reaction (ie, lasting > 24 hours)

Newly diagnosed asthma or worsening of asthma

Infections
o
Any severe infection or any infection requiring treatment with parenteral 
antibiotics or with oral antibiotics/antivirals/antifungals for > 2 weeks
o
Any confirmed or suspected coronavirus disease (COVID)-19 infection

Peripheral edema: limbs, bilateral

Facial edema

Elevated ALT or AST (> 3 × ULN) in combination with elevated bilirubin (> 2 × 
ULN)
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.
DOSE SELECTION RATIONALE
The dose was selected based on the phase 2 study results contained in PN subjects
(RD.03.SPR.115828 ). PN subjects enrolled in the phase 2 study received a 0.5 mg/kg 
weight-based dose, administered every 4 weeks (Q4W), and successfully demonstrated 
efficacy in the treatment of PN with an acceptable safety profile. The same weight-based 
dose was administered in the phase 2a study CIM003JP in AD subjects, allowing a direct 
comparison between the two populations. Similarity in the PK profiles between subjects 


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with AD and subjects with PN was established, and no effect of disease on nemolizumab 
systemic exposure was identified.
This phase 3 study will utilize a flat dose. This fixed dose is considered safer and more
efficient as it avoids errors that could be made in calculating, preparing, and 
administering a weight-based dose. 
The switch from a body weight-based dose to a flat dose was supported by previous 
observed clinical data in subjects with AD. During the phase 2b study 
RD.03.SPR.114322 in AD subjects, a 30-mg flat dose (with 60-mg loading dose) 
administered Q4W provided the best benefit/risk ratio and produced a similar exposure 
compared to the 0.5 mg/kg dose used in the AD phase 2a study CIM003JG.
The switch from mg/kg to a flat dose was further supported by popPK and PK/PD 
modeling and simulation tools. PK/PD modelling was conducted using the two primary 
clinical efficacy endpoints, ie, PP NRS responder and IGA 0-1 success.
-
The PK/PD model for PP NRS were initially developed based on data from AD 
subjects, tested against observations of study RD.03.SPR.115828 and considered 
suitable to be used for modelling and simulation in PN populations. 
-
Conversely, due to the difference in IGA scale between the two indications (ie, PN 
and AD), a PN-specific model was built based on data from study 
RD.03.SPR.115828. 
Overall, the PopPK and PK/PD models were used to select a flat dose that produce 
similar systemic exposure and efficacy results than the ones observed in the phase 2 study
RD.03.SPR.115828.
Dose for subjects with a body weight below 90 kg:  The popPK and PK/PD modeling 
demonstrated that similar exposure and similar clinical efficacy are expected in this sub-
population after a 30-mg dose administered Q4W (with a loading dose of 60 mg at 
baseline) compared to the dose regimen used in the phase 2 study (0.5 mg/kg Q4W). 
Dose for subjects with a body weight superior or equal to 90 kg: The switch from a 
body weight-based dose (0.5 mg/kg) to a flat 30 mg dose (with a loading dose of 60 mg


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at baseline) will produce a lower systemic exposure in the heavier subjects. The clinical 
relevance of this lower systemic exposure was assessed using PK/PD models. 
-
Simulations showed that no differences in PP NRS efficacy endpoint is expected for 
those subjects.
-
Simulations with the PN-specific model for the IGA endpoint showed a lower 
responder rate for those subjects after administration of the 30-mg dose with a 60-mg 
loading dose. The PK/PD model confirmed that IGA responder rate would be
comparable to that observed after 0.5 mg/kg administration when using a flat 60-mg 
dose without a loading dose. 
For this reason, a 60-mg dose without a loading dose will be used for subjects with a 
body weight superior or equal to 90 kg, in order to guarantee an IGA responder rate 
comparable with that obtained in the overall population in study RD.03.SPR.115828.
Of note, for subjects with a body weight superior or equal to 90 kg, PopPK simulation 
showed that a 60-mg dose will provide similar nemolizumab exposure with respect to 
that observed with the 0.5 mg/kg dose. Based on the similarity in systemic exposure 
between the 2 doses, no major change in the drug safety is expected in adults. 
Loading dose: Subcutaneous administration of nemolizumab results in slow absorption 
with peak serum concentrations achieved after 4 to 9 days. Plateau systemic exposure 
levels are achieved after at least 16 weeks of repeated monthly administrations. 
Therefore, loading doses are necessary to rapidly achieve targeted systemic levels, and to 
ensure a fast onset of action. Rapid inhibition of pruritus in PN is an important treatment 
goal in itself and is also expected to contribute to breaking the itch-scratch cycle and thus, 
to improve the skin condition in PN subjects. These outcomes were achieved in a phase 
2b study in AD subjects using a 60-mg loading dose (ie, 2 doses of 30 mg nemolizumab) 
at the baseline visit. No loading dose will be used for the subjects with a body weight 
superior or equal to 90 kg.


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6
STUDY OBJECTIVES AND ENDPOINTS
STUDY OBJECTIVES
Primary Objective
The primary objective is to assess the efficacy of nemolizumab (CD14152) compared to
placebo in subjects ≥ 18 years of age with PN after a 16-week treatment period.
Secondary Objectives
The secondary objectives are to assess safety, pharmacokinetics, and immunogenicity of 
nemolizumab (CD14152) compared to placebo.
STUDY ENDPOINTS
Primary Endpoints

Proportion of subjects with an improvement of ≥ 4 from baseline in PP NRS at 
Week 16

Proportion of subjects with an IGA success (defined as an IGA of 0 [Clear] or 1 
[Almost clear] and a ≥ 2-point improvement from baseline) at Week 16.
Secondary Endpoints
6.2.2.1
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoints are as follows:

Proportion of subjects with an improvement of ≥ 4 from baseline in PP NRS at 
Week 4

Proportion of subjects with PP NRS < 2 at Week 16

Proportion of subjects with an improvement of ≥ 4 from baseline in SD NRS at 
Week 16


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
Proportion of subjects with an improvement of ≥ 4 from baseline in SD NRS at
Week 4

Proportion of subjects with PP NRS < 2 at Week 4
6.2.2.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:

IGA success rate at each visit through Week 16

Percentage of pruriginous lesions with excoriations/crusts (Prurigo Activity Score 
[PAS] item 5a) at each visit through Week 16

Percentage of healed prurigo lesions (PAS item 5b) at each visit through Week 16

Change from baseline in number of lesions in representative area (PAS item 4) at 
each visit through Week 16

Proportion of subjects with an improvement of ≥ 4 from baseline in PP NRS 
through Week 16

Proportion of subjects with PP NRS < 2 from baseline through Week 16

Proportion of subjects with PP NRS < 3 from baseline through Week 16

Absolute change from baseline in PP NRS through Week 16

Percent change from baseline in PP NRS through Week 16

Proportion of subjects with an improvement of ≥ 4 from baseline in AP NRS 
through Week 16

Proportion of subjects with PP NRS improvement ≥ 4 from baseline and IGA 
success at Week 16

Proportion of subjects with AP NRS < 2 from baseline through Week 16

Absolute change from baseline in AP NRS through Week 16

Percent change from baseline in AP NRS through Week 16


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
Proportion of subjects with an improvement of ≥ 4 from baseline in SD NRS 
through Week 16

Absolute change from baseline in SD NRS through Week 16

Percent change from baseline in SD NRS through Week 16

Change from baseline in sleep diary endpoints (sleep onset latency, wakefulness 
after sleep onset [WASO], total awake time, total sleep time, sleep efficiency, 
WASO related to PN, number of WASO related to PN) based on recordings from 
subject sleep diary through Week 16

Change from baseline in PN-associated pain frequency through Week 16

Change from baseline in PN-associated pain intensity through Week 16

Proportion of subjects reporting low disease activity (clear, almost clear, or mild) 
based on Patient Global Assessment of Disease (PGAD) at Week 16

Proportion of subjects satisfied with study treatment (good, very good, or 
excellent) based on Patient Global Assessment of Treatment (PGAT) at Week 16

Proportion of subjects with an improvement of ≥ 4 in DLQI through Week 16

Change from baseline in DLQI through Week 16Change from baseline in 
Hospital Anxiety and Depression Scale (HADS) for each subscale (ie, depression 
and anxiety) at Week 16

Change from baseline in EuroQoL 5-Dimension (EQ-5D) at Week 16
6.2.2.3
Safety Endpoints
The safety endpoints of this study are the incidence and severity of AEs, including 
TEAEs, AESIs, and SAEs.
6.2.2.4
Pharmacokinetic Endpoints
Nemolizumab (CD14152) serum concentrations


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6.2.2.5
Immunogenicity Endpoints
ADA assay (screening, confirmatory, titer, NAb)


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7
INVESTIGATIONAL PLAN
DESCRIPTION OF OVERALL STUDY DESIGN AND PLAN
This phase 3, multicenter, double-blind, placebo-controlled, randomized, parallel-group
study is designed to evaluate the efficacy and safety of nemolizumab in subjects with PN.
Considering a screen failure rate of 35-40%, 415-450 subjects will be screened so that 
approximately 270 adult subjects with PN will be randomized 2:1 to receive either 
nemolizumab (CD14152) or placebo. Subjects weighing < 90 kg at baseline will receive 
either 30 mg nemolizumab (with 60 mg loading dose at baseline) or placebo Q4W. 
Subjects weighing ≥90 kg at baseline will receive either 60 mg nemolizumab or placebo 
Q4W. Subjects will be stratified by study center and baseline body weight (< 90 kg and ≥
90 kg). Subjects will be enrolled in approximately 70 study centers in Europe, North 
America, and Asia Pacific.
Subjects’ participation in the study will be up to 28 weeks. The study consists of a 
screening period (up to 4 weeks), a 16-week treatment period, and an 8-week follow up 
period (12 weeks after the last study drug injection). Refer to Figure 2 for an overview of 
study design.
Following provision of written informed consent, subjects with PN will be screened for 
enrolment in the study. Eligible subjects will return for a baseline visit where, following 
randomization, they will be administered either 60 mg of nemolizumab or placebo via 2 
SC injections. Thereafter, study drug will be administered Q4W at Weeks 4, 8, and 12 by 
a single SC injection of either nemolizumab 30 mg or placebo for subjects weighing < 90
kg at baseline or by two SC injections of either nemolizumab 30 mg or placebo for 
subjects weighing ≥90 kg at baseline. Refer to Table 3 for an overview of the study 
therapy. Efficacy and safety assessments will be performed at visits throughout the 
screening and treatment period, as outlined in the Schedule of Assessments (Table 5).
At the end of the 16-week treatment period, consenting subjects may be eligible to enter 
an active treatment/long-term extension (LTE) study (RD.06.SPR.202699). Subjects who 
participate in the LTE are not required to complete the follow-up visit. Subjects who do 


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not participate in the LTE will return for a follow-up visit at Week 24 (12 weeks after the 
last study drug injection).
Subjects who prematurely discontinue the study drug will be asked to continue 
participation in the study and return for all remaining visits and assessments (including 
daily assessment of pruritus and sleep disturbance). Subjects who discontinue study drug 
due to required rescue therapy may be eligible to participate in the LTE study following 
completion of study visits through Week 16. Subjects who discontinue the study 
prematurely should complete an early termination (ET) visit and a follow-up visit 12 
weeks after the last study drug injection.
An IDMC will review and monitor subject safety throughout the study, and an IAC will 
review all asthma-related events throughout the study. The IDMC and IAC charters 
provide details on the IDMC and IAC, including the plan of analysis for outputs; the 
composition of the committees; and procedures, roles, responsibilities and 
communications.


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Figure 2.
Study Design
Abbreviations: BL, baseline; W, week.


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DISCUSSION OF STUDY DESIGN
This study will evaluate the safety and efficacy of nemolizumab (CD14152) in adult 
subjects with PN. The rationale for the general study design is based upon the prior phase 
2a study design conducted in adult subjects with PN. The rationale for the nemolizumab 
dose/dose regimen is provided in Sections 5.2 and 5.4.
Eligible subjects for this clinical study will be adults with a clinical diagnosis (≥ 6 
months) of PN, manifested by pruriginous nodular lesions on the trunk and/or limbs, and 
at least 20 nodules bilaterally distributed on the entire body. The inclusion criterion for 
IGA is consistent with the disease severity targeted in the study: An IGA of 3 or 4 
corresponds to moderate or severe PN, respectively. Severe pruritus will be defined by 
PP NRS scores within the past 24 hours at screening and the mean PP NRS score during 
the previous week at baseline. Subjects with chronic pruritus due to other active 
conditions or unilateral pruriginous lesions are ineligible. Further, subjects must undergo 
specific required washout periods from restricted topical and systemic treatments before 
enrolling in the study. The study population is selected based on the current unmet need 
in the management of PN, the mode of action of nemolizumab (CD14152), and the need 
to understand the efficacy and safety of nemolizumab (CD14152) in the adult population
with PN.
As no approved medicine for PN exists with which to compare nemolizumab, a placebo-
controlled design was implemented in this study to allows blinding, randomization, and 
identical administration procedures to control for human bias or other influences on the 
disease (eg, natural disease course), while enabling demonstration of differences in 
clinical effect and safety profile of investigational treatment, if present. All subjects will 
have access to rescue medication to minimize risk and for ethical considerations. It is the 
position of the Committee for Medicinal Products for Human Use (CHMP) that, where 
ethical and feasible, a placebo control arm should be included in the pivotal trial(s) used 
to support marketing authorisation application.
A 16-week treatment period is considered adequate to evaluate the efficacy and safety of 
nemolizumab based on the results of the phase 2a study (RD.03.SPR.115828) in subjects 
with PN. All subjects who complete the treatment period (Week 16 visit) can be 


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considered for LTE study eligibility. A 2-to-1 randomization is selected to minimize the 
number of subjects exposed to placebo for an extended period of time. 
Although the pathophysiology of PN is still not fully understood, the efficacy endpoints 
selected for the phase 3 trial are relevant to the underlying manifestations associated with 
the disease under study (ie, skin lesions, chronic itch, sleep disturbance, and quality of 
life impairment). The selected endpoints for assessing the safety and PK of nemolizumab 
(CD14152) are in accordance with current standards. Blinding subjects and the 
designated study team to the treatment assignment(s) helps ensure objectivity and 
minimize bias. Randomization through the Interactive Response Technology (IRT)
guards against selection bias.
The study includes an 8-week follow-up period (ie, 12 weeks after the last study drug 
injection) for subjects who decline or are not eligible to enroll in the LTE study. The 
duration of the follow-up period from the final nemolizumab dose (12 weeks) 
corresponds to approximately 5 half-lives of nemolizumab, which is considered adequate 
to ensure subject safety. The follow-up visit is not required for subjects who participate in 
the LTE, where the primary objective is long-term evaluation of safety.
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 drug for injection, including confirmation of complete 
reconstitution, prior to delivery of study drug for injection. The pharmacist (or other 
qualified personnel) preparing study drug 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.
The placebo-controlled design includes a provision for rescue therapy for pruritus, based 
on the investigator’s clinical judgment. Subjects requiring rescue therapy may be eligible 
for the LTE study but will be required to continue scheduled study visits until the Week 
16 visit before LTE eligibility will be assessed. 
To avoid bias and to ensure the integrity of the blind, personnel directly involved with the 
ongoing conduct of the study from the Sponsor, contract research organization (CRO), or 


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other investigational study centers will not have access to any information that may lead 
to unblinding.
END OF STUDY 
A subject will have fulfilled the requirements for study completion if/when the subject 
has completed all study periods, including Week 16 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 or the last subject’s scheduled visit
as indicated in the Schedule of Assessments (Table 5).


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8
SELECTION OF STUDY POPULATION
Section 7.1 provides information regarding number of subjects planned to be enrolled.
INCLUSION CRITERIA
Individuals must meet all of the following criteria to be included in the study:
1. Male or female and aged ≥18 years at the time of screening
2. Clinical diagnosis of PN for at least 6 months with:
a.
Pruriginous nodular lesions on upper limbs, trunk, and/or lower limbs
b. At least 20 nodules on the entire body with a bilateral distribution
c.
Investigator Global Assessment (IGA) score ≥ 3 (based on the IGA scale 
ranging from 0 to 4, in which 3 is moderate and 4 is severe) at both the 
screening and baseline visits
3. Severe pruritus defined as follows on the PP NRS:

At the screening visit (Visit 1): PP NRS score is ≥ 7.0 for the 24-hour period 
immediately preceding the screening visit

At the baseline visit (Visit 2): Mean of the daily intensity of the PP NRS score 
is ≥ 7.0 over the previous week;
Note: PP NRS score should be measured on at least 4 days during the week 
preceding the baseline visit. Rounding of the mean PP NRS score is not 
permitted.
4. Female subjects of childbearing potential (ie, fertile, following menarche and until 
becoming post-menopausal unless permanently sterile) must agree to use at least 
1 adequate and approved method of contraception throughout the study and for 12 
weeks after the last study drug injection. 
Adequate and approved methods of contraception applicable for the subject 
and/or her partner are defined below:

True abstinence, when in line with the preferred and usual lifestyle of the 
subject. See Appendix 1 for details. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception 


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
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 (eg, 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 3 
months before the study

Bilateral vasectomy of male partner at least 3 months before the study
5. Female subjects of non-childbearing potential must meet 1 of the following 
criteria:

Absence of menstrual bleeding for 1 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 3 months before the study
6. Subject is willing and able to comply with all of the time commitments and 
procedural requirements of the clinical study protocol, including daily diary 
recordings by the subject using an electronic handheld device provided for this 
study
7. Read, understood and signed an informed consent form (ICF) before any 
investigational procedure(s) are performed
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


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2. Chronic pruritus resulting from another active condition other than PN, such as 
but not limited to scabies, lichen simplex chronicus, psoriasis, atopic dermatitis, 
contact dermatitis, acne, folliculitis, lichen planus, habitual picking/excoriation 
disorder, sporotrichosis, bullous autoimmune disease, end-stage renal disease, 
cholestatic liver disease (eg, primary biliary cirrhosis), or diabetes mellitus or 
thyroid disease that is not adequately treated, as per standard of care
3. Unilateral lesions of prurigo (eg, only one arm affected)
4. History of or current confounding skin condition (eg, Netherton syndrome, 
cutaneous T-cell lymphoma [mycosis fungoides or Sezary syndrome], chronic 
actinic dermatitis, dermatitis herpetiformis)
5. Subjects meeting 1 or more of the following criteria at screening or baseline:
5a. Had an exacerbation of asthma requiring hospitalization in the preceding 12 
months
5b. Reporting asthma that has not been well-controlled (ie, symptoms occurring 
on > 2 days per week, nighttime awakenings 2 or more times per week, or 
some interference with normal activities) during the preceding 3 months
5c. Asthma Control Test ≤ 19 (only for subjects with a history of asthma)
5d. Peak expiratory flow < 80% of the predicted value
Note: In the event that PEF is < 80% of the predicted value at the screening 
visit in patients without any history of asthma or in patients with history of 
asthma but with the ACT score > 19, PEF testing can be repeated once within 
48 hours.
6. Subjects with a current medical history of chronic obstructive pulmonary disease 
and/or chronic bronchitis
7. Cutaneous infection within 1 week before the baseline visit, any infection 
requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics, or 
antifungals within 2 weeks before the baseline visit, or any confirmed or 
suspected COVID-19 infection within 2 weeks before the screening or baseline 


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visit. Subjects may be rescreened once the infection has resolved. Resolution of 
COVID-19 infection can be confirmed by recovery assessment methods, as 
described in Section 8.4.2.
8. Positive serology results (hepatitis B surface antigen [HBsAg] or hepatitis B core 
antibody [HBcAb], hepatitis C [HCV] antibody with positive confirmatory test 
for HCV [eg, polymerase chain reaction (PCR)], or human immunodeficiency 
virus 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). Subjects with negative confirmatory test for HCV can be 
included in this clinical study.
In the event of rescreening, the serology tests results (eg, HBV, HCV, HIV) from 
the first screening can be used by the investigator to assess the eligibility of 
rescreened subjects if those tests were performed within 6 weeks prior to the 
baseline visit.
9. Requiring rescue therapy for PN during the screening period or expected to 
require rescue therapy within 4 weeks following the baseline visit
10. Subjects with active atopic dermatitis (signs and symptoms other than dry skin) in 
the last 3 months
Note: Subjects with atopic diathesis, as diagnosed by the medical history and/or 
laboratory analysis (ie, specific IgE), are eligible for the study.
11. Neuropathic and psychogenic pruritus such as but not limited to notalgia 
paresthetica, brachioradial pruritus, small fiber neuropathy, skin picking 
syndrome, or delusional parasitosis
12. Having received any of the following treatments in the table below within the 
specified timeframe before the baseline visit


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Table 2.
Restricted Prior Treatments
Treatments
Timeframe
Topical calcineurin inhibitors (tacrolimus, pimecrolimus), and topical 
corticosteroids, 
2 weeks
Topical vitamin D analogs
2 weeks
Topical or systemic PDE-4 inhibitors
2 weeks
Any other topical treatment other than moisturizer (eg, capsaicin, cryotherapy for 
treatment of PN)
2 weeks
Emollients or moisturizers with menthol, polidocanol or other having “anti-itch” 
claim
1 week
Systemic or intralesional corticosteroids (corticosteroid inhalers are permitted)
4 weeks 
Oral antihistamines (unless these treatments were taken at a stable dose for 3 
months prior to screening or for a seasonal allergy)
1 week
Drugs with sedative effect such as benzodiazepines, imidazopyridines, 
barbiturates, sedative anti-depressants (eg, amitriptyline), SSRIs (eg, 
paroxetine), or SNRIs, except if these treatments were taken at a stable dose 
for at least 3 months before screening
1 week
Phototherapy or tanning beds
4 weeks
Immunosuppressive or immunomodulatory drugs (eg, cyclosporine, 
methotrexate, thalidomide, oral tacrolimus, cyclophosphamide, azathioprine, 
mycophenolate mofetil, JAK inhibitors)
8 weeks or 5 half-
lives (whichever 
is longer)
Biologics and their biosimilars (eg, etanercept, adalimumab, infliximab, 
omalizumab, etc)
8 weeks or 5 half-
lives (whichever 
is longer)
Dupilumab
10 weeks
Systemic retinoids
8 weeks or 5 half-
lives (whichever 
is longer)
Systemic roxithromycin, erythromycin
1 week


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Treatments
Timeframe
Opioid antagonists (eg, naltrexone, naloxone), opioid partial/mixed agonists (eg, 
nalbuphine, butorphanol), or opioid agonists (except when used for short 
term/acute pain); NK1 receptor antagonists (eg, aprepitant, serlopitant)
4 weeks or 5 half-
lives (whichever 
is longer)
Gabapentinoids, unless used at a stable dose for at least 6 months or used for 
non-prurigo conditions
4 weeks 
Cannabinoids (eg, dronabinol)
2 weeks
Alternative medicine for PN (eg, traditional Chinese medicine)
2 weeks
Live vaccines
12 weeks
Non-live vaccines
4 weeks
Abbreviations: JAK, Janus kinase; NK1, neurokinin; PDE-4, phosphodiesterase-4; PN, prurigo nodularis;
SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
Note: Subjects should not interrupt ongoing treatment with medications important for the subject’s health 
for the sole purpose of participating in this study.
13. Previous participation in a clinical study with nemolizumab
14. Pregnant women (positive serum pregnancy test result at the screening visit or 
positive urine pregnancy test at the baseline visit), breastfeeding women, or 
women planning a pregnancy during the clinical study
15. History of lymphoproliferative disease or history of malignancy of any organ 
system within the last 5 years, except for:

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 screening visit, or;

Actinic keratoses that have been treated 
16. History of hypersensitivity (including anaphylaxis) to an immunoglobulin product 
(plasma-derived or recombinant, eg, monoclonal antibody) or to any of the study 
drug excipients


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17. Current active or 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 active or latent TB with no history of re-exposure to TB 
since their treatment was completed are eligible to participate in the study.
In the event of rescreening, the TB tests result from the first screening can be used 
by the investigator to assess the eligibility of rescreened subjects if the test was 
performed within 6 weeks prior to the baseline visit.
18. Known or suspected immunosuppression or unusually frequent, recurrent, severe, 
or prolonged infections as per investigator judgment
19. Any medical or psychological condition or 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, or may interfere with study assessments 
(eg, poor venous access or needle-phobia)
20. History of alcohol or substance abuse within 6 months of the screening visit
21. Planned or expected major surgical procedure during the clinical study
22. Subject is unwilling to refrain from using prohibited medications during the 
clinical study (see Section 9.10.3)
23. Currently participating or participated in any other study of an investigational
drug or device, within the past 8 weeks (or 5 half-lives of the investigational drug, 
whichever is longer), before the screening visit, or is in an exclusion period (if 
verifiable) from a previous study
For subjects accepting optional biopsy sampling (by signing an additional consent), the 
following exclusion criteria also apply. If any of the below criteria are met, biopsy 
samples must not be collected:


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24. History of coagulation disorders 
25. Known sensitivity to local anesthetics 
26. Using platelet aggregation inhibitors, or anticoagulants (sporadic intake or 
continuous low-dose intake of aspirin or other non-steroidal anti-inflammatory 
drugs is allowed) 
27. History or physical evidence of keloids or hypertrophic scarring resulting from 
skin trauma. The clinical examination will include the observation of scars.
RESCREENING
Screen failures may be allowed to rescreen up to 1 time, unless the reason for screen 
failure is related to disease severity inclusion criteria. Subjects who screen fail due to 
disease severity are not allowed to rescreen. Subjects who are rescreened must sign a new 
ICF and be assigned a new subject identification number. See also Section 10.1.
In the event of rescreening, the serology and TB tests results from the first screening can 
be used by the investigator to assess the eligibility of rescreened subjects if those tests 
were performed within 6 weeks prior to the baseline visit.
In the event that PEF is < 80% of the predicted value at screening in patients without any 
history of asthma or in patients with history of asthma but with ACT score > 19, PEF 
testing can be repeated once within 48 hours.
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. Investigators or the 
Sponsor can also withdraw subjects from the clinical study if deemed to be necessary.


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Reasons for discontinuing study drug include:

Subject request (ie, consent withdrawal)

Non-compliance with the study drug or study schedule

Lost to follow-up

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
o
Any serious infection or any severe infection requiring treatment with 
parenteral antibiotics or oral antibiotics/antivirals/antifungals for > 2 
weeks considered to be related to study drug administration
o
Serious worsening of asthma considered to be related to study drug 
administration
o
Diagnosis of a malignancy (except curatively treated in situ cervical 
carcinoma, squamous cell carcinoma in situ [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
Confirmed or suspected COVID-19 infection (temporary discontinuation 
may be acceptable; for instructions on resuming study drug administration,
see Section 8.4.2)

Pregnancy

Use of non-permitted concurrent therapy (unless discussed and agreed upon with 
the investigator and medical monitor)

Use of systemic rescue therapy (other than oral antihistamines), intralesional 
corticosteroids, or oral psoralen + ultraviolet A (PUVA) treatment, as specified in 
Section 9.10.2 and Table 4 of Section 9.10.3

Treatment failure

Investigator request

Sponsor request, including any of the above criteria
If a subject is withdrawn from the study for any reason, the date and the reason for study 
withdrawal must be recorded on the electronic case report form (eCRF). Subjects who 


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have been enrolled and treated will not be replaced by another subject. Once a subject is 
withdrawn from the study, the subject may not re-enter the study.
Subjects who prematurely discontinue from the study should undergo final study 
assessments and attend an Early Termination (ET) visit. Subjects should also complete a
follow-up visit 12 weeks after the last study drug administration.
Subjects who prematurely discontinue study drug will be encouraged to complete all 
remaining visits and assessments (including daily assessment of pruritus and sleep 
disturbance). 
Subjects requiring rescue medication (with or without study drug discontinuation) may be 
eligible for LTE participation, following completion of study visits through Week 16. 
Reasonable efforts will be made to contact subjects who are lost to follow-up. These 
efforts must be documented in the subject’s file.
In the event that a subject discontinues prematurely from the study because of a TEAE or 
serious TEAE, the TEAE or serious TEAE will be followed up until it resolves (returns to 
normal or baseline values) or stabilizes, or until it is judged by the investigator to no 
longer be clinically significant.
Additionally, the Sponsor may stop the study at any time for safety, regulatory, legal, or 
other reasons aligned with GCP. This study may be terminated at the discretion of the 
Sponsor or any regulatory agency. 
Pregnancy
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.


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The investigator must:

Follow the procedures for reporting/follow-up of a pregnancy within 24 hours 
(see Section 12.7.7) of receipt of the information.

Complete as fully as possible the applicable Pregnancy Surveillance Form(s) (see 
Section 12.7.7).

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 2 phone calls and a letter (certified with return receipt) is 
required.

If the pregnancy leads to an abortion (ie, voluntary abortion, spontaneous 
abortion, or therapeutic abortion), in utero death or congenital anomaly, follow 
the procedure for declaration of/reporting an SAE (Section 12.7.4). 
The investigator 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 12.7.7.


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COVID-19 Infection
Study drug administration will be discontinued in a subject in whom a COVID-19 
infection 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 infection based on investigator judgement 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 (eg, 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 2 for additional guidance for management of subjects and study conduct 
during the COVID-19 pandemic.


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9
STUDY TREATMENTS
“Study drug” refers to nemolizumab (CD14152) or placebo drug product for purposes of 
this double-blind study. The list of excipients are detailed in the IB.
DETAILS OF STUDY DRUG
Study drug will be supplied as a lyophilized powder in a pre-filled, single-use, dual-
chamber syringe (DCS) for solution for subcutaneous injection only after reconstitution. 
The lyophilized nemolizumab (CD14152) 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 (CD14152) after reconstitution. 
The study drugs to be used in this study are outlined in Table 3:


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Table 3.
Study Drugs
Investigational product
Placebo
Name
Nemolizumab
Nemolizumab placebo
Internal code
CD14152
NA
Pharmaceutical 
form
Lyophilized powder in a DCS 
for solution for injection 
Lyophilized powder in a DCS for 
solution for injection 
Packaging
DCS
DCS
Storage 
conditions
Stored between 2°C to 8°C 
(36°F to 46°F); protected from 
light, protected from freezing
Stored between 2°C to 8°C (36°F
to 46°F); protected from light, 
protected from freezing
Dosage
Subjects weighing < 90 kg at 
baseline: 30 mg, with a
loading dose of 60 mg at 
baseline; Subjects weighing ≥90
kg at baseline: 60 mg
Not applicable
Route
SC use by subjects or clinic staff 
after reconstitution
SC use by subjects or clinic staff 
after reconstitution
Dose regimen
Subjects weighing < 90 kg at 
baseline: 2 injections at baseline, 
then 1 injection Q4W; Subjects 
weighing ≥90 kg at baseline: 2 
injections at baseline, then 2 
injections Q4W
Subjects weighing < 90 kg at
baseline: 2 injections at baseline, 
then 1 injection Q4W; Subjects 
weighing ≥90 kg at baseline: 2 
injections at baseline, then 2 
injections Q4W
Treatment 
duration
16 weeks with last injection at 
Week 12
16 weeks with last injection at 
Week 12
Abbreviations: DCS, dual chamber syringe; Q4W, every 4 weeks; SC, subcutaneous.
PACKAGING AND LABELING
All 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 


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is for use in a clinical study. Each DCS will be packaged in an individual carton, 
including a 27G 1/2” needle and a plunger rod (not assembled), and will be identified by 
a unique kit number. Local adaptation of the kit design may be required; specific details 
for each country are provided in the pharmacy manual.
STUDY DRUG PREPARATION
A pharmacist (or other qualified personnel) will prepare study drug for injection 
according to the instructions for use and instructions provided in the current version of 
the pharmacy manual. Study drug 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 apply at all times.
Differences may be detectable during the study drug reconstitution process between 
active and placebo, but active and placebo appear similar after reconstitution is complete 
(approximately 10 minutes). Throughout the study, a pharmacist (or other qualified 
personnel) will prepare study drug for injection, including confirmation of complete 
reconstitution, prior to delivery of study drug for injection. The pharmacist (or other 
qualified personnel) preparing the study drug 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.
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 1 hour) after reconstitution. If 
not used immediately, the study drug has to be used within 4 hours maximum after 
reconstitution stored at room temperature (below 30°C) and only if the preparation has 
taken place applying strictly good hygiene practices and clean techniques to ensure 
controlled aseptic conditions.
STUDY DRUG INJECTION/ADMINISTRATION
All study drug injections will occur at the study center, following instructions provided in 
the instructions for use and the current version of the pharmacy manual. After confirming 
that the study drug is fully reconstituted, the pharmacist (or other qualified personnel) 


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will deliver the DCS to the investigator or other qualified personnel, for SC injection in 
the subject’s abdomen or an alternative injection site. A different injection site should be 
selected for each injection. Refer to the current version of the pharmacy manual and 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 center staff will provide training on 
study drug injections. Subjects will be allowed to inject medication following appropriate 
training and 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 does not wish to perform injections. The eCRF will 
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 2 visits 
where study drug is administered, subjects should remain at the study center for at least 
30 minutes following study drug administration. 
STUDY DRUG MANAGEMENT
Storage of Study Drug
All DCS units must be stored together in a safe and secure area with restricted access. 
Upon receipt, the DCS must be removed from the shipping cooler, kept in the outer 
carton until use, and stored in a refrigerator between 2°C to 8°C (36°F to 46°F), protected 
from light, and protected from freezing.
The refrigerator must be monitored daily, and if a temperature excursion occurs, the 
designated personnel should promptly inform the study monitor, as specified in the 
current version of the pharmacy manual.
Study Drug Accountability
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 


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content. If a damaged shipment is received and/or a temperature excursion has been 
experienced, he/she will notify the Sponsor/contract research organization (CRO) and 
follow the guidelines according to 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 9.6 for product technical complaints.
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 not destroyed by the site. 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.
Dispensing and Return of Study Drug
All study drug preparation must be appropriately performed and documented by the 
designated personnel. Any error in the preparation of dosing solution 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 sites’ SOPs, local regulations, and best practices, as described in the 
current version of the pharmacy manual. If the site does not have the capability to destroy 
drug, then the unused study drug will be returned to the CRO/drug depot for destruction.


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PRODUCT TECHNICAL COMPLAINTS
All DCS units, including the needle and plunger rod, 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. 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 forms 
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/items 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.
MEASURES TO MINIMIZE BIAS: STUDY TREATMENT ASSIGNMENT 
AND BLINDING 
Method of Study Treatment Assignment
Upon confirmation of eligibility for a given subject to participate in the study, a unique 
randomization number will be assigned to that subject via Interactive Response 
Technology (IRT). 
The randomization number for a given subject will be used to identify the treatment arm 
the subject will be assigned to.


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Subjects will be randomized in a 2:1 ratio to receive treatment of either nemolizumab 
(CD14152) or placebo. The randomization scheme will be stratified by the study site and 
baseline body weight (< 90 kg and ≥90 kg) using the IRT system.  
Study 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 (CD14152) or placebo treatments, 
according to the current version of the pharmacy manual and 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 drug 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 integrity of the study blinding, the bioanalytical laboratory staff who 
process/analyze the PK/anti-drug antibody (ADA)/pharmacodynamic (PD)/ 
pharmacogenomic (PGx) samples will not provide any information to the Sponsor, CRO, 
or investigational study center personnel directly involved with the ongoing conduct of 
the study that may lead to unblinding during the ongoing study. PK and ADA results will 
released by the bioanalytical laboratory after data base lock. 
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 (ie, when the health of the subject is not immediately at risk), 


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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 Randomization and Trial Supply Management (RTSM) User Guide for 
information on the steps for breaking the blind in the IRT system.
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 and must also 
be appropriately followed for a minimum of 12 weeks after the last dose of study drug.
The reporting requirements for unblinding are the same for reporting an SAE. See also 
Section 12.7.4.
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
treatment assignment remains undisclosed to all individuals involved in the direct 
execution and management of the study until the final database is locked.
DOSAGE MODIFICATION
Dose 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 and 
documented in the eCRF.
In the event of a missed dose (ie, 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 (eg, for safety). Subjects will be asked to return to the study 


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centers for all remaining visits and complete all study assessments and procedures as 
described in the Schedule of Assessments (Table 5).
Dosing frequency is scheduled for Q4W, based on the baseline/Day 1 visit date. If a 
study visit occurs outside the visit window defined in the Schedule of Assessments
(Table 5), study drug can still be administered provided there is a minimum of 3 weeks 
but not more than 5 weeks since the last injection. If beyond 5 weeks, the next injection 
should then occur at the next planned visit. Future visits should be scheduled as soon as 
possible and within the required windows based on the baseline/Day 1 visit date, while 
maintaining the minimum 3-week interval between 2 injections.
TREATMENT COMPLIANCE
Treatment compliance will be assessed through the treatment records and drug 
dispensation logs.
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.
PRIOR AND CONCOMITANT THERAPY
Prior therapies are defined as therapies that have been stopped within the 3 months before 
the screening visit, unless relevant to the inclusion/exclusion criteria. Whenever possible, 
all prior therapies for PN 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 2 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, and homeopathic preparations.

Medical and surgical procedures (eg, phototherapy, exodontia, etc); 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.
See Appendix 1 for details. 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 an inadvertent dose 
modification (see Section 9.8), in which case the therapy/medication will be linked to an 
item in the subject’s medical history.
Permitted Concomitant Therapy
Unless specified as prohibited therapies (see Section 9.10.3), all therapies are authorized, 
including basic skin care (cleansing and bathing), moisturizers, bleach baths, and topical 
anesthetics.
Starting from the screening visit, subjects can use their daily moisturizer, if it does not 
contain any compound with known anti-itch effect (eg, menthol, polidocanol, etc.). 
Subjects should not change emollients or moisturizers or apply products for itching relief 
during the course of the study.
Sedatives and antidepressants as described in Table 4 are allowed if they have been 
administrated for at least 3 months at a stable dose before screening baseline and dose 
changes are not planned during the study.


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The formation of cytochrome P450 (CYP450) metabolic enzymes can be altered by 
increased levels of certain cytokines (eg, IL-1, IL-6, IL-10) during chronic inflammation. 
Treatment with a biologic agent with an anti-inflammatory effect such as nemolizumab
may indirectly upregulate CYP450 expression by decreasing cytokine levels. Although 
there is no known evidence suggesting that IL-31 affects the level or activity of CYP450 
enzymes, the impact of nemolizumab (CD14152) 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 (CD14152) 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 3.
Rescue Therapy
If deemed to be medically necessary by the investigator (eg, to control intolerable PN
signs/symptoms), rescue therapies can be prescribed to the subjects. 
Rescue therapy must not be prescribed during the screening period.
As a general guideline and per individual investigator judgment, rescue therapy should 
not be prescribed within the first 4 weeks after baseline to allow a minimum time for 
study drug exposure.
Rescue therapies include:

Topical corticosteroids

Topical calcineurin inhibitors

Oral antihistamines

Systemic or intralesional corticosteroids

Biologics (including their biosimilars)

Systemic nonsteroidal immunosuppressants/immunomodulators

Phototherapy


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
Gabapentinoids
Whenever possible, investigators should first use topical medication or oral 
antihistamines as rescue therapy before escalating to other systemic therapies. If subjects 
receive topical treatments, oral antihistamines, or ultraviolet B (UVB) phototherapy as 
rescue therapy, study drug administration should be continued unless there is a concern 
according to the investigator’s judgment. If subjects receive systemic rescue therapy 
(other than oral antihistamines), intralesional corticosteroids, or oral psoralen + 
ultraviolet A (PUVA) treatment, the study drug administration must be permanently 
discontinued. In the event study drug administration is discontinued due to receipt of 
systemic rescue therapy, subjects will be encouraged to complete the remaining 
scheduled study visits according to the Schedule of Assessments in Table 5. Subjects who 
complete the Week 16 visit may be eligible to participate in the LTE if screening criteria 
are met.
For the purpose of efficacy analysis, subjects receiving any rescue therapies will be 
considered as treatment failures. 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. Further, the use of any rescue therapies should 
be documented in the eCRF.
Prohibited Therapy
Treatment with the following concomitant medications/therapies in Table 4 is prohibited 
during the study unless otherwise specified. 


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Table 4.
Prohibited Therapy
Treatments
Timeframe
Before 
Baseline/Day 1
Day 1 – Week 
24
Topical calcineurin inhibitors (tacrolimus, 
pimecrolimus) and topical corticosteroids
2 weeks
Prohibited*
Topical vitamin D analogs
2 weeks
Prohibited
Topical or systemic PDE-4 inhibitors
2 weeks
Prohibited
Any other topical treatment other than moisturizer 
(eg, capsaicin, cryotherapy for treatment of PN)
2 weeks
Prohibited
Emollients or moisturizers with menthol, 
polidocanol or other having “anti-itch” claim
1 week
Prohibited
Systemic or intralesional corticosteroids 
(corticosteroid inhalers are permitted)
4 weeks 
Prohibited*
Oral antihistamines (unless these treatments were 
taken at a stable dose for 3 months prior to 
screening or for a seasonal allergy)
1 week
Prohibited*
Drugs with sedative effect such as benzodiazepines, 
imidazopyridines, barbiturates, sedative anti-
depressants (eg, amitriptyline), SSRIs (eg, 
paroxetine), or SNRIs except if these treatments 
were taken at a stable dose for at least 3 months 
before screening
1 week
Prohibited
Phototherapy 
4 weeks
Prohibited*
Tanning beds
4 weeks
Prohibited
Immunosuppressive or immunomodulatory drugs 
(eg, cyclosporine A, methotrexate, thalidomide, 
oral tacrolimus, cyclophosphamide, azathioprine, 
mycophenolate mofetil, JAK inhibitors)
8 weeks or 5 
half-lives 
(whichever is 
longer)
Prohibited*
Biologics and their biosimilars (eg, etanercept, 
adalimumab, infliximab, omalizumab, etc)
8 weeks or 5 
half-lives 
Prohibited*


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Treatments
Timeframe
Before 
Baseline/Day 1
Day 1 – Week 
24
(whichever is 
longer)
Dupilumab
10 weeks
Prohibited*
Systemic retinoids
8 weeks or 5 
half-lives 
(whichever is 
longer)
Prohibited
Systemic roxithromycin, erythromycin
1 week
Prohibited
Opioid antagonists (eg, naltrexone, naloxone), 
opioid partial/mixed agonists (eg, nalbuphine, 
butorphanol), or opioid agonists (except when used 
for short term/acute pain); NK1 receptor 
antagonists (eg, aprepitant, serlopitant)
4 weeks or 5 
half-lives 
(whichever is 
longer)
Prohibited
Gabapentinoids, unless used at a stable dose for at 
least 6 months or used for non-prurigo conditions
4 weeks 
Prohibited*
Cannabinoids (eg, dronabinol)
2 weeks
Prohibited
Investigational topical or systemic medication 
12 weeks or 5 
half-lives 
(whichever is 
longer)
Prohibited
Alternative medicine for PN (eg, traditional 
Chinese medicine)
2 weeks
Prohibited
Live vaccines
12 weeks
Prohibited
Non-live vaccines
4 weeks
Prohibited 
(exceptions 
apply)
Abbreviations: JAK, Janus kinase; NK1, neurokinin; PDE-4, phosphodiesterase-4; PN, prurigo nodularis;
SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
* Unless used as rescue therapy during the study.


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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 (eg, 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.
Specifically, the use of systemic corticosteroids during the study is prohibited except 
when used as rescue therapy for PN (in accordance with the instructions in 
Section 9.10.2). If the use of systemic corticosteroids becomes necessary for the safety of 
the subject to treat condition(s) other than PN, the study drug should be temporarily 
discontinued for the duration of treatment with systemic corticosteroids plus 5 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, 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. 
Vaccinations during the study and follow-up period are not permitted, except for use of 
the following non-live vaccines:

seasonal vaccinations (eg, influenza) 

emergency vaccinations (eg, rabies or tetanus),

COVID-19 vaccinations. 
Wherever possible, it is recommended to avoid administration of seasonal and COVID-
19 vaccinations within 1 week before or after study drug dosing, and a different 
anatomical location should be used for study drug administration and vaccine 
administration.
In the event of emergency vaccination during the study, the study drug administration 
should be discontinued until the immune response to vaccination is verified.


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10
STUDY PROCEDURES
INFORMED CONSENT
Before performing any study-related procedures, the investigator (or designee) will 
obtain written informed consent from the subject; including separate photography and 
PGx consent, if applicable. 
Upon ICF signature, each subject will be assigned, via electronic data capture (EDC), a 
unique subject identification number (SIN) which will be used for the entire duration of 
the study. In the event that rescreening occurs, the individual is required to sign a new 
ICF and must be assigned a new subject identification number. See also Section 8.3.
STUDY ASSESSMENTS AND PROCEDURES
Assessments and procedures are to be performed as outlined in the Schedule of 
Assessments (Table 5). 
At each visit, assessments/procedures should be performed in the following order: 
1. Patient-reported efficacy and safety measurements
2. Investigator assessments (including efficacy and safety)
3. Sample collections for laboratory assessments
4. Sample collections for correlative assessments (PK, ADA, PD, and optional PGx)
5. Administration of study drug injections
Efficacy assessments are described in Section 11; quality of life assessments are 
described in Section 11.7. Safety assessments are described in further detail in Section 
12. Section 12.5 specifies laboratory assessment samples to be obtained. Pharmacokinetic 
assessments are described in Section 13; pharmacogenomic and anti-drug antibody 
assessments are described in Section 14.


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Study discontinuation procedures, including early termination visit and follow-up of 
TEAEs, are described in Section 8.4.
Unscheduled visit procedures are described in Section 10.2.1.


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Table 5.
Schedule of Assessments
Study period
Screening 
period
(Day -28 to 
Day-1)
Treatment period
Follow-
up c
Early 
Termination
Unscheduled 
visit d
Visit
V1
V2
No visit b
V3
V4
V5
V6
V7
(if applicable) (if applicable)
Week Screening a
Baseline
W1
W4
W8
W12
W16
W24
Day
D-28 to D-8
Day 1
Day 8
Day 29
Day 57
Day 85
Day 113
Day 169
Visit window 
±0 days
±2 days
±2 days
±5 days
±5 days
±7 days
Informed consent form
X
Photography, skin biopsy, and PGx 
consent form(s) (if applicable)
X
(X)
Inclusion/exclusion criteria
X
X
Demographics
X
Medical history, previous therapies 
and procedures, smoking status
X
(X)
PATIENT-REPORTED OUTCOME ASSESSMENTS
PP NRS/AP NRS/SD NRS/ 
subject sleep diary e,f
X-----------------------------------------------------------------------------X
X
(X)
PGIS-P/PGIS-SD e,f
X
X b
X
X
(X)
PGIC-P/PGIC-SD e,f
X b
X
X
(X)
PGAD g
X
X b
X
X
(X)
PGAT g
X
X
(X)
PN-associated pain frequency and 
intensity g
X
X
X
X
X
X
(X)


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Study period
Screening 
period
(Day -28 to 
Day-1)
Treatment period
Follow-
up c
Early 
Termination
Unscheduled 
visit d
Visit
V1
V2
No visit b
V3
V4
V5
V6
V7
(if applicable) (if applicable)
Week Screening a
Baseline
W1
W4
W8
W12
W16
W24
Day
D-28 to D-8
Day 1
Day 8
Day 29
Day 57
Day 85
Day 113
Day 169
Visit window 
±0 days
±2 days
±2 days
±5 days
±5 days
±7 days
DLQI g
X
X
X
X
(X)
EQ-5D/HADS g
X
X
X
(X)
CLINICAL PHOTOGRAPHS
Full body clinical photographs 
(optional)
h
X
X
X
(X)
CLINICAL EFFICACY ASSESSMENTS
IGA
X
X
X
X
X
X
X
(X)
PAS 
X
X
X
X
X
X
X
(X)
SAFETY ASSESSMENTS
ACT g, i
X
X
X
X
X
X
X
X
(X)
Respiratory exam
X
X
X
X
X
X
X
X
(X)
PEF testing j
X
X
X j
X
X j
X
X
X
(X)
Vital signs
X
X
X
X
X
X
X
X
(X)
Full physical examination
X
X
X
X
X
X
(X)
Height
X
(X)
Weight
X
X
X
X
(X)
12-lead ECG k
X
X
X
X
(X)


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Study period
Screening 
period
(Day -28 to 
Day-1)
Treatment period
Follow-
up c
Early 
Termination
Unscheduled 
visit d
Visit
V1
V2
No visit b
V3
V4
V5
V6
V7
(if applicable) (if applicable)
Week Screening a
Baseline
W1
W4
W8
W12
W16
W24
Day
D-28 to D-8
Day 1
Day 8
Day 29
Day 57
Day 85
Day 113
Day 169
Visit window 
±0 days
±2 days
±2 days
±5 days
±5 days
±7 days
Contraceptive counseling
X
(X)
Adverse Events g
X
X
X
X
X
X
X
X
(X)
Concomitant therapies and 
procedures g
X
X
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 l
X
(X)
Blood samples for hematology and 
biochemistry m, n
X
X
X
X
X
X
X
(X)
Urinalysis n
X
X
X
X
X
X
(X)
Pregnancy test o
Serum
Urine
Urine
Urine
Urine
Urine
Urine
Urine
(Urine)
FSH p
X
PK, ADA, PD AND PGx ASSESSMENTS
Blood sample for PK d, n, q
X
X
X
X
X
X
X
(X)
Blood sample for ADA d, n
X
X
X
X
(X)
Blood sample for PD r
X
X
X
(X)
Stratum corneum sample for PD r
X
X
(X)


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Study period
Screening 
period
(Day -28 to 
Day-1)
Treatment period
Follow-
up c
Early 
Termination
Unscheduled 
visit d
Visit
V1
V2
No visit b
V3
V4
V5
V6
V7
(if applicable) (if applicable)
Week Screening a
Baseline
W1
W4
W8
W12
W16
W24
Day
D-28 to D-8
Day 1
Day 8
Day 29
Day 57
Day 85
Day 113
Day 169
Visit window 
±0 days
±2 days
±2 days
±5 days
±5 days
±7 days
Skin biopsy for PD (optional) r
X
X
(X)
PGx sample (optional) s
X
(X)
STUDY DRUG ADMINISTRATION
Randomization
X
(X)
Study drug injection t, u, v, w
X t
X
X
X
(X)
Abbreviations: ACT, asthma control test; ADA, anti-drug antibodies; AP NRS, Average Pruritus Numeric Rating Scale; DLQI, Dermatology Life Quality 
Index; ECG, electrocardiogram; EQ-5D, EuroQoL 5-Dimension; FSH, follicle-stimulating hormone; HADS, Hospital Anxiety and Depression Scale; HIV, 
human immunodeficiency virus; IGA, Investigator Global Assessment; NRS, numeric rating scale; PAS, prurigo activity score; PD, pharmacodynamics; PEF, 
peak expiratory flow; PGAD, Patient Global Assessment of Disease; PGAT, Patient Global Assessment of Treatment; PGIC-P, Patient Global Impression of 
Change – Pruritus; PGIC-SD, Patient Global Impression of Change – Sleep Disturbance; PGIS-P, Patient Global Impression of Severity – Pruritus; PGIS-SD, 
Patient Global Impression of Severity – Sleep Disturbance; PGx, pharmacogenomic; PK, pharmacokinetic; PP NRS, Peak Pruritus Numeric Rating Scale; SD 
NRS, Sleep Disturbance Numeric Rating Scale; TB, tuberculosis; UPT, urine pregnancy test.
Notes:
a)
Screening visit must be performed at least 7 days prior to Day 1 visit. Subjects deemed eligible will be provided with electronic handheld devices.
b)
Subjects will complete PGIS-P, PGIC-P, PGIS-SD, PGIC-SD, and PGAD assessments at Week 1 (ie, 7 days after the Day 1/Baseline visit) for test-
retest validation of itch and sleep PRO measures. 
c)
The follow-up visit will be conducted for subjects who decline or are not eligible to enter the LTE study (including early termination) and should be 
conducted 12 weeks after the last study drug injection. (The follow-up visit is not required for subjects who will rollover to the LTE study.)
d)
Assessments to be conducted at the unscheduled visit depend on the reason for the visit. PK and ADA analyses are required only at unscheduled visits 


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that are conducted for safety reasons. Subjects requiring rescue therapy between scheduled visits should return to the clinic for an unscheduled visit for 
investigator assessments of efficacy before starting rescue therapy. See Section 10.2.1 for details.
e)
SD NRS and sleep diary questions to be recorded by subjects once daily in the morning and if possible, within 1 hour of getting out of bed (Visit 
1/Screening through Visit 6/Week 16). PP NRS and AP NRS to be recorded by subjects once daily in the evening (Visit 1/Screening through Visit 
6/Week 16), beginning after the screening visit. On designated visits, PGIS-SD and PGIC-SD should be recorded after the SD NRS and sleep diary in 
the morning; PGIS-P and PGIC-P should be recorded after the PP NRS and AP NRS in the evening. 
f)
Pruritus assessments scheduled for clinic visit days that are recorded by subjects in the evening (ie, PP NRS, AP NRS, PGIS-P, PGIC-P) will be 
recorded the evening before the clinic visit.
g)
Patient-reported outcome assessments and designated safety measurements should occur before investigator assessments, laboratory sample collections, 
and study drug administration.
h)
Optional for consenting subjects and only for selected equipped sites; see Section 11.8 for details on clinical photographs.
i)
Subjects with a medical history of asthma will complete the ACT testing at each scheduled visit. Subjects with de novo asthma will complete the ACT 
testing beginning from de novo diagnosis and at all subsequent scheduled visits.
j)
PEF testing will be performed for all subjects at screening, baseline, Week 8, Week 16, and follow-up visits. For subjects reporting a medical history of 
asthma, PEF testing will be performed at all visits during the clinical study. For subjects diagnosed with de novo asthma, PEF testing will be performed 
at all visits, starting with the visit in which the diagnosis was confirmed. Subjects should be asked to withhold asthma medication on study visit days 
until after PEF testing is complete, to the extent it does not pose an undue risk to the subject. See Section 12.6.3 for details. 
k)
12-lead ECGs should be performed in the supine position, before any scheduled vital sign measurements and blood draws. See Section 12.4.
l)
In case of indeterminate result for TB test, the test should be repeated (only 1 retest is allowed). If the test is still indeterminate, the subject must not be 
included in the study, unless subject has a documented history of completion of an appropriate TB treatment regimen with no history of re-exposure to 
TB since their treatment was completed.
m) Subjects should be well hydrated and fast for at least 8 hours before the visit(s) when blood chemistry testing is planned, except for the screening visit.
n)
At scheduled visits with laboratory, PK, and ADA assessments, samples are to be collected before study drug injection(s).
o)
Only for females of childbearing potential. Serum pregnancy test to be performed at screening visit and UPT for all other visits. If UPT is positive, it 
must be confirmed with a serum pregnancy test. See Section 12.5.4 for details.
p)
For postmenopausal subjects (ie, no menses for 12 consecutive months), confirm status with a high FSH level in the postmenopausal range. 
q)
As a guideline, PK samples should be collected at approximately the same time of day throughout the study, to the extent possible, before study drug 


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injection (pre-dose samples). See Section 13.1 for details on PK assessments.
r)
Blood, stratum coreum, and biopsy samples for PD assessments are only collected at selected sites. Biopsy samples are optional and only for subjects 
who provide additional consent. See Section 14.3 for details.
s)
Optional PGx sample collection is only for subjects who provide additional consent. See Section 14.1 for details.
t)
Subjects weighing < 90 kg at baseline will receive a loading dose on Day 1 (ie, 2 injections of nemolizumab 30 mg or placebo) then single injections of 
either 30 mg nemolizumab or placebo Q4W. Subjects weighing ≥90 kg at baseline will receive either 60 mg nemolizumab or placebo via 2 injections 
Q4W at all study visits.
u)
Study drug reconstitution will be performed by the pharmacist (or other qualified personnel) throughout the study, and complete reconstitution 
confirmed, prior to delivery for injection. Study center staff will provide study drug injection training for subjects willing and able to self-inject study 
drug. Based on the subject’s preference, study center staff can also perform all injections.
v)
After study drug administration, subjects will be monitored closely for any signs or symptoms of hypersensitivity reaction before being discharged. For 
the first 2 visits where study drug is administered, subjects should remain at the study center for at least 30 minutes following study drug administration. 
w) If a study visit occurs outside the visit window, study drug injection(s) can still be administered provided there is a minimum of 3 weeks but not more 
than 5 weeks since the last injection. If beyond 5 weeks, the next study drug injection should then occur at the next planned visit. Future visits should be 
scheduled as soon as possible and within the required windows based on the baseline/Day 1 visit date, while maintaining the minimum 3-week interval 
between 2 injections.


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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.
Assessments to be conducted at the unscheduled visit will depend on the reason for the 
visit. Any of the procedures/assessments listed in Table 5 may be conducted, but not all 
are required. However, blood sample collection for PK and ADA analyses are required 
only during unscheduled visits that are conducted for safety reasons.


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11
EFFICACY ASSESSMENTS
The Schedule of Assessments (Table 5) outlines the efficacy assessments to be performed 
throughout the study and their timing. Whenever possible, the same evaluator should 
perform all assessments for the same subject in order to reduce intra-subject variability. 
INVESTIGATOR GLOBAL ASSESSMENT
The IGA is a 5-point scale used by the investigator or trained designee to evaluate the 
global severity of PN. The Investigator will review the subject’s skin and give a score of 
0 (Clear), 1 (Almost clear), 2 (Mild), 3 (Moderate), or 4 (Severe). Treatment 
response/success is defined as 0 (Clear) or 1 (Almost clear) and a ≥ 2-point improvement
from baseline (see Appendix 4).
PRURIGO ACTIVITY SCORE
The Investigator or designee will use the PAS as an evaluation of the disease. This 
includes a count of the number of lesions in a representative area and a calculated staging 
(stage 0 to stage 4) based on the percentage of lesions with excoriations/crusts and healed 
lesions compared to all lesions. 
A copy of the PAS can be found in Appendix 5.
NUMERIC RATING SCALES
Itch/Pruritus Numeric Rating Scales
Two NRSs relating to itch/pruritus (average and maximum intensity) will be completed 
by the subject once daily in the evening (see Appendix 6).32 Each NRS will ask for a unit 
score on an 11-point scale (0 to10) where 0 is “no itch” and 10 is the “worst itch 
imaginable”. The 2 questions asked will be:

For average itch intensity (AP NRS): “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 
overall during the previous 24 hours?”


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
For maximum itch intensity (PP NRS): “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?”
If a subject does not complete the NRS assessments in the evening before a scheduled 
visit, the subject will be allowed to complete the assessment the following day at the 
clinic visit. Site staff will be asked to ensure that the answer to the second question (PP 
NRS) is equal to or higher than the answer to the first question (AP NRS). If it is not,
then further explanation will be given to the subject.
Sleep Disturbance Numeric Rating Scale
An NRS relating to sleep disturbance will be completed by the subject once daily in the 
morning and if possible, within 1 hour of getting out of bed, to report the degree of their 
sleep loss related to PN (see Appendix 7). Each NRS will ask for a unit score on an 11-
point scale (0-10). The question asked will be “On a scale of 0 to 10, with 0 being “no 
sleep loss related to the symptoms of my skin disease (prurigo nodularis)” and 10 being 
“I did not sleep at all due to the symptoms of my skin disease (prurigo nodularis)”, how 
would you rate your sleep last night?”
If a subject does not complete the SD NRS in the morning before a scheduled visit, the 
subject will be allowed to complete the assessment at the clinic visit.
SUBJECT SLEEP DIARY
Subjects will be given a morning sleep diary to record the quality of their sleep. See
Appendix 8. The subject sleep diary is a modification of the consensus sleep diary,33 and 
is designed to gather information about the subject’s sleep pattern and how symptoms 
related to PN (eg, itching, burning) affect their sleep. Subject sleep diary items used to 
derive sleep parameters (eg, sleep onset latency, WASO) are defined in Appendix 8.
Subjects will be instructed to complete the sleep diary (Questions 1 to 11) once daily in 
the morning (ie, within 1 hour of getting out of bed), with the daily SD NRS (Appendix 
7). If a subject does not complete the sleep diary in the morning before a scheduled visit, 
the subject will be allowed to complete the assessment at the clinic visit.


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PAIN FREQUENCY AND INTENSITY 
Subjects will be asked to report the frequency and intensity of pain they endure related to 
their skin disease (prurigo nodularis) (see Appendix 9). Subjects will rate the frequency 
of their pain on a 6-point scale (0-5) in response to the following question:

“How often would you say that you experience pain from your skin disease (prurigo 
nodularis)?” 
Subjects will rate the intensity of their pain using an 11-point NRS (0-10) in response to 
the following question:

“On a scale of 0 to 10, with 0 being “no pain” and 10 being “the worst unbearable 
pain”, how would you rate the pain associated with your skin disease (prurigo 
nodularis) at the worst moment during the past week?”
PATIENT-REPORTED OUTCOMES ASSESSMENTS
Patient Global Assessment of Disease 
For the PGAD, subjects will be asked to rate their overall impression of their skin disease 
(prurigo nodularis) severity using a 5-point scale from “clear” to “severe” (see Appendix 
10). Subjects will be asked the following question:

“Overall, how would you describe your skin disease (prurigo nodularis) right 
now?”
The PGAD will also serve as an anchor for the patient-reported outcome (PRO) 
psychometric validation.
Patient Global Assessment of Treatment 
The PGAT utilizes a 5-point Likert scale for subjects to rate the way they feel their skin 
disease (prurigo nodularis) is responding to the study treatment. See Appendix 11.
Subjects will be asked the following question:


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“How would you rate the way your skin disease (prurigo nodularis) responded to the 
study medication?”
Patient Global Impression of Severity - Pruritus
For the PGIS-P, subjects will be asked to rate their impression of their overall itch 
severity during the last week using a 5-point scale from “none” to “very severe”
(Appendix 12). Subjects will record their PGIS-P scores in the evening after completing 
the Pruritus (PP and AP) NRS (Appendix 6). If a subject does not complete the PGIS-P in 
the evening before a scheduled visit, the subject will be allowed to complete the 
assessment the following day at the clinic visit. The PGIS-P will serve as an anchor for 
the PRO psychometric validation. 
Patient Global Impression of Change - Pruritus
The PGIC-P utilizes a 5-point Likert scale (from “much better” to “much worse”) for 
subjects to rate their impression of how their overall itch has changed since beginning 
study drug. See Appendix 13. Subjects will record their PGIC-P scores in the evening 
after completing the Pruritus (PP and AP) NRS (Appendix 6). If a subject does not 
complete the PGIC-P in the evening before a scheduled visit, the subject will be allowed 
to complete the assessment the following day at the clinic visit. The PGIC-P will serve as 
an anchor for the PRO psychometric validation. 
Patient Global Impression of Severity - Sleep Disturbance
For the PGIS-SD, subjects will be asked to rate their impression of the severity of their 
sleep disturbance due to the symptoms of PN during the past week using a 5-point scale 
from “none” to “very severe” (See Appendix 14). Subjects will record their PGIS-SD 
score in the morning after completing the SD NRS and Subject Sleep Diary (Appendix 7
and Appendix 8, respectively). If a subject does not complete the PGIS-SD in the 
morning before a scheduled visit, the subject will be allowed to complete the assessment 
at the clinic visit. The PGIS-SD will serve as an anchor for the PRO psychometric 
validation. 


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Patient Global Impression of Change - Sleep Disturbance
The PGIC-SD utilizes a 5-point Likert scale for subjects to rate their impression of how 
their overall sleep disturbance, due to the symptoms of their skin disease (prurigo 
nodularis), has changed since beginning study drug (see Appendix 15). Subjects will 
record their PGIC-SD score in the morning after completing the SD NRS and Sleep Diary
(Appendix 7 and Appendix 8, respectively). If a subject does not complete the PGIC-SD 
in the morning before a scheduled visit, the subject will be allowed to complete the 
assessment at the clinic visit. The PGIC-SD will serve as an anchor for the PRO 
psychometric validation. 
QUALITY OF LIFE QUESTIONNAIRES
Dermatology Life Quality Index
The DLQI is a validated 10-item questionnaire covering domains including 
symptoms/feelings, daily activities, leisure, work/school, personal relationships, and 
treatment (see Appendix 16).34
The subject will rate each question ranging from 0 (not at all) to 3 (very much). A higher 
total score indicates a poorer QoL. 
Hospital Anxiety and Depression Scale
The Hospital Anxiety and Depression Scale (HADS) is a 14-question validated
questionnaire completed by the subject.35 Each question has a multiple choice answer 
which is scored between 0 and 3. Questions are identified as relating to anxiety (A) or 
depression (D) and a summation for each area is performed leading to a total score of 0 to 
21 for each area. Scores of 0 to 7 are considered normal, 8 to 10 are borderline, and ≥ 11 
indicates clinical effects.
A copy of the HADS can be found in Appendix 17.
EuroQoL 5 Dimension Instrument
The EQ-5D instrument is a validated questionnaire, completed by the subject that 
consists of 2 parts. The first part consists of 5 multiple choice QoL questions and the 


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second is a 100 point VAS scale with 0 being “Worst imaginable health state” and 100 
being “Best imaginable health state”.
A copy of the EQ-5D can be found in Appendix 18.
CLINICAL PHOTOGRAPHS
The optional clinical photography assessment will take place at selected equipped study 
centers. Subjects will be asked to provide separate consent to be involved in this section 
of the study. Declining to participate in this section of the study will not affect subject 
involvement in the main part of the study.
The Investigator or designee will be asked to take clinical photographs of the entire 
subject’s body on 2 occasions throughout the study. Additional details will be provided in 
the photographic manual. 


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12
SAFETY ASSESSMENTS
Safety assessments (vital signs, physical examinations, ECG recording, AEs, respiratory 
examination and assessments, and clinical laboratory results [routine hematology and 
biochemistry]) are to be performed at protocol-specified visits, beginning at the screening 
visit (upon signing the ICF), as specified in the Schedule of Assessments (Table 5).
VITAL SIGNS
Vital signs will be evaluated at all visits, as indicated in the Schedule of Assessments 
(Table 5). Vital signs will include pulse rate, systolic and diastolic blood pressure (after 
the subject has been sitting for at least 5 minutes), and body temperature. All abnormal 
values at the screening visit identified as clinically significant by the investigator will be 
recorded in the medical history form. Any clinically significant changes from the 
screening visit (and onwards) will be recorded as an AE. 
HEIGHT AND WEIGHT
Height and weight will be measured according to the Schedule of Assessments (Table 5).
PHYSICAL EXAMINATION
Complete physical examination should be performed at the screening, baseline, and 
specified subsequent scheduled visits, according to the Schedule of Assessments 
(Table 5). 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 12.6), 
gastrointestinal system, musculoskeletal system, lymph nodes, nervous system, and 
extremities.
The investigator should assess all abnormal findings for clinical significance. All 
clinically significant abnormal findings at the screening visit will be recorded in the 
medical history form. Any clinically significant changes from the screening visit will be 
recorded as an AE.


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12-LEAD ELECTROCARDIOGRAM
A 12-lead, resting ECG will be performed and read centrally according to visits indicated 
in the Schedule of Assessments (Table 5) using the ECG machine provided. ECGs for 
each subject should be obtained using the electrocardiograph machine provided for the 
study. ECGs will be performed in the supine position and before any scheduled vital sign 
measurements and blood draws. Subjects should be monitored for potentially clinically 
significant ECG results (refer to the current version of the central laboratory manual). 
Tests with abnormal results that are deemed clinically significant 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 clinically significant after the screening visit are to be recorded as AEs 
and discussed with the medical monitor, as needed.
CLINICAL LABORATORY EVALUATION
The hematology laboratory analyses, clinical chemistry 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 clinically significant, 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, eg, 
discontinuation of the drug, close observation, more frequent follow-up 
assessments, or further diagnostic investigation.


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If the investigator observes a clinically significant laboratory result, 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. This should occur only after 
discussion with medical monitor.
All clinically significant 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 clinically significant 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 (ie, changed 
significantly from the screening visit). Whenever possible, the investigator should 
provide a diagnosis of an AE when reporting the abnormal laboratory value. See Section 
12.7 for details. 
Subjects should be reminded to be well hydrated before all visits for phlebotomy 
purposes. Subjects should fast for at least 8 hours before the visits when blood chemistry 
testing is planned, except for the screening visit. 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 (eg, at unscheduled 
visits for safety reasons, when an abnormal laboratory value is observed and requires a 
re-test).
Laboratory assessment samples are to be obtained at designated visits as detailed in the 
Schedule of Assessments (Table 5).


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Hematology
The hematology tests include: hemoglobin, hematocrit, white blood cell count (with 
differential including eosinophils), red blood cell count, platelet count, and mean cell 
volume.
Clinical Chemistry
The clinical chemistry tests include: 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, creatine 
phosphokinase (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 (ie, no menses for 12 consecutive months), postmenopausal 
status will be confirmed with a high follicle-stimulating hormone level in the 
postmenopausal range.
Urinalysis
The urinalysis tests include: pH, glucose, ketones, blood, protein, leukocytes, nitrites, 
bilirubin, urobilinogen, and specific gravity.
Pregnancy Testing
All women of childbearing potential will have a serum pregnancy test at the screening 
visit and UPTs at subsequent visits according to the Schedule of Assessments (Table 5). 
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.
Urine pregnancy tests with a sensitivity < 25 IU/L will be provided to the study centers 
for use in the trial.
UPTs will be performed at the study centers, and all other samples will be sent to central
laboratory for analysis.


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If the result of a UPT is positive, it must be confirmed with a serum pregnancy test, and 
no study drug should be administered pending the serum pregnancy test result. Subjects 
with a positive serum pregnancy test result during the trial must discontinue treatment 
and be withdrawn from the trial.
Virology
Virology including HBsAg, HBcAb, hepatitis C, human immunodeficiency virus 1, and 
human immunodeficiency virus 2 antibodies 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 (eg, PCR).
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. Subjects 
will be screened for active or latent TB before entry into this study.
12.5.6.1 Tuberculosis Definitions
Active TB is a disease caused by Mycobacterium tuberculosis 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 M tuberculosis, as 
evidenced by a positive Interferon Gamma Release Assay36 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.


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12.5.6.2 Tuberculosis Screening
Ideally, 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 (eg, 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 their 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.
RESPIRATORY ASSESSMENTS
At screening, the investigator should specifically question all subjects about any medical 
history of asthma and their respiratory health (eg, wheezing, coughing, allergies, and
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.
Asthma Control Test
Subjects with a medical history of asthma will take the ACT at visits according to the 
Schedule of Assessments (Table 5) 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 thereafter, at all subsequent 
study visits. Subjects with an ACT score ≤ 19 will be referred to the physician managing 
their asthma.


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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 5 questions. For each question, the subject will choose the best answer out 
of 5 possible answers. The test provides a numerical score ranging from 5 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. A copy of the ACT can be found 
in Appendix 19.
Respiratory Examination
A respiratory examination will be required to be performed for all subjects at all 
scheduled visits, according to the Schedule of Assessments (Table 5). The ACT will also 
aid the investigator’s questioning of subjects with a medical history of asthma and should 
be completed before the clinical questioning. 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 (exam findings or newly-
reported signs and/or symptoms suggestive of asthma) will be referred to a respiratory 
specialist.
Peak Expiratory Flow
All subjects will undergo PEF testing at screening, baseline, and specified visits 
according to the Schedule of Assessments (Table 5). For subjects reporting a medical 
history of asthma, PEF testing will be conducted at all visits. 
In the event that PEF is < 80% of the predicted value at screening in patients without any 
history of asthma or in patients with history of asthma but with the ACT score > 19, PEF 
testing can be repeated once within 48 hours.
Subjects with a new (de novo) diagnosis of asthma will undergo PEF testing at all visits 
after the diagnosis is first made according to the Schedule of Assessments (Table 5).


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Peak expiratory flow testing during the clinical study will be performed under the 
supervision of qualified study personnel. Peak expiratory flow measurements should 
consist of 3 good efforts, with the best result documented. It is preferable that the PEF 
measurement be performed before noon or at the same time during each study visit 
whenever possible. Obtained PEF values will be compared to predicted values based on 
the subject’s age, sex and height.37,38
To avoid interference with PEF measurements, attempts should be made to withhold 
asthma medication on study visit days until after PEF testing is complete; to the extent it 
does not pose an undue risk to the subject. 
Subjects with a medical history of asthma with a PEF < 80% of the predicted value will 
be referred to the physician managing their asthma.
Respiratory Referrals
Subjects with a medical history of asthma will be referred to the physician who manages 
their asthma when:

PEF < 80% of the predicted value

ACT score ≤19 because 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:

Signs and/or symptoms suggestive of asthma are newly observed or reported.

Respiratory assessments (ie, examination, PEF) suggest a decline in the subject’s 
respiratory health.


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ADVERSE EVENTS
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 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 12.7.7.

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 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 non persuasive 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. 


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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.  
Adverse events 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.
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.
If there is a change in severity of an AE, it must be recorded as a separate event.
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 (ie, nemolizumab or placebo) 
and/or study procedure (eg, injection, blood sample collection). Medical judgment should 
be used to determine the relationship, considering all relevant factors including the 


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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).
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 (ie, suggestive 
evidence or arguments) that there is a causal relationship irrespective of the dose 
administered:

Between the study drug (nemolizumab) and the AE, and/or

Between the clinical study protocol procedure (eg, injection, 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.
Action Taken
The investigator will describe the action taken in the appropriate section of the eCRF, as 
follows:

None

Study drug stopped

Study drug temporarily interrupted

Concomitant medication (any additions or discontinuations)

Other, specify


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Follow-up of Adverse Events
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.
Documentation and Reporting of Adverse Events
Adverse events 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

Causal relationship

Outcome of event (unknown, recovered, not yet recovered, recovered with 
sequelae, death [with date and cause reported])
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 12.7.5 for reporting procedure(s). 
An AESI can be either serious or nonserious.


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Based on the potential risks of nemolizumab (CD14152) and the risks associated with 
biologics (and their biosimilar equivalents) in general (ie, class effects), the following 
AEs will be considered AESIs:

Injection-related reactions (IRRs)
o
Anaphylactic reactions
o
Acute allergic reactions requiring treatment
o
Severe injection site reaction (ie, lasting > 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.

PEF < 80% of the predicted value: An AESI should be reported.

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 (ie, examination, PEF) suggest a decline 
in the subject’s respiratory health. An AESI is reported based on 
the investigator’s clinical judgment of the specialist’s report.

Infections
o
Any severe infection or any infection requiring treatment with parenteral 
antibiotics or oral antibiotics/antivirals/antifungals for > 2 weeks
o
Any confirmed or suspected COVID-19 infection

Peripheral edema: limbs, bilateral

Facial edema


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
Elevated ALT or AST (> 3 × ULN) in combination with elevated bilirubin (> 2 × 
ULN)
Serious Adverse Events
An SAE is any untoward medical occurrence, in the view of either the investigator or 
Sponsor, that:

results in death

is life-threatening

results in inpatient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization, based upon appropriate medical judgment, are considered SAEs 
if they are thought to jeopardize the subject and/or require medical or surgical 
intervention to prevent one of the outcomes defining an SAE. 
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 enrolment in 
the clinical trial, admission to a day care facility, social admission (eg, if the subject has 
no place to sleep), or administrative admission (eg, for a yearly examination).
SAEs are critically important for the identification of significant safety problems; 
therefore, it is important to take into account both the investigator’s and the Sponsor’s 
assessment. If either the Sponsor or the investigator believes that an event is serious, the 
event must be considered serious and evaluated by the Sponsor for expedited reporting.
Procedure for Reporting Serious Adverse Events
For any SAE occurring during the clinical study, regardless of whether or not related to 
the study drug and/or procedure, the investigator must:


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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 Syneos Health Safety and Pharmacovigilance group of an 
SAE report, by email or fax:
Fax Number: 001-877-464-7787 
Safety email: SafetyReporting@SyneosHealth.com 
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 the eCRF, at that time.
3. Send any relevant information or anonymized medical records (eg, laboratory test 
results) to the Syneos Health Safety and Pharmacovigilance group (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 


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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 (ie, the CRO) will comply with country-specific regulatory requirements
relating to safety 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 a SAE(s) or 
other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
or its delegate (ie, the CRO) will file it accordingly (ie, within the Trial Master File), 
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.
Procedure for Reporting Adverse Events of Special Interest
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 3 days of receipt of the 
event) the Syneos Health Safety and Pharmacovigilance group of an AESI report, by 
email or fax. Refer to Section 12.7.4.
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 the eCRF, at that time.


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3. Send any relevant information or medical records (eg, laboratory test results) to the 
Syneos Health Safety and Pharmacovigilance group within 3 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 report within 3 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 report, if appropriate.
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 (ie, the event is not consistent with the safety information in the IB)

there is at least a reasonable possibility that there is a causal relationship between 
the event and the study treatment
The investigator will assess whether an event is causally related to study treatment. The 
Sponsor (or Syneos Health) will consider the investigator’s assessment and determine 
whether the event meets the criteria for being reportable as a 7-day or 15-day safety 
report. SUSARs that are fatal or life-threatening must be reported to the regulatory 
authorities and the IEC/IRBs (where required) ≤ 7 days after the Sponsor (or Syneos 
Health) has first knowledge of them, with a follow-up report submitted within a further 8 
calendar days. Other SUSARs must be reported to the relevant regulatory authorities and 
the IEC/IRBs within 15 calendar days after the Sponsor (or Syneos Health) first has 
knowledge of them.


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The Sponsor (or Syneos Health) is responsible for reporting SUSARs and any other 
events required to be reported in an expedited manner to the regulatory authorities and for 
informing investigators of reportable events, in compliance with applicable regulatory 
requirements within specific timeframes. Investigators will notify the relevant IEC/IRBs 
of reportable events within the applicable timeframes, according to local requirements.
Procedures for Reporting Pregnancy
Women of childbearing potential (WOCBP) must have a negative pregnancy test at 
screening. Following administration of study drug, any known cases of pregnancy in 
female subjects will be reported until the subject completes or withdraws from the study. 
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 
injection of the study drug.
2. Complete as fully as possible the Pregnancy Surveillance Form – Part I: History and 
Start of Pregnancy. Send by email or fax along with the exit form within 24 hours of 
receipt of the information, to the Syneos Health Safety and Pharmacovigilance group. 
Refer to Section 12.7.4.
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 email or fax to the 
Syneos Health Safety and Pharmacovigilance group within 24 hours of receipt of the 


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information. If the subject can no longer be reached (ie, lost to follow-up), 
documentation of the non-response/contact with 2 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 email or fax to the Syneos Health Safety and Pharmacovigilance group 
within 24 hours of receipt of the information.
6. If the pregnancy leads to an abortion (ie, voluntary abortion, spontaneous abortion, or 
therapeutic abortion), in utero death or congenital anomaly, follow the procedure for 
declaration of/reporting an SAE (see Section 12.7.4).
Overdose
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.
Although overdose of nemolizumab occurred in the phase 2 AD study (ie, accidental 
injection of more than 2.0 mg/kg SC), no related AEs were reported.
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. The IDMC charter will provide 
details on the IDMC, including the plan of analysis for IDMC outputs; the composition of 
the IDMC; and the procedures, roles, responsibilities, and communications.
INDEPENDENT ADJUDICATION COMMITTEE
An IAC will review all asthma-related AEs throughout the study. The IAC charter will 
provide details on the IAC, including the plan of analysis for IAC outputs; the 
composition of the IAC; and its procedures, roles, responsibilities, and communications.


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PHARMACOKINETICS
PHARMACOKINETIC SAMPLING
Blood Samples
Blood samples for PK analysis of nemolizumab levels will be collected at the time points 
indicated in the Schedule of Assessments (Table 5) and the clinical laboratory manual to 
determine the PK profile of nemolizumab. At each sampling time point for PK 
assessments, the collected blood will be placed to clot at room temperature (no more than 
60 minutes after collection) and then centrifuged. The serum will be collected into 
storage tubes.
As a guideline, PK samples should be collected at approximately the same time of day 
throughout the study, to the extent possible, before study drug injection (pre-dose 
samples). The date and the time of each sample collection will be recorded in the eCRF, 
together with the time of study drug injection at the same visit (or missed injection if 
applicable).
CD14152 Quantification in Biological Sampling
Concentration of nemolizumab (CD14152) in the serum will be determined by the 
designated CRO using a validated enzyme-linked immunosorbent assay method. Details 
related to the processing of serum samples and the assessments of nemolizumab will be 
described in the bioanalytical plan, which will be finalized before the beginning of 
sample analysis. Results will be described in the bioanalytical report, which will be 
included as an appendix in the final clinical study report.
PK parameters, PopPK and PK/PD analyses 
Population PK parameters of nemolizumab (CD14152) will be derived, by a designated 
CRO, using a non-linear mixed effect modeling approach with NONMEM software. A 
pre-specified PopPK model based on existing information from previous studies in adults 
(first-order absorption and a 1-compartment distribution model) will be updated with the 
nemolizumab serum concentrations obtained in this study.


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Observed Ctrough will be listed for each subject and summarized with descriptive statistics 
(see Section 15.6).
In addition, PK/PD analyses will be conducted using pre-specified models based on 
existing information from previous studies in adults. For efficacy, PD endpoints are 
defined as the 2 primary clinical efficacy endpoints of the study: PP NRS responder and 
IGA success. If needed PK/PD analysis might be conducted for safety.
PopPK and PK/PD analyses will be described in an ad hoc Modeling & Simulation Plan.
PopPK and PK/PD analyses results will be described in ad hoc Modeling & Simulation
Report.


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OTHER ASSESSMENTS
PHARMACOGENOMICS 
Pharmacogenomic testing (DNA analysis) is optional for this study, and will apply to 
subjects who provide written consent for this procedure. Subjects are not required to 
participate in the DNA analysis sub-study in order to enroll in the main study.
DNA analysis will be performed using a blood sample collected at baseline. If 
inadvertently not collected at baseline, the sample may be collected at a post-baseline 
visit.
Samples will be stored by the Sponsor or designated CRO for up to 15 years after the end 
of the study. Candidate sequences in DNA analysis may include but are not limited to 
genes that encode IL-31 and its receptor (IL-31RA). DNA analysis will be conducted for 
the purpose of understanding inter-individual variability in nemolizumab (CD14152) 
efficacy, safety, and PK.
These data may be used or combined with data collected from other studies to identify 
genomic markers that may predict response and elucidate mechanisms of disease. 
Analyses may include sequence variation or single nucleotide polymorphism 
identification within candidate genes and surrounding genomic regions. Genome-wide 
studies may also be performed.
It is the intent of the Sponsor to assure that PGx information obtained remains 
confidential. The Sponsor maintains rigorous confidentiality standards for clinical studies 
by “coding” (ie, assigning a unique subject ID number at the investigational study center) 
for all subjects enrolled in the study. All samples taken for DNA analysis will undergo a 
second level of “coding” (each sample will receive a double-coded ID), according to the 
International Council for Harmonisation (ICH)-15 standards. Records will exist to trace 
double-coded samples to individual subjects for destruction if a subject provides a written 
request to withdraw their sample for DNA analysis. The data from samples that have 
already been analyzed will not be destroyed.


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Blood samples for DNA analysis will be destroyed after 15 years have elapsed from the 
completion of this study.
IMMUNOGENICITY
Blood samples will be collected at the time points indicated in the Schedule of 
Assessments (Table 5) and the clinical laboratory manual to assess anti-nemolizumab 
ADA.
The ADA will be determined by the designated CRO using a validated 
electrochemiluminescence immunoassay (ECLIA). The serum concentration will be 
assessed using a multi-tiered approach.
Details related to the processing of serum samples and the assessments of ADA will be 
described in the bioanalytical plan, which will be finalized before the beginning of 
sample analysis. Results will be described in the bioanalytical report, which will be 
included as an appendix in the final clinical study report.
If serum circulating ADA is detected, presence will be confirmed and characterized (eg, 
for titer and neutralizing potential). Incidence of positive ADA results will be 
summarized (absolute occurrence and percent of subjects).
PHARMACODYNAMIC BIOMARKERS
Blood and stratum corneum (D-Squames) samples will be collected from approximately 
100 subjects at selected sites to investigate the effect of nemolizumab (CD14152) on 
selected RNA and protein biomarkers, including but not limited to IL-31. Optional skin 
biopsies for RNA and immunohistochemistry analyses will be collected from 
approximately 30 subjects at selected sites who sign the additional consent form. Samples 
will be collected according to Table 5. 
The details of the procedures for PD samples and storage conditions are further described 
in the clinical laboratory manual. Samples will be shipped to the designated CRO for 
biomarker assessment, unless otherwise specified. Samples will be stored by the sponsor 
or designated CRO for up to 15 years after the end of the study.


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Blood Samples for PD
Blood samples will be collected for assessment of IgE by the central laboratory. 
Additional blood samples will be collected and shipped to the designated CRO for RNA 
and protein biomarkers assessment. Total blood volumes to be drawn at each visit are 
provided in the clinical laboratory manual.
Stratum Corneum (D-Squames) Samples for PD
Stratum corneum samples will be collected using D-Squames (ie, tape strips) to evaluate 
biomarker expression levels.39,40,41 Body location for D-Squames sampling should be 
identified at baseline. D-Squames should be performed as much as possible in a clinically 
representative body location for all applicable subjects throughout the study and recorded 
on the central laboratory requisition form.
At baseline prior to administration of study drug, 1 lesional and 1 non-lesional area will 
be identified, and 20 consecutive D-Squames will be collected from each area, making 40 
D-Squames in total (20 from lesional skin and 20 from non-lesional skin). At Week 16, 
20 consecutive D-Squames will be collected from the exact anatomical location of the 
lesional area identified at baseline, regardless if the lesion has regressed (20 D-Squames 
in total). The samples will be shipped to the designated CRO for analysis of selected 
protein and RNA biomarkers.
Skin biopsies for PD (optional)
Three 4-mm punch biopsies will be performed (only for subjects who accept skin 
biopsies by signing the additional consent form) for RNA biomarkers and 
immunohistochemistry. Biopsies should be collected according to the investigator’s usual 
procedure, including follow-up.
Body location for biopsy sampling should be identified at baseline. Biopsies should be 
performed as much as possible in a clinically representative body location for all 
applicable subjects throughout the study and recorded on the central laboratory 
requisition form.


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The samples will be collected as much as possible on the same anatomical area as D-
Squames, in an adjacent lesion with as much as possible a similar clinical presentation. 
Skin biopsies will be performed as follows:

Baseline visit:
o
One 4 mm punch biopsy on lesional skin (nodule)
o
One 4 mm punch biopsy on non lesional skin: approx. 5 cm apart from 
lesional skin

Week 16 visit:
o
One 4 mm punch biopsy on lesional skin after treatment (on a nodule 
selected at baseline).


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15
STATISTICAL ANALYSIS
A statistical analysis plan (SAP) will be created and finalized before database lock
(DBL). This document will provide details regarding the definition of analysis variables 
and analysis methodology to address all study objectives. The SAP will contain further 
detailed and technical descriptions of specific data conventions, calculations and of 
statistical procedures for executing the analyses that are specified in this protocol. Any 
changes made to the analysis after finalization of the SAP (ie, post-DBL) will be 
discussed and documented in the clinical study report.
The statistical evaluation will be performed using SAS® software version 9.4 or higher 
(SAS Institute, Cary, NC). All data will be listed, and summary tables will be provided. 
Summary statistics will be presented by treatment group. For continuous variables, data 
will be summarized with the number of subjects (N), mean, standard deviation (SD), 
median, 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.
Unless otherwise stated, the baseline value for any variable will be the last non-missing 
value taken prior to the receipt of study treatment at the Baseline visit (Day 1). 
Unless otherwise stated, all statistical tests will be 2-sided and conducted at the 5% level. 
All presented CIs will be 2-sided 95% CIs.
A Blind Data Review Meeting (BDRM) will be convened to finalize assignments to the 
analysis populations, including the Per-Protocol (PP) immediately prior to DBL, ie, once 
all subjects have completed the study and data cleaning activities are essentially 
complete. The agenda for this meeting, along with any decisions made to determine 
analysis population inclusion/exclusion, decisions on data handling and other topics will 
be documented in the BDRM Plan and subsequently in the BDRM Report.


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DATASETS OR STUDY POPULATIONS ANALYZED
Screened Population
The Screened population comprises all subjects who signed the ICF and have screening 
data entered into the database. This population includes screen failures and randomized 
subjects. Screen failed subjects are defined as those subjects who fail to meet inclusion 
criteria or meet exclusion criteria and discontinue the study prior to randomization. 
Subjects that are re-screened will only be counted once, under the subject ID assigned for 
the repeat screening.
Intent-to-Treat Population (ITT)
The ITT population will consist of all randomized subjects. The ITT population will be 
the primary population for efficacy analyses. All analyses under the ITT population will 
be analyzed under the treatment group as randomized.
Per-Protocol Population (PP)
The PP population will consist of all subjects in the ITT population and have no major 
protocol deviations that would have a significant effect on the efficacy of the study 
treatment. Only primary and key secondary endpoints will be analyzed using the PP
population, under the treatment group as randomized. For further information on protocol 
deviations, please refer to Section 15.9.
Safety Population (SAF)
The SAF will consist of all randomized subjects who received at least 1 administration of 
study drug. The treatment group assignment in this population will be defined by the 
treatment actually received. This population will be used for the analyses of safety.
Pharmacokinetic (PK) Analysis Population (PKAP)
The PKAP will consist of all subjects included in the SAF, with at least one measurable 
post-baseline PK assessment. Similar to SAF, the treatment group assignment in this 
population will be defined by the treatment actually received. This population will be 
used for the descriptive analyses of PK parameters.


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SUBJECT DISPOSITION
The number of subjects screened and randomized in each analysis population will be 
presented. The number of subjects that discontinue the study and the reasons for 
discontinuation will be summarized. In addition, subjects’ status with regard to study 
treatment and follow-up will also be summarized.
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Demographic and other baseline characteristics (eg, age, sex, race, height, body weight, 
body mass index, and applicable disease baseline characteristics) will be summarized for 
the ITT, PP, and SAF populations. Medical history, plus prior and concomitant therapies 
(including prohibited therapies) will be summarized for the SAF population.
EFFICACY ANALYSIS
Unless otherwise stated, all efficacy analyses will be performed on the ITT population.
Primary Efficacy Endpoints
  The primary endpoints include the following endpoints:
1. The proportion of subjects with an improvement of ≥4 from baseline in PP NRS 
at Week 16.
2. The proportion of subjects reporting success on the IGA at Week 16, defined as 
an IGA response of 0 [Clear] or 1 [Almost clear] and a ≥2-point reduction from 
baseline;
For both primary endpoints, any subjects with missing data at Week 16 will be regarded 
as a non-responder for the respective endpoint. If a subject is in receipt of rescue 
medication at any point on or prior to Week 16, data after receipt of rescue medication 
will be set to missing, and subsequently regarded as a non-responder for respective 
primary endpoint based on the same imputation method as for purely missing data. 
Analysis of Primary Efficacy Endpoints
The statistical hypotheses associated with the primary analysis of improvement in PP 
NRS ≥4 from baseline at Week 16 using treatment difference is, similarly:


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H0: PPP NRS_nemo - PPP NRS_Pla = 0;
H1: PPP NRS_nemo - PPP NRS_Pla ≠ 0,
where PPP NRS_nemo and PPP NRS_Pla are the proportion of subjects categorized as having a PP 
NRS improvement from baseline to Week 16 of ≥4, for nemolizumab and Placebo, 
respectively.
The statistical hypotheses associated with the primary analysis of IGA success at Week 
16 using treatment difference is:
H0: PIGA_nemo - PIGA_Pla = 0;
H1: PIGA_nemo - PIGA_Pla ≠ 0,
where PIGA_nemo and PIGA_Pla are the proportion of subjects categorized as success under 
IGA at Week 16 for nemolizumab and Placebo, respectively.
Both primary endpoints will be analyzed using a Cochran-Mantel-Haenszel (CMH) test 
adjusted for the randomization strata analysis center and baseline body weight cut-off (<
90 kg and ≥90 kg), in order to test the difference between nemolizumab and placebo for 
the proportion of subjects achieving success in each endpoint. The estimate of the 
treatment difference and corresponding 2-sided 95% CI and p-values will be presented. 
The confidence intervals will be based on Wald statistic controlling for stratification 
variables. Strata-adjusted proportion differences will be obtained using weighted average 
of stratum-specific proportion using CMH. This primary analysis will be conducted on 
the ITT population. To control type I error at 5% significance level, a fixed sequential 
testing approach, as described in Section 15.4.5, will be implemented.
Sensitivity Analyses of the Primary Endpoint
Sensitivity analyses for both primary endpoints will be conducted in order to test for the 
robustness of the primary analyses. The following sensitivity analyses will be conducted: 

PP population

To assess the robustness of non-responder analysis, a tipping point analysis will 
be performed by converting non-responders due to missing data to responders in 
successive increments (∆) for both treatment groups. The value of ∆ that 
overturns (ie, non-significant) the primary results will represent the tipping point. 
A graphic display of all possible combinations of the number of responders 


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among both treatment groups will be presented.

Multiple Imputation (MI) method for missing data (or where rescue medication is 
received), assuming all missing data are Missing at Random (MAR)
The MI imputation will be carried out as follows: 
Imputation Phase:
1. A 50 imputed datasets with a monotone missing pattern will be created using 
SAS MI procedure based on the observed data (Markov-Chain-Monte-Carlo 
method, MCMC). The seed to be used is 203065 (the Protocol number). 
Pattern of missing data will be evaluated and it is expected that the pattern of 
missing data will be monotonic. For non-monotone missing data patterns, 
MCMC method of MI procedure will be used to impute enough data so that 
the remaining missing data is monotone.
2. Each of the imputed datasets will be used to generate 50 complete datasets, 
using following approaches:
a.
A logistic regression method to impute the ordinal IGA missing data, 
including treatment, randomization strata, and assessments from 
earlier time points as covariates. IGA responder variable will be 
derived using these imputed data. 
b. For PP NRS endpoint, a linear regression model including treatment, 
randomization strata, and assessments from earlier time points as 
covariates will be used to impute the weekly average score. PP NRS 
responder variable will be derived using these imputed data. 
Analysis Phase:
3. The complete datasets will be modelled for the endpoint using CMH method 
as per analysis described in Section 15.4.2. Proportion of responders in each 
treatment arm, difference and standard error will be calculated.


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Pooling Phase:
4. The results from the CMH analysis of the multiple imputed datasets will be 
combined using the Rubin (1987) and Li et al (1991) approach to produce 
pooled CMH statistics and p-value. Proportion of responders in each treatment 
arm, difference and standard error will be combined using the MIANALYZE 
procedure in SAS.

Pattern-mixture model under assumption Missing Not at Random (MNAR) 
controlled-based pattern imputation. MI-based imputation will be applied as 
described above. Under MNAR assumption, a controlled based pattern imputation 
where only observation in placebo treatment group will be used to impute. 

Last Observation Carried Forward (LOCF) imputation method for missing data 
(or where rescue medication is received)

Observed Case (OC) - No data will be imputed. For this analysis, if any rescue 
medication is received, and data are collected post rescue receipt, data post-rescue 
will be analyzed as observed (ie, not set to missing) by ignoring the use of rescue 
medication
Sensitivity analyses may be performed to evaluate the impact COVID-19 deviations. 
Further details will be provided in SAP.
Key Secondary Efficacy Endpoints
The following key secondary endpoints are to be analyzed, in order:
1. Proportion of subjects with an improvement of ≥ 4 from baseline to Week 4 in PP 
NRS;
2. Proportion of subjects with PP NRS < 2 at Week 16
3. Proportion of subjects with an improvement of ≥ 4 from baseline in SD NRS at 
Week 16
4. Proportion of subjects with an improvement of ≥ 4 from baseline in SD NRS at 
Week 4
5. Proportion of subjects with PP NRS < 2 at Week 4


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All key secondary endpoints will be analyzed on the ITT population as primary, and 
additionally on the PP population as supportive. 
Additionally, the same sensitivity analyses as for the primary endpoints will be 
employed. For these endpoints, similar to the primary, the continuous response will be 
imputed first, and the response will then be categorized. 
Multiplicity/Multiple comparisons
To control the type I error at 5%, a fixed sequential testing approach will be 
implemented. For testing purposes both primary endpoints will be tested first in a 
predefined order (as listed in Section 15.4.1) at 5% significance level, and testing of key 
secondary endpoints will start only if both primary endpoints are successful at 5% level 
of significance. Key secondary endpoints will be tested in an order listed in Section 
15.4.4, stopping when non-significant result (p > 0.05) is found.
Secondary Efficacy/QoL Endpoints
The following secondary endpoints are to be analyzed at the following visits: 
Endpoint
Analysis Visit
IGA success rate at each visit
Baseline, W4, W8, W12, W16
PAS items 5a (excoriation/crusts), 5b (healed 
lesion stages) at each visit
Baseline, W4, W8, W12, W16
Change from baseline in PAS item 4 (number of 
lesions in representative area) at each visit
Baseline, W4, W8, W12, W16
Proportion of subjects with PP NRS at each visit: 
a) Improvement ≥4 from baseline;
b) < 2 at visit
c) < 3 at visit
Baseline, W4, W8, W12, W16
Proportion of subjects with PP NRS improvement 
≥ 4 from baseline and IGA success
Baseline, W16
Absolute and Percent change from baseline in PP
NRS at each visit
Baseline, W4, W8, W12, W16


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Endpoint
Analysis Visit
Proportion of subjects with AP NRS at each visit: 
a) Improvement ≥4 in change from baseline;
b) < 2 at visit
Baseline, W4, W8, W12, W16
Absolute and Percent change from baseline in AP
NRS at each visit
Baseline, W4, W8, W12, W16
Proportion of subjects with change from baseline
improvement ≥4 in SD NRS at each visit
Baseline, W4, W8, W12, W16
Absolute and Percent change from baseline in SD
NRS at each visit
Baseline, W4, W8, W12, W16
Change from baseline in sleep diary endpoints at 
each visit (sleep onset latency, WASO, total awake 
time, total sleep time, sleep efficiency, WASO 
related to PN, number of WASO related to PN)
Baseline, W4, W8, W12, W16
Change from baseline in PN-Associated Pain 
Frequency and Intensity at each visit
Baseline, W4, W8, W12, W16
Proportion of subjects reporting low disease 
activity (clear, almost clear, mild) based on Patient 
Global Assessment of Disease (PGAD) at each 
visit
Baseline, W16
Proportion of subjects satisfied with study 
treatment (good, very good, excellent) based on 
Patient Global Assessment of Treatment (PGAT) at 
each visit 
W16
Proportion of subjects with an improvement of ≥ 4
in DLQI at each visit
Baseline, W4, W16
Change from baseline in DLQI at each visit
Baseline, W4, W16
Change from baseline in HADS for each subscale 
at each visit
Baseline, W16
Change from baseline in EQ-5D for each subscale 
at each visit
Baseline, W16
Abbreviations: AP, Average Pruritis; DLQI, Dermatology Life Quality Index; EQ-5D, EuroQoL 5-
Dimension; HADS, Hospital Anxiety and Depression Scale; IGA, Investigator Global Assessment; NRS, 
Numeric Rating Scale; PAS, Prurigo Activity Score; PGAD, Patient Global Assessment of Disease; 
PGAT, Patient Global Assessment of Treatment; PP, Peak Pruritis; SD, Sleep Disturbance; W, Week.


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Binary secondary endpoints will be analyzed in the same manner as the primary 
endpoint; missing values will be imputed as non-responder. 
Continuous secondary endpoints (except EQ-5D, HADS) will be analyzed using 
multiple-imputation assuming MAR and using mixed effect model for repeated measure 
(MMRM) approach, including analysis center and baseline body weight cut-off (< 90 kg 
and ≥90 kg) as factor and baseline as covariate where applies. The estimated treatment 
difference for each endpoint at each visit will be displayed in the summary of statistical 
analysis together with the 95% CI and associated p-value. EQ-5D and HADS endpoints 
will be analyzed using ANCOVA including analysis center and baseline body weight cut-
off (< 90 kg and ≥90 kg) as factor and baseline as covariate. All secondary endpoints 
will be presented descriptively using OC. 
Further details will be provided in the SAP.
Handling of small study sites
A small center is defined as a center which randomizes less than 12 subjects. Small 
centers will be pooled prior to analyses. First, centers will be sorted by 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 with the smallest center 
within that country. If there is a further need to combine data (the size of the pooled 
centers includes less 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 country. Any remaining centers will be pooled with the last pooled center within the 
country. The pooled centers will be referred to as ‘analysis centers’ in the statistical 
analyses.
Subgroup Analysis
Descriptive summary and analysis for primary and key secondary endpoints will be 
produced for the following subgroups:

Region (Europe, North America, Asia-Pacific)

Age groups (18-65, and > 65)


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
Sex (Male, Female)

Race (White, Black, Asian, Other)

Baseline weight (< 90 kg, ≥ 90 kg)
SAFETY ANALYSIS
All safety analyses will be conducted on the SAF, by treatment group.
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 22.0 or later. A TEAE will be defined as those AEs occurring on or 
after the date/time of first administration of study treatment until the last study visit. The 
incidence of TEAEs (events with onset dates on or after the start of the study drug), drug-
related TEAEs, SAEs, TEAEs leading to study drug discontinuation and TEAEs of 
Special Interest will be included in incidence tables, summarized by System Organ Class 
(SOC) and Preferred Term (PT). If a subject experiences more than 1 occurrence of the 
same AE, the occurrence with the greatest severity and the closest association with the 
study drug will be used in the summary tables. SAEs and AEs causing discontinuation 
will be tabulated. The incidence of TEAEs by severity, counting multiple AEs under 
SOC and PT for a subject at the maximum severity will be presented. All AEs will be 
listed by subject, along with information regarding onset, duration, relationship and 
severity to study drug, action taken with study drug, treatment of event, and outcome.
Clinical laboratory data and vital signs will be summarized using descriptive statistics, 
including observed values and change from baseline values, as well as numbers of 
subjects with values outside limits of the normal range, including shifts from baseline at 
each time point.
Summary tables will also be provided for 12-Lead ECG, Physical Examination, ACT, 
PEF, and Respiratory Exam, by treatment group. Listings will also be provided.
PHARMACOKINETIC ANALYSIS
Descriptive statistics (arithmetic and geometric mean, standard deviation [SD], 
coefficient of variation [CV%], minimum [min.], maximum [max.], and median) will be 
used to summarize the observed nemolizumab Ctrough in serum.


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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.
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. 
OTHER ANALYSES
Pharmacogenomic and pharmacodynamics analyses will be reported separately from the 
main study report. 
Anti-drug antibody concentrations will be reviewed. Depending on the data provided,
exploratory statistical analyses may be performed. Further details will be provided in the 
SAP.
Psychometric Validation Analyses
Confirmatory psychometric analyses will be conducted on the phase 3 data for the 
evaluation of the PP NRS, SD NRS, and subject sleep diary in the PN population. These 
analyses will be performed by the designated CRO on the basis of a separate 
psychometric validation SAP.
DETERMINATION OF SAMPLE SIZE
In order to achieve at least 90% power for both primary endpoints at 5% significance 
level, 270 (180 nemolizumab, 90 placebo) subjects will be randomized to detect the 
following differences in both primary endpoints between treatment groups with 2:1 
randomization, assuming a 15% dropout rate during treatment period.
NRS responders (≥4 point reduction from baseline): Based on phase 2a data, it is 
expected that the NRS response at Week 16 would be 50% in Nemolizumab 30 mg and 
20% in placebo. 
IGA response (0/1): It is expected that the IGA response at Week 16 would be 30% in 
Nemolizumab 30 mg and 10% in placebo.


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The table below provides the resulting power with 270 subjects (180 nemolizumab, 90 
placebo) for different responses in primary endpoints.
Endpoint
Placebo 
Nemolizumab 30 mg
Power at 5% 
significance level 
(N= 270 [180 
nemolizumab, 90 
placebo])
IGA responder
10%
30%
90%
10%
27%
83%
10%
25%
77%
PP-NRS Responder
20%
50%
>90%
20%
45%
>90%
20%
40%
84%
Assuming 15% attrition rate during treatment period. Based on continuity corrected Chi-square test.
PROTOCOL DEVIATIONS
Major deviations are categorized into the following categories:

Eligibility deviations (inclusion/exclusion criteria) 

Improper reconstitution and administration of study drug

Noncompliance with study drug per the investigator’s discretion

Noncompliance with study procedures if the consequence of noncompliance 
would compromise either the subject’s safety and/or the study integrity, primary 
endpoint(s), and/or is not in line with Good Clinical Practice (GCP)/ICH 
guidelines

Use of prohibited concomitant therapies

Visit/treatment windows (ie, if a study visit occurs outside the visit window 
defined in the Schedule of Assessments)


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All protocol deviations will be identified, evaluated, and closed before the respective 
database lock (final analysis) and will be discussed 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.
INTERIM ANALYSIS 
No interim analysis will be performed.


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16
STUDY MANAGEMENT
APPROVAL AND CONSENT
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 Code of Federal Regulations (CFR), in compliance with ICH 
and GCP guidelines and according to the appropriate regulatory requirements in the 
countries where the study was conducted.
Institutional Review Board/Independent Ethics Committee
Conduct of the study must be approved by an appropriately constituted IEC/IRB.
Approval is required for the study protocol, protocol amendments (if applicable), IB, 
ICFs, recruitment material and subject information sheets and other subject-facing 
material.
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 (PI) 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 PI will provide the Sponsor or its representative 
with a copy of the IEC-/IRB-approved ICF before the start of the study.
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 


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resolution of queries. All data management activities will be detailed in the data 
management plan.
Study centers will enter data directly into an 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.
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.
RECORD RETENTION
Study records and source documents must be preserved for at least 15 years after the 
completion or discontinuation of/withdrawal from the study, at least 2 years after the drug
being studied has received its last approval for sale, or at least 2 years after the drug 
development has stopped, and in accordance with the applicable local privacy laws, 
whichever is the longer time period.


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The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of subject health information, including, but not limited 
to, the Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 
164 (the Health Insurance Portability Accountability Act of 1996 [HIPAA] Privacy 
Regulation). The investigator shall ensure that study subjects authorize the use and 
disclosure of protected health information in accordance with HIPAA Privacy Regulation 
(for US) or with applicable national and/or local laws and regulations and in a form 
satisfactory to the Sponsor.
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.
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.


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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.
PROTOCOL AMENDMENT AND PROTOCOL DEVIATION
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 acknowledgement 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.
Protocol Deviations
Protocol deviations and/or violations and the reasons they occurred will be included in 
the clinical study report. See Section 15.9 for details. Protocol deviations will be reported 
to the IRB/IEC and in accordance with applicable regulatory authority mandates.
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.


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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.
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.


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17
REFERENCES
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2. Bobko S, Zeidler C, Osada N, et al. Intraepidermal Nerve fibre density is decreased in 
lesional and inter-lesional prurigo nodularis and reconstitutes on healing of lesions. 
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3. Warlich B, Fritz F, Osada N, et al. Health-related quality of life in chronic pruritus: 
An analysis related to disease etiology, clinical skin conditions and itch intensity. 
Dermatology. 2015;231(3):253-9.
4. Iking A, Grundmann S, Chatzigeorgakidis E, Phan NQ, Klein D, Ständer S. Prurigo 
as a symptom of atopic and non-atopic diseases: aetiological survey in a consecutive 
cohort of 108  patients. J Eur Acad Dermatol Venereol. 2013;27:550-7.
5. Huang AH, Canner JK, Khanna R, et al. Real-world prevalence of prurigo nodularis 
and burden of associated diseases. J Invest Dermatol. 2020;140(2):480-3.
6. Zeidler C, Ständer S. The pathogenesis of prurigo nodularis–‘super-itch’ in 
exploration. Eur J Pain. 2016;37-40.
7. Bharati A, Wilson NJE. Peripheral neuropathy associated with nodular prurigo. Clin 
Exp Dermatol. 2007;32:67-70.
8. Schuhknecht B, Marziniak M, Wissel A, et al. Reduced intraepidermal nerve fibre 
density in lesional and nonlesional prurigo nodularis skin as a potential sign of 
subclinical cutaneous neuropathy. Br J Dermatol. 2011;165:85-91.
9. Hughes JM, Woo TE, Belzberg M, et al. Association between prurigo nodularis and 
etiologies of peripheral neuropathy: Suggesting a role for neural dysregulation in 
pathogenesis. Medicines (Basel). 2020;7(1).
10. Fostini AC, Girolomoni G, Tessari G. Prurigo nodularis: an update on 
etiopathogenesis and therapy. J Dermatol Treat. 2013;24(6):458-62.


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11. Ständer S, Weisshaar E, Mettang T, et al. Clinical classification of itch: a position 
paper of the International Forum for the Study of Itch. Acta Derm Venereol. 
2007;87:291-4.
12. Boozalis E, Tang O, Patel S, et al. Ethnic differences and comorbidities of 909 
prurigo nodularis patients. J Am Acad Dermatol. 2018;79(4):714-9.
13. Tanaka M, Aiba S, Matsumura N, Aoyama H, et al. Prurigo nodularis consists of two 
distinct forms: early-onset atopic and late-onset nonatopic. Dermatology.
1995;190:269-76.
14. Rowland Payne CM, Wilkinson JD, McKee PH, et al. Nodular prurigo-- a 
clinicopathological study of 46 patients. Br J Dermatol. 1985;113:431-9.
15. Weisshaar E, Szepietowski JC, Darsow U, et al. European guideline on chronic 
pruritus. Acta Derm Venereol. 2012;92(5):563-81.
16. Berth-Jones J, Smith SG, Graham-Brown RA. Nodular prurigo responds to 
cyclosporine. Br J Dermatol. 1995;132:795-9.
17. Mazza M, Guerriero G, Marano G, Janiri L, Bria P, Mazza S. Treatment of prurigo 
nodularis with pregabalin. J Clin Pharm Ther. 2013;38(1):16-8.
18. Andersen TP, Fogh K. Thalidomide in 42 patients with prurigo nodularis Hyde. 
Dermatology. 2011;223(2):107-12.
19. Brune A, Metze D, Luger TA, Ständer S. Antipruritic therapy with the oral opioid 
receptor antagonist naltrexone. Open, non-placebo controlled administration in 133 
patients [in German]. Hautarzt. 2004;55:1130-6.
20. Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger TA. Targeting the 
neurokinin receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One. 
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21. Horiuchi Y, Bae S, Katayama I. Uncontrollable prurigo nodularis effectively treated 
by roxithromycin and tranilast. J Drugs Dermatol. 2006;5(4):363-5.


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22. Sonkoly E, Muller A, Lauerma AI, et al. IL-31: a new link between T-cells and 
pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006;117(2):411-7.
23. Park K, Mori T, Nakamura M, Tokura Y. Increased expression of mRNAs for IL-4, 
IL-17, IL-22 and IL-31 in skin lesions of subacute and chronic forms of prurigo. Eur 
J Dermatol. 2011;21(1):135-6.
24. Stott B, Lavender P, Lehmann S, Pennino D, Durham S, and Schmidt-Weber CB. 
Human IL-31 is induced by IL-4 and promotes TH2-driven inflammation. Allergy 
Clin Immunol. 2013;132:446-54.
25. Diveu C, Lak-Hal AHL, Froger J, et al. Predominant expression of the long isoform 
of GP130-like (GPL) receptor is required for interleukin-31 signaling. Eur Cytokine 
Netw. 2004;15(4):291-302.
26. Dillon SR, Sprecher C, Hammond A, et al. Interleukin 31, a cytokine produced by 
activated T cells, induces dermatitis in mice. Nat Immunol. 2004;5(7):752-60.
27. Takaoka A, Arai I, Sugimoto M, et al. Involvement of IL-31 on scratching behavior 
in NC/Nga mice with atopic-like dermatitis. Exp Dermatol. 2006;15:161-7.
28. Grimstad O, Sawanobori Y, Vestergaard C, et al. Anti-interleukin-31-antibodies 
ameliorate scratching behavior in NC/Nga mice: a model of atopic dermatitis. Exp 
Dermatol. 2009;18:35-43.
29. Michels GM, Ramsey DS, Walsh KF, et al. A blinded, randomized, placebo-
controlled, dose determination trial of lokivetmab (ZTS-00103289), a caninized, anti-
cannine IL-31 monoclonal antibody in client owned dogs with atopic dermatitis. Vet 
Dermatol. 2016;27(6):478-e129.
30. Lewis KE, Holdren MS, Maurer MF, et al. Interleukin (IL) 31 induces in cynomolgus 
monkeys a rapid and intense itch response that can be inhibited by an IL-31 
neutralizing antibody. J Eur Acad Dermatol Venereol. 2017;31:142-50.
31. Oyama S, Kitamura H, Kuramochi T, et al. Cynomolgus monkey model of 
interleukin-31-induced scratching depicts blockade of human interleukin-31 receptor 
A by a humanized monoclonal antibody. Exp Dermatol. 2016;1-8.


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32. Ständer S, Blome C, Anastasiadou Z, et al. Dynamic Pruritus Score: evaluation of the 
validity and reliability of a new instrument to assess the course of pruritus. Acta Derm 
Venereol. 2017;97(2):230-234.
33. Carney CE, Buysse DJ, Ancoli-Isreal S, et al. The consensus sleep diary: 
standardizing prospective sleep self-monitoring. Sleep. 2012;35(2):287-302.
34. Finlay AY and Khan GK. Dermatology Life Quality Index (DLQI) – a simple 
practical measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-216.
35. Zigmond AS and Snaith RP. The Hospital Anxiety and Depression Scale. Acta 
Psychiatr Scand. 1983;67(6):361-370.
36. Mazurek GH, Jereb J, Vernon A, et al. Updated guidelines for using interferon 
gamma release assays to detect Mycobacterium tuberculosis infection—United 
States, 2010. MMWR Recomm Rep. 2010;59(RR-5):1-25.
37. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung 
volumes and forced ventilatory flows. Eur Respir J. 1993;6 Suppl 16:5-40.
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39. Guttman-Yassky E, Diaz A, Pavel AB, et al. Use of tape strips to detect immune and 
barrier abnormalities in the skin of children with early-onset atopic dermatitis. JAMA 
Dermatol. 2019; 155(12):1358-1370.
40. Dyjack N, Goleva E, Rios C, et al. Minimally invasive skin tape strip RNA sequencing 
identifies novel characteristics of the type 2-high atopic dermatitis disease endotype. J
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41. Olesen CM, Fuchs CSK, Philipsen PA, et al. Advancement through epidermis using 
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9(1):12217.


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18
APPENDICES
APPENDIX 1: CONTRACEPTION GUIDELINES
Women of childbearing potential (WOCBP) must use at least 1 effective method of 
contraception during the study and for 12 weeks after the last dose of study treatment. 
A woman is considered to be a WOCBP (fertile) following menarche and until becoming 
postmenopausal, unless she is permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A 
postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient. 
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy.
Adequate methods of contraception include:

combined (containing estrogen and progestogen) hormonal contraception 
associated with inhibition of ovulation (administration may be oral, intravaginal, 
or transdermal)

progestogen-only hormonal contraception associated with inhibition of ovulation
(administration may be oral, injectable, or implantable)

intrauterine device

intrauterine hormone-releasing system

combination of male condom with cap, diaphragm, or sponge with spermicide
(double barrier methods)

bilateral tubal ligation or occlusion


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
bilateral vasectomy (provided that the male partner has a medical assessment of 
surgical success) at least 12 weeks (3 months) before the study

true abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk in relation to the duration of the clinical trial, in line with the 
preferred and usual lifestyle of the subject)
All subjects will be strongly advised that they should not become pregnant while on study 
treatment or for 12 weeks (3 months) after the last dose. A female subject will be advised 
that she must report immediately to the study site for pregnancy testing and appropriate 
management in the event that she may be pregnant.
Reference:
1. Heads of Medicines Agencies. Clinical Trial Facilitation Group page. 
Recommendations related to contraception and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. 
Published September 15, 2014. 


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APPENDIX 2: SPECIFIC GUIDANCE FOR STUDY CONDUCT AND SUBJECT 
SAFETY DURING THE COVID-19 PANDEMIC
This guidance applies during the COVID-19 pandemic, as defined by regional and/or 
local authorities. The updates summarized below are relevant to the referenced sections 
of the protocol.
Section 5.3
Risk/Benefit Assessment
During the COVID-19 pandemic, additional risks to participants may exist, including 
general environmental risks (e.g. being outside the home, possible contact with 
unsanitized surfaces) and study-related activities (e.g. interaction with study staff). 
Potential new subjects with known or suspected COVID-19 infection are ineligible for 
study enrolment until the infection has resolved. Furthermore, potential new subjects in a 
high-risk population for COVID-19 (e.g. 60 years and older or with comorbidities), 
should be temporarily deferred until the COVID-19 risk has subsided at the location of 
the enrolling site, according to investigator judgement. Risk mitigation measures to be 
implemented for enrolled subjects and for new subjects during the COVID-19 pandemic 
are detailed in Additional Measures for Subjects Amidst COVID-19 Pandemic below. 
Subjects with a known or suspected COVID-19 infection will immediately discontinue 
study drug; instructions for resuming treatment are described in Section 8.4.2. Known or 
suspected COVID-19 infection will also be followed as an AESI.
New Subsection to Section 7.1, Overall Study Design and Plan:
Additional Measures for Subjects Amidst COVID-19 Pandemic
All investigational sites should act according to applicable site regulations, to 
guidelines and restrictions implemented by local authorities, and to best practices 
for conducting clinical research during the COVID-19 pandemic. 
- Guidance for New Subjects:
Best practices currently in place must be followed when evaluating eligibility of 
subjects to participate in the study during the COVID-19 pandemic.
For potential subjects in a high-risk population for COVID-19 as defined by the 
American Academy of Dermatology (AAD)1 (e.g. 60 years and older or with 


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comorbidities) or local guidelines, deferring participation in the study should be 
considered. Deferment of enrollment is based on the potential risk posed by 
general environmental risks (e.g. being outside home, possible contact with 
unsanitized surfaces) and study-related activities (e.g. interaction with study 
staff).
For potential subjects in the low-risk population for COVID-19 (e.g. less than 60 
years of age and without comorbidities), the risks and benefits of participation in 
the study should be assessed on a case by case basis. 
If at the time of screening, in the opinion of the Investigator, the subject will not 
be willing and able to reach the investigational site and comply with all of the 
time commitments and requirements of the clinical study protocol, the subject 
should not be considered for enrolment. The subject may be rescreened at a later 
time.
Pre-screening phone calls should be conducted to exclude potential 
candidates/subjects who display possible symptoms of COVID-19 or are at high 
risk of having been exposed to COVID-19.
- Guidance for Enrolled Subjects:
If the local situation allows for subjects to reach the clinical investigational site 
and complete all study procedures, the following measures should be taken:
-
Implement and document in the subject records regular 
communication with the subject between visits to attempt to ensure 
early detection of potential signs/symptoms of COVID-19 infection, 
and provide adequate advice, as per local medical practice and public 
health guidelines for suspected COVID-19 infection. Please refer to 
the Centers for Disease Control (CDC; https://www.cdc.gov/ 
coronavirus/2019-ncov/symptoms-testing/symptoms.html)/European 
CDC (https://www.ecdc.europa.eu/en/covid-19/questions-
answers)/local disease prevention agency and applicable local 
guidelines for assessment of subjects’ COVID-19 status.
-
Following the same guidelines, implement and document in the 
subject records an additional communication to the subject just before 
the scheduled visit. 


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-
Discontinue study drug administration in case of confirmed or 
suspected COVID-19 infection until the infection is resolved. See 
Section 8.4.2. 
-
Report any COVID-19 infection (confirmed or suspected) as an AE:

if any seriousness criterion is met, also report as an SAE
(see Section 12.7.4).

if it occurs during the clinical study following the first 
dose of study drug administration, also report as an AESI 
(see Section 12.7.5).
-
Implement preventive infection control measures against COVID-19 
infection following local guidelines (e.g. good hygiene practice, clean 
techniques, and use of personal protective equipment such as gloves, 
goggles, and masks).
-
Implement preventive measures in handling all subject-facing study-
mandated assessment devices and parts: 

PEF meter device body is to be cleaned after each use, with 
recommended wipes, as per user manual 

PEF meter flow sensor is to be disposed of after each set of 
measurements is taken

Approved bacterial/virus filters may be used; if used, they 
must be disposed of after each set of measurements is taken

Offer protective gloves to subjects for use while filling out 
assessments on a tablet and provide training on hygienic 
removal and disposal of gloves
If the local situation allows for subjects to reach the investigational site and 
complete only some study procedures where visit duration needs to be limited, 
the above measures also apply. All assessments should be conducted if possible. 
Subject-reported assessments that would usually be collected on the site tablet 
(e.g. ACT, PGAD, PGAT, EQ-5D, DLQI, and PN-associated pain intensity and 
frequency) may be collected remotely (e.g. completed over the phone), as 
available. (See Appendix 20 for EQ-5D remote version.)


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Subjects can be dosed only if, taking into account the local situation and risk of 
exposure to COVID-19, the site considers that:
-
The study drug subcutaneous injection can be performed at the 
investigational site according to the instructions in the protocol, 
pharmacy manual and instruction for use, including preparation of 
study drug by an independent pharmacist or other qualified personnel.
-
ACT (for subjects with a medical history of asthma) and PEF (for all 
subjects) can be performed according to the protocol. 

Exceptionally, if sites cannot perform PEF safely on site, the 
subjects should perform it at home prior to the onsite visit, on 
the same day. See section below for remote PEF testing 
instructions.
-
All other safety assessments are to be performed as per protocol: 
physical exam, vital signs, ECG, laboratory assessments, pregnancy 
test, monitoring of AEs and concomitant medications. 
-
All missing assessments should be appropriately documented with 
COVID-19 recorded as the reason, where applicable.
If the local situation does not allow for subjects to reach the investigational site:
-
See New Subsection to Section 9.8, Dose Modification: 
Management of Subjects with Missed Doses of Study Drug due to 
COVID-19 Pandemic (below) for guidance on further dosing of 
subjects
-
Remote collection of data by Investigator or delegate is still to be 
done for the following assessments at the regularly scheduled visit 
time, by phone or video call:

AE collection

ACT (for subjects with history of asthma)

Concomitant therapies used

Moisturizer use/background topical therapy


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
UPT results (for WOCBP)

PEF results
Note: For remote PEF measurements the following should be 
done:
-
To prepare subjects to do remote PEF measurement at 
home in case it is needed during the course of the study, 
all subjects should be previously trained onsite. 
-
During the remote visits, subjects can receive additional 
support (if needed) over the phone or video call by site 
staff when performing PEF 
-
If a subject has a PEF <80% of the predicted value:

Site staff can try to evaluate whether this is due to 
poor technique and ask the subject to repeat the set 
of measurements

If the subject’s best PEF measurement is still 
<80% of the predicted value or if there are other 
concerns regarding the subject’s respiratory health, 
refer to appropriate physician and report an AESI 
(see Section 12.7.5)
-
All laboratory samples should be collected at the site and analyzed at 
the central lab. Only in exceptional situations when subject safety 
cannot be assured otherwise and subject cannot reach the site, a local 
laboratory test (i.e. hematology, blood chemistry, urinalysis) can be 
performed and reported, based on investigator judgement. 
-
Subject-reported assessments that would usually be collected on the 
site tablet (e.g. ACT, PGAD, PGAT, EQ-5D, DLQI, and PN-
associated pain frequency and intensity) may be completed over the 
phone, as available. (See Appendix 20 for EQ-5D remote version.)
All missing assessments should be appropriately documented with COVID-19 recorded 
as the reason, where applicable.
New Subsection to Section 9.8, Dose Modification:
Management of Subjects with Missed Doses of Study Drug due to COVID-19 
Pandemic


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If a subject misses a dose of study drug due to the COVID-19 pandemic, study drug 
administration may be continued. The following dosing schedules apply. 
For subjects with a missed dose(s) during the treatment period, study drug administration 
can be continued based on one of the following scenarios (see also Diagram 1, below):
1) Subject has missed one or more doses between Baseline and Week 16 but can 
come to the clinical site at Week 16 (see also Diagram 2a):
-
Subjects who complete the Week 16 visit may be eligible to enroll in the 
long-term extension (LTE) study RD.06.SPR.202699.
-
Subjects who required rescue therapy before Week 16 may be considered 
for the LTE study but will be required to continue with study visits until 
the Week 16 visit is due.
2) Subject has no missed doses through Week 12 but cannot reach the clinical site at 
Week 16 (see also Diagram 2b):
-
The Week 16 visit can be delayed by up to 4 weeks from the originally 
planned date. A remote Unscheduled visit should be planned between 
Week 12 and the delayed Week 16 visit for safety follow-up.
o
Subjects who complete the rescheduled Week 16 visit may be 
eligible to enroll in the LTE study.
-
If the subject still cannot come to the delayed Week 16 visit within 4
weeks of the originally planned date, the delayed Week 16 visit should be 
performed remotely at the rescheduled date. A remote Unscheduled visit 
should be planned between Week 12 and the delayed Week 16 visit for 
safety follow-up. The subject may be considered for rollover into the LTE 
study after the delayed Week 16 visit is complete.
3) Subject has missed one or more doses between Baseline and Week 16 and cannot 
reach the clinical site at Week 16:
-
For subjects who cannot come to the clinical site at week 12 but with an 
administered dose at Week 8 (with or without Week 4), the Week 12 visit 
can be delayed up to 3 weeks, and the Week 16 visit can be delayed up to 
4 weeks from the rescheduled Week 12 visit (see also Diagram 2c). 


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-
For subjects with an administered dose at week 12 but with a missed dose 
at Week 4 and/or Week 8, the Week 16 visit can be delayed by up to 4 
weeks from the originally planned date (see also Diagram 2d).
o
Subjects who complete the rescheduled Week 16 visit may be 
eligible to enroll in LTE study.
-
For subjects with a missed dose at week 12, the Week 16 visit will be 
performed remotely at Week 16 (cannot be delayed) and The subject may 
be considered for rollover into the LTE study (see also Diagram 2d).
In all scenarios, study drug can be administered provided that there is a minimum 3-week 
interval between injections. If a subject cannot come to a planned visit due to COVID-19, 
the visit should be conducted remotely according to Additional Measures for Subjects 
Amidst COVID-19 Pandemic. If a subject misses 3 consecutive doses of study drug, an 
early termination visit should be conducted. Subject may still be eligible to participate in 
the LTE. Enrolment of subjects into the LTE study must be done in accordance with the 
LTE study protocol. Subjects who decline or are not eligible to enter into the LTE study 
will complete a follow-up visit 12 weeks after the last study drug injection.
16.5
Monitoring
On-site interim monitoring visits may not be feasible during COVID-19 restrictions; 
therefore, remote monitoring will be completed until on-site monitoring can be conducted 
again. Site monitoring activity will comply with the processes documented within the 
COVID-19 Site Management Risk Assessment Form.
1
https://assets.ctfassets.net/1ny4yoiyrqia/PicgNuD0IpYd9MSOwab47/2461e6c12cd88953
632a13cd68952b71/Guidance_on_medications__10-12-20.pdf


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Diagram 1. Flow Chart of Management of Subjects with Missed Visits Before Week 16 
due to COVID-19


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Diagram 2. Management of Subjects Based on Missed Dosing Scenarios
a. Diagram of Management of Subjects due to Scenario 1
b. Diagram of Management of Subjects due to Scenario 2


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c. Diagram of Management of Subjects due to Scenario 3: Cannot reach site at Visit 
12
d. Diagram of Management of Subjects due to Scenario 3: Cannot reach site at Visit 
16


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APPENDIX 3: CYP SUBSTRATES WITH NARROW THERAPEUTIC INDEX
CYP enzymes 
Substrates with narrow therapeutic index(1)
CYP1A2
Theophylline, Tizanidine
CYP 2B6
-
CYP2C8
Paclitaxel
CYP2C9
Warfarin, Phenytoin
CYP2C19
S-mephenytoin
CYP3A
Alfentanil, Astemizole, Cisapride, Cyclosporine, 
Dihydroergotamine, Ergotamine, Fentanyl, Pimozide, 
Quinidine, Sirolimus, Tacrolimus, Terfenadine
CYP2D6
Thioridazine, Pimozide
(1) CYP substrates with a narrow therapeutic index refers to drugs whose exposure-
response relationship indicates that small increases in their exposure levels by the 
concomitant use of CYP inhibitors may lead to serious safety concerns (eg, Torsades de 
Pointes). This is not an exhaustive list.
Source: Center for Drug Evaluation and Research (CDER), Food and Drug Administration, U.S. Department of Health
and Human Services. Guidance for Industry: Drug Interaction Studies—Study Design, Data Analysis, Implications for
Dosing, and Labeling Recommendations (Draft Guidance). February 2012.


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APPENDIX 4: INVESTIGATOR GLOBAL ASSESSMENT (IGA)
Score
Category
Description
0
Clear
No nodules 
1
Almost 
Clear
Rare palpable pruriginous nodules 
2
Mild
Few palpable pruriginous nodules 
3
Moderate
Many palpable pruriginous nodules 
4
Severe
Abundant palpable pruriginous nodules 


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APPENDIX 5: PRURIGO ACTIVITY SCORE (PAS)
PAS: Baseline assessment


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PAS: Follow-up assessment


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These are instructions for filling out the Prurigo Activity Score 1.0. 
Two versions of the PAS 1.0 exist:
1 baseline: For screening and the baseline visit
1 Follow up: For all subsequent visits
These differ in instructions for Item 4.
Item 1a) Please mark all existing lesions that you see with a cross. Multiple 
answers are possible.
Papules= Pruriginous, elevated, solid, palpable lesions≤1 cm diameter*
Nodules= Pruriginous, elevated, solid, palpable lesions>1 cm diameter
Plaques= Pruriginous, palpable and flat lesions>1 cm in diameter, often on the 
lower leg
Umbilicated= Ulcers surrounded by a raised, erythematous rim - formerly referred 
to as M. Kylre
Ulcers= Ulcerations, excoriations
Linear= linear pruriginous lesions
Hypo-/Hyperpigmented maculae= Maculae or scarification as a post-inflammatory 
reaction
*According to the definition of the ILDS (Nast A et al. Br J Dermatol. 2016;174:1351-8) and Task 
Force Pruritus (Pereira et al. J Eur Acad Dermatol Venereol. 2018;32:1059-1065)
Item 1b) Please mark the clinically predominant type of prurigo with a cross. 
Please choose only one answer. 
2) Please estimate how many palpable pruriginous lesions are present. Counting 
the exact number of lesions is necessary for the first 20 lesions; if over 20 lesions, 
estimate. Healed lesions, scars or excoriations without prurigo should not be 
considered. Please choose only one answer.


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3) Please indicate all locations of the body with evidence of pruriginous lesions. 
Healed lesions, scars or excoriations without prurigo should not be considered. 
The gluteal region belongs to the trunk in this case (see figure). Multiple answers 
are possible. 
4) Please select one area representing the dominant, representative type of prurigo. 
It is not necessary to select the most severe area. The purpose is to select an area 
in order to monitor the exact course of the lesions. The representative area must 
be the same at each visit! Once determined, you will repeat counting in this
area at each visit.
It is thus advisable to select an area with lesions that are not bunched together. 
This should be the forearm or upper arm, if possible. Please avoid the lower legs. 
Please indicate the bodily localization code from Item 3a. Count the nodules (in 
case of prurigo nodularis) or the typical pruriginous lesions (in case of other types 
of prurigo) in that area. Please identify all lesions and count each. When nodules 
are merged, count only one.
5) A. This item reflects the current itch/scratch activity. Please estimate what 
percentage of the pruriginous legions show excoriations/crusts. 
100% = All pruriginous lesions have excoriations/crusts. 
B. This item reflects the stage of the prurigo. Please estimate what percentage of 
the pruriginous lesions have healed. 
100% = all pruriginous leasions have healed. 
Items 7A and 7 B are to be considered separately and do not have to total 100% together.


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APPENDIX 6: PRURITUS (PEAK AND AVERAGE) NUMERIC RATING SCALE 
(PP NRS and AP NRS)
For average 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 overall during the previous 24 
hours?”
     No 
                  Worst 
      itch                                                                                                       itch 
                   imaginable
For maximum 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?”
      No 
                  Worst 
      itch                                                                                                       itch 
                   imaginable
0
1
2
3
4
5
6
7
8
9
10
0
1
2
3
4
5
6
7
8
9
10


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APPENDIX 7: SLEEP DISTURBANCE NUMERIC RATING SCALE (SD NRS)
“On a scale of 0 to 10, with 0 being “no sleep loss related to the symptoms of my skin 
disease (prurigo nodularis)” and 10 being “I did not sleep at all due to the symptoms of 
my skin disease (prurigo nodularis)”, how would you rate your sleep last night?”
     No                                                                                                               I did 
     sleep 
not sleep 
     loss
at all
0
1
2
3
4
5
6
7
8
9
10


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APPENDIX 8: MORNING SUBJECT SLEEP DIARY
Example
Items to be administered in the morning
Question
Example
Instructions
Today’s date
4/5/08
Write the date you are filling out the diary.
1. What time did you get into bed? 
10:00 pm
Write the time that you got into bed. This 
may not be the time you began “trying” to 
fall asleep
2. What time did you try to go to 
sleep?
11:00 pm
Record the time that you began “trying” to 
fall asleep.
3. How long did it take you to fall 
asleep?
1 hour
Beginning at the time you wrote in 
question 2, how long did it take you to fall 
asleep.
4. How many times did you wake up 
due to the symptoms of prurigo 
nodularis (for example itching, 
burning), not counting the final 
time you woke up for the day?   
2 times
For example, if you fell asleep at 11pm, and 
woke up at 2am (to go to the bathroom), 4am 
(to scratch), 5am (to drink water), 6am (to 
scratch) and finally woke up at 7:30am, you 
woke up twice due to the symptoms of 
prurigo nodularis.
5. In total, how long did the 
awakenings related to the 
symptoms of prurigo nodularis 
(for example itching, burning)
last?
55 min
For example, if you woke up 4 times during 
the night: 5 minutes (to go to the bathroom), 
35 minutes (to scratch), 5 minutes (to drink 
water) and 20 minutes (to scratch), only two 
times were related to the symptoms of 
prurigo nodularis, for a total of 55 minutes 
awake (35+20=55 minutes).
6. How many times did you wake 
up, for other things (for example 
to drink water, to go to the 
bathroom), not counting the final 
time you woke up for the day?
2 times
For example, if you fell asleep at 11pm, and 
woke up at 2am (to go to the bathroom), 4am 
(to scratch), 5am (to drink water), 6am (to 
scratch) and finally woke up at 7:30am, you 
woke up twice due to other things not related 
to prurigo nodularis.
7. In total, how long did these 
awakenings related to other things 
(for example to drink water, to go 
10 min
For example, if you woke 4 times during the 
night: 5 minutes (to go to the bathroom), 35 
minutes (to scratch), 5 minutes (to drink 
water) and 20 minutes (to scratch), only two 


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Items to be administered in the morning
Question
Example
Instructions
to the bathroom) last? 
times were related to other things, for a total 
of 10 minutes (5 + 5 =10 minutes).
8. What time did you wake up for 
the day? 
6:35 am
Record the last time you woke up in the 
morning.
9. What time did you get out of bed 
for the day?  
7:20 am
What time did you get out of bed with no 
further attempt at sleeping? This may be 
different from the time you wake in the 
morning (eg, you may have woken up at 6:35 
am but did not get out of bed to start your 
day until 7:20 am) 
10. How would you rate the quality 
of your sleep?
☐Very poor
☒Poor
☐Fair
☐Good
☐Very good
“Sleep Quality” is your sense of whether 
your sleep was good or poor.
11. How rested or refreshed did you 
feel when you woke-up for the day?
☐Not at all 
rested
☒Slightly 
rested
☐Somewhat 
rested
☐Well-rested
☐Very well-
rested
This refers to how you felt after you were 
done sleeping for the night, during the first 
few minutes that you were awake.


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General Instructions
What is a Sleep Diary? A sleep diary is designed to gather information about your daily 
sleep pattern.
How often and when do I fill out the sleep diary? The morning sleep diary should be 
completed in the morning on designated days, and if possible, within one hour of getting 
out of bed, together with the daily Sleep Disturbance Numeric Rating Scale (SD NRS). 
What should I do if I miss a day? If you forget to fill in the diary or are unable to finish 
it, leave the diary blank for that day.
What do the words “bed” and “day” mean on the diary? This diary can be used for 
people who are awake or asleep at unusual times. In the sleep diary, the word “day” is the 
time when you choose or are required to be awake. The term “bed” means the place 
where you usually sleep.
Will answering these questions about my sleep keep me awake? This is not usually a 
problem. You should not worry about giving exact times, and you should not watch the 
clock. Just give your best estimate.
Scoring Algorithm of Subject Sleep Diary
Sleep Parameter
SSD Items Used to Derive the Sleep Parameter 
Sleep onset latency (SOL)
Q3
Wakefulness after sleep onset (WASO)
Q5 + Q7
Terminal WASO (TWASO)
Q9 – Q8
Total awake time (TWT)
SOL+ WASO + TWASO
Time in bed (TIB)
Q9 – Q1
Total sleep time (TST)
TIB – TWT
Sleep efficiency (SE)
TST/TIB
WASO related to PN (WASO-PN)
Q5
Number of WASO related to PN (NWASO-PN)
Q4
Sleep quality/refresh (SQR)
Q10 + Q11
Abbreviations: Q = question; SSD=Subject Sleep Diary


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Reference:
Carney CE, Buysse DJ, Ancoli-Israel S, et al. The consensus sleep diary: standardizing 
prospective sleep self-monitoring. Sleep. 2012;35(2):287-302.


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APPENDIX 9: PAIN FREQUENCY AND INTENSITY
How often would you say that you experience pain from your skin disease (prurigo 
nodularis)?
0. Never
1. Less than once a week
2. 1-2 days a week
3. 3-4 days a week
4. 5-6 days a week
5. Every day
On a scale of 0 to 10, with 0 being “no pain” and 10 being “the worst unbearable pain”, 
how would you rate the pain associated with your skin disease (prurigo nodularis) at the 
worst moment during the past week?
No                                                                                         
Worst 
pain 
unbearable 
pain
0
1
2
3
4
5
6
7
8
9
10


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APPENDIX 10: PATIENT GLOBAL ASSESSMENT OF DISEASE (PGAD)
Overall, how would you describe your skin disease (prurigo nodularis) right now?
  
Clear
  
Almost clear
Mild
Moderate
Severe


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APPENDIX 11: PATIENT GLOBAL ASSESSMENT OF TREATMENT (PGAT)
How would you rate the way your skin disease (prurigo nodularis) responded to the study 
medication?  
Poor
Fair 
Good
Very Good
Excellent


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APPENDIX 12: PATIENT GLOBAL IMPRESSION OF SEVERITY – PRURITUS 
(PGIS-P)
Please choose the response below that best describes the severity of your overall itch 
over the past week:
None
Mild
Moderate
Severe
Very severe


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APPENDIX 13: PATIENT GLOBAL IMPRESSION OF CHANGE – PRURITUS 
(PGIC-P)
Please choose the response below that best describes the overall change in your itch 
since you started taking the study medication:
Much better
A little better 
No change
A little worse
Much worse


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APPENDIX 14: PATIENT GLOBAL IMPRESSION OF SEVERITY – SLEEP
DISTURBANCE (PGIS-SD)
Please choose the response below that best describes the severity of your sleep 
disturbance due to the symptoms of your skin disease (prurigo nodularis) over the 
past week:
None
Mild
Moderate
Severe
Very severe


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APPENDIX 15: PATIENT GLOBAL IMPRESSION OF CHANGE – SLEEP
DISTURBANCE (PGIC-SD)
Please choose the response below that best describes the overall change in your sleep 
disturbance due to the symptoms of your skin disease (prurigo nodularis) since you 
started taking the study medication:  
Much better
A little better 
No change
A little worse
Much worse


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APPENDIX 16: DERMATOLOGY LIFE QUALITY INDEX (DLQI)
DERMATOLOGY LIFE QUALITY INDEX
DLQI
Hospital No:
Date:
Name:
Score:
Address:
Diagnosis:
The aim of this questionnaire is to measure how much your skin problem has affected your life 
OVER THE LAST WEEK.  Please tick one box for each question.
1.
Over the last week, how itchy, sore, 
Very much

painful or stinging has your skin 
A lot

been? 
A little

Not at all

2.
Over the last week, how embarrassed
Very much

or self conscious have you been because 
A lot

of your skin?
A little

Not at all

3.
Over the last week, how much has your 
Very much

skin interfered with you going
A lot

shopping or looking after your home or 
A little

garden?       
Not at all

Not relevant 
4.
Over the last week, how much has your 
Very much

skin influenced the clothes
A lot

you wear?
A little

Not at all

Not relevant 
5.
Over the last week, how much has your 
Very much

skin affected any social or 
A lot

leisure activities?
A little

Not at all

Not relevant 
6.
Over the last week, how much has your 
Very much

skin made it difficult for 
A lot

you to do any sport?
A little

Not at all

Not relevant 
7.
Over the last week, has your skin prevented
Yes

you from working or studying?
No

Not relevant 
If "No", over the last week how much has 
A lot

your skin been a problem at 
A little

work or studying?
Not at all

8.
Over the last week, how much has your 
Very much

skin created problems with your 
A lot

partner or any of your close friends
A little

or relatives? 
Not at all

Not relevant 
9.
Over the last week, how much has your 
Very much

skin caused any sexual
A lot

difficulties?
A little

Not at all

Not relevant 
10.
Over the last week, how much of a 
Very much

problem has the treatment for your
A lot

skin been, for example by making
A little

your home messy, or by taking up time? 
Not at all

Not relevant 
Please check you have answered EVERY question. Thank you.
AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the authors.


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Instructions for Dermatology Life Quality Index scoring:
3 = “Very much”
2 = “A lot”
1 = “A little”
0 = “Not at all”
0 = “Not relevant”
Question 7, “prevented work or studying/yes” = 3; “no or not relevant” = 0
The Dermatology Life Quality Index is calculated by summing the score of each question 
resulting in a maximum score of 30 and a minimum of 0. The higher the score, the more 
quality of life is impaired.
Reference:
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)–a simple practical 
measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-6.


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APPENDIX 17: HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS)


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Questions relating to anxiety are indicated by an “A” while those relating to depression 
are shown by a “D”. Scores of 0-7 in respective subscales are considered normal, with 8-
10 borderline and 11 or over (more) indicating clinical “caseness”.


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APPENDIX 18: EUROQoL-5 DIMENSION (EQ-5D)
© 1998 EuroQol Group EQ-5DTM is a trade mark of the EuroQol Group
Source: European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the SCORAD index. 
Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31.


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APPENDIX 19: ASTHMA CONTROL TEST (ACT)
Asthma Control Test™: This survey was designed to help you describe your asthma and how 
your asthma affects how you feel and what you are able to do.  To complete it, please mark an X
in the one box that best describes your answer.
1.
In the past 4 weeks, how much of the time did your asthma keep you from getting as 
much done at work, school or at home?
All of the time
Most of the time 
Some of the time
A little of the time
None of the time 
1
2
3
4
5
2. During the past 4 weeks, how often have you had shortness of breath? 
More than 
once a day 
Once a day 
3 to 6 
times a week
Once or twice 
a week
Not at all
1
2
3
4
5
3. During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, 
shortness of breath, chest tightness or pain) wake you up at night or earlier than usual in 
the morning? 
4 or more 
nights a week 
2 to 3 
nights a week 
Once a week
Once or Twice
Not at all
1
2
3
4
5
4.
During the past 4 weeks, how often have you used your rescue inhaler or nebulizer 
medication (such as Albuterol, Ventolin®, Proventil®, or Maxair®)?
3 or more 
times per day 
1 or 2 
times per day 
2 or 3 
times per week
Once a week 
or less
Not at all
1
2
3
4
5
5.
How would you rate your asthma control during the past 4 weeks? 
Not Controlled
at all
Poorly
Controlled
Somewhat 
Controlled
Well
Controlled
Completely
Controlled
1
2
3
4
5
Asthma Control Test™ copyright, QualityMetric Incorporated 2002, 2004. All Rights Reserved.
Asthma Control Test™ is a trademark of QualityMetric Incorporated.


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APPENDIX 20: EUROQoL-5 DIMENSION (EQ-5D) REMOTE VERSION
For use for remote collection of EQ-5D assessment during the COVID-19 pandemic 
only, according to Appendix 2.


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© 2019 EuroQol Research Foundation. EQ-5D™ is a trade mark of the EuroQol Research Foundation. 

SAP_001.pdf: 
 
 
 
This document is confidential. 
SAP Version: Final Version 1.0, 20-May-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
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Page 1 of 99 
Statistical Analysis Plan 
 
SAP Text Version Number: Final Version 1.0 
SAP Text Date: 20-May-2022 
 
Sponsor Name: Galderma S.A./Galderma R&D, LLC 
 
Protocol Number: RD.06.SPR.203065 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Study to Assess the 
Efficacy and Safety of Nemolizumab (CD14152) in Subjects with Prurigo Nodularis 
 
Protocol Version and Date:  
V1.0, 21-Feb-2020; 
V3.0, 25-Jun-2020; 
V4.0, 22-Dec-2020 
V5.0, 19-Nov-2021 
 
Syneos Health Project Code: 7009814 
 
Author: 
, Biostatistician II 
 
 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Galderma S.A./Galderma R&D, 
LLC. Acceptance of this document constitutes agreement by the recipient that no information contained 
herein will be published or disclosed without prior written authorization from an official of Galderma 
S.A./Galderma R&D, LLC. However, this document may be disclosed to appropriate Institutional Review 
Board and Ethics Committees or duly authorized representatives of a national regulatory authority under 
the condition that they are requested to keep it confidential. In the event of an actual or suspected breach 
of this obligation, Syneos Health should be notified promptly. 
 
 
 
 
 
 
 






Statistical Analysis Plan for Interventional Studies 
Sponsor: Galderma S.A./Galderma R&D, LLC; Protocol No.: RD.06.SPR.203065 
 
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Table of Contents 
Revision History .......................................................................................................................... 2 
Approvals .................................................................................................................................. 3 
 
Glossary of Abbreviations ................................................................................................... 8 
 
Purpose ............................................................................................................................ 12 
 
Study Objectives .............................................................................................................. 13 
 
Study Details/Design ........................................................................................................ 14 
 
Endpoints ......................................................................................................................... 24 
 
Analysis Sets .................................................................................................................... 26 


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Estimands ........................................................................................................................ 28 
 
General Aspects for Statistical Analysis ........................................................................... 31 
 
Demographic, Other Baseline Characteristics and Medication ......................................... 36 
 
Efficacy ............................................................................................................................ 40 


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Pharmacokinetics ............................................................................................................. 53 
 
Immunogenicity ................................................................................................................ 54 
 
Safety ............................................................................................................................... 55 
 
Changes from Analysis Planned in Protocol ..................................................................... 63 
 
Reference List .................................................................................................................. 64 
 
Programming Considerations ........................................................................................... 65 


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Quality Control ................................................................................................................. 70 
 
Index of Tables ................................................................................................................. 71 
 
Index of Figures................................................................................................................ 87 
 
Index of Listings ............................................................................................................... 89 
 
Appendices ...................................................................................................................... 91 










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Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables and 
figures which will be produced, and the statistical methodologies that will be used, are complete and 
appropriate to allow valid conclusions regarding the study objectives. The planned analyses identified in 
this SAP will be included in regulatory submissions and/or future manuscripts. Exploratory analyses not 
identified or defined in this SAP may be performed to support the clinical development program. Any post-
hoc or unplanned analyses performed and not identified in this SAP will be documented in the respective 
clinical study report (CSR). 
 
Responsibilities 
Syneos Health will perform the statistical analyses and is responsible for the production and quality control 
of all tables, figures and listings. 
Descriptive summary and listing will be provided for pharmacokinetic concentration. Definition of the 
Pharmacokinetic analysis population and derivation of Pharmacokinetic parameters will be performed by a 
designated CRO. This designated CRO will be responsible for the ad-hoc Modeling / Simulation Plan and 
the Modeling & Simulation Report. Any analysis of pharmacokinetic parameters will not be included in the 
CSR final TFLs but in the dedicated Modeling & Simulation Report. For further details see Section 11. 
 
Timings of Analyses 
A primary analysis will be carried out once all subjects have completed the final study visit or terminate 
early from the study. No personnel directly involved with the conduct of the study shall have access to the 
unblinded data before the completion of the trial in order to avoid introducing bias to the remaining study 
data. 
The final analysis will be performed after all subjects completed the study. 
An independent data monitoring committee (IDMC) will review and monitor subject safety throughout the 
study, and an independent adjudication committee (IAC) will review all asthma-related adverse events 
throughout the study. Details on the IDMC and IAC, including the plan of analysis for outputs; the 
composition of the committees; and the procedures, roles, responsibilities, and communications are 
provided in the respective IDMC (v2.0, dated 01-Nov-2021) and Appendix 2 of IAC charters (v2.0, dated 
13-Jan-2022). 


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Study Objectives 
 
Primary Objective 
The primary objective is to assess the efficacy of Nemolizumab (CD14152) compared to placebo in subjects 
≥ 18 years of age with prurigo nodularis (PN) after a 16-week treatment period. 
 
Secondary Objectives 
The secondary objectives are to assess safety, pharmacokinetics, and immunogenicity of Nemolizumab 
(CD14152) compared to placebo. 


Statistical Analysis Plan for Interventional Studies 
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Study Details/Design 
 
Brief Description 
This phase 3, multicenter, double-blind, placebo-controlled, randomized, parallel group study is designed 
to evaluate the efficacy and safety of Nemolizumab in subjects with PN. 
Subjects’ participation in the study will be up to 28 weeks. The study consists of a screening period (up to 
4 weeks), a 16-week treatment period, and an 8-week follow up period (12 weeks after the last study drug 
injection). Refer to Figure 4-1 for an overview of study design. 
Figure 4-1: Study Design 
 
Abbreviations: BL = baseline; W = week. 
Following provision of written informed consent, subjects with PN will be screened for enrolment in the 
study. Eligible subjects will return for a baseline visit where, following randomization, they will be 
administered either 60 mg of Nemolizumab or placebo via 2 SC injections. Thereafter, study drug will be 
administered Q4W at Weeks 4, 8, and 12 by a single SC injection of either Nemolizumab 30 mg or placebo 


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for subjects weighing < 90 kg at baseline or by two SC injections of either Nemolizumab 30 mg or placebo 
for subjects weighing ≥ 90 kg at baseline. Efficacy and safety assessments will be performed at visits 
throughout the screening and treatment period, as outlined in the Schedule of Assessments (Table 4-2). 
At the end of the 16-week treatment period, consenting subjects may be eligible to enter an active 
treatment/long-term extension (LTE) study (RD.06.SPR.202699). Subjects who participate in the LTE are 
not required to complete the follow-up visit. Subjects who do not participate in the LTE will return for a 
follow-up visit at Week 24 (12 weeks after the last study drug injection). 
Subjects who prematurely discontinue the study drug will be asked to continue participation in the study 
and return for all remaining visits and assessments (including daily assessment of pruritus and sleep 
disturbance). Subjects who discontinue study drug due to required rescue therapy may be eligible to 
participate in the LTE study following completion of study visits through Week 16. Subjects who discontinue 
the study prematurely should complete an early termination (ET) visit and a follow-up visit 12 weeks after 
the last study drug injection. 
As no approved medicine for PN exists with which to compare Nemolizumab, a placebo-controlled design 
was implemented in this study to allow blinding, randomization, and identical administration procedures to 
control for human bias or other influences on the disease (e.g., natural disease course), while enabling 
demonstration of differences in clinical effect and safety profile of investigational treatment, if present. All 
subjects will have access to rescue medication to minimize risk and for ethical considerations. It is the 
position of the Committee for Medicinal Products for Human Use (CHMP) that, where ethical and feasible, 
a placebo control arm should be included in the pivotal trial(s) used to support marketing authorization 
application. 
A 16-week treatment period is considered adequate to evaluate the efficacy and safety of Nemolizumab 
based on the results of the phase 2a study (RD.03.SPR.115828) in subjects with PN. All subjects who 
complete the treatment period (Week 16 visit) can be considered for LTE study eligibility. A 2-to-1 
randomization is selected to minimize the number of subjects exposed to placebo for an extended period 
of time. 
Although the pathophysiology of PN is still not fully understood, the efficacy endpoints selected for the 
phase 3 trial are relevant to the underlying manifestations associated with the disease under study (i.e., 
skin lesions, chronic itch, sleep disturbance, and quality of life impairment). The selected endpoints for 
assessing the safety and PK of Nemolizumab (CD14152) are in accordance with current standards. Blinding 
subjects and the designated study team to the treatment assignment(s) helps ensure objectivity and 
minimize bias. Randomization through the Interactive Response Technology (IRT) guards against selection 
bias. 
The study includes an 8-week follow-up period (i.e., 12 weeks after the last study drug injection) for subjects 
who decline or are not eligible to enroll in the LTE study. The duration of the follow-up period from the final 
Nemolizumab dose (12 weeks) corresponds to approximately 5 half-lives of Nemolizumab, which is 
considered adequate to ensure subject safety. The follow-up visit is not required for subjects who participate 
in the LTE, where the primary objective is long-term evaluation of safety. 
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 drug for injection, including confirmation 


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of complete reconstitution, prior to delivery of study drug for injection. The pharmacist (or other qualified 
personnel) preparing study drug 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. 
The placebo-controlled design includes a provision for rescue therapy for pruritus, based on the 
investigator’s clinical judgment. Subjects requiring rescue therapy may be eligible for the LTE study but will 
be required to continue scheduled study visits until the Week 16 visit before LTE eligibility will be assessed. 
To avoid bias and to ensure the integrity of the blind, personnel directly involved with the ongoing conduct 
of the study from the Sponsor, blinded statistical team at Syneos Health, or other investigational study 
centers will not have access to any information that may lead to unblinding. 
A subject will have fulfilled the requirements for study completion if/when the subject has completed all 
study periods, including Week 16 or the last scheduled visit as indicated in the Schedule of Assessments 
(Table 4-2). 
The end of the study will be the last subject’s last visit or the last subject’s scheduled visit as indicated in 
the Schedule of Assessments (Table 4-2). 
 
Subject Selection 
Eligible subjects for this clinical study will be adults with a clinical diagnosis of PN for at least 6 months, 
manifested by pruriginous nodular lesions on the trunk and/or limbs, and at least 20 nodules on the entire 
body bilaterally distributed. The inclusion criterion for IGA is consistent with the disease severity targeted 
in the study: An IGA of 3 or 4 corresponds to moderate or severe PN, respectively. Severe pruritus will be 
defined by PP NRS scores ≥ 7.0 within the past 24 hours at screening and the mean PP NRS score ≥ 7.0 
during the previous week at baseline. Subjects with chronic pruritus due to other active conditions or 
unilateral pruriginous lesions are ineligible. Further, subjects must undergo specific required washout 
periods from restricted topical and systemic treatments before enrolling in the study. The study population 
is selected based on the current unmet need in the management of PN, the mode of action of Nemolizumab 
(CD14152), and the need to understand the efficacy and safety of Nemolizumab (CD14152) in the adult 
population with PN. 
 
Inclusion Criteria 
For a detailed description of subject’s inclusion criteria see protocol Section 8.1.  
 
Exclusion Criteria 
For a detailed description of subject’s exclusion criteria see protocol Section 8.2. 
 
Determination of Sample Size 
In order to achieve at least 90% power for both primary endpoints at 5% significance level, 270 (180 
Nemolizumab, 90 placebo) subjects will be randomized to detect the following differences in both primary 
endpoints between treatment groups with 2:1 randomization, assuming a 15% dropout rate during treatment 
period. 
NRS responders (≥ 4 point reduction from baseline): Based on phase 2a data, it is expected that the NRS 
response at Week 16 would be 50% in Nemolizumab and 20% in placebo. 


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IGA response (0/1): It is expected that the IGA response at Week 16 would be 30% in Nemolizumab and 
10% in placebo. 
Table 4-1 provides the resulting power with 270 subjects (180 Nemolizumab, 90 placebo) for different 
responses in primary endpoints. 
Table 4-1: Results of Power Analysis 
Endpoint 
Placebo  
Nemolizumab  
Power at 5% significance 
level (N= 270 [180 
Nemolizumab, 90 placebo]) 
IGA responder 
10% 
30% 
90% 
10% 
27% 
83% 
10% 
25% 
77% 
PP-NRS Responder 
20% 
50% 
> 90% 
20% 
45% 
> 90% 
20% 
40% 
84% 
Assuming 15% attrition rate during treatment period. Based on continuity corrected Chi-square test. 
 
Treatment Assignment and Blinding 
Upon confirmation of eligibility for a given subject to participate in the study, a unique randomization number 
will be assigned to that subject via Interactive Response Technology (IRT). 
The randomization number for a given subject will be used to identify the treatment arm the subject will be 
assigned to. 
Subjects will be randomized in a 2:1 ratio to receive treatment of either Nemolizumab (CD14152) or 
placebo. The randomization scheme will be stratified by the study site and body weight at randomization (< 
90 kg and ≥ 90 kg) using the IRT system.   
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 dual-chamber syringe (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 (CD14152) or placebo treatments, according to the current version 
of the pharmacy manual and 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 drug 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 integrity of the study blinding, the bioanalytical laboratory staff who process/analyze the 
PK/anti-drug antibody (ADA)/pharmacodynamic (PD)/ pharmacogenomic (PGx) samples will not provide 
any information to the Sponsor, CRO, or investigational study center personnel directly involved with the 
ongoing conduct of the study that may lead to unblinding during the ongoing study. PK and ADA results will 
released by the bioanalytical laboratory after data base lock (DBL).  


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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 Randomization and Trial Supply Management (RTSM) User Guide for information on the steps 
for breaking the blind in the IRT system. 
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 and must also be appropriately followed for a 
minimum of 12 weeks after the last dose of study drug. 
The reporting requirements for unblinding are the same for reporting an SAE. See also Section 12.7.4 of 
protocol. 
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 treatment assignment remains 
undisclosed to all individuals involved in the direct execution and management of the study until the final 
database is locked. 
 
Administration of Study Medication 
All study drug injections will occur at the study center, following instructions provided in the instructions for 
use and the current version of the pharmacy manual. 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 an alternative injection site. A different 
injection site should be selected for each injection. Refer to the current version of the pharmacy manual 
and 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 center staff will provide training on study drug injections. 
Subjects will be allowed to inject medication following appropriate training and 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 does not wish to perform injections. The eCRF will record who performed 
study drug injection at each visit. 


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After study drug administration, subjects will be monitored closely for any signs or symptoms of 
hypersensitivity reaction before being discharged. For the first 2 visits where study drug is administered, 
subjects should remain at the study center for at least 30 minutes following study drug administration. 
 
Study Procedures and Flowchart 
See Table 4-2  for study procedures.  
 








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diagnosis was confirmed. Subjects should be asked to withhold asthma medication on study visit days until after PEF testing is complete, to the extent it does not pose an undue risk 
to the subject. See Section 12.6.3 of protocol for details.  
k) 
12-lead ECGs should be performed in the supine position, before any scheduled vital sign measurements and blood draws. See Section 12.4 of protocol. 
l) 
In case of indeterminate result for TB test, the test should be repeated (only 1 retest is allowed). If the test is still indeterminate, the subject must not be included in the study, 
unless subject has a documented history of completion of an appropriate TB treatment regimen with no history of re-exposure to TB since their treatment was completed. 
m) 
Subjects should be well hydrated and fast for at least 8 hours before the visit(s) when blood chemistry testing is planned, except for the screening visit. 
n) 
At scheduled visits with laboratory, PK, and ADA assessments, samples are to be collected before study drug injection(s). 
o) 
Only for females of childbearing potential. Serum pregnancy test to be performed at screening visit and UPT for all other visits. If UPT is positive, it must be confirmed with a 
serum pregnancy test. See Section 12.5.4 of protocol for details. 
p) 
For postmenopausal subjects (i.e., no menses for 12 consecutive months), confirm status with a high FSH level in the postmenopausal range.  
q) 
As a guideline, PK samples should be collected at approximately the same time of day throughout the study, to the extent possible, before study drug injection (pre-dose 
samples). See Section 13.1 of protocol for details on PK assessments. 
r) 
Blood, stratum coreum, and biopsy samples for PD assessments are only collected at selected sites. Biopsy samples are optional and only for subjects who provide 
additional consent. See Section 14.3 of protocol for details. 
s) 
Optional PGx sample collection is only for subjects who provide additional consent. See Section 14.1 of protocol for details. 
t) 
Subjects weighing < 90 kg at baseline will receive a loading dose on Day 1 (i.e., 2 injections of Nemolizumab 30 mg or placebo) then single injections of either 30 mg 
Nemolizumab or placebo Q4W. Subjects weighing ≥ 90 kg at baseline will receive either 60 mg Nemolizumab or placebo via 2 injections Q4W at all study visits. 
u) 
Study drug reconstitution will be performed by the pharmacist (or other qualified personnel) throughout the study, and complete reconstitution confirmed, prior to delivery for 
injection. Study center staff will provide study drug injection training for subjects willing and able to self-inject study drug. Based on the subject’s preference, study center staff can also 
perform all injections. 
v) 
After study drug administration, subjects will be monitored closely for any signs or symptoms of hypersensitivity reaction before being discharged. For the first 2 visits where 
study drug is administered, subjects should remain at the study center for at least 30 minutes following study drug administration.  
w) 
If a study visit occurs outside the visit window, study drug injection(s) can still be administered provided there is a minimum of 3 weeks but not more than 5 weeks since the 
last injection. If beyond 5 weeks, the next study drug injection should then occur at the next planned visit. Future visits should be scheduled as soon as possible and within the required 
windows based on the baseline/Day 1 visit date, while maintaining the minimum 3-week interval between 2 injections.


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Endpoints   
 
Primary Efficacy Endpoints 
• 
Proportion of subjects with an improvement of ≥ 4 from baseline in PP NRS at Week 16 
• 
Proportion of subjects with an IGA success (defined as an IGA of 0 [Clear] or 1 [Almost clear] and 
a ≥ 2-point improvement from baseline) at Week 16 
 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are as follows: 
• 
Proportion of subjects with an improvement of ≥ 4 from baseline in PP NRS at Week 4 
• 
Proportion of subjects with PP NRS < 2 at Week 16 
• 
Proportion of subjects with an improvement of ≥ 4 from baseline in SD NRS at Week 16 
• 
Proportion of subjects with an improvement of ≥ 4 from baseline in SD NRS at Week 4 
• 
Proportion of subjects with PP NRS < 2 at Week 4 
 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• 
IGA success rate at each visit through Week 16 
• 
Percentage of pruriginous lesions with excoriations/crusts (Prurigo Activity Score [PAS] item 5a) at 
each visit through Week 16 
• 
Percentage of healed prurigo lesions (PAS item 5b) at each visit through Week 16 
• 
Change from baseline in number of lesions in representative area (PAS item 4) at each visit through 
Week 16 
• 
Proportion of subjects with an improvement of ≥ 4 from baseline in PP NRS through Week 16 
• 
Proportion of subjects with PP NRS < 2 from baseline through Week 16 
• 
Proportion of subjects with PP NRS < 3 from baseline through Week 16 
• 
Absolute change from baseline in PP NRS through Week 16 
• 
Percent change from baseline in PP NRS through Week 16 
• 
Proportion of subjects with an improvement of ≥ 4 from baseline in Average Pruritus (AP) NRS 
through Week 16 
• 
Proportion of subjects with PP NRS improvement ≥ 4 from baseline and IGA success at Week 16 
• 
Proportion of subjects with AP NRS < 2 from baseline through Week 16  
• 
Absolute change from baseline in AP NRS through Week 16 
• 
Percent change from baseline in AP NRS through Week 16 
• 
Proportion of subjects with an improvement of ≥ 4 from baseline in SD NRS through Week 16 


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• 
Absolute change from baseline in SD NRS through Week 16 
• 
Percent change from baseline in SD NRS through Week 16 
• 
Change from baseline in sleep diary endpoints (sleep onset latency, wakefulness after sleep onset 
[WASO], total awake time, total sleep time, sleep efficiency) based on recordings from subject sleep 
diary through Week 16 
• 
Change from baseline in PN-associated pain frequency through Week 16 
• 
Change from baseline in PN-associated pain intensity through Week 16 
• 
Proportion of subjects reporting low disease activity (clear, almost clear, or mild) based on Patient 
Global Assessment of Disease (PGAD) at Week 16 
• 
Proportion of subjects satisfied with study treatment (good, very good, or excellent) based on 
Patient Global Assessment of Treatment (PGAT) at Week 16 
• 
Proportion of subjects with an improvement of ≥ 4 in Dermatology Life Quality Index (DLQI) through 
Week 16  
• 
Change from baseline in DLQI through Week 16 
• 
Change from baseline in Hospital Anxiety and Depression Scale (HADS) for each subscale (i.e., 
depression and anxiety) at Week 16 
• 
Change from baseline in EuroQoL 5-Dimension (EQ-5D) at Week 16 
 
Pharmacokinetic Endpoints 
• 
Nemolizumab (CD14152) serum concentrations 
 
Immunogenicity Endpoints 
• 
ADA assay (screening, confirmatory, titer, NAb) 
 
Safety Endpoints 
• 
Incidence and severity of AEs, including TEAEs, AESIs, SAEs and Adjudicated AEs  
• 
Clinical laboratory tests 
• 
Vital signs 
• 
Electrocardiogram 
• 
Physical examination 
• 
Respiratory assessment including respiratory examination, Peak expiratory flow, and Asthma Control 
Test (ACT) 
 


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Analysis Sets 
 
Screened Population 
The Screened population comprises all subjects who signed the ICF and have screening data entered into 
the database. This population includes screen failures and randomized subjects. Screen failed subjects are 
defined as those subjects who fail to meet inclusion criteria or meet exclusion criteria and discontinue the 
study prior to randomization. Subjects that are re-screened will only be counted once, under the subject ID 
assigned for the repeat screening. 
Unless specified otherwise, this set will be used for subject listings and summaries of subject disposition.  
 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will consist of all randomized subjects. The ITT population will be the 
primary population for efficacy analyses. All analyses under the ITT population will be analyzed under the 
treatment group as randomized. 
 
Per-Protocol Population 
The Per-Protocol (PP) population will consist of all subjects in the ITT population and have no major protocol 
deviations that would have a significant effect on the efficacy of the study treatment (see Section 6.6). Only 
primary and key secondary endpoints will be analyzed using the PP population, under the treatment group 
as randomized. 
 
Safety Population  
The Safety (SAF) population will consist of all randomized subjects who received at least 1 administration 
of study drug. The treatment group assignment in this population will be defined by the treatment actually 
received. This population will be used for the analyses of safety.  
 
Pharmacokinetic Analysis Population  
The PK analysis population will consist of all subjects included in the SAF, with at least one measurable 
post-baseline PK assessment. Similar to SAF, the treatment group assignment in this population will be 
defined by the treatment actually received. This population will be used for the descriptive analyses of PK 
concentrations. 
 
Protocol Deviations 
Protocol deviations will be recorded by the Clinical Research Associate (CRA) in the Clinical Trial 
Management System (CTMS). All protocol deviations will be categorized by the associated deviation type 
and will be assessed individually on a regular basis on whether they are major or minor. Details can be 
found in the Protocol Deviation and Non-compliance Management Plan. 
Major protocol deviations that are analysis relevant lead to an exclusion of the subject from the per-protocol 
population. A case by case decision regarding exclusions of subjects from the per-protocol analysis will be 
made in a blind data review meeting (BDRM) which will take place prior to unblinding the study. The criteria 
for exclusion from the PP population will be specified in the BDRM Preparation Plan. Only major protocol 
deviation which have a significant effect on the primary efficacy will result in exclusion from the PP 
population.  
A summary table for number and percentage of subjects with major protocol deviation will be generated by 
type of deviation and treatment group for the ITT population. 


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Protocol deviations incurred as a direct result of the COVID-19 pandemic should be specifically recorded 
and presented as a COVID-19 deviation. The number and percentage of subjects with major (including 
major COVID-19) deviation will be provided by type of deviation and treatment group for the ITT population 
and additionally provided by Site.  
All protocol deviations and the protocol deviations related to COVID-19 will be listed for the ITT population.  
 
 








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General Aspects for Statistical Analysis 
 
General Methods 
• All data will be listed, and summary tables will be provided.  
• Unless otherwise specified, summaries will be presented for each treatment and overall, if indicated, 
by visit.  
• Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (SD), median, 1st Quartile (Q1), 3rd Quartile (Q3), minimum, and maximum. Categorical 
variables will be summarized using number of observations (n), frequency and percentages of 
subjects 
• Unless otherwise stated, all statistical tests will be two-sided and conducted at the 5% level; all 
presented confidence intervals (CIs) will be two-sided 95% CIs. 
 
Key Definitions 
Screening period is a period of up to 4 weeks before Baseline/Day 1 during which subject eligibility is 
evaluated. Subjects receiving rescue therapies during the screening period are not eligible to participate in 
the study. 
The 16-week treatment period is defined as Baseline/Day 1 to Week 16. If early discontinued during 
treatment period, it is defined as the period until 4 weeks (<=28 days) after last dosing date or early 
termination date whichever is earlier. 
Follow-up period is defined as the post end of treatment period to follow-up visit in respective treatment 
period. 
The Baseline value is defined as the last non-missing value before the first dose of study drug. In case 
that the date of first injection is not available, the date of randomization is considered.  
For diary data (PP NRS, SD NRS), the Baseline values will be derived from data collected during the 7 
days prior to the first administration of study drug, if subject is treated. Otherwise, the data collected during 
7 days prior to randomization will be used. Baseline score will be the weekly prorated average of non-
missing subject diary scores reported during the 7 days. A minimum of 4 daily scores out of the 7 days is 
required to calculate the weekly prorated average score. If there are less than 4 non-missing assessments 
in the baseline diary window, the interval lower bound can be extended up to 7 additional days, one day at 
a time, to obtain the most recent 4 non-missing values. For sensitivity analysis, a minimum of 2 or 3 daily 
scores out of the 7 days will be used to calculate the weekly prorated average score for primary and key 
secondary endpoints and the interval will not be extended with additional days. 
The date of first treatment is defined as the date of first injection of study drug. 
The date of last treatment is defined as the date of last injection of study drug. 
Study day is defined as the number of days from the date of first treatment (randomization date if not 
treated) and will be calculated as follows: 
• 
If the event date ≥ date of first treatment, then study day = event date - date of first treatment + 1. 
Treatment Day 1 is therefore defined as the day of first treatment. 


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• 
If the event date < date of first treatment, then study day = event date - date of first treatment. 
• 
If subject is randomized, but not treated, then study day = event date - date of randomization. 
A subject’s date of last participation in the trial is the last date of contact and is recorded as the date of 
completion or date of withdrawal on the completion page of the case report form (CRF). 
Only the subjects infected by COVID-19 during study participation will be considered subjects with 
COVID-19 infection.  
 
Missing Data 
The primary method to impute the missing values will be as follows: 
Continuous Endpoints: For continuous secondary endpoints (except EQ-5D, HADS) during treatment 
period, the MI under MAR assumption approach and the MMRM approach will be used to handle the 
missing data.  
Binary Endpoints: All missing values will be treated as a non-responder for the binary endpoints for 
primary, key secondary and secondary endpoints. To assess the robustness of non-responder analysis for 
primary and key secondary endpoints, a tipping point analysis will be performed. The MI under MAR 
assumption, last observation carried forward (LOCF) approach, and observed case (OC) approach will be 
used as sensitivity analysis to impute the missing values for the primary and key secondary endpoints. If 
applicable, the continuous response will be imputed first, and the response will then be categorized. 
Use of rescue therapy: All efficacy data, except OC, will be treated as treatment failure and considered 
as non-responder on or after rescue therapy is used. In OC analysis, no observed data after subject has 
received rescue treatment will be excluded. There will be no imputations for missing data. 
Adverse events and concomitant medications/procedures: Missing assessment times will have 
imputed times for the purposes of assessing treatment emergence for AEs or classifying 
medications/procedures into prior/concomitant. However, the assessment date and time (start date, stop 
date, and time if collected from CRF) without imputation will be presented in the listings. 
For the start of a concomitant medication/procedure or AE: 
• 
Only the year is reported: If the subject received the first study drug dose in the year reported, then 
the date of the first dose of study drug will be used as the start date; otherwise, January 1 of the 
year reported will be used as the start date. 
• 
The month and year are reported: If the subject received the first study drug in the month and year 
reported, then the date of the first dose of study drug will be used as the start date; otherwise, the 
first day of the month and year will be used as the start date. 
• 
The time is collected but missing: If the start date is the same as the date the subject started 
receiving study drug, then the time of the first dose of study drug will be used as the start time; 
otherwise, 00:00 will be used as the start time. 
For the end of a concomitant medication/procedure or AE: 


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• 
Only the year is reported: The earlier between December 31 of the year reported and the date of 
the last study contact with the subject will be used as the stop date. 
• 
The month and year are reported: The earlier between the last date of the month and year reported 
and the date of the final contact with the subject will be used as the stop date. 
• 
The time is collected but missing: 23:59 (or 23:59:59 if collected up to seconds) will be used as the 
stop time. 
If an AE has the start date completely missing and the stop date on/after the first dose date of study drug, 
this AE will be considered as treatment emergent (TEAE). 
If a medication/procedure has the stop date completely missing, this medication/procedure will be 
considered as ongoing and concomitant. If the start date of a medication/procedure is completely missing 
and impossible to identify different by stop date, this medication will be considered as concomitant. 
 
Visit Windows 
Efficacy by-visit summaries will use the analysis visit. Unscheduled and early termination visits will be 
windowed based on the analysis visit window in Table 8-1 which is based on study day. If multiple 
measurements are taken within the same window, the one taken closest to the target study day will be used 
for the analysis. If there are multiple measurements with same difference from target day, the later 
assessment should be used for the analysis. 
 
Table 8-1: Analysis Visit Window 
Analysis Visit 
Target Study 
Day 
Visit Window for 
IGA, PAS, PN 
associated Pain 
frequency and 
intensity 
Visit Window for 
PGIS-P, PGIS-SD, 
PGIC-P, PGIC-SD, 
PGAD, PGAT, EQ-
5D, HADS 
Visit Window for 
DLQI 
Baseline 
1 
≤ 1 
≤ 1 
<=1 
Week 1  
8 
NA 
2 to 60 
NA 
Week 4 
29 
2 to 42 
NA 
2 to 60 
Week 8 
57 
43 to 70 
NA 
NA 
Week 12 
85 
71 to 98 
NA 
NA 
Week 16 
113 
99 to 154 
61 to 154 
61 to 154 
Week 24 Follow-
up 
169 
155 to 182 
NA 
NA 
All daily diary efficacy data will be classified into analysis visits as described in Table 8-2 considering the 
data during the 7 days immediately preceding the target day of analysis visit.  
Analysis visit of diary (ePRO) data will be defined depending on the data collection as below.  
Diary data assessed within the extended timeframe below will be considered for analysis. The following 
rule will be applayed for post-treatment assessments only.  
• 
Evening assessment (PP/AP NRS) recorded from 17:00:00 to 00:59:59 
• 
Morning assessment (SD NRS, morning sleep diary) recorded from 5:00:00 to 17:59:59 


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Consecutive daily assessment: 
For the evening assessments (PP NRS, AP NRS), the daily data collected up to Week 16 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 (SD NRS, morning sleep diary), the 7 days data up to 
the target study day will be classified into analysis visit. Details of the analysis visit window are in Table 8-2 
below.  
Table 8-2: Analysis Visit Window for Evening and Morning Assessments 
Analysis Visit 
Target Study Day 
of Analysis Visit 
Visit Window for evening 
assessment (PP NRS, AP 
NRS) 
Visit Window for morning 
assessment (SD NRS, 
morning sleep diary) 
Baseline a 
1 
-7 to -1 
-6 to 1 before dosing 
Week 1 
8 
1 to 7 
2 to 8 
Week 2 
15 
8 to 14 
9 to 15 
Week 3 
22 
15 to 21 
16 to 22 
Week 4 
29 
22 to 28 
23 to 29 
Week 5 
36 
29 to 35 
30 to 36 
Week 6 
43 
36 to 42 
37 to 43 
Week 7 
50 
43 to 49 
44 to 50 
Week 8 
57 
50 to 56 
51 to 57 
Week 9 
64 
57 to 63 
58 to 64 
Week 10 
71 
64 to 70 
65 to 71 
Week 11 
78 
71 to 77 
72 to 78 
Week 12 
85 
78 to 84 
79 to 85 
Week 13 
92 
85 to 91 
86 to 92 
Week 14 
99 
92 to 98 
93 to 99 
Week 15 
106 
99 to 105 
100 to 106 
Week 16b 
113 
106 to 112 
107 to 113 
a If there are less than 4 non-missing assessments within last 7 days prior to the first dose, the interval 
lower bound will be extended up to 7 additional days, one day at a time, to obtain the most recent 4 non-
missing values. The extention will not be applied for the sensitivity analysis by using a minimum of 2 (or 3) 
daily scores out of the 7 days.  
b If there are less than 4 assessments during Week 16 visit window, upper bound of the visit window (106 
- 112) or (107 - 113) will be extended for 5 additional days. If there are still less than 4 assessments after 
extending upper bound of the visit window, lower bound of the visit window will be extended for another 5 
days until 4 assessments are reached. 
Safety and pharmacokinetics data will not be windowed for by-visit summary. i.e., scheduled visit data will 
be used for analysis. 
 
 
Pooling of Centers 
A small center is defined as a center with less than 12 randomized subjects. Small centers will be pooled 
prior to analyses.  
First, centers will be sorted by 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 with the 


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smallest center within that country. If there is a further need to combine data (the size of the pooled centers 
includes less 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 country. Any 
remaining centers will be pooled with the last pooled center within the country. The pooled centers will be 
referred to ‘analysis centers’ in the statistical analyses. 
 
Subgroups 
Descriptive summary and analysis for primary and key secondary endpoints will be produced for the 
following subgroups: 
• 
Region (Europe, North America, Asia Pacific) 
• 
Age groups (18-65, and > 65) 
• 
Sex (Male, Female)  
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Pacific Islander, Other (including Multiple)) 
• 
Weight at randomization (< 90 kg, ≥ 90 kg) 
• 
Baseline IGA score (Moderate [3], Severe [4]).  


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Demographic, Other Baseline Characteristics and Medication 
 
Subject Disposition and Withdrawals 
All subjects of the Screened population will be accounted for in this study. 
Subject accounting will summarize subjects screened, re-screened, screen failed, randomized and 
randomized but not treated for all subjects by overall, country and site. 
Subject accounting by visit will be summarized by treatment group and overall at each visit (scheduled visits 
only). 
Subject disposition will be summarized based on the ITT population by treatment and overall. Summaries 
will include subjects randomized, subjects randomized but not treated, subjects treated, subjects completed 
treatment, subjects discontinued treatment, primary reason for discontinuation of treatment (including 
summary of subjects who stopped treatment due to COVID-19), subjects completed the study, subjects 
discontinued from the study, primary reason for discontinuation from the study (including summary of 
subjects who discontinued due to COVID-19), subjects rolled over to long term extension (LTE), and 
subjects completed Follow-up. Subjects who stopped treatment or discontinued study due to COVID-19 will 
be identified using other specify field in CRF. 
Subject disposition will also be summarized by site on the ITT population. 
Screen failure will be summarized for all screened subjects. Number of subjects screened and failed will be 
presented. Number and percentage of reason for screen failure (including summary of subjects who failed 
due to COVID-19) will be summarized. 
Subjects in each analysis population (ITT, SAF, PP, PK analysis population) will be summarized by 
treatment group on the ITT population. 
In addition, time (days since the first dose of study drug) to permanent discontinuation of study drug by 
reason for discontinuation will be displayed graphically in subjects having permanently discontinued from 
the study drug. 
Randomization, study completion, drug completion, visit dates will be listed for the ITT population. Screen 
failure reason will also be listed. Additional listing of missed assessment for subjects who discontinued due 
to COVID-19 will be presented for the ITT population. 
Analysis populations will be summarized and listed on the ITT population. 
All inclusion and exclusion criteria not met will be listed on the Screened population. 
 
Demographic and Baseline Disease Characteristics 
Summary statistics for demographic and other Baseline disease characteristics will be presented for the 
ITT, SAF, PP and PK analysis population. 
Age (years), height (cm), weight (kg), and BMI (kg/m2) will be summarized using summary statistics for 
continuous variables. Age groups (18-65, and > 65), sex, region (Europe, North America, and Asia Pacific), 


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race, ethnicity, and smoking status will be summarized using the summary statistics for categorical 
variables. Weight will additionally be presented for each subgroup < 90 kg and ≥ 90 kg.  
The Baseline disease characteristics IGA, weekly average PP NRS, weekly average AP NRS, weekly 
average SD NRS, pain frequency and intensity, PAS item 4 (number of lesion in representative area), item 
5a (excoriation/crusts), item 5b (healed lesion stages), and baseline DLQI will be summarized. IGA, pain 
frequency, PAS item 5a and 5b will be summarized as a categorical variable.  
A summary table for the stratification factor weight at randomization will be provided to show any 
discrepancies between what was reported through Interactive Voice Response System (IVRS)/Interactive 
Web Response System (IWRS) versus eCRF data (at baseline visit). 
All demographic and baseline disease characteristics data will be listed on the ITT population. 
 
Medical History  
Medical history will be collected only at screening and will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA), Version 25.0. 
Medical history will be summarized by treatment group. The summary will include number and percentage 
of subjects reporting each system organ class (SOC), preferred term (PT) and lowest level term (LLT) and 
will be sorted alphabetically by SOC and descending frequency of PT within SOC and descending 
frequency of LLT within PT in the Nemolizumab treatment group. Summary tables will be presented for the 
ITT population. 
Medical history data listings will be presented by subject number for the ITT population. 
 
Medical and Surgical Procedure 
Medical and surgical procedures will be coded using MedDRA, Version 25.0. 
Prior medical and surgical procedures are defined as those which have been stopped before first treatment. 
• 
Procedure before informed consent signed is defined as those stopped before the date of informed 
consent signed to the study. 
• 
Procedure during screening period is defined as those stopped on or after the date of informed 
consent signed until before first treatment date. 
Concomitant medical and surgical procedures will be defined as those started or stopped on or after the 
first treatment, or were ongoing during the study. If a procedure is started before the first treatment but is 
ongoing or stopped on or after the first treatment, it will be considered concomitant. 
• 
Procedures during treatment period will be defined from start of treatment till 4 weeks (<= 28 days) 
after the last treatment or early discontinuation date whichever is earlier. 
• 
Procedures during follow-up period is defined from post treatment period (4 weeks (> 28 days) after 
the last treatment or early discontinuation date, whichever is earlier) to follow-up visit date. 
If the stop date and ‘ongoing’ are missing then the procedure will be considered concomitant.  


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The following medical and surgical procedures (prior, concomitant and rescue procedures) will be 
summarized by treatment group using the number and percent of subjects reporting each SOC and PT and 
sorted alphabetically by SOC and descending frequency of PT within SOC in the Nemolizumab treatment 
group. Summary tables will be presented for the ITT population. 
• 
Prior procedure before screening (before informed consent date) 
• 
Prior procedure before first dosing (from screening [informed consent date] before the first 
treatment) 
• 
Concomitant procedure during treatment period 
• 
Concomitant procedure during follow-up period 
• 
Rescue procedure during treatment period 
• 
Rescue procedure during follow-up period 
Medical and surgical procedures listings and rescue procedure listing will be presented by treatment group 
on the ITT population and sorted by subject number, start date, stop date, SOC, and PT. 
 
Medication 
Medications will be classified and summarized on the ITT population as follows: 
Prior medications are defined as those which stop before the first injection of study drug during the study. 
• 
Prior medication before informed consent signed is defined as those stopped before the date of 
informed consent signed to the study. 
• 
Prior medication during screening period is defined as those stopped during screening period (on 
or after the informed consent date, until before the first treatment date). 
Concomitant medications are defined as those started, stopped, or ongoing on or after the first injection of 
study drug. 
• 
Medication during treatment period is defined from start of treatment till 4 weeks (<= 28 days) after 
the last treatment or early discontinuation date whichever is earlier. 
• 
Medication during follow-up period is defined from post treatment period (4 weeks (> 28 days) after 
the last treatment or early discontinuation date, whichever is earlier) to follow-up visit date 
If the stop date and ‘ongoing’ are missing then the medication will be considered as concomitant medication.  
Medications (prior, concomitant and rescue medications) will be coded using Version Global B3, March 
2022 of the World Health Organization’s Drug Dictionary (WHO DD). Preferred Anatomical Therapeutic 
Chemical (ATC) coding will be performed.  
The following summaries by ATC level 2, ATC level 4 and preferred term (PT) will be produced on the ITT 
population. Subjects with more than one medication in a given ATC level and preferred name will be 
counted only once in that category. It will be sorted ATC level alphabetically and descending frequency in 
PT within ATC level term. 
• 
Prior medication before screening (before informed consent date) 


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• 
Prior medication before first dosing (from screening [informed consent date] before the first 
treatment) 
• 
Concomitant medication during treatment period  
• 
Concomitant medication during follow-up period 
• 
Rescue medication during treatment period  
• 
Rescue medication during follow-up period 
 
All medications (prior and concomitant medications, rescue medications) will be listed for the ITT 
population.  
 
Extent of Exposure 
Following parameters will be summarized:  
 
• 
Treatment duration (in days) is calculated as follows, where date of first treatment is defined as the 
first day: [(date of last treatment – date of first treatment) + 1]. 
• 
Total dose administered (mg) will be calculated as the sum of all doses of study drug administered. 
• 
Total dose planned (mg) will be calculated as the sum of all doses of study drug planned 
(dispensed) according to the treatment schedule of the treatment group. 
• 
The number of subjects who missed at least one dose 
• 
The number of subjects who missed at least one dose due to COVID-19 
• 
The number of doses missed 
• 
The number of doses missed due to COVID-19 
• 
Treatment Compliance as described in Section 9.7. 
Note: The missed dose due to COVID-19 are captured as other-reason reported in CRF.  
 
Treatment Compliance  
Treatment compliance will be assessed through the treatment records and drug dispensation logs. 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). 
Treatment compliance (%) is calculated as the total number of actual injections / the total number of 
expected injections * 100. The total number of actual injections is counted based on collected study drug 
administration data. The total number of expected injections is counted based on the dosage schedule and 
dispensed as per protocol. 


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Efficacy 
Unless otherwise stated, all efficacy analyses will be performed on the ITT population. 
All efficacy variables will be summarized by treatment group at each analysis visit. The primary comparison 
of interest is Nemolizumab compared to placebo. 
To control the type I error at 5%, a fixed sequential testing approach will be implemented. For testing 
purposes, both primary endpoints will be tested first in a predefined order as listed in Section 5.1 at 5% 
significance level, and testing of key secondary endpoints will start only if both primary endpoints are 
successful at 5% level of significance. Key secondary endpoints will be tested in an order listed in Section 
5.2, stopping when non-significant result (p > 0.05) is found. 
 
Primary Efficacy Endpoints 
 
Primary Analysis of Primary Efficacy Endpoint 
The primary endpoints include the following endpoints: 
• 
The proportion of subjects with an improvement of ≥ 4 from baseline in PP NRS at Week 16. 
• 
The proportion of subjects reporting success on the IGA at Week 16, defined as an IGA response 
of 0 [Clear] or 1 [Almost clear] and a ≥ 2-point reduction from baseline; 
For both primary endpoints, any subjects with missing data at Week 16 will be considered as a non-
responder for the respective endpoint. If a subject is in receipt of rescue medication at any point on or prior 
to Week 16, data on or after receipt of rescue medication will be regarded as a non-responder. 
The statistical hypotheses associated with the primary analysis of improvement in PP NRS ≥ 4 from 
baseline at Week 16 using treatment difference is, similarly: 
Null hypothesis H0:  
  
PPP NRS_nemolizumab - PPP NRS_placebo = 0; 
Alternative hypothesis H1:  
PPP NRS_nemolizumab - PPP NRS_placebo ≠ 0, 
where PPP NRS_nemolizumab and PPP NRS_placebo are the proportion of subjects categorized as having a PP NRS 
improvement from baseline to Week 16 of ≥ 4, for Nemolizumab and placebo, respectively. 
The statistical hypotheses associated with the primary analysis of IGA success at Week 16 using treatment 
difference is: 
Null hypothesis H0:  
  
PIGA_nemolizumab - PIGA_ placebo = 0; 
Alternative hypothesis H1: 
PIGA_nemolizumab - PIGA_placebo ≠ 0, 
where PIGA_nemolizumab and PIGA_ placebo are the proportion of subjects categorized as success under IGA at 
Week 16 for Nemolizumab and Placebo, respectively. 
Both primary endpoints will be analyzed using a Cochran-Mantel-Haenszel (CMH) test adjusted for the 
randomization strata analysis center and body weight at randomization (< 90 kg, ≥ 90 kg), in order to test 
the difference between Nemolizumab and placebo for the proportion of subjects achieving success in each 
endpoint. The estimate of the treatment difference and corresponding two-sided 95% CI and p-values will 
be presented. The confidence intervals will be based on Wald statistic controlling for stratification variables. 
Strata-adjusted proportion differences will be obtained using weighted average of stratum-specific 
proportion using CMH.  
In addition an unadjusted CMH test will be performed. 


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Bar charts for the proportions of subjects with an improvement of ≥ 4 from baseline in PP NRS and IGA 
success at Week 16 will be presented. 
 
Sensitivity Analyses of Primary Efficacy Endpoint 
Sensitivity analyses for both primary endpoints will be conducted in order to test for the robustness of the 
primary analyses. The following sensitivity analyses will be conducted: 
• 
Same analysis on PP population (including the bar charts for the proportion of subjects with an 
improvement of ≥ 4 from baseline in PP NRS and IGA success at Week 16). 
• 
Tipping point analysis: To assess the robustness of non-responder analysis, a tipping point analysis 
will be performed by converting non-responders due to missing data to responders in successive 
increments (Δ) for both treatment groups. The value of Δ that overturns (i.e., non-significant) the 
primary results will represent the tipping point (see Appendix 21.1). A graphic display of all possible 
combinations of the number of responders among both treatment groups will be presented. 
• 
Multiple Imputation (MI) method for missing data (or where rescue medication is received), assuming 
all missing data are Missing at Random (MAR) (see Appendix 21.2). 
• 
Pattern-mixture model under assumption Missing Not at Random (MNAR) controlled-based pattern 
imputation. MI-based imputation will be applied as described above. Under MNAR assumption, a 
controlled based pattern imputation where only observation in placebo treatment group will be used 
to impute. 
• 
Last Observation Carried Forward (LOCF) imputation method for missing data (or where rescue 
medication is received). Missing post-baseline values will be carried forward from the last non-missing 
post-baseline value. Baseline value will not be carried forward to post-baseline value. 
• 
Observed Case (OC) - no data will be imputed. For this analysis, if any rescue medication is received, 
data on or post rescue therapy will be analyzed as observed (i.e., not treated as non-responders). 
• 
Removal of COVID-19 affected visits (i.e. exclusion of subjects from visit, if visit was missed due to 
COVID-19). 
• 
‘Actual stratum’ instead of ‘stratum at the randomization’ for subjects stratified incorrectly. 
• 
Using at least 2 assessments for calculation of weekly average PP NRS instead of 4. 
• 
Using at least 3 assessments for calculation of weekly average PP NRS instead of 4. 
Tipping point analysis, multiple imputation methods, LOCF and OC analysis, analysis without COVID-19 
affected visits and analysis with actual stratum will be performed on the ITT population. Except for OC 
analyses, assessments on or after rescue therapy used will be considered as non-responders. 
 
Subgroup Analyses of Primary Efficacy Endpoints 
In addition, the same analyses as described in Section 10.1.1 will be performed for the following 
subgroups: 
• 
Region (Europe, North America, Asia-Pacific) 
• 
Age groups (18-65, and > 65) 
• 
Sex (Male, Female) 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian 
or Pacific Islander, Other (including Multiple)) 
• 
Weight at randomization (< 90 kg, ≥ 90 kg) 
• 
Baseline IGA Score (Moderate (3), Severe (4)) 


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The subgroup analyses will be performed on the ITT population. Forest plot will be presented along with 
subgroup analysis results. 
 
Key Secondary Efficacy Endpoints 
The following key secondary endpoints are to be analyzed, in order: 
1. Proportion of subjects with an improvement of ≥ 4 from baseline to Week 4 in PP NRS; 
2. Proportion of subjects with PP NRS < 2 at Week 16  
3. Proportion of subjects with an improvement of ≥ 4 from baseline in SD NRS at Week 16 
4. Proportion of subjects with an improvement of ≥ 4 from baseline in SD NRS at Week 4 
5. Proportion of subjects with PP NRS < 2 at Week 4 
All key secondary endpoints will be analyzed on the ITT population as primary endpoints (Section 10.1.1) 
including graphical presentation. 
Additionally, the same sensitivity analyses as for the primary endpoints will be performed (Section 10.1.2), 
including bar charts for the key secondary endpoints or PP population.  
Analysis of key secondary endpoints will be produced for the subgroups, too (Section 10.1.3). 
 
Secondary Efficacy Endpoints 
The following secondary endpoints are to be analyzed at the scheduled visits (Table 10-1): 
  






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Binary secondary endpoints will be analyzed as described in Section 10.1.1. if not specified otherwise. 
Missing values will be imputed as non-responder except for OC analysis. If a subject is in receipt of rescue 
medication at any point, data on or after receipt of rescue medication will be regarded as a non-responder.  
Continuous secondary endpoints (except EQ-5D, HADS) will be analyzed using multiple-imputation (MI) 
assuming MAR and using mixed effect model for repeated measure (MMRM) approach, including analysis 
center and body weight at randomization cut-off (< 90 kg and ≥ 90 kg) as factor and baseline as covariate 
where applies. The estimated treatment difference for each endpoint at each visit will be displayed in the 
summary of statistical analysis together with the 95% CI and associated p-value. EQ-5D and HADS 
endpoints will be analyzed using ANCOVA including analysis center and body weight at randomization cut-
off (< 90 kg and ≥ 90 kg) as factor and baseline as covariate. All secondary endpoints will be presented 
descriptively using OC. 
 
Investigator’s Global Assessment (IGA) 
The IGA is a 5-point scale ranging from 0 (clear) to 4 (severe) used by the investigator or trained designee 
to evaluate the global severity of PN and the clinical response to a treatment (see Table 10-2). 
 
Table 10-2: Investigator Global Assessment Scale 
0 
Clear 
No nodules 
1 
Almost Clear 
Rare palpable pruriginous nodules 
2 
Mild 
Few palpable pruriginous nodules 
3 
Moderate 
Many palpable pruriginous nodules 
4 
Severe 
Abundant palpable pruriginous nodules 
IGA treatment success is defined as 0 (clear) or 1 (almost clear) on the IGA scale and a ≥ 2-point reduction 
from Baseline. 
IGA will be collected at Baseline/Day 1, Week 4, Week 8, Week 12, Week 16 and Early Termination. In 
case of missing assessment at Baseline, the last available assessment prior study drug administration will 
be considered as Baseline.  
IGA will be summarized as a categorical and continuous variable at each analysis visit. Absolute change 
from Baseline for the IGA score will also be presented in the summary on the ITT and PP population. 
The proportion of subjects with IGA success (OC, non-responder, LOCF) will be summarized on the ITT 
and PP Population. It will also be analyzed using non-responder imputation and a Cochran-Mantel-
Haenszel (CMH) test adjusted for the randomization strata analysis center and body weight at 
randomization (< 90 kg, ≥ 90 kg).The estimate of treatment unadjusted and strata-adjusted differences with 
the corresponding two-sided 95% confidence intervals, and p-values from the CMH test will be presented. 
Line plots for proportion of subject with IGA success using non-responder imputation will be generated for 
the ITT and PP population. 
 


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Prurigo Activity Score (PAS) 
The Investigator or designee will use the PAS as an evaluation of the disease. This includes a count of the 
number of lesions in a representative area and a calculated staging (stage 0 to stage 4) based on the 
percentage of lesions with excoriations/crusts and healed lesions compared to all lesions. 
Following items will be summarized at Baseline, Week 4, Week 8, Week 12, Week 16: 
• 
PAS item 1a/1b: Type of prurigo  
• 
PAS item 2: Number of pruriginous lesions 
• 
PAS item 3: Affected area(s) 
• 
PAS item 4: Number of lesions in representative area. 
• 
PAS item 5a: Pruriginous lesions with excoriations/crusts 
• 
PAS item 5b: Healed prurigo lesions 
PAS items will be summarized as a categorical or continuous variable at each analysis visit, respectively. 
Absolute change from Baseline for continuous parameter PAS item 4 will also be presented in the summary 
on the ITT and PP population. 
The proportion of subjects with pruriginous lesions with excoriation/crusts (PAS item 5a = 76-100%) and of 
subjects with healed lesion stages (PAS item 5b = 0-25%) will be presented using non-responder approach. 
The estimate of treatment unadjusted and strata-adjusted proportion differences with the corresponding 
two-sided 95% CI, and p-values from the CMH test will be presented. 
Absolute and percentage change from Baseline in PAS item 4 will be analyzed using ANCOVA with MI 
assuming MAR approach, including analysis center and body weight at randomization cut-off (< 90 kg and 
≥ 90 kg) as factor and baseline as covariate. The least squares means (LSMeans), standard error of 
LSMeans, and 95% CI for change from baseline, as well as the difference in LSMeans between the 
treatment groups, the two-sided 95% CI, and associated p-value will be presented for ITT and PP 
population.  
 
Pruritus Numeric Rating Scale (NRS) 
The Pruritus NRS is a scale to be used by the subjects to report the intensity of their pruritus (itch) during 
the last 24 hours. Peak pruritus (PP NRS) is an assessment of the maximum itch intensity in that period 
while average pruritus (AP NRS) provides a measure of overall pruritus intensity. 
Subjects will be asked the following question: 
• 
For maximum itch intensity (PP NRS): “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?” 
• 
For average itch intensity (AP NRS): “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 overall during the previous 24 hours?” 
The screening PP/AP NRS will be determined by a single assessment using the PP/AP NRS (score ranging 
from 0 to 10) for the 24-hour period immediately preceding the screening visit.  


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The Baseline PP/AP NRS will be determined based on the average of daily PP/AP NRS (score ranging 
from 0 to 10) respectively during the 7 days immediately preceding Baseline (rounding to nearest whole 
number is not permitted). A minimum of 4 daily scores out of the 7 days immediately preceding Baseline 
(up to one day before date of first treatment) is required for this calculation. If there are less than 4 non-
missing assessments in the baseline diary window, the interval lower bound can be extended up to 7 
additional days, one day at a time, to obtain the most recent 4 non-missing values. 
PP/AP NRS at all follow-up visits will be determined in the same manner. Subjects will receive instructions 
on how to record their PP/AP NRS scores and will complete the assessment once daily in the evening 
throughout the clinical study (including the run-in and the follow-up period).  
PP NRS will be determined by an average as described above at every week from Baseline to Week 16 as 
a continuous variable.  
Descriptive summary of PP NRS will be provided on the ITT and PP populations using observed cases. 
Absolute change and percentage change from Baseline for the PP NRS will also be included in the 
summary on the ITT and PP populations. 
AP NRS will be determined by an average as described above at every week from Baseline to Week 16 as 
a continuous variable. Descriptive summary of AP NRS will be provided on the ITT population. Absolute 
change and percent change from Baseline for the AP NRS score will also be included in the summary. 
Absolute and percentage change from Baseline in PP/AP NRS will be analyzed using ANCOVA with MI 
assuming MAR and using MMRM approach, including analysis center and body weight at randomization 
cut-off (< 90 kg and ≥ 90 kg) as factor and baseline as covariate on ITT population. The least squares 
means (LSMeans), standard error of LSMeans, and 95% CI for change from baseline, as well as the 
difference in LSMeans between the treatment groups, the two-sided 95% CI, and associated p-value will 
be presented.  
Proportion of subjects with PP NRS at each analysis visit will be summarized:  
• 
Improvement ≥ 4 from baseline 
• 
< 2 at visit 
• 
< 3 at visit  
Proportion of subjects with AP NRS at each visit will be summarized: 
• 
Improvement ≥ 4 in change from baseline 
• 
 < 2 at visit 
The proportions of subjects will be presented on the ITT population using OC and non-responder for AP 
NRS and using OC, non-responder and LOCF for PP NRS. The estimate of treatment unadjusted and 
strata-adjusted proportion differences with the corresponding two-sided 95% CI, and p-values from the 
CMH test will be presented using non-responder. 
Line plots for proportion of subjects with PP NRS improvement ≥ 4 and proportion of subjects with PP NRS 
< 2 using non-responder imputation will be presented on the ITT and PP population. 
Additionally the weekly average PP NRS will be recalculated by using at least 2 assessments, or 3 
assessments, instead of at least 4 assessments and without extending the visit window for sensitivity 
analysis.  


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The proportion of subjects with the weekly average PP NRS using 2, or 3 assessments, will be summarized 
at each analysis visit:  
• 
PP NRS Improvement ≥ 4 from baseline 
• 
PP NRS < 2  
In addition, proportion of subjects with PP NRS improvement ≥ 4 from baseline and IGA success (see 
Section 10.3.1) at Week 16 will be summarized on the ITT and PP population. The proportion of subjects 
will be presented using OC, non-responder and LOCF. The estimate of treatment unadjusted and strata-
adjusted proportion differences with the corresponding two-sided 95% CI, and p-values from the CMH test 
will be presented. 
Line plots for the change and percentage change from Baseline in PP NRS using OC on the ITT population 
will also be presented. 
 
Sleep Disturbance Numeric Rating Scale (SD NRS) 
The SD NRS is a scale to be used by the subjects to report the degree of their sleep loss related to PN. 
The Baseline SD NRS will be determined based on the average of daily SD NRS (score ranging from 0 to 
10) during the 7 days up to the treatment start (including until treatment start time) (rounding to nearest 
whole number is not permitted). A minimum of 4 daily scores out of the 7 days up to Baseline study day is 
required for this calculation. SD NRS at all following visits will be determined following the rules described 
in Table 8-2. If there are less than 4 non-missing assessments in the baseline diary window, the interval 
lower bound can be extended up to 7 additional days, one day at a time, to obtain the most recent 4 non-
missing values. 
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 my skin disease 
(prurigo nodularis)’ and 10 being ‘I did not sleep at all due to the symptoms of prurigo nodularis’, 
how would you rate your sleep last night?” 
Summary using OC will be provided on the ITT population. Absolute change and percentage change from 
Baseline will also be included in the summary. 
Absolute and percentage change from Baseline at each analysis visits will be analyzed using ANCOVA 
with MI assuming MAR and using MMRM approach, including analysis center and body weight at 
randomization cut-off (< 90 kg and ≥ 90 kg) as factor and baseline as covariate on ITT population. The 
LSMeans, standard error of LSMeans, and 95% CI for change from baseline, as well as the difference in 
LSMeans between the treatment groups, the two-sided 95% CI, and associated p-value will be presented. 
Improvement in SD NRS will be calculated using Baseline as the reference point for change in SD NRS 
score.  
The proportion of subjects with an improvement of SD NRS ≥ 4 will be summarized using OC and non-
responder imputation on ITT population. The estimate of treatment unadjusted and strata-adjusted 
differences with the corresponding two-sided 95% confidence intervals, and p-values from the CMH test 
will be presented using non-responder imputation on ITT population. 
Line plot for proportion of subjects with SD NRS improvement ≥ 4 using non-responder imputation will be 
presented on the ITT population. 




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If Q8 (wake up time) is before Q1 (get into bed), the time on the next day will be considered for Q9 as only 
time is collected.  
If the duration between Q1 and Q9 is >24 hours, this data will be considered as uncalculable and the derived 
parameters (total awake time and total sleep time) are set to missing.  
If total sleep time is negative, it will be considered as missing (not zero) for analysis. The same applies for 
total awake time. 
No hypothesis testing will be performed. 
 
PN Associated Pain Intensity and Frequency 
Subjects will be asked to report the intensity and frequency of pain they endure related to their PN. Pain 
intensity is captured using a NRS. 
Subjects will rate the frequency of their pain on a 6-point scale (0 = Never, 1 = Less than once a week, 2 = 
1-2 Days a week, 3 = 3-4 Days a week, 4 = 5-6 Days a week, 5 = Everyday) in response to the following 
question: 
“How often would you say that you experience pain from your skin disease (prurigo nodularis)?”  
Subjects will rate the intensity of their pain using an 11-point NRS (0-10) in response to the following 
question:  
“On a scale of 0 to 10, with 0 being “no pain” and 10 being “the worst unbearable pain”, how would you rate 
the pain associated with your skin disease (prurigo nodularis) at the worst moment during the past week?” 
Summaries using OC will be generated for PN associated pain frequency and intensity at Baseline, Week 
4, Week 8, Week 12, and Week 16 on ITT population. Pain frequency will be summarized as a categorical 
variable. Pain intensity will be summarized as a continuous variable. Absolute change from Baseline in PN 
associated pain intensity from Baseline will also be summarized. 
No hypothesis testing will be performed. 
 
Patient Global Assessment of Disease (PGAD) 
For the PGAD, subjects will be asked to rate their overall impression of their skin disease (prurigo nodularis) 
severity using a 5-point scale (0 = clear, 1 = almost clear, 2 = mild, 3 = moderate, 4 = severe). Subjects will 
be asked the following question: 
“Overall, how would you describe your skin disease (prurigo nodularis) right now?” 
PGAD will be collected at Baseline/Day 1, Week 1, Week 16 and Early Termination and be summarized for 
Baseline, Week 1 and Week 16 as a categorical variable using OC on the ITT population. 
The proportion of subjects reporting low disease activity (clear, almost clear, or mild) based on PGAD will 
be summarized using OC on the ITT population. The estimate of treatment unadjusted and strata-adjusted 
differences with the corresponding two-sided 95% CI, and p-values from the CMH test will be presented. 


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Patient Global Assessment of Treatment (PGAT) 
The PGAT utilizes a 5-point Likert scale (0 = poor, 1 = fair, 2 = good, 3 = very good, 4 = excellent) or 
subjects to rate the way they feel their skin disease (prurigo nodularis) is responding to the study treatment. 
Subjects will be asked the following question at Week 16 and Early Termination: 
“How would you rate the way your skin disease (prurigo nodularis) responded to the study medication?” 
PGAT will be summarized as a categorical variable for Week 16 using OC on the ITT population.  
The proportion of subjects satisfied with study treatment (good, very good, or excellent) based on PGAT 
will be summarized using OC on the ITT population. The estimate of treatment unadjusted and strata-
adjusted differences with the corresponding two-sided 95% CI, and p-values from the CMH test will be 
presented. 
 
Dermatology Life Quality Index 
The DLQI is a validated 10-item questionnaire covering domains including symptoms/feelings, daily 
activities, leisure, work/school, personal relationships, and treatment. 
The subject will rate each question ranging from 0 (not at all) to 3 (very much). The DLQI total score is 
calculated by summing each questionnaire. Total score will have a maximum score of 30 and a minimum 
of 0. The higher the score, the more quality of life is impaired. 
DLQI will be collected at Baseline/Day 1, Week 4, Week 16 and Early Termination. DLQI total score will be 
summarized as a continuous variable using OC on the ITT population for Baseline, Week 4 and Week 16. 
Absolute change from Baseline in DLQI total score will also be summarized. 
Absolute change from Baseline in DLQI total score at Week 4 and Week 16 will be analyzed using ANCOVA 
with MI assuming MAR and using MMRM approach, including analysis center and body weight at 
randomization cut-off (< 90 kg and ≥ 90 kg) as factor and baseline as covariate. The LSMeans, standard 
error of LSMeans, and 95% CI for change from baseline, as well as the difference in LSMeans between the 
treatment groups, the two-sided 95% CI, and associated p-value will be presented on ITT population.  
Improvement of ≥ 4 in DLQI will be calculated using Baseline as the reference point for change in DLQI 
total score. The proportion of subjects with an improvement of ≥ 4 will be summarized on the ITT population 
using OC and non-responder imputation. The estimate of treatment unadjusted and strata-adjusted 
differences with the corresponding two-sided 95% CI, and p-values from the Cochran-Mantel-Haenszel test 
using non-responder will be presented for ITT population. 
A line plot for proportion of subjects with DLQI improvement ≥4 using non-responder imputation will be 
presented on the ITT population. 
 
Hospital Anxiety and Depression Scale (HADS) 
HADS is a 14-question validated questionnaire completed by the subject. Each question has a multiple 
choice answer which is scored between 0 and 3. Questions are identified as relating to anxiety (A) or 
depression (D) and a summation for each area is performed leading to a total score of 0 to 21 for each 
area. Scores of 0 to 7 are considered normal, 8 to 10 are borderline, and ≥ 11 indicate clinical effects. 
HADS will be collected at Baseline/Day 1, Week 16 and Early Termination and subscales will be 
summarized separately for each subscale (Total Score Anxiety and Total Score Depression) as continuous 


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variable using OC for Baseline and Week 16. on the ITT Population. Absolute change from Baseline in 
HADS subscale scores will also be summarized. 
Absolute change from Baseline in HADS subscale scores will be analyzed for Week 16 using ANCOVA 
using observed case, including analysis center and body weight at randomization cut-off (< 90 kg and ≥ 90 
kg) as factor and baseline as covariate. The LSMeans, standard error of LSMeans, and 95% CI for change 
from baseline, as well as the difference in LSMeans between the treatment groups, the two-sided 95% CI, 
and associated p-value will be presented. 
 
EuroQoL 5 Dimension Instrument 
The EQ-5D instrument is a validated questionnaire, completed by the subject and consists of 2 parts. The 
first part consists of 5 multiple choice QoL questions and the second is a 100 point VAS scale with 0 being 
“Worst imaginable health state” and 100 being “Best imaginable health state”. 
EQ-5D VAS will be collected at Baseline/Day 1, Week 16 and Early Termination and be summarized as a 
continuous variable using OC for Baseline and Week 16 on the ITT Population. Absolute change from 
Baseline in EQ-5D VAS will also be summarized using OC. 
Absolute change from Baseline in EQ-5D VAS at Week 16 will be analyzed using ANCOVA using observed 
case, including analysis center and body weight at randomization cut-off (< 90 kg and ≥ 90 kg) as factor 
and baseline as covariate. The LSMeans, standard error of LSMeans, and 95% CI for change from 
baseline, as well as the difference in LSMeans between the treatment groups, the two-sided 95% CI, and 
associated p-value will be presented. 
Five dimensions of EQ-5D (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) will 
be summarized as a categorical variable using OC. 
 
Rescue Therapy Used 
Subjects who used either medication or procedure as rescue therapy will be summarized using OC. 
The number and percentage of subjects receiving any prior or concomitant rescue therapy will be 
summarized by rescue treatment type (topical, phototherapy, systemic, intralesional corticosteroids, and 
corresponding subgroups), preferred term within treatment type and overall.  
If a subject used multiple rescue therapies (e.g., use a rescue therapy again after completing to use the 
previous one), count both therapies into each duration.  
In addition, the time to first rescue therapy use will be calculated. The data will be analyzed using Kaplan-
Meier methodology by presenting the point estimates of the quartiles estimates with the corresponding 95% 
CI. Kaplan-Meier estimates of time to first rescue therapy use will be summarized by visit. Subjects who do 
not use any rescue therapy will be censored for the analysis and date of last visit will be used as the 
censoring date. Subjects who discontinued without intake of rescue therapy will also be censored as 
described above. A Kaplan-Meier curve will also be provided. 


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Pharmacokinetics 
The serum concentration of Nemolizumab will be assessed at Baseline, Week 4, Week 8, Week 12, Week 
16, Week 24 Follow-up and Early Termination visit. PK analyses are required during any unscheduled visit 
conducted for safety reasons. As a guideline, PK samples should be collected at approximately the same 
time of day throughout the study, to the extent possible, before study drug injection (pre-dose samples). 
 
Pharmacokinetic Concentration Presentation 
Serum concentration data (unit: ng/mL) will be summarized on the PK analysis population by visit and by 
body weight at randomization cut-off (< 90 kg or ≥ 90 kg) from Baseline to Week 24, using the following 
statistics: arithmetic mean, SD, coefficient of variation (CV), geometric mean, geometric CV, median, 
minimum, maximum, 95% CI of the arithmetic mean, and number below the limit of quantification (BLQ). 
Mean and individual (spaghetti plot) serum concentration(s) will be plotted by visit and by body weight at 
randomization cut-off (< 90 kg or ≥ 90 kg) on both a linear and semi-logarithmic scale on the PK analysis 
population (2 plots). 
Individual serum concentrations will be listed on the PK analysis population. 
 
Pharmacokinetic and Pharmacodynamics Parameters Estimation 
PopPK and PK/PD analyses will be conducted by a designated CRO using pre-specified models based on 
existing information from previous studies in adults. For efficacy, PD endpoints are defined as the 2 primary 
clinical efficacy endpoints of the study: PP NRS responder and IGA success. If needed, specific PK/PD 
analyses might be conducted for safety. 
Results of PopPK and PK/PD analyses will not be included in the CSR final TFLs. PopPK and PK/PD 
analyses will be described in an ad hoc Modeling & Simulation Plan. PopPK and PK/PD analyses results 
will be described in ad hoc Modeling & Simulation Report. 
 
 
Biomarkers 
Blood and stratum corneum (D-Squames) samples will be collected from approximately 100 subjects at 
selected sites to investigate the effect of Nemolizumab (CD14152) on selected RNA and protein 
biomarkers, including but not limited to IL-31. Optional skin biopsies for RNA and immunohistochemistry 
analyses will be collected from approximately 30 subjects at selected sites who sign the additional consent 
form. Samples will be collected at Baseline and Week 16. 
These biomarker data will be analyzed according to a separate Analysis Plan and presented in a 
separate biomarkers report. 


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Immunogenicity 
Blood samples to assess anti-Nemolizumab ADA will be collected at Baseline, Week 8, Week 16, and Early 
Termination. Immunogenicity analyses will be summarized on the PK analysis population. 
Details related to the processing of serum samples and the assessments of ADA will be described in the 
bioanalytical plan, which will be finalized before the beginning of sample analysis. Results will be described 
in the bioanalytical report, which will be included as an appendix in the final clinical study report. 
Incidence of ADA results will be summarized (absolute occurrence and percent of subjects) by treatment 
group at each visit. The concentration of ADA titer (ng/mL) and neutralizing antibodies (ng/mL) will be 
summarized depending on the data requirement. 
The number and percentage of subjects with treatment related ADA will be summarized. A treatment-
related ADA is defined when the Baseline screening or confirmatory ADA result is negative and the post-
baseline confirmatory ADA result is positive in the Nemolizumab treated group only.  


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Safety 
All safety data will be summarized and listed on the SAF population. 
Safety assessments will be conducted for all subjects at the screening visit (upon signing of the ICF) and 
at every subsequent visit. Safety will be assessed on the basis of AEs (including TEAEs, AESIs, SAEs and 
adjudicated AEs), physical examination and vital signs, clinical laboratory tests, electrocardiogram (ECG), 
respiratory examination and assessments. Summary of all safety endpoints will be presented for each 
treatment group. 
 
Adverse Events 
AEs will be coded using MedDRA Version 25.0. 
Treatment-emergent AEs (TEAEs), defined as those AEs occurring after the first administration of study 
treatment until the last study visit, will be tabulated in frequency tables by System Organ Class (SOC) and 
Preferred Term (PT) based on the Medical Dictionary for Regulatory Activities for treatment and follow-up 
periods. Missing date information will be handled using the algorithm described in Section 8.3. 
TEAEs during treatment period are defined as AEs with onset date on or after the first dose date till 4 weeks 
after the last treatment or early discontinuation date whichever is earlier. TEAEs during follow-up period 
are defined as AEs with onset date post treatment period (4 weeks after the last treatment or early 
discontinuation date, whichever is earlier) to follow-up visit date.  
AEs will be summarized using the number and percent of subjects reporting each SOC and PT and sorted 
alphabetically by SOC and by descending frequency of PT within SOC. 
Subjects who experienced multiple events within the same SOC will be counted once in the SOC summary. 
Subjects who experienced multiple occurrences of events with the same PT will be counted once in the PT 
summary. 
When summarizing by causality or maximum severity, if a subject experiences more than 1 occurrence of 
the same AE, the occurrence with the greatest severity and the closest association with the study drug will 
be used in summary tables. TEAEs related to study drug/study procedure are those that are identified as 
reasonable possibility. If relationship or severity are missing, the event will be considered as AE related to 
study drug/study procedure or severe AE. 
An AESI is a noteworthy treatment-emergent event for the study drug that should be monitored closely and 
reported promptly. An AESI can be either serious or non-serious. Based on the potential risks of 
Nemolizumab and the risks associated with biologics in general (i.e., class effects), the following AEs will 
be considered as AESIs:  
• 
Injection-related reactions,  
• 
Newly diagnosed asthma or worsening of asthma,  
• 
Infections,  
• 
Peripheral oedema: limbs, bilateral,  
• 
Facial oedema 
• 
Elevated ALT or AST (> 3 x ULN) in combination with elevated bilirubin (> 2 x ULN). 
The following summary tables for TEAEs will be presented for all TEAEs (i.e., TEAE all causalities) and 
study drug related TEAEs separately by treatment period and follow-up period.  


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• 
Overall Summary of TEAEs :  
o 
Overall summary table includes summary of subjects reporting TEAEs,  
o 
Overall summary table includes summary of subjects reporting TEAEs by Country,  
o 
TEAE by maximum severity [Mild, Moderate, Severe], 
o 
TEAE related to study drug,  
o 
TEAE related to study drug by maximum severity [Mild, Moderate, Severe], 
o 
TEAE related to protocol procedure,  
o 
Serious TEAE,  
o 
Serious TEAE related to study drug,  
o 
Severe TEAE,  
o 
TEAE of special interest,  
o 
TEAE leading to study drug interruption,  
o 
TEAE leading to study drug withdrawal,  
o 
TEAE leading to study discontinuation,  
o 
TEAE leading to death,  
o 
TEAE related to study drug leading to death 
• 
TEAEs by SOC and PT 
• 
TEAEs by SOC and PT and by Country 
• 
Serious TEAEs by SOC and PT 
• 
TEAEs by SOC, PT and maximum severity 
• 
Severe TEAEs by SOC and PT 
• 
TEAEs leading to study drug withdrawal by SOC and PT 
• 
TEAEs leading to study discontinuation by SOC and PT 
• 
TEAEs of special interest by category by SOC and PT 
• 
TEAEs occurred in > 5% of subjects by SOC and PT 
• 
TEAEs occurred in > 5% of subjects by Preferred Term 
• 
Adjudicated TEAEs by SOC and PT 
• 
TEAEs of Asthma and AESI reported by investigator with adjudication outcome by IAC  
• 
Confirmed adjudicated TEAEs by SOC, PT and maximum severity 
• 
TEAEs of special interest by category, SOC, PT and maximum severity 
For overall study period which includes all periods (treatment and follow-up), the following summary tables 
will also be presented and repeated for all TEAEs (all causalities) and study drug related TEAEs. 
• 
Overall Summary of TEAEs 


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• 
TEAEs by SOC and PT 
For the subset of subjects with COVID-19 infection, the following summary tables will be provided 
additionally for all TEAEs and study drug related TEAEs, separately. 
• 
Overall summary of TEAEs 
• 
TEAEs by SOC and PT 
• 
Serious TEAEs, by SOC and PT 
• 
TEAEs of Special Interest by category by SOC and PT 
In addition, the exposure-adjusted incidence rate (i.e., number of subjects per 100 patient-years) will be 
summarized for all TEAEs (all causalities) and study drug related TEAEs during treatment period.   
Exposure-adjusted incidence rates of TEAEs is defined as the number of subjects exposed to treatment 
and experiencing a certain event divided by the total time of all subjects who are at risk for the event. 
Specially, for subjects with no event the exposure time is the time from the first drug intake to the end of 
treatment period. Exposure years is calculated as last study drug exposure date minus first study drug 
exposure date plus one, divided by 365.25 which is the number of days count in a year. This exposure year 
calculated for each subject is then added cumulatively and is derived for each treatment arm. So each 
treatment arm will have one value for exposure years (also known as “patient years”). The exposure year 
calculation is different in case of subjects who have completed the study or discontinued from the study or 
having withdrawn from the study due to any reason. Only the event occurred during the treatment period 
will account for calculation. 
Subject listings will be presented for all  
• 
TEAEs,  
• 
TEAEs of special interest,  
• 
Serious TEAEs,  
• 
Severe TEAEs,  
• 
TEAE leading to permanent discontinuation of study drug,  
• 
TEAEs leading to deaths,  
• 
Pre-treatment AEs, 
• 
Adjudicated Asthma AEs, 
• 
TEAE comments, 
• 
Adjudicated Asthma AE comments by Independent Adjudication Committee. 
Subject listings of TEAEs for subjects with COVID-19 infection will also be generated. 
 
Laboratory Evaluations 
 
Clinical Laboratory Evaluations 
The hematology laboratory analyses, clinical chemistry 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. Reference 
ranges will be provided in the laboratory manual. 


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The following parameters will be reported for laboratory data. 
• 
Hematology: Hemoglobin, hematocrit, white blood cell (WBC) count (with differential including 
eosinophils), red blood cell (RBC) count, platelet count, and mean cell volume (MCV). 
• 
Chemistry: Creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma 
glutamyltransferase (GGT), alkaline phosphatase, lactate dehydrogenase (LDH), total bilirubin, direct 
bilirubin, creatinine phosphokinase ([CPK], CPK isoenzyme test will be performed only if CPK is 
elevated to > 2.5 × ULN), albumin, total protein, uric acid, sodium, potassium, calcium, chloride, 
glucose, urea, total cholesterol, triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein 
(HDL). Follicle-stimulating hormone (FSH) will be collected for postmenopausal subjects. 
• 
Urinalysis: pH, glucose, ketones, blood, protein, leukocytes, nitrites, bilirubin, urobilinogen, and 
specific gravity. 
Laboratory assessments are performed at Screening, Baseline/Day 1, Week 4, Week 8, Week 16, Early 
Termination and Week 24/Follow-up. 
Hematology and chemistry laboratory data (absolute values and change from Baseline) will be summarized 
as continuous variables by visit (Baseline and scheduled visits only). Urinalysis laboratory data will be 
summarized by visit (Baseline and scheduled visits only). Last post-baseline, worst post-baseline and 
maximum post-baseline results will also be included in the summaries and will include unscheduled visits 
in the derivation. Worst post-baseline value will be defined as the highest or lowest value relative to the 
reference range. Parameters will be presented in alphabetically order.  
Shift tables will be generated using the reference ranges (Low, Normal, High and Missing) for hematology 
and chemistry laboratory data. The number and percentage of subjects shifting from reference ranges 
between Baseline and each visit (scheduled visits only) will be summarized. Last, worst and maximum post 
baseline values will also be included in the shift tables and will include unscheduled visits in the derivation.  
Summary of the number and percentage of subjects who met criteria of potential clinically significant (CS) 
value will be summarized (Baseline and scheduled visits only) for hematology and chemistry laboratory 
data. Last, worst and maximum post-baseline results will also be included in the summaries. Potentially CS 
ranges are listed in Section 21.4. 
For statistical and graphical summaries of the laboratory tests, values below or above the limit of detection 
(e.g. ‘< 3’ or ‘> 500’) are substituted with the lower limit of detection minus 1% for values below the lower 
limit and are substituted with the upper limit of detection plus 1% for values above the upper limit (e.g. ‘< 3’ 
is substituted by ‘2.97’, ‘> 500’ is substituted by ‘505’). In data listings, the values are shown including the 
< or > sign. 
Distribution of continuous hematology and chemistry laboratory data (in particular, Aspartate 
Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Total Bilirubin 
(BILI), Creatinine Kinase (CK) and Leukocytes (WBC)) will be displayed graphically as boxplot by treatment 
group for baseline and for each scheduled visits and the maximum post-Baseline (including unscheduled 
visits in the derivation) values. 
Individual subject plots will be generated for all subjects with at least one abnormal result (outside of 
reference range). These plots will be provided for the chemistry laboratory parameters. 


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By-subject listing will be presented for all laboratory data. By-subject listing for subjects with at least one 
abnormal result will be provided for hematology and clinical chemistry. By-subject listing for subjects with 
at least one potentially CS result will be provided for hematology, clinical chemistry and urinalysis. 
All laboratory data will be listed for the Safety population. 
 
Pregnancy Testing 
All women of childbearing potential will have a serum pregnancy test at the screening visit and urine 
pregnancy tests (UPTs) at Baseline, Week 4, Week 8, Week 12 and Week 16, Early Termination visit, and 
Week 24/Follow-up. Pregnancy test results must be available prior to the administration of the study drug. 
All test results including Tests not done will be summarized by visit on the Safety population. 
All confirmed pregnancy test results together with the premenses status and childbearing potential 
assessment results will be listed on the Safety population. 
 
Virology and TB Testing 
Virology including HBsAg, HBcAb, hepatitis C, human immunodeficiency virus 1, and human 
immunodeficiency virus 2 antibodies 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). All virology and genomics results will be listed 
on the Safety population. All Immunoglobulin E results will also be listed on the Safety population. 
Subjects will be assessed for TB infection with a QuantiFERON-TB Gold test at the screening visit. All TB 
test results will be listed on the Safety population. 
 
Vital Signs  
Vital signs will include pulse rate, systolic and diastolic blood pressure (after the subject has been sitting 
for at least 5 minutes) and body temperature. 
Vital signs will be collected at the Screening visit and at Baseline/Day 1, Week 4, Week 8, Week 12 and 
Week 16, Early Termination visit, and at Week 24/Follow-up. 
Height and weight will be measured at Screening for all subjects. Weight assessments will be conducted 
at Baseline/Day 1, and Week 16 and Early Termination. 
All vital signs including height and weight (absolute values and change from Baseline) will be summarized 
as continuous (Baseline and scheduled visits only). Last post-Baseline results (including unscheduled visits 
in the derivation) will also be included. 
The number and percentage of subjects who met criteria of potential CS value (Section 21.4) for vital signs 
and weight will be summarized (Baseline and scheduled visits only). Last post-Baseline results (including 
unscheduled visits in the derivation) will also be included. 
Distribution of pulse rate, systolic and diastolic blood pressure will be displayed graphically as boxplot by 
treatment group for Baseline and each scheduled visit and maximum post-Baseline (including unscheduled 
visits in the derivation) values. 
By-subject listing of subjects with potentially CS vital signs and weight will be provided. 


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All vital signs results will be listed on the Safety population. 
 
ECG 
A 12-lead electrocardiogram (ECG) will be performed and read centrally at Screening, Baseline/Day 1, 
Week 16 and Early Termination visit. 
All ECG data (absolute values and change from Baseline) will be summarized as continuous variables by 
visit (Baseline and scheduled visits only). All parameters will be presented in alphabetically order. 
The overall results of the ECGs recorded as ‘Normal’, ’Abnormal, NCS’ or ‘Abnormal, CS’ will be 
summarized by treatment group and visit (scheduled visits only). Clinical significance will be determined by 
the investigator. 
Additionally all ECG findings will be summarized with numbers and percentages by visit (Baseline and 
scheduled visits only. 
All ECG results will be listed on the Safety population. 
 
Physical Examination 
Following body system assessments will be performed at Screening, Baseline/Day 1, Week 8, Week 16, 
Early Termination, and Week 24/Follow-up:  
• 
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. 
The number and percentage of subjects with physical examination results by body system classified as 
‘Normal’, ’Abnormal, NCS’ or ‘Abnormal, CS’ will be summarized (Baseline and scheduled visits only). 
Shift from Baseline of the physical examination category will also be summarized by body system and by 
visit. 
By-subject listing will be provided for subjects who have at least one abnormal result from any body system 
or who missed the assessment due to any reason. 
All physical examination results will be listed on the Safety population. 


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Respiratory Assessments 
 
Respiratory Examination  
A respiratory examination consists of medical interview. Questions regarding medical history of asthma, 
wheeze, dyspnea, and cough, will be performed for all subjects at Screening. At Baseline/Day 1, Week 4, 
Week 8, Week 12, Week 16, Early Termination and Week 24/Follow-up questions are asked regarding:  
• 
newly diagnosed (de novo) with Asthma / experience a worsening of Asthma since last visit 
• 
newly diagnosed with Wheeze since last visit / experience a worsening of Wheeze since last visit 
• 
newly diagnosed with Dyspnea since last visit / experience a worsening of Dyspnea since last visit 
• 
newly diagnosed with Cough since last visit / experience a worsening of Cough since last visit 
Newly diagnosed asthma or unexpected worsening of asthma are also reported as AESI. All Respiratory 
examination questionnaire results will be summarized with numbers and percentages by visit and listed on 
the Safety population. 
 
Peak Expiratory Flow 
Peak expiratory flow (PEF) testing during the clinical study will be performed under the supervision of 
qualified study personnel. Peak expiratory flow measurements should consist of 3 good efforts, with the 
best result documented. Obtained PEF values will be compared to predicted values based on the subject’s 
age, sex and height. 
PEF testing will be performed for all subjects at screening, Baseline/Day 1, Week 8, Week 16, Early 
Termination, and Week 24/Follow-up visits. For subjects reporting a medical history of asthma, PEF testing 
will be performed at all visits during the clinical study. For subjects diagnosed with de novo asthma, PEF 
testing will be performed at all visits, starting with the visit in which the diagnosis was confirmed. 
Following PEF parameters will be summarized as a continuous variable (Baseline and scheduled visits 
only):  
• 
Actual peak expiratory flow rate 
• 
Predicted peak expiratory flow rate  
• 
Actual PEF of predicted value (%). 
These PEF parameters will be summarized separately for the subset of subjects with and without history 
of asthma. 
The number and percentage of subjects with PEF < 80% of predicted value will be summarized by treatment 
group, visit (baseline and scheduled visits only), and medical history of asthma (with and without history of 
asthma). 
All PEF results will be listed on the Safety population. 
 
Asthma Control Test 
Subjects with a medical history of asthma will take an Asthma Control Test (ACT) at Screening, 
Baseline/Day 1, Week 4, Week 8, Week 12 and Week 16, Early Termination visit, and Week 24/Follow-up. 


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Subjects with de novo asthma will complete the ACT testing beginning from de novo diagnosis and at all 
subsequent scheduled visits. 
The ACT is composed of 5 questions. For each question, the subject will choose the best answer out of 5 
possible answers. The test provides a numerical score ranging from 5 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. 
ACT total score (absolute values and change from Baseline) will be summarized as a continuous variable 
(Baseline and scheduled visits only). 
The number and percentage of subjects with an ACT score ≤ 19 will be summarized (scheduled visits only). 
The ACT results and the ACT score will be listed on the Safety population. 
 


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Changes from Analysis Planned in Protocol 
In Sections 5.3 and 10.3, “Proportion of subjects with PP NRS improvement ≥ 4 from baseline and IGA 
success at Week 16” was added as endpoint.  
In protocol Section 9.10 (Prior and Concomitant Therapy), concomitant medications/therapies are defined 
as any therapies taken during the study (i.e., from the screening visit to the end of study). 
However, for the analysis purpose, concomitant medications/therapies are defined as medications/ 
therapies which start or stop or ongoing on or after the 1st injection of study drug. 
In protocol stratification variable weight is named ‘body weight at baseline’. This wording is corrected to 
‘weight at randomization’, to clarify that this is the body weight at the time of randomization and how this 
information is provided by the investigator. 


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Reference List 
1. Liublinska V., Rubin DB. Sensitivity analysis for a partially missing binary outcome in a two-arm 
randomized clinical trial. Stat Med. 2014 October 30; 33(24): 4170–4185. doi:10.1002/sim.6197.  


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Programming Considerations 
All TFLs and statistical analyses will be generated using SAS® 9.4 or higher (SAS® Institute Inc., Cary, NC, 
USA) on a SAS Server. Changes to the software version (e.g. upgrades), or use of additional software 
consistent with the SAP will not be considered a violation of the SAP.  
 
General Considerations 
All TFLs will be produced in accordance to Syneos Health QC Processes (see Section 17).  
• 
A separate SAS program will be created for each output. 
• 
Each output will be stored in a separate file. 
• 
Output files will be provided in separate Word rtf and as combined PDF format including all outputs 
in one PDF file. 
• 
Numbering of TFLs will follow International Conference on Harmonization (ICH) E3 Guidance. 
 
Table, Figure, and Listing Format 
 
General 
• 
All TFLs will be produced in landscape format, unless otherwise specified. 
• 
All TFLs will be produced on paper size A4 using the Courier New font, size 8. 
• 
The data displays for all TFLs will have a 1 inch binding margin on top and bottom of a landscape 
oriented page and a minimum 1.25 inch margin on the left side and a minimum of 0.75 inch right 
side. 
• 
Headers and footers for figures will be in Courier New font, size 8. 
• 
Legends will be used for all figures with more than 1 variable, group, or item displayed. 
• 
TFLs will be in black and white (no color), unless otherwise specified. 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
• 
Only standard keyboard characters will be used in the TFLs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help display 
math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be employed on 
a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied formats, 
as appropriate. 


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Headers 
• All output should have the following header at the top left of each page: 
Galderma Protocol RD.06.SPR.203065 
Dry-run/Draft/Final 
• All output should have Page n of N at the top corner of each page. TFLs are internally paginated in 
relation to the total length (i.e., the page number should appear sequentially as page n of N, where 
N is the total number of pages in the table). 
• The date output was generated should appear along with the program name as a footer on each 
page.  
 
Display Titles 
• 
Each TFL are identified by the designation and a numeral. (i.e., Table 14.1.1.1). ICH E3 numbering 
is used. A decimal system (x.y and x.y.z) are used to identify TFLs with related contents. The title 
is centered. The analysis population are identified on the line immediately following the title. The 
title and table designation are single spaced. A solid line spanning the margins will separate the 
display titles from the table. 
• 
 Column headers. There will be 1 blank line between the last title and the solid line. 
Table 14.1.1.1 
Subject Disposition 
Screened Population 
 
Column Headers 
• 
Column headings are displayed immediately below the solid line described above in Initial upper-
case characters. 
• 
In the case of efficacy tables, the variable (or characteristic) column will be on the far left followed 
by the treatment group column. 
• 
For numeric variables, include “unit” in column or row heading when appropriate. 
• 
Analysis population sizes will be presented for dose group in the column heading as “N=XX” (or in 
the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive statistics 
representing the number of subjects in the analysis population. 
 
Body of the Data Display 
16.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
• Alphanumeric values will be left-justified; 
• Whole numbers (e.g., counts) will be right-justified; and 
• Numbers containing fractional portions will be decimal aligned. The “%” is not presented for example 
“5 (0.6)” 


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16.2.5.2. 
Table Conventions 
• Units will be included where available. 
• If the categories of a parameter are ordered, then all categories between the maximum and minimum 
category are presented in the table, even if n=0 for all treatment groups in a given category that is 
between the minimum and maximum level for that parameter. For example, the frequency distribution 
for symptom severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be presented and so 
counts of 0 will be presented as 0 and not as 0 (0). 
• If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation from the Study, 
etc.), then only those categories for which there is at least 1 subject represented are included. 
• An Unknown or Missing category will be added to each parameter for which information is not 
available for 1 or more subjects. 
• Unless otherwise specified, the estimated mean, median, Q1 and Q3 for a set of values are printed 
out to 1 more significant digit than the original values, and standard deviations are printed out to 2 
more significant digits than the original values. The minimum and maximum should report the same 
significant digits as the original values. Missing descriptive statistics or p-values which cannot be 
estimated are reported as “-”. 
• Percentage values will be printed to one decimal place without the “%”, with the “.” in alignment, one 
space after the count (e.g., 7 (12.8), 13 (5.4)). Unless otherwise noted, for all percentages, the 
number of subjects in the analysis set for the treatment group who have an observation will be the 
denominator. Percentages after zero counts will not be displayed and percentages equating to 100% 
will be presented as 100, without decimal places. 
• Tabular display of data for medical history, prior/concomitant medications, and all tabular displays of 
adverse event data are presented by the body system, treatment class, or SOC. The body system, 
drug class and SOC are displayed in alphabetically order. Within body system, drug class and SOC, 
preferred term will be display in descending frequency. If incidence for more than 1 preferred term is 
identical, they should then be sorted alphabetically. 
• P-values will be output in the format: ‘0.xxxx’, where xxx is the value rounded to 4 decimal places. 
Every p-value less than 0.0001 will be presented as “<0.0001”. If the p-value is returned as >0.9999, 
then present as “>0.9999”. 
• The percentage of subjects is normally calculated as a proportion of the number of subjects assessed 
in the relevant treatment group (or overall) for the analysis population presented. However, careful 
consideration is required in many instances due to the complicated nature of selecting the 
denominator, usually the appropriate number of subjects exposed. These details are described in 
footnotes or programming notes. 


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• For categorical summaries (number and percentage of subjects) where a subject can be included in 
more than one category, it is described in a footnote or programming note as needed if the subject 
are included in the summary statistics for all relevant categories or just 1 category and the criteria for 
selecting the criteria. 
• Where a category with a subheading (such as system organ class) has to be split over more than 
one page, output the subheading followed by “(continued)” at the top of each subsequent page. The 
overall summary statistics for the subheading should only be output on the first relevant page. 
16.2.5.3. 
Listing Conventions 
• Listings will be sorted for presentation in order of subject number, visit/collection day, and 
visit/collection time. 
• Missing data will be represented on subject listings as either a hyphen (‘-’) with a corresponding 
footnote (‘- = unknown or not evaluated’), or as ‘N/A’, with the footnote ‘N/A = not applicable’, 
whichever is appropriate. 
• Dates will be printed in SAS DATE9.format (‘DD_MMM_YYYY’: 01JUL2000). Missing portions of 
dates will be represented on subject listings as dashes (--JUL2000). Dates that are missing because 
they are not applicable for the subject will be output as ‘N/A’, unless otherwise specified. 
• All observed time values will be presented using a 24-hour clock HH:MM or HH:MM:SS format (e.g., 
11:26:45, or 11:26). Time will only be reported if it was measured as part of the study. 
• Units will be included where available. 
16.2.5.4. 
Figure Conventions 
• Unless otherwise specified, for all figures, study visits will be displayed on the X-axis and endpoint 
(e.g., treatment mean change from Baseline) values will be displayed on the Y-axis. 
 
Footnotes 
• A solid line spanning the margins will separate the body of the data display from the footnotes.  
• All footnotes will be left justified with single-line spacing immediately below the solid line underneath 
the data display. 
• Footnotes will always begin with ‘Notes:’ if an informational footnote, or 1, 2, 3, etc. if a reference 
footnote. Each new footnote will start on a new line, where possible. 
• Subject specific footnotes are avoided, where possible. 
• Footnotes will be used sparingly and add value to the TFL. If more than 10 lines of footnotes are 
planned, then a cover page is strongly recommended to be used to display footnotes, and only those 
essential to comprehension of the data will be repeated on each page. 
• The last line of the footnote section will be a standard source line that indicates the name of the 
program used to produce the data display, date the program was run, the date of extraction indicated 


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with “Data Cut-off: DDMMMYYYY” and the listing source (i.e., ‘Program: t-14-01-03-02-01.sas, 
Run date: 16MAR2021 12:57’, date cut-off: DDMMMYYYY, Listing Source(s): 16.x.y.z ). 
• Sources and/or cross-references in footnotes will use the keyword prefix (in singular form) for each 
reference and will be separated by a comma when multiple cross-references are displayed. 
Example 
Listing source: 16.2.1.1 


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Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data listings, 
figures or statistical analyses. An overview of the development of programs is detailed in Syneos Health 
Developing Statistical Programs Standard Operation Procedure (SOP) (3907). 
Syneos Health SOPs Developing Statistical Programs (3907) and Conducting the Transfer of Biostatistical 
Deliverables (SDTM, ADaM, TFL) (3908) describes the quality control procedures that are performed for 
all SAS programs and output. Quality control is defined here as the operational techniques and activities 
undertaken to verify that the SAS programs produce the output by checking for their logic, efficiency and 
commenting and by review of the produced output. A detailed description of project specific QC procedure 
can be found in the document “SAS Programming and Validation Plan” (version 1.0, dated 18-May-2020).  










































Statistical Analysis Plan for Interventional Studies 
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Appendices 
 
Tipping Point Analysis 
Tipping point analysis will be performed by converting non-responders due to missing data to responders 
in successive increments (∆) for both treatment groups to assess the robustness of analysis (Liublinska, 
2015, see Section 15). The value of ∆ that overturns (i.e. non-significant) the primary results will represent 
the tipping point. A graphic display of all possible combination of the number of responders among both 
treatment groups will be presented. 
 
Multiple Imputation 
Multiple imputation (MI) methods will be done for monotone missing data. The MI imputation will be carried 
out as follows. 
 
Imputation Phase 
50 imputed datasets with a monotone missing pattern will be created using SAS MI procedure based on 
the observed data (Markov-Chain-Monte-Carlo method, MCMC). The seed to be used is 203065 (the 
Protocol number). Pattern of missing data will be evaluated and it is expected that the pattern of missing 
data will be monotonic. For non-monotone missing data patterns, MCMC method of MI procedure will be 
used to impute enough data so that the remaining missing data is monotone. 
Each of the imputed datasets will be used to generate 50 complete datasets, using following approaches: 
• 
Binary endpoint: A logistic regression method to impute the ordinal missing data, including 
treatment, randomization strata, and assessments from earlier time points as covariates. Response 
or total score of the subjects will be derived using these imputed data. 
• 
Continuous endpoint: A linear regression model including treatment, randomization strata, and 
assessments from earlier time points as covariates will be used to impute the score. Response or 
total score of the subjects will be derived using these imputed data. 
 
Analysis Phase 
The analysis will be conducted using the complete datasets. 
• 
Binary endpoint: The complete datasets will be modelled for the endpoint using CMH method. 
Proportion of responders in each treatment arm, difference and standard error will be calculated. 
• 
Continuous endpoint: The complete datasets will be analyzed using ANCOVA including treatment 
group and randomization stratification factors as factors and appropriate Baseline values as a 
covariate, if applicable. LSMeans in each treatment arm, difference and standard errors will be 
calculated. 
 
Pooling Phase 
The results from the analysis phase will be combined as follows. 
• 
Binary endpoint: The results from the CMH analysis of the multiple imputed datasets will be 
combined to produce pooled CMH statistics and p-value. Proportion of responders in each 
treatment arm, difference and standard error will be combined using the MIANALYZE procedure in 
SAS. 


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• 
Continuous endpoint: The LSMeans in each treatment arm, difference and standard errors from 
the ANCOVA of the multiple imputed datasets will be combined using the MIANALYZE procedure 
in SAS. 
 
Example SAS Code 
1. The example SAS code for CMH model is listed as below: 
proc freq data=analysis_data; 
tables stratum*trt*resp/ cmh alpha=0.1; 
run; 
2. The example SAS code for MMRM model is listed as below: 
proc mixed data = analysis_data; 
class stratum trtp avisit subjid; 
model chg = base stratum trtp avisit trtp*avisit/ ddfm=kr; 
repeated avisit / subject=subjid(trtp) type=un; 
lsmeans trtp/ cl diff; 
lsmeans trtp*avisit/ slice=avisit cl diff; 
run; 
3. The example SAS code for ANCOVA model is listed as below: 
proc mixed data = analysis_data; 
class stratum trtp; 
model chg = base stratum trtp; 
lsmeans trtp/ cl diff;  
run; 
4. The example SAS code for imputation phase by PROC MI: 
proc mi data=analysis_data seed=203065  minimum=xx maximum=xx nimpute=50 out=out_data; 
mcmc impute=monotone chain = multiple; 
var base stratum y4 y8 y12 y16;    
run; 
proc mi data = analysis_data seed=203065  minimum=xx maximum=xx nimpute=number_of_imputations 
out=out_data; 
by imputation; 
class trtp stratum; 
monotone reg (/details); [OR montone logistic;] 
mnar model (y4 / modelobs = (trtp = ‘Placebo’)); 
mnar model (y8 / modelobs = (trtp = ‘Placebo’)); 
mnar model (y12 / modelobs = (trtp = ‘Placebo’)); 
mnar model (y16 / modelobs = (trtp = ‘Placebo’)); 
var base stratum y4 y8 y12 y16; 
run; 
5. The example SAS code for pooling phase for ANCOVA model by PROC MIANALYZE: 


Statistical Analysis Plan for Interventional Studies 
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proc sort data=diff;  
by avisitn trtp;  
run; 
proc sort data=lsm;  
by avisitn trtp;  
run; 
proc mianalyze data=diff;  
by avisitn trtp; 
modeleffects estimate; 
stderr stderr; 
ods output ParameterEstimates=estdiff; run; 
proc mianalyze data=lsm;  
by avisitn trtp; 
modeleffects estimate; 
stderr stderr; 
ods output ParameterEstimates=estlsm; run; 


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Potentially Clinically Significant Ranges  
Potentially clinically significant ranges for Hematology parameters are defined in Table 21-1.  
Table 21-1: Potentially Clinically Significant Ranges for Hematology Parameters 
Test Parameter 
Test 
Parameter 
Code 
Normal Range Lower 
Limit (LLN) 
Normal Range Upper 
Limit (ULN) 
Potentially Clinically Significant Ranges 
Basophils (x10^9/L) 
BASO 
0.00 
0.20 
> 0.2 at post-baseline, if baseline value ≤ 0.2 
Eosinophils (x10^9/L) 
EOS 
0.00 
0.57 
> 0.7 at post-baseline, if baseline value ≤ 0.7 
 
 
80 (≥59 years old) 
100 (≥59 years old) 
> 105 at post-baseline, if baseline value ≤ 105 
Hematocrit (L/L) 
HCT 
0.39 (12-<59 years old, 
Male) 
0.54 (12-<59 years 
old, Male) 
< 0.30 at post-baseline, if baseline value ≥ 0.30 
 
 
0.37 (≥ 59 years old, 
Male) 
0.51 (≥ 59 years old, 
Male) 
> 0.6 at post-baseline, if baseline value ≤ 0.6 
 
 
0.34 (Female) 
158.00 (Female) 
 
Hemoglobin (g/L) 
HGB 
127 (12-<59 years old, 
Male) 
181 (12-<59 years old, 
Male) 
Male < 100 at post-baseline, if baseline value ≥ 
100 
 
 
116 (12-<59 years old, 
Female) 
164 (12-<59 years old, 
Female) 
Male ≥ 200 at post-baseline, if baseline value < 
200 
 
 
125 (≥ 59 years old, 
Male) 
170 (≥ 59 years old, 
Male) 
Female <90 g/L at post-baseline and ≥ 90 g/L at 
baseline 
 
 
115 (≥ 59 years old, 
Female) 
158 (≥ 59 years old, 
Female) 
Female ≥180 g/L at post-baseline and < 180 g/L at 
baseline 
Leukocytes (x10^9/L) 
WBC 
3.80 
10.70 
< 3.0 at post-baseline, if baseline value ≥ 3.0 
 
 
 
 
> 15.0 at post-baseline, if baseline value ≤ 15.0 
Lymphocytes (x10^9/L) 
LYM 
0.91 (18 – <59 years 
old) 
4.28 (18 – <59 years 
old) 
< 0.8 at post-baseline, if baseline value ≥ 0.8 
 
 
0.80 (≥ 59 years old) 
3 (≥ 59 years old) 
> 4.28 at post-baseline, if baseline value ≤ 4.28 
(age 18 - < 59); > 3.00 at post-baseline, if baseline 
value ≤ 3.00 (age ≥ 59) 
Monocytes (x10^9/L) 
MONO 
0.12 
0.92 
> 0.92 at post-baseline, if baseline value ≤ 0.92 
Neutrophils, 
Segmented (GI/L) 
NEUTSG 
1.96 
7.23 
< 1.5 at post-baseline, if baseline value is ≥ 1.5 
 
 
 
 
> 9 at post-baseline, if baseline value is ≤ 9 
Platelets (x10^9/L) 
PLAT 
140 (18 - <60 years old) 
400 (18 - <60 years 
old) 
< 100 at post-baseline, if baseline value ≥ 100 


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130 (≥ 60 years old) 
394 (≥ 60 years old) 
> 700 at post-baseline, if baseline value ≤ 700 
 
 
 
 
 
 
Potentially clinically significant ranges for Blood Chemistry parameters are defined in Table 21-2.  
Table 21-2: Potentially Clinically Significant Ranges for Blood Chemistry Parameters 
Test Parameter 
Test 
Parameter 
Code 
Normal Range Lower 
Limit (LLN) 
Normal Range Upper 
Limit (ULN) 
Potentially Clinically Significant Ranges 
Aspartate 
Aminotransferase (U/L) 
AST 
8.00 
40.00 
> 3 x ULN at post-baseline, if baseline value ≤ 3 x 
ULN 
Alkaline Phosphatase 
(U/L) 
ALP 
55 (< 19 years old, 
Male) 
149 (< 19 years old, 
Male) 
> 2.5 x ULN at post-baseline, if baseline value ≤ 2.5 
x ULN 
 
 
45 (< 19 years old, 
Female) 
87 (< 19 years old, 
Female) 
 
 
 
40 (≥ 19 years old, 
Male) 
129(≥ 19 years old, 
Male) 
 
  
  
35 (≥ 19 years old, 
Female) 
104 (≥ 19 years old, 
Female) 
 
Alanine 
Aminotransferase (U/L) 
ALT 
5 (Male) 
48 (Male) 
> 3 x ULN at post-baseline, if baseline value ≤ 3 x 
ULN 
 
 
4 (Female) 
43 (Female) 
 
Bilirubin (umol/L) 
BILI 
3.00 
21.00 
> 1.5 x ULN at post-baseline, if baseline value ≤ 1.5 
* ULN 
Calcium (mmol/L) 
CA 
2.07 
2.64 
< 2 at post-baseline, if baseline value ≥ 2 
 
 
 
 
> 2.9 at post-baseline, if baseline value ≤ 2.9 
Chloride (mmol/L) 
CL 
94.00 
112.00 
< 94 at post-baseline, if baseline value ≥ 94 
  
  
 
 
> 115 at post-baseline, if baseline value ≤ 115 
Cholesterol (mmol/L) 
CHOL 
2.95 (< 20 years old, 
Male) 
5.12 (< 20 years old, 
Male) 
> 7.75 at post-baseline, if baseline value ≤ 7.75 
(Female ≤ 60 years old, Male ≤ 70 years old); > 
8.28 at post-baseline, if baseline value ≤ 8.28 
(Female < 60 - 70 years old);  
> 7.76 at post-baseline, if baseline value ≤ 7.76 
(Male > 70 years old);  
> 9.10 at post-baseline, if baseline value ≤ 9.10 
(Female > 70 years old) 


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Test Parameter 
Test 
Parameter 
Code 
Normal Range Lower 
Limit (LLN) 
Normal Range Upper 
Limit (ULN) 
Potentially Clinically Significant Ranges 
 
 
3.23 (< 20 years old, 
Female) 
5.48 (< 20 years old, 
Female) 
 
 
 
3.31 (20 - < 30 years 
old, Male) 
6.10 (20 - < 30 years 
old, Male) 
 
 
 
3.31 (20 - < 30 years 
old, Female) 
5.64 (20 - < 30 years 
old, Female) 
 
 
 
3.88 (30 - < 40 years 
old, Male) 
6.83 (30 - < 40 years 
old, Male) 
 
 
 
3.65 (30 - < 40 years 
old, Female) 
6.21 (30 - < 40 years 
old, Female) 
 
 
 
4.19 (40 - < 50 years 
old, Male) 
7.24 (40 - < 50 years 
old, Male) 
 
 
 
4.01 (40 - < 50 years 
old, Female) 
6.85 (40 - < 50 years 
old, Female) 
 
 
 
4.40 (50 - < 60 years 
old, Male) 
7.53 (50 - < 60 years 
old, Male) 
 
 
 
4.42 (50 - < 60 years 
old, Female) 
7.53 (50 - < 60 years 
old, Female) 
 
 
 
4.53 (60 - < 70 years 
old, Male) 
7.71 (60 - < 70 years 
old, Male) 
 
 
 
4.86 (60 - < 70 years 
old, Female) 
8.28 (60 - < 70 years 
old, Female) 
 
 
 
4.58 (≥ 70 years old, 
Male) 
7.76 (≥ 70 years old, 
Male) 
 
 
 
5.35 (≥ 70 years old, 
Female) 
9.10 (≥ 70 years old, 
Female) 
 
Creatinine (umol/L) 
CREAT 
40 (18 - < 50 years 
old, Male) 
110 (18 - < 50 years 
old, Male) 
> 1.5 x ULN at post-baseline, if baseline value ≤ 1.5 
x ULN 
  
  
31 (18 - < 50 years 
old, Female) 
101 (18 - < 50 years 
old, Female) 
 
  
  
40 (50 - < 70 years 
old, Male) 
119 (50 - < 70 years 
old, Male) 
 
 
 
31 (50 - < 70 years 
old, Female) 
101 (50 - < 70 years 
old, Female) 
 


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Test Parameter 
Test 
Parameter 
Code 
Normal Range Lower 
Limit (LLN) 
Normal Range Upper 
Limit (ULN) 
Potentially Clinically Significant Ranges 
 
 
40 (70 - < 80 years 
old, Male) 
137 (70 - < 80 years 
old, Male) 
 
 
 
31 (70 - < 80 years 
old, Female) 
110 (70 - < 80 years 
old, Female) 
 
 
 
40 (≥ 80 years old, 
Male) 
145 (≥ 80 years old, 
Male) 
 
 
 
31 (≥ 80 years old, 
Female) 
128 (≥ 80 years old, 
Female) 
 
Creatine Kinase (U/L) 
CK 
39 (Male) 
308 (Male) 
> 2.5 x ULN at post-baseline, if baseline value ≤ 2.5 
x ULN 
 
 
26 (Female) 
192 (Female) 
 
Direct Bilirubin (umol/L) 
BILDIR 
<2.00 
7.00 
> 1.5 x ULN at post-baseline, if baseline value ≤ 1.5 
x ULN 
Gamma Glutamyl 
Transferase (U/L) 
GGT 
10 (< 59 years old, 
Male) 
61 (< 59 years old, 
Male) 
> 2.5 x ULN at post-baseline, if baseline value ≤ 2.5 
x ULN 
 
 
4 (< 59 years old, 
Female) 
49 (< 59 years old, 
Female) 
 
 
 
10 (≥ 59 years old, 
Male) 
50 (≥ 59 years old, 
Male) 
 
 
 
5 (≥ 59 years old, 
Female) 
50 (≥ 59 years old, 
Female) 
 
Glucose (mmol/L) 
GLUC 
3.90 
5.60 
< 3 at post-baseline, if baseline value ≥ 3 
  
  
 
 
> 13.9 at post-baseline, if baseline value ≤ 13.9 
Potassium (mmol/L) 
K 
3.5 
5.2 
< 3.5 at post-baseline, if baseline value ≥ 3.5 
 
 
 
 
> 5.5 at post-baseline, if baseline value ≤ 5.5 
Sodium (mmol/L) 
SODIUM 
132 (18 – < 59 years 
old) 
147 (18 – < 59 years 
old) 
< 129 at post-baseline, if baseline value ≥ 129 
 
 
135 (≥ 59 years old) 
145 (≥ 59 years old) 
> 150 at post-baseline, if baseline value ≤ 150 
Triglycerides (mmol/L) 
TRIG 
0.42 (< 20 years old, 
Male) 
1.67 (< 20 years old, 
Male) 
> 3.69 at post-baseline, if baseline value ≤ 3.69 
 
 
0.44 (< 20 years old, 
Female) 
1.40 (< 20 years old, 
Female) 
 
 
 
0.50 (20 – < 30 years 
old, Male) 
2.81 (20 – < 30 years 
old, Male) 
 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Galderma S.A./Galderma R&D, LLC; Protocol No.: RD.06.SPR.203065 
 
This document is confidential. 
SAP Version: Final Version 1.0, 20-May-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF  
Page 98 of 99 
Test Parameter 
Test 
Parameter 
Code 
Normal Range Lower 
Limit (LLN) 
Normal Range Upper 
Limit (ULN) 
Potentially Clinically Significant Ranges 
 
 
0.41 (20 – < 30 years 
old, Female) 
1.63 (20 – < 30 years 
old, Female) 
 
 
 
0.56 (30 – < 40 years 
old, Male) 
3.62 (30 – < 40 years 
old, Male) 
 
 
 
0.44 (30 – < 40 years 
old, Female) 
1.99 (30 – < 40 years 
old, Female) 
 
 
 
0.62 (40 – < 50 years 
old, Male) 
3.69 (40 – < 50 years 
old, Male) 
 
 
 
0.51 (40 – < 50 years 
old, Female) 
2.42 (40 – < 50 years 
old, Female) 
 
 
 
0.65 (50 – < 60 years 
old, Male) 
3.61 (50 – < 60 years 
old, Male) 
 
 
 
0.59 (50 – < 60 years 
old, Female) 
2.96 (50 – < 60 years 
old, Female) 
 
 
 
0.65 (≥ 60 years old, 
Male) 
2.94 (≥ 60 years old, 
Male) 
 
 
 
0.63 (≥ 60 years old, 
Female) 
2.71 (≥ 60 years old, 
Female) 
 
Urate (mmol/L) 
URATE 
125 (< 50 years old, 
Male) 
488 (< 50 years old, 
Male) 
> 494 at post-baseline, if baseline value ≤ 494 
(Male);  
> 446 at post-baseline, if baseline value ≤ 446 
(Female) 
 
 
125 (< 50 years old, 
Female) 
428 (< 50 years old, 
Female) 
 
 
 
149 (50 - < 70 years 
old, Male) 
494 (50 - < 70 years 
old, Male) 
 
 
 
149 (50 - <70 years 
old, Female) 
446 (50 - < 70 years 
old, Female) 
 
 
 
149 (≥ 70 years old, 
Male) 
494 (≥ 70 years old, 
Male) 
 
 
 
149 (≥ 70 years old, 
Female) 
446 (≥ 70 years old, 
Female) 
 
Urea Nitrogen (mmol/L) 
UREAN 
1.40 (< 70 years old) 
8.60 (< 70 years old) 
> 8.6 at post-baseline, if baseline value ≤ 8.6 (<70 
years old); > 10.4 at post-baseline, if baseline value 


Statistical Analysis Plan for Interventional Studies 
Sponsor: Galderma S.A./Galderma R&D, LLC; Protocol No.: RD.06.SPR.203065 
 
This document is confidential. 
SAP Version: Final Version 1.0, 20-May-2022 
Controlled Document ID: 3903A.02, Effective Date 31-Aug-2020 
Filing requirements: TMF  
Page 99 of 99 
Test Parameter 
Test 
Parameter 
Code 
Normal Range Lower 
Limit (LLN) 
Normal Range Upper 
Limit (ULN) 
Potentially Clinically Significant Ranges 
≤ 10.4 (70 - <80 years old); > 12.1 at post-baseline, 
if baseline value ≤ 12.1 (≥ 80 years old) 
 
 
1.40 (70 - < 80 years 
old) 
10.40 (70 - < 80 years 
old) 
 
 
 
1.40 (≥ 80 years old) 
12.10 (≥ 80 years old) 
 
 
Potentially clinically significant ranges for vital signs parameters are defined in Table 21-3.  
Table 21-3: Potentially Clinically Significant Ranges for Vital Signs Parameters 
Test Parameter 
Test Parameter Code 
Potentially Clinically Significant Ranges 
Pulse rate (beats/min) 
PULSE 
≥120 bpm and increase from baseline ≥20 bpm  
 
 
 
≤50 bpm and decrease from baseline ≥20 bpm   
 
Diastolic blood pressure (mmHg) 
DIABP 
≥110 mmHg and increase from baseline ≥10 mmHg 
 
 
 
≤45 mmHg and decrease from baseline ≥10 mmHg  
 
Systolic blood pressure (mmHg) 
SYSBP 
≥160 mmHg and increase from baseline ≥20 mmHg 
 
 
 
≤95 mmHg and decrease from baseline ≥20 mmHg 
 
Weight 
WEIGHT 
≥5% increase from baseline 
 
 
 
≥5% decrease from baseline