A Randomized, Double-Blind, Placebo-Controlled Study to Assess Immunization Responses in Adult and Adolescent Subjects With Moderate-to-Severe Atopic Dermatitis Treated With Nemolizumab
Phase: PHASE2
Conditions: Dermatitis, Atopic
Sponsor: Galderma R&D

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1
CLINICAL STUDY PROTOCOL
Galderma S.A.
Galderma Research and Development, LLC
A Randomized, Double-Blind, Placebo-Controlled Study to Assess Immunization 
Responses in Adult and Adolescent Subjects with Moderate-to-Severe Atopic Dermatitis 
Treated with Nemolizumab
Protocol Number: RD.06.SPR.118380
IND Number:
117122
EudraCT Number:
Not applicable
Name of Investigational Product:
Nemolizumab (CD14152)
Phase of Development:
2
Indication:
Moderate-to-severe atopic dermatitis 
Sponsor:
Galderma S.A.
Zählerweg 10
6300 Zug
Switzerland 
Galderma Research and Development, LLC
14501 North Freeway
Fort Worth, Texas 76177
United States
Protocol Version: 
4.0
Protocol Date:
06JUL22
-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.
 
              
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PROTOCOL APPROVAL SIGNATURES
Protocol Title:
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled 
Study to Assess Immunization Responses in Adult and 
Adolescent Subjects with Moderate-to-Severe Atopic Dermatitis 
Treated with Nemolizumab
Protocol Number:
RD.06.SPR.118380
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation (ICH) guidelines for current 
Good Clinical Practice (GCP) and applicable regulatory requirements.
 
              
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INVESTIGATOR SIGNATURE PAGE
Protocol Title:
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled 
Study to Assess Immunization Responses in Adult and Adolescent 
Subjects with Moderate-to-Severe Atopic Dermatitis Treated with 
Nemolizumab
Protocol Number:
RD.06.SPR.118380
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 (ICH)
guidelines.

I am thoroughly familiar with the appropriate use of the study drug, as described 
in this protocol and any other information provided by Galderma 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. 
 
              
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
I understand that all information obtained during the conduct of the study with 
regard to the subjects’ state of health will be regarded as confidential. No 
subjects’ names will be disclosed. All subjects will be identified by assigned 
numbers on all case report forms, laboratory samples, or source documents 
forwarded to the sponsor. Clinical information may be reviewed by the sponsor or 
its agents or regulatory agencies. Agreement must be obtained from the subject
before disclosure of subject information to a third party.

Information developed in this clinical study may be disclosed by Galderma S.A./
Galderma R&D, LLC to other clinical investigators, regulatory agencies, or other 
health authority or government agencies as required.
 
              
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2
SYNOPSIS
Title of Study:
A Randomized, Double-Blind, Placebo-Controlled Study to Assess Immunization 
Responses in Adult and Adolescent Subjects with Moderate-to-Severe Atopic Dermatitis 
Treated with Nemolizumab
Protocol Number:
RD.06.SPR.118380
Investigators/Study 
Sites:
Approximately 60 study sites are planned in the United States
Phase of 
Development:
Phase 2
Objectives:
Primary objective: The primary objective is to assess the effect of nemolizumab 
(CD14152) on humoral immune responses to tetanus and meningococcal vaccination in 
adult and adolescent subjects with moderate-to-severe atopic dermatitis (AD).
Secondary objective: The secondary objectives are to assess the safety and efficacy of 
nemolizumab (CD14152) after a 16-week treatment period in adult and adolescent 
subjects with moderate-to-severe AD.
Study Endpoints:
Primary endpoint: 
Proportion of subjects with a positive serum IgG response to tetanus toxoid at Week 16 
(4 weeks post-vaccination) defined as:
≥ 4-fold increase in anti-tetanus IgG concentrations from baseline in subjects with 
pre-vaccination anti-tetanus IgG concentrations ≥ 0.1 IU/mL
OR
≥ 0.2 IU/mL anti-tetanus IgG concentrations in subjects with pre-vaccination anti-
tetanus IgG concentrations < 0.1 IU/mL
Secondary endpoints:
Vaccine response endpoints:
Proportion of subjects with a positive serum IgG response to tetanus toxoid at Week 16 
defined as: 
o
≥ 2-fold increase in anti-tetanus IgG concentrations from baseline in subjects 
with pre-vaccination anti-tetanus IgG concentrations ≥ 0.1 IU/mL
OR
o
≥ 0.2 IU/mL anti-tetanus IgG concentrations in subjects with pre-vaccination 
anti-tetanus IgG concentrations < 0.1 IU/mL
Proportion of subjects with serum anti-tetanus IgG concentrations of ≥ 0.1 IU/mL at 
Week 16
 
              
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Proportion of subjects with serum anti-tetanus IgG concentrations of ≥ 1.0 IU/mL at 
Week 16
Proportion of subjects with a positive serum bactericidal antibody response to 
meningococcal serogroup C polysaccharide at Week 16 (4 weeks post-vaccination) 
defined as ≥ 4-fold increase in serum bactericidal assay (SBA) reciprocal titer from 
baseline
Proportion of subjects with a positive serum bactericidal antibody response to 
meningococcal serogroup C polysaccharide at Week 16 defined as SBA reciprocal titer 
≥ 8 
Safety endpoints:
Incidence and severity of adverse events (AEs), including AEs of special interest 
(AESI), treatment-emergent AEs (TEAEs), and serious AEs (SAEs)
Study Design:
This is a randomized, double-blind, placebo-controlled, multi-center, parallel-group study 
in adult and adolescent subjects (≥ 12 to 54 years) with moderate-to-severe AD. Eligible 
subjects must have a documented history of inadequate response to topical AD 
medication(s). 
Approximately 245 subjects will be randomized 1:1 to receive either 30 mg nemolizumab 
(with a 60 mg loading dose) or placebo, stratified by baseline disease severity (
 
 
 
              
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is safe. Following Independent Ethics Committees/Institutional Review Boards
approval, the sponsor will send a written communication to the site confirming 
that the study is open for enrollment of adolescents. Adolescents must not be 
enrolled in the study until such communication is received.
2.
Chronic AD for at least 2 years before the screening visit, and confirmed according 
to American Academy of Dermatology Consensus Criteria (Appendix 1)2 at the time 
of the screening visit. 
3.
EASI score ≥ 16 at both the screening and baseline visits.
4.
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.
5.
AD involvement ≥ 10% of BSA at both the screening and baseline visits.
6.
Peak (maximum) pruritus NRS score of at least 4.0 at the screening and baseline 
visit. 
Peak pruritus (PP) NRS score at screening will be determined by a single NRS 
assessment (score ranging from 0 to 10) for the 24-hour period immediately 
preceding the screening visit.
Baseline PP NRS score will be determined based on the average of daily NRS scores 
(score ranging from 0 to 10) during the 7 days immediately preceding baseline 
(rounding is not permitted). A minimum of 4 daily scores out of the 7 days 
immediately preceding baseline is required for this calculation.
 
              
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Exclusion Criteria: 
Individuals meeting any of the following criteria at screening or baseline are ineligible to 
participate in this study
1.
Body weight < 30 kg.
2.
History of hypersensitivity (including anaphylaxis) to an immunoglobulin product 
(plasma-derived or recombinant, eg, monoclonal antibody) or to any of the study 
drug excipients.
3.
History of severe allergic reaction to either vaccine or to vaccine components,
including alum, thimerosal, phenol.
4.
Subjects for whom administration of the meningococcal vaccine provided in this 
study is contraindicated or medically inadvisable, according to prescribing 
information of the commercially available vaccine.
5.
Subjects for whom administration of the tetanus, diphtheria, and pertussis vaccine 
provided in this study is contraindicated or medically inadvisable, according to 
prescribing information of the commercially available vaccine, especially a history 
of seizures or progressive encephalopathy after previous dosing.
6.
Receipt of any vaccine (except inactivated influenza vaccine) within 12 weeks prior 
to screening, any meningococcal vaccine within 1 year prior to screening, or any 
tetanus-, diphtheria-, or pertussis-containing vaccine within 5 years prior to 
screening. 
 
              
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Planned Sample Size:
Approximately 245 subjects are planned to be randomized in this study.
Therapies:
Investigational Therapy
Nemolizumab (CD14152) 30 mg and placebo will be provided as lyophilized powder for 
solution for injection for subcutaneous use only after reconstitution in a single-use pre 
filled dual-chamber syringe [DCS]. Subjects will receive a loading dose of nemolizumab 
(eg, 60 mg) or placebo by 2 subcutaneous injections at baseline and a single 30-mg dose 
at Weeks 4, 8, and 12. 
Immunization
At the Week 12 visit, subjects will receive single doses of Tdap and MCV4 vaccines.
Moisturizer 
Subjects will apply a moisturizer at least once daily, and liberally as needed, to dry skin 
and AD lesions beginning at screening, and throughout the study. The subjects’ current 
moisturizer or a moisturizer recommended by the investigator may be used. Use should 
not occur within 8 hours before each clinic/office visit. Whenever possible, subjects 
should use the same moisturizer throughout the study.
Topical Background Therapy
At the screening visit (≥14 days prior to baseline), subjects who are using a stable 
regimen of medium- or low-potency TCS therapy, with or without TCI therapy, should 
continue their therapy regimen in the study. Background therapy use should be adjusted 
to the disease activity and tolerability of the subject, including tapering when signs and 
symptoms improve, discontinuation when lesions clear, and restarting if signs and 
symptoms recur, at the discretion of the investigator.
Subjects who are not using a stable regimen of topical therapy at the screening visit 
should not use topical background therapy during the study, unless required as rescue 
therapy.
Subjects with a history of intolerance to TCS or for whom TCS is not advisable (eg, 
hypersensitivity, significant skin atrophy) must not use TCS background therapy. 
Rescue Therapy
If deemed to be medically necessary by the investigator (eg, to control intolerable AD 
signs/symptoms), topical and/or phototherapy rescue treatments can be prescribed to the 
subjects at any time during the study except during the screening period. Subjects 
receiving any rescue therapy during the screening period are not eligible to participate in 
the study. Subjects receiving systemic rescue during the treatment period must 
discontinue study treatment.
As a general guideline and per individual investigator judgment, rescue therapy should 
not be prescribed within the first 2 weeks after baseline (ie, Week 2) to allow a minimum 
time for study drug exposure.
 
              
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Permitted rescue therapies during the treatment period include: 
•
TCS (higher potency than used at baseline for subjects using TCS background 
therapy; any potency for subjects not using TCS background therapy)
•
TCI (only for subjects not using TCI background therapy at baseline)
•
Phototherapy
Rescue treatments are only approved and/or standard of care treatments that directly treat 
AD. Antihistamines, sleep aids, topical and systemic antibiotics, and anti-itch creams are 
not considered to be rescue therapy because they do not directly treat AD.
Whenever possible, investigators should first use topical medications as rescue therapy 
before escalating to systemic. If subjects receive topical treatments or phototherapy as 
rescue therapy, study drug administration should be continued unless there is a safety 
concern according to the investigator’s judgment. If subjects receive systemic rescue 
therapy, they should permanently discontinue study treatment.
Reference Therapy:
Matching placebo
Treatment Duration:
The expected duration of each subject’s participation in the study is up to 28 weeks, 
including an up to 4-week screening period, a 16-week treatment period, and an 8-week 
follow-up period (12 weeks after the last study medication injection).
The 12-week follow-up visit is not required for subjects who will continue in the LTE 
study (Protocol 118163).
Immunogenicity:
The following vaccine response assessments are planned according to the schedule of 
assessments:
• Tetanus toxoid IgG antibody concentration
• Meningococcal serogroup C SBA reciprocal titer
Efficacy:
Safety:
The following safety assessments are planned according to the schedule of assessments:
• AEs, including TEAE, AESIs, and SAEs
• Clinical laboratory tests 
 
              
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• Physical examination and vital signs
• Respiratory examination and assessments (ie, asthma control test [ACT], peak 
expiratory flow [PEF])
• Electrocardiogram
Statistical Methods 
and Planned 
Analyses:
The Intent-to-Treat population (ITT) will consist of all randomized subjects. The 
modified Intent-to-Treat population (mITT) will consist of all randomized subjects who 
received at least one dose of study drug and vaccine injection, have an evaluable vaccine 
response and did not receive any systemic rescue therapy prior to the post-vaccination 
vaccine response assessment. The Safety population (SAF) will include all randomized 
subjects who receive at least 1 dose of study drug. The mITT population will be the 
primary population for vaccine response analyses. The ITT populationwill be the primary 
population for all efficacy analyses, and all safety data will be summarized based on the 
SAF population.
Vaccine Response Endpoints:
For the primary vaccine response endpoint, the estimate of the corresponding proportion 
of subjects with a positive serum IgG response to tetanus toxoid at Week 16 will be
adjusted for the randomization stratum baseline 
 (Moderate vs Severe) using 
the Cochran-Mantel-Haenszel (CMH) estimate of the risk difference and corresponding 
2-sided 90% CI. This primary analysis will be conducted on the mITT population.
Subjects in receipt of systemic rescue medication will not be vaccinated. As the primary 
analysis will be conducted on the mITT, no imputation is required. As sensitivity 
analysis, the same analysis will be conducted on the ITT population, and any subjects 
without an evaluable vaccine response will be regarded as a Non-Responder. A further 
analysis will be performed on the ITT with data as observed (ie, no imputation of missing 
data at Week 16).
All secondary vaccine response endpoints will be analyzed on the mITT, analyzed using 
the same methods as for the primary vaccine response endpoint above.
 
              
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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 ..........................................................................................17
3.1
List of In-text Tables ............................................................................................22
3.2
List of In-text Figures...........................................................................................22
4
LIST OF ABBREVIATIONS ...................................................................................23
5
INTRODUCTION.....................................................................................................26
5.1
Background on Moderate-to-Severe Atopic Dermatitis.......................................26
5.2
Background on Nemolizumab..............................................................................27
Nonclinical Studies ......................................................................................27
Pharmacokinetic Profile...............................................................................28
Clinical Studies ............................................................................................29
5.3
Clinical Risks/Benefits.........................................................................................32
Nemolizumab...............................................................................................32
Vaccines.......................................................................................................34
5.4
Study Rationale and Dose Selection.....................................................................34
6
STUDY OBJECTIVES AND ENDPOINTS ............................................................36
6.1
Study Objectives...................................................................................................36
Primary Objective ........................................................................................36
Secondary Objectives...................................................................................36
6.2
Study Endpoints....................................................................................................36
Primary Endpoint .........................................................................................36
Secondary Endpoints....................................................................................36
 
              
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7
INVESTIGATIONAL PLAN ...................................................................................39
7.1
Description of Overall Study Design and Plan.....................................................39
7.2
Discussion of Study Design..................................................................................41
7.3
End of Study.........................................................................................................43
8
SELECTION OF STUDY POPULATION...............................................................44
8.1
Inclusion Criteria..................................................................................................44
8.2
Exclusion Criteria.................................................................................................47
8.3
Rescreening ..........................................................................................................51
8.4
Study Withdrawal, Removal, and Replacement of Subjects................................51
Pregnancy.....................................................................................................53
COVID-19 Infection ....................................................................................53
9
TREATMENTS.........................................................................................................55
9.1
Details of Study Drug and Vaccines ....................................................................55
Study Drug ...................................................................................................55
Vaccines.......................................................................................................57
9.2
Dosage Schedule ..................................................................................................58
9.3
Measures to Minimize Bias: Study Treatment Assignment and Blinding ...........58
Method of Study Treatment Assignment.....................................................58
Blinding........................................................................................................59
9.4
Dosage Modification ............................................................................................60
9.5
Accountability and Compliance ...........................................................................61
9.6
Prior and Concomitant Therapies.........................................................................62
Permitted Concomitant Therapy ..................................................................63
Prohibited Medication/Therapy ...................................................................65
Product Technical Complaints.....................................................................67
9.7
Duration of Subject Participation.........................................................................67
Early Termination Visit ...............................................................................68
 
              
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Unscheduled Visit........................................................................................68
10
STUDY PROCEDURES...........................................................................................69
11
IMMUNOGENICITY ASSESSMENTS ..................................................................74
11.1
Vaccine Response.................................................................................................74
Tetanus Toxoid IgG Antibody Concentration .............................................74
Meningococcal Serogroup C SBA Reciprocal Titer....................................74
13
SAFETY ASSESSMENTS .......................................................................................78
13.1
Adverse Events.....................................................................................................78
Adverse Events of Special Interest ..............................................................82
Serious Adverse Events ...............................................................................83
Procedure for Reporting a Serious Adverse Event ......................................84
Procedure for Reporting an Adverse Event of Special Interest ...................86
Procedure for Reporting Pregnancies ..........................................................87
Unexpected Adverse Reactions ...................................................................88
13.2
Clinical Laboratory Assessments .........................................................................88
Hematology..................................................................................................90
Clinical Chemistry .......................................................................................90
Urinalysis .....................................................................................................90
Pregnancy Testing........................................................................................90
 
              
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Virology .......................................................................................................91
Tuberculosis Testing....................................................................................91
13.3
Vital Signs ............................................................................................................92
13.4
Height and Weight................................................................................................92
13.5
Physical Examination...........................................................................................92
13.6
Respiratory Assessments......................................................................................93
Asthma Control Test ....................................................................................93
Respiratory Examination..............................................................................94
Peak Expiratory Flow...................................................................................94
Respiratory Referrals ...................................................................................95
13.7
Electrocardiogram ................................................................................................95
14
PHARMACOKINETICS ..........................................................................................96
14.1
Pharmacokinetic Sampling...................................................................................96
14.2
Nemolizumab (CD14152) Quantification in Biological Sampling......................96
15
OTHER ASSESSMENTS.........................................................................................97
15.1
Independent Data Monitoring Committee............................................................97
15.2
Independent Adjudication Committee..................................................................97
16
STATISTICAL ANALYSIS .....................................................................................98
16.1
Analysis Populations ............................................................................................99
16.2
Subject Disposition.............................................................................................100
16.3
Demographics and Other Baseline Characteristics ............................................100
16.4
Vaccine Response Analysis................................................................................100
Definition of Primary Vaccine Response Endpoint...................................100
Analysis of Primary Vaccine Response Endpoint .....................................101
Sensitivity Analyses of the Primary Vaccine Response Endpoint.............101
Secondary Vaccine Response Endpoints ...................................................101
16.5
Efficacy Analyses...............................................................................................102
 
              
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4
LIST OF ABBREVIATIONS
ACT
Asthma Control Test
AD
atopic dermatitis
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AP
Average pruritus
AST
aspartate aminotransferase
CI
confidence interval
COVID-19
coronavirus disease-19
CPK
creatine phosphokinase
CRO
contract research organization
CYP450
cytochrome P450
DCS
dual-chamber, single-use syringe
ECG
electrocardiogram
eCRF
electronic case report form
GCP
Good Clinical Practice
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HIPAA
Health Insurance Portability and Accountability Act 
HIV
human immunodeficiency virus
IAC
Independent Adjudication Committee
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
IDMC
independent data monitoring committee
IEC
Independent Ethics Committee
 
              
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IgE/G/M
immunoglobulin E/G/M
IL
interleukin
IRB
Institutional Review Board
IRR
injection-related reaction
IRT
interactive response technology
ITT
intent-to-treat
KLH
keyhole limpet hemocyanin
LOCF
last observation carried forward
LTE
long-term extension
MCV4
quadrivalent meningococcal conjugate vaccine
MI
multiple imputation
mITT
modified intent-to-treat
NAb
neutralizing antibody
NCA
non-compartmental analysis
NRS
numeric rating scale
PEF
peak expiratory flow
PK
pharmacokinetics
PRN
pro re nata (when necessary or as needed)
PRO
patient-reported outcome
PT
preferred term
PTC
product technical complaint
Q4W
every 4 weeks
SAE
serious adverse event
SAF
safety analysis population
SAP
statistical analysis plan
SC
subcutaneous
SIN
subject identification number
SNRI
serotonin-norepinephrine reuptake inhibitor
 
              
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SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TCI
topical calcineurin inhibitor
TCS
topical corticosteroid
TEAE
treatment-emergent adverse event
Th2
type 2 helper T [cell]
TMF
Trial Master File
ULN
upper limit of normal
UPT
urine pregnancy test
US
United States
WOCBP
women of childbearing potential
 
              
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5
INTRODUCTION
5.1
Background on Moderate-to-Severe Atopic Dermatitis
Atopic dermatitis (AD) is a chronic inflammatory skin disease estimated to occur in 10% 
to 20% of the population1 and up to 25% of children.2 The disease is characterized by 
pruritus (itching), xerosis (skin dryness), and eczematous lesions whose features include 
erythema, infiltration/papulation, oozing with crusting, excoriations, and lichenification.
The cause of AD, although still not completely understood, is probably multifactorial and 
involves complex interrelation between susceptibility genes, immunological factors, 
infections, and environmental factors to produce a skin barrier disturbance as well as 
immunologic dysregulation and inflammation.3,4,5 There are abundant data indicating 
cross-talk between the immune and neural system in induction of pruritus through 
activation of cytokine receptors on peripheral nerves. 6
Upon stimulation with allergens, dendritic cells in the skin stimulate type 2 helper T cells 
(Th2) and cause the subsequent release of pro-inflammatory cytokines, including 
interleukin (IL)-4, IL-5 and IL-13. High levels of Th2 cytokines in AD skin increase 
serine protease, which leads to further skin barrier dysfunction, and IL-31, which leads to 
pruritus and further inflammation and barrier dysfunction.7,8 The AD pathogenesis also 
involves Th17 and Th22 cells and Th1 cells in the chronic phase of AD. 9
IL-31 is involved in both primary AD pathophysiology and perpetuation of the 
itch-scratch cycle. IL-31 is preferentially produced by Th2 cells, following induction by 
IL-4, and its expression is consistently increased in the skin lesions of AD patients.7,10,11
Furthermore, the IL-31 receptor A (IL-31 RA) was found to be expressed in several 
tissues including the dorsal root spinal ganglia, which contain sensory nerve cells,12 and 
keratinocytes.13 Through interaction with its receptor, IL-31 promotes pruritus, Th2-
driven inflammation, and interrupts keratinocyte proliferation and differentiation.7,8,14,15
Together, these findings suggest that IL-31 is involved in the pathogenesis of pruritus and 
in inflammation in AD.
The scratching behavior associated with pruritus is believed to exacerbate AD lesions by 
causing mechanical damage to the skin, allowing the penetration of foreign antigens, 
 
              
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triggering inflammatory responses, and leading to further aggravation of dermatitis and 
itching. This vicious circle of scratching → exacerbation of dermatitis → aggravation of 
itching is known as the “itch-scratch cycle”.16
Topical agents are the mainstay of AD therapy. Despite the demonstrated efficacy of 
topical treatments, they are not always sufficient to control moderate-to-severe AD in 
some patients, who therefore require the addition of phototherapy or a systemic treatment
to achieve sufficient control of AD.17 Due to the above described predominant role of IL-
31 in mediation of inflammatory itch, targeting and blocking the IL-31 pathway is 
expected to have a therapeutic effect in patients with AD, as well as those with other 
inflammatory pruritic conditions such as prurigo nodularis (PN), which are not 
adequately controlled by existing therapies. 
5.2
Background on Nemolizumab
Nemolizumab (CD14152) 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 transduction of the IL-31 signal into the cell.
Nonclinical Studies
The Investigator’s Brochure (IB) contains detailed information on non-clinical studies. 
In in vitro pharmacology studies, the characteristics of nemolizumab as an anti-IL-31RA 
neutralizing antibody were investigated. It was shown that nemolizumab binds to human 
and monkey IL-31RA, inhibits binding of IL-31 to IL-31RA and inhibits signaling via 
IL-31A. Nemolizumab did not affect the behavior of IL-6 and oncostatin M that utilize 
gp130, a cytokine receptor that has homology to IL-31RA. FcγRs and complement C1q 
are important molecules for eliciting the constant region-mediated effector activity of an 
antibody. Based on its binding affinity to FcγRs and human complement C1q, the risk of 
constant region-mediated effector activity was considered to be lower for nemolizumab 
than for IgG1. Nemolizumab did not show any antibody-dependent cell-mediated 
 
              
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cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct cell death-
inducing activities in IL-31RA overexpressing A549 cells. 
In non-clinical safety studies, nemolizumab was well tolerated and safe in cynomolgus 
monkeys at doses of up to 25 mg/kg once every 2 weeks in 3- and 6-month intermittent 
SC dose toxicity studies. There was no immunotoxic effect after repeat dosing in the 
monkey. In the 6-month toxicology study, nemolizumab did not affect immunoglobulin 
(Ig)M or IgG responses to the T-cell dependent antigen keyhole limpet hemocyanin
(KLH) compared to controls when KLH was administered after 23 weeks of 
nemolizumab treatment.18
Pharmacokinetic Profile
The pharmacokinetic (PK) profile of nemolizumab was extensively assessed in subjects 
with AD. PK 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 administrations of flat doses between 30 and 90 mg. 
The terminal elimination half-life of nemolizumab was approximately 2 weeks after 
single and repeated administrations. No significant systemic accumulation was observed,
and steady state concentrations were achieved from 16 weeks of treatment without a 
loading dose and from 4 weeks of treatment when a loading (flat 2×) dose was 
administered. The systemic exposure to nemolizumab appeared to be slightly lower in 
AD subjects compared to healthy volunteers.
The PK profile of nemolizumab was also assessed in the phase 2a study with PN subjects, 
where a nemolizumab dose of 0.5 mg/kg was administered. Similar nemolizumab PK 
profiles were observed in subjects with AD and in subjects with PN. The similarity in 
nemolizumab exposure between the 2 populations was also confirmed using population 
PK modeling. The IB contains additional detailed information on the nemolizumab PK 
profile.
 
              
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Clinical Studies
The IB contains detailed information on clinical studies.
Studies have been completed in healthy subjects and subjects with AD, PN and uremic 
pruritus. Results of Phase 2 studies in AD and PN subjects are summarized below. 
5.2.3.1
Phase 2b Dose-Ranging Study: Atopic Dermatitis
The phase 2b study 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 
 
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 
 
to Week 24. At the Week 24 visit, a greater percent change 
reduction in 
 was observed with the nemolizumab 30-mg dose (least squares mean
difference vs placebo = 16.7%) and the difference was statistically significant (95%
confidence interval [CI] = -30.2, -3.2; p = 0.016) compared to placebo. The nemolizumab
10-mg dose showed a marginally statistically significant difference vs 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.
The 
 rate was statistically significant 
(p < 0.05) for all nemolizumab doses at all timepoints from Week 2. 
 
              
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All doses of nemolizumab were associated with a slightly higher incidence of treatment-
emergent adverse events (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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5.2.3.2
Phase 2a Safety and Efficacy Study: Prurigo Nodularis
The phase 2a study was a randomized, placebo-controlled, double-blind, parallel-group, 
multi-center 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 
 compared with the placebo group.
The primary efficacy endpoint was percent change from baseline in 
 to Week 4 
(weekly average of the peak). Nemolizumab was clinically and statistically significantly 
superior to placebo in reducing the 
 at Week 4 (difference between 
treatment groups -38.0%; 95% CI -51.0, -25.0; p<0.001). 
The proportion of subjects with 
, 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 
 at other time points, Average Pruritus 
 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 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 nemolizumab group (2 subjects, 5.9%). The incidence of AD
was higher in the nemolizumab group (3 subjects, 8.8%) compared with the placebo 
 
              
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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.
5.3
Clinical Risks/Benefits 
Nemolizumab
Results of previous clinical studies in adults demonstrated that treatment with 
nemolizumab had a marked effect on AD, pruritus, and pruritus-related sleep loss. 
Overall, nemolizumab was well tolerated when used as monotherapy or concomitantly 
with a topical corticosteroid (TCS). 
Based on the currently available information on nemolizumab and the risks associated 
with biologic agents in general, the important potential risks of nemolizumab treatment
include local and systemic IRRs, newly diagnosed asthma or worsening of asthma, 
exacerbation of AD, and skin and non-skin infections.
The following specific risk-minimization and safety follow-up measures have been 
planned in this clinical study: 
a.
The protocol will exclude subjects with asthma exacerbation requiring hospitalization 
in the preceding 12 months before screening, subjects whose asthma has not been 
 
              
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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 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 regular 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. 
c.
A slight trend of dose-dependent increase of peripheral edema was reported in the 
nemolizumab phase 2a study CIM003JG. Most events were mild (11 of 21), no case 
was serious, and none resulted in premature treatment discontinuation; no case was 
associated with renal or cardiac AEs. There were a few subjects reporting peripheral 
edema in the phase 2b 114322 study (2 [3.6%], 2 [3.6%], 4 [7%], and 2 [3.5%] in
placebo, 10-mg, 30-mg, and 90-mg groups, respectively). Peripheral edema will be 
followed as an AE of special interest (AESI) in this study.
d. As nemolizumab has not been evaluated in pediatric populations, with studies in 
adolescents currently ongoing, safety will be evaluated closely throughout the study, 
 
              
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including a follow-up visit 12 weeks after the last study drug administration for 
subjects who do not rollover into the nemolizumab long-term extension (LTE) study.
e.
An independent data monitoring committee (IDMC) will monitor the safety data 
regularly throughout the study, including the AESIs listed in Section 13.1.1, which 
were defined based on the currently available safety information on nemolizumab and 
the risks associated with biologic agents in general.
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.
Vaccines
During the study, subjects will also receive single doses of tetanus toxoid, reduced 
diphtheria toxoid, and acellular pertussis (
 and 
meningococcal (Groups A, C, Y, and W-135) polysaccharide dipththeria toxoid 
conjugate 
 vaccines. Contraindications, risks, 
warnings, and precautions of vaccination are as outlined in the respective prescribing 
information (Appendix 2, Appendix 3).19,20
Based on known cellular and immunological responses of IL-31RA signaling, putative 
risks of immune interference by nemolizumab following vaccination have not been 
previously identified.
5.4
Study Rationale and Dose Selection
The aim of the study is to investigate whether nemolizumab has an effect on the 
immunological response to vaccination in AD subjects. Although nemolizumab is not 
expected to impact immunization responses, the mechanism of IL-31 signaling in 
immunity is not yet fully elucidated, and the effect of blocking Th2 cell signaling via 
IL-31 on vaccination response has not been tested.
Two different common vaccines (Tdap and MCV4) that result in activation of both T 
cells and B cells to elicit an effective immune response were selected for use in this study 
 
              
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to evaluate a broad immunological impact of coadministration of vaccines and 
nemolizumab.
The nemolizumab dose was selected based on the outcome of the Phase 2b dose-ranging 
study in adults SPR.114322, where the 30-mg dose (with 60-mg loading dose), when 
administered every 4 weeks (Q4W), provided the best benefit/risk ratio of the 3 doses 
(10 mg, 30 mg, and 90 mg) evaluated. The 30-mg dose was therefore selected as the dose 
to be developed for the treatment of AD. Across the full range of subject body weights in 
the Phase 2b study, the 30-mg dose (with 60-mg loading dose) provided a comparable 
observed exposure with respect to the body weight-based dose of 0.5 mg/kg tested during 
the Phase 2a AD and PN studies.
Adolescent subjects will be enrolled after the sponsor confirms the safety of the 30-mg 
Q4W dose in adolescents in a separate clinical study (SPR.116912).
 
              
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6
STUDY OBJECTIVES AND ENDPOINTS
6.1
Study Objectives
Primary Objective
The primary objective is to assess the effect of nemolizumab (CD14152) on humoral 
immune responses to tetanus and meningococcal vaccination in adult and adolescent 
subjects with moderate-to-severe AD.
Secondary Objectives
The secondary objectives are to assess the safety and efficacy of nemolizumab 
(CD14152) after a 16-week treatment period in adult and adolescent subjects with 
moderate-to-severe AD.
6.2
Study Endpoints
Primary Endpoint
The primary endpoint of this study is the proportion of subjects with a positive serum IgG 
response to tetanus toxoid at Week 16 (4 weeks post-vaccination) defined as:

≥ 4-fold increase in anti-tetanus IgG concentrations from baseline in subjects with 
pre-vaccination anti-tetanus IgG concentrations ≥ 0.1 IU/mL
OR

≥ 0.2 IU/mL anti-tetanus IgG concentrations in subjects with pre-vaccination anti-
tetanus IgG concentrations < 0.1 IU/mL
Secondary Endpoints
6.2.2.1
Vaccine Response Endpoints
The secondary vaccine response endpoints are as follows:

Proportion of subjects with a positive serum IgG response to tetanus toxoid at 
Week 16 defined as: 
 
              
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o
≥ 2-fold increase in anti-tetanus IgG concentrations from baseline in 
subjects with pre-vaccination anti-tetanus IgG concentrations ≥ 0.1 IU/mL
OR
o
≥ 0.2 IU/mL anti-tetanus IgG concentrations in subjects with pre-
vaccination anti-tetanus IgG concentrations < 0.1 IU/mL

Proportion of subjects with serum anti-tetanus IgG concentrations of ≥ 0.1 IU/mL 
at Week 16

Proportion of subjects with serum anti-tetanus IgG concentrations of ≥ 1.0 IU/mL 
at Week 16

Proportion of subjects with a positive serum bactericidal antibody response to 
meningococcal serogroup C polysaccharide at Week 16 (4 weeks post-
vaccination) defined as ≥ 4-fold increase in serum bactericidal assay (SBA) 
reciprocal titer from baseline

Proportion of subjects with a positive serum bactericidal antibody response to 
meningococcal serogroup C polysaccharide at Week 16 defined as SBA 
reciprocal titer ≥ 8 
 
              
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6.2.2.3
Safety Endpoint
The safety endpoint of this study is as follows:

Incidence and severity of adverse events (AEs), including AESI (see 
Section 13.1.1), treatment-emergent AEs, and serious AEs
 
              
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7
INVESTIGATIONAL PLAN
7.1
Description of Overall Study Design and Plan
This is a randomized, double-blind, placebo-controlled, multi-center, parallel-group study 
in adult and adolescent subjects (≥ 12 to 54 years) with moderate-to-severe AD. Eligible 
subjects must have a documented history of inadequate response to topical AD 
medication(s). 
Approximately 245 subjects will be randomized 1:1 to receive either 30 mg nemolizumab 
(with a 60 mg loading dose) or placebo, stratified by baseline disease severity 
 
16.9). 
The study consists of 3 periods with up to 28 weeks total study duration: a 2- to 4-week 
screening period, a 16-week treatment period, and an 8-week follow-up period (12 weeks 
after the last study drug injection). 
Screening Period
The screening period will evaluate subject eligibility. Subjects will apply a moisturizer at 
least once daily, beginning at screening. Subjects using a stable regimen of low- or 
medium-potency TCS with or without topical calcineurin inhibitor (TCI) at the screening 
visit (ie, ≥ 14 days prior to the baseline visit) should continue their therapy regimen. 
Subjects not using a stable regimen of TCS with or without TCI at the screening visit 
should not use these topical therapies during the study unless required as rescue therapy.
Rescue therapies are not permitted during the screening period.
Treatment Period
At the baseline visit, subjects will receive a loading dose of nemolizumab (60 mg) or 
placebo via 2 subcutaneous injections. Nemolizumab (30 mg) or placebo will then be 
administered via a single subcutaneous injection Q4W at Week 4, 8, and 12. At the 
Week 12 visit, subjects will also receive single doses of 
 
vaccines. Clinical assessments will 
occur according to the schedule of assessments in Table 4.
 
              
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Subjects will continue to apply a moisturizer at least once daily. Subjects using 
background topical therapy (TCS with or without TCI) from the screening visit will 
continue use in the treatment period, which should be adjusted according to the disease 
activity and tolerability, based on investigator clinical judgment. (Subjects not using 
background topical therapy from the screening visit should not apply background topical 
therapy in the study.) If deemed to be medically necessary by the investigator (eg, to 
control intolerable AD signs/symptoms), topical and/or phototherapy rescue therapies can 
be prescribed to any subject at any time during the study, except during the screening 
period.
Subjects who complete the Week 16 treatment period may be eligible to enroll into an
LTE study (Protocol 118163). 
Follow-Up Period
The follow-up visit is not required for subjects who participate in the LTE study.
Subjects who decline or are not eligible to enter into the LTE study will complete a 
follow-up visit at Week 24 (12 weeks after their last study drug injection).
Subjects who discontinue the study prematurely should complete an early termination 
visit and a follow-up visit 12 weeks after their last study drug injection.
The follow-up visit will be conducted 8 weeks after completing the treatment period 
and/or 12 weeks after the last study drug injection. Twelve weeks corresponds to 
approximately 5 half-lives when nemolizumab 30 mg is dosed subcutaneously every 
4 weeks.
An IDMC will review and monitor subject safety throughout the study, and an IAC will 
review all asthma-related AEs. Details on the IDMC and IAC, including the plan of 
analysis for outputs, the composition of the committees, the procedures, roles, 
responsibilities and their communications are provided in the IDMC and IAC charters, 
respectively.
An overview of the study design is present in Figure 1.
 
              
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Figure 1:
Study Design
7.2
Discussion of Study Design
The study population is selected based on the need to understand the effect of 
nemolizumab on immune responses to vaccination in subjects with AD. Tetanus and 
meningococcal vaccines were selected for evaluation in subjects ≥ 12 years through 
54 years of age based on their standard use, heterogeneous preparation (toxoid and 
conjugate polysaccharide), and indicated population. A placebo arm is included in the 
study to ensure any effect on vaccination response by nemolizumab can be detected.
 
              
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To evaluate the effect of nemolizumab on humoral immune responses to vaccination, the 
PK profile of nemolizumab was considered. No accumulation in serum is observed after 
repeated administration of nemolizumab. Nemolizumab demonstrates a time linear PK 
profile with steady state concentrations achieved by Week 4 following administration of a 
loading dose. The PK profile of Nemolizumab is predictable with time and is not affected 
by the immunogenicity of Nemolizumab; therefore, a treatment duration > 4 weeks is 
acceptable to evaluate this response.
The 16-week treatment period is considered adequate to measure immune responses to 
tetanus and meningococcal vaccination administered at Week 12 (immune response 
measured 4 weeks post-vaccination) as well as to evaluate the safety and efficacy of 
nemolizumab, with final study dose scheduled for Week 12. 
Immunization response to Tdap will be measured as anti-tetanus antibody titers (absolute 
anti-tetanus IgG concentrations and fold-increase in anti-tetanus IgG concentrations from 
baseline), taking into account subjects’ pre-vaccination anti-tetanus IgG concentrations. 
Immunization response to MCV4 will be assessed as anti-meningococcal serogroup C 
functional humoral response (SBA reciprocal titer and fold-increase in SBA reciprocal 
titer from baseline). These endpoints were selected based on positive response criteria 
defined by each vaccine 19,20 and by regulatory guidance 21,22,23 to demonstrate antibody 
quantitative and qualitative effects, respectively.
As the anti-tetanus IgG titer of ≥0.1 IU/mL is generally recognized as seroprotective, the 
primary endpoint was defined for subjects with and without existing pre-vaccination
seroprotective titers. Response for subjects with existing anti-tetanus IgG (≥0.1 IU/mL)
at baseline was defined as a 4-fold increase in anti-tetanus IgG titer from baseline, 
indicative of a booster response. Response for subjects without existing IgG 
(< 0.1 IU/mL) was defined as 0.2 IU/mL, a concentration 2-fold higher than the 
recognized seroprotection level. As subjects with already high anti-tetanus IgG titers at 
baseline may not achieve a 4-fold increase in IgG following vaccination, a secondary 
endpoint identical to the primary endpoint but with response defined as a 2-fold increase 
in titer for subjects with pre-existing anti-tetanus IgG was also included. 
 
              
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A follow-up visit is scheduled for subject safety and will occur at the Week 24 visit 
(12 weeks after the last dose of study medication). The duration of the follow-up period 
corresponds to approximately 5 half-lives of nemolizumab, which is considered adequate 
to ensure subject safety.
7.3
End of Study
A subject will have fulfilled the requirements for study completion if/when the subject
has completed all study periods, including the follow-up visit at Week 24 or the last 
scheduled visit as indicated in the schedule of assessments (Table 4).
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).
 
              
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8
SELECTION OF STUDY POPULATION
Section 7.1 provides information regarding the number of subjects planned to be 
randomized.
8.1
Inclusion Criteria
Individuals must meet all of the following criteria to be included in the study:
1. Male or female subjects aged ≥ 12 years through 54 years at the screening visit.
Note: Enrollment of subjects aged 12 to 17 years will begin after an interim PK 
and safety analysis of data from the phase 2 study SPR.116912 are conducted by 
the sponsor and an IDMC to determine whether enrollment of this age group is 
safe. Following Independent Ethics Committees (IECs)/Institutional Review 
Boards (IRBs) approval, the sponsor will send a written communication to the 
site confirming that the study is open for enrollment of adolescents. Adolescents 
must not be enrolled in the study until such communication is received.
2. Chronic AD for at least 2 years before the screening visit, and confirmed according to 
American Academy of Dermatology Consensus Criteria (Appendix 1)2 at the time of 
the screening visit.
3. EASI score ≥ 16 at both the screening and baseline visits.
4. 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.
5. AD involvement ≥ 10% of BSA at both the screening and baseline visits.
6. Peak (maximum) pruritus NRS score of at least 4.0 at the screening and baseline visit. 
Peak pruritus (PP) NRS score at screening will be determined by a single NRS 
assessment (score ranging from 0 to 10) for the 24-hour period immediately 
preceding the screening visit.
Baseline PP NRS score will be determined based on the average of daily NRS scores 
(score ranging from 0 to 10) during the 7 days immediately preceding baseline 
 
              
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(rounding is not permitted). A minimum of 4 daily scores out of the 7 days 
immediately preceding baseline is required for this calculation.
 
              
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8.2
Exclusion Criteria
Individuals meeting any of the following criteria at screening or baseline are ineligible to 
participate in this study:
1. Body weight < 30 kg.
2. History of hypersensitivity (including anaphylaxis) to an immunoglobulin product 
(plasma-derived or recombinant, eg, monoclonal antibody) or to any of the study drug 
excipients.
3. History of severe allergic reaction to either vaccine or to vaccine components 
including alum, thimerosal, phenol.
4. Subjects for whom administration of the meningococcal vaccine provided in this 
study is contraindicated or medically inadvisable, according to prescribing 
information of the commercially available vaccine.
5. Subjects for whom administration of the tetanus, diphtheria, and pertussis vaccine 
provided in this study is contraindicated or medically inadvisable, according to 
prescribing information of the commercially available vaccine, especially a history of 
seizures or progressive encephalopathy after previous dosing.
6. Receipt of any vaccine (except inactivated influenza vaccine) within 12 weeks prior 
to screening, any meningococcal vaccine within 1 year prior to screening, or any 
tetanus-, diphtheria-, or pertussis-containing vaccine within 5 years prior to screening. 
 
              
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8.3
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 informed consent form (ICF) and be assigned a new 
subject identification number (SIN).
8.4
Study Withdrawal, Removal, and Replacement of Subjects
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.
If a subject discontinues study treatment or is withdrawn from the study for any reason, 
the study site must immediately notify the medical monitor. The date and the reason for 
study drug discontinuation must be recorded on the electronic case report form (eCRF). 
Subjects who prematurely discontinue study drug will be encouraged to complete the 
scheduled study visits. Subjects who complete or discontinue early from the study will be 
asked to return to the study site to complete the follow-up assessments as indicated in the 
schedule of assessments (Table 4).
In the event that a subject discontinues prematurely from the study because of a TEAE or 
serious TEAE, he/she 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.
 
              
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Once a subject is withdrawn from the study, the subject may not reenter the study.
Reasons for discontinuing study drug include, but are not limited to, the following:

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
Serious worsening of asthma considered related to study drug administration
o
Diagnosis of a malignancy (except curatively treated in situ cervical 
carcinoma, squamous cell carcinoma [Bowen’s disease] or basal cell 
carcinoma)
o
Opportunistic infections such as but not limited to active TB and other 
infections whose nature or course suggest an immune-compromised or 
immune-suppressed status
o
Any serious infection or any severe infection requiring treatment with 
parenteral antibiotics or oral antibiotics/antivirals/antifungals for > 2 weeks
considered related to study drug administration
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 as indicated in Section 8.4.1

Use of non-permitted concurrent therapy (unless discussed and agreed upon with 
the investigator and medical monitor)

Use of systemic rescue therapy, as specified in Section 9.6.1.3 and Table 3 of 
Section 9.6.2

Treatment failure
 
              
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
Investigator request

Sponsor request, including any of the above criteria
Additionally, the sponsor may stop the study at any time for safety, regulatory, legal, or 
other reasons aligned with Good Clinical Practice (GCP) guidelines. This study may be 
terminated at the discretion of the sponsor or any regulatory agency. An investigator may 
elect to discontinue or stop the study at his or her study site for any reason, including 
safety or low enrollment.
Pregnancy
Subjects will be instructed that a known or suspected pregnancy occurring during the 
study should be confirmed and reported to the investigator (see Section 13.1.5). 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 or vaccinations.
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 (e.g. cough, shortness of breath)

For asymptomatic subjects: At least 21 days have passed since the positive 
polymerase chain reaction test and no symptoms.
 
              
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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 4 for additional guidance for management of subjects and study conduct 
during the COVID-19 pandemic.
 
              
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9
TREATMENTS
9.1
Details of Study Drug and Vaccines
Study Drug
“Study drug” or “study medication” refers to nemolizumab or placebo drug product for 
purposes of this double-blind study. The list of excipients are detailed in the IB.
Nemolizumab 30 mg and placebo will be provided as lyophilized powder for solution for 
injection for subcutaneous use only after reconstitution in a pre-filled, single-use, dual-
chamber syringe (DCS). 
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. 
Subjects will receive a loading dose of nemolizumab (eg, 60 mg) or placebo by 2 SC
injections at baseline and a single 30-mg dose at Weeks 4, 8, and 12.
 
              
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9.1.1.2
Study Drug Injection
All study drug injections will be performed by the study center staff at the study centers, 
following instructions provided in the current version of the pharmacy manual and the 
instructions for use. After confirming that the study drug is fully reconstituted, the 
pharmacist (or other qualified personnel) will deliver the DCS to the investigator or other 
qualified personnel, for subcutaneous injection in the subject’s abdomen, front upper 
thigh, or outer upper arm. Good hygiene practices and clean techniques must apply at all 
times. 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.
After study drug administration or vaccine 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 and after vaccines are administered, 
subjects should remain at the study center for at least 30 minutes following the 
injection(s).
 
              
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9.1.2.1
Preparation of Vaccines
A pharmacist (or other qualified personnel) will prepare the vaccines for injection 
according to the instructions in the respective prescribing information. 
9.1.2.2
Injection of Vaccines
Vaccine administration will occur at the study centers by study center/clinical staff. 
Intramuscular injections of vaccines will be done according to the instructions in the 
prescribing information. The vaccines will be administered separately (with 2 different 
syringes) at 2 different injection sites. 
After administration of the vaccines, subjects should stay in the office for 15 to 
20 minutes to observe for potential severe reactions to the vaccine including dyspnea, 
wheezing, dizziness, and/or rash accompanied with itching.
 
              
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9.2
Dosage Schedule
Table 2 summarizes study drug dosing for the 16 week treatment period. 
Table 2:
Treatment Period Dosing By Treatment Group
Treatment 
Group
Dose/route
Week(s)
Schedule
Nemolizumab 
(CD14152)
30 mg × 2 SC injections
30 mg × 1 SC injections
Baseline
4, 8, 12
Baseline
Q4W
Placebo
Placebo× 2 SC injections
Placebo× 1 SC injections
Baseline
4, 8, 12
Baseline
Q4W
Abbreviation(s): Q4W=every 4 weeks; Q8W=every 8 weeks; SC=subcutaneous.
Tdap and MCV4 will be administered separately each as a 0.5 mL intramuscular injection 
at Week 12.
Subjects requiring any rescue therapy during the screening period are ineligible for 
participation in the study. Subjects requiring systemic rescue therapy during the treatment 
period prior to Week 16 must discontinue study treatment.
9.3
Measures to Minimize Bias: Study Treatment Assignment and Blinding
Method of Study Treatment Assignment
At the baseline visit, a unique randomization number will be assigned to an eligible
subject via interactive response technology (IRT). Subjects will be randomized in a 1:1 
ratio to receive either nemolizumab or placebo. The randomization scheme will be 
 
              
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stratified by baseline disease severity 
to ensure 
appropriate distribution of assignment to the 2 treatment groups.
Blinding
All attempts will be made to keep the study center staff and subjects blinded throughout 
the study. Members of the study center staff, including those responsible for DCS 
preparation, will not have access to the randomized treatment assignment. 
To ensure double-blind administration of study drug, the study center pharmacist(s) or 
other qualified personnel will prepare all nemolizumab or placebo treatments, according 
to the current version of the pharmacy manual, the instructions for use, 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 medication 
should not be involved with any study assessments and should not discuss any aspects of 
study drug reconstitution with the subject/caregiver or study staff involved in subject 
interviews or study assessments.
To maintain the integrity of the study blinding, the bioanalytical laboratory staff who 
process/analyze the PK/
samples will not provide any information to sponsor, 
clinical research organization (CRO), or investigational study center personnel directly 
involved with the ongoing conduct of the study that may lead to unblinding during the 
ongoing study. 
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),
the investigator or sub-investigator is encouraged to consult with the medical monitor and
the sponsor before breaking the blind.
 
              
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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 
Section 13.1.3).
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. Although 
initial treatment period results will be analyzed after all subjects have either completed 
the Week 16 visit, or have withdrawn or been discontinued from the study before 
Week 16, personnel from sponsor, CRO, and investigational sites directly involved with 
the ongoing conduct of the study will not have access to any information that may lead to 
unblinding for the ongoing maintenance evaluation.
The IDMC will review data at periodic intervals throughout the study as defined in the 
IDMC charter. The IDMC charter will specify the procedures for unblinding to ensure 
that treatment assignment remains undisclosed to all individuals involved in the direct 
execution and management of the study until the final database is locked. 
9.4
Dosage Modification
Dose modification of the study drug and vaccines will not be permitted during the clinical 
study. 
Any inadvertent dose modification(s) should be reported to the sponsor/CRO. 
 
              
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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 
centers for all remaining visits and complete all study assessments and procedures as 
described in Section 10.
Dosing frequency of study drug (nemolizumab and placebo) is scheduled for Q4W, based 
on the baseline/Day 1 visit date. If a study visit occurs outside the visit window, study 
drug can be administered provided there is a minimum of 3 weeks since the last injection. 
Future visits should be scheduled within the required windows based on the 
baseline/Day 1 visit date, while maintaining the minimum 3-week interval between 
2 injections. Vaccines will be administered as single separate doses at Week 12. 
9.5
Accountability and Compliance
Study drug (nemolizumab and placebo) and vaccines will be provided to the 
investigational site. Site personnel will acknowledge receipt of the study drug using IRT 
to confirm the shipment condition and content. If a damaged shipment is received and/or 
a temperature excursion has been experienced, he/she will notify the sponsor/CRO and 
follow the guidelines according to the current version of the pharmacy manual.
The designated personnel will maintain accurate records of the study drug and vaccines 
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 and vaccine 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 and vaccine units can be disposed of 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 9.6.3
for PTCs.
 
              
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The study monitor may check the study supplies at each study center at any time during 
the study. It is the responsibility of the study monitor to ensure that the investigator (or 
designee) has correctly documented the amount of the study drug and vaccines 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 and vaccines at the close-out visit to 
the study center. All discrepancies must be accounted for and documented.
9.6
Prior and Concomitant Therapies
Prior therapies and medications are defined as therapies/medications that have been 
stopped within the 3 months before the screening visit, unless relevant to the 
inclusion/exclusion criteria. Whenever possible, all prior therapies/medications for AD 
and all prior vaccinations 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  
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, homeopathic preparations, and other alternative 
medications

Medical and surgical procedures (eg, phototherapy, exodontia). Procedures whose 
sole purpose is diagnosis (non-therapeutic) are not included
Prior and concomitant therapies or medical/surgical procedures are to be recorded in the 
appropriate eCRF. 
 
              
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Concomitant therapies are to be recorded, reviewed, and updated at each visit. 
At each visit, investigators should also confirm concomitant therapies for contraception. 
Contraceptive counseling should occur at screening or at appropriate visits when pre-
pubertal subjects begin menses. 
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.
Restricted prior therapies are provided in Section 8.2.
Permitted Concomitant Therapy
Unless specified as prohibited therapies (see Section 9.6.2), all therapies are authorized, 
including basic skin care (cleansing and bathing), moisturizers, bleach baths, topical 
anesthetics, and antihistamines without a sedative effect.
The formation of cytochrome P450 (CYP450) metabolic enzymes can be altered by 
increased levels of certain cytokines (eg, IL-1, IL-6, and IL-10) during chronic 
inflammation. Although there is no known evidence suggesting that IL-31 affects the 
level or activity of CYP450 enzymes, the impact of nemolizumab on such enzymes has 
not been studied. Therefore, investigators should be attentive to clinical or laboratory 
signs that might indicate a potential effect of nemolizumab in subjects using other 
therapies that are CYP450 substrates and have a narrow therapeutic index.
Only the following non-live vaccinations are permitted during the study and follow-up 
period, besides the vaccines specifically administered in this study (ie, Tdap, MCV4):

seasonal vaccinations (eg, inactivated influenza)

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. For guidance on administration of COVID-19 vaccines and study 
vaccinations, see Appendix 4.
 
              
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9.6.1.1
Topical Background Therapy
At the screening visit (≥14 days prior to baseline), subjects who are using a stable 
regimen of medium- or low-potency TCS therapy, with or without TCI therapy, should 
continue their therapy regimen. 
Background therapy use should be adjusted to the disease activity and tolerability of the 
subject, including tapering when signs and symptoms improve, discontinuation when 
lesions clear, and restarting if signs and symptoms recur, at the discretion of the 
investigator.
Subjects who are not using a stable regimen of topical therapy at the screening visit 
should not use topical background therapy during the study, unless required as rescue 
therapy (see Section 9.6.1.3).
Subjects with a history of intolerance to TCS or for whom TCS are not advisable (eg, 
hypersensitivity, significant skin atrophy) must not use TCS background therapy.
9.6.1.2
Moisturizer
Subjects will apply a moisturizer at least once daily, and liberally as needed, to dry skin 
and AD lesions beginning at screening, and throughout the study. The subject’s current 
moisturizer or a moisturizer recommended by the investigator may be used. Use should 
not occur within 8 hours before each clinic/office visit. Whenever possible, subjects 
should use the same moisturizer throughout the study. Moisturizer used and any 
adjustments should be documented in the eCRF.
9.6.1.3
Rescue Therapy
If deemed to be medically necessary by the investigator (eg, to control intolerable AD 
signs/symptoms), topical and/or phototherapy rescue treatments can be prescribed to the 
subjects at any time during the study except during the screening period. Subjects 
receiving any rescue therapy during the screening period are ineligible for participation in 
the study. Subjects receiving systemic rescue during the treatment period must 
discontinue study treatment. 
 
              
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As a general guideline and per individual investigator judgment, rescue therapy should
not be prescribed within the first 2 weeks after baseline (ie, Week 2) to allow a minimum 
time for study drug exposure.
Permitted rescue therapies during the treatment period include: 

TCS (higher potency than used at baseline for subjects using TCS background 
therapy; any potency for subjects not using TCS background therapy)

TCI (only for subjects not using TCI background therapy at baseline)

Phototherapy
Rescue treatments are only approved and/or standard of care treatments that directly treat 
AD. Antihistamines, sleep aids, topical and systemic antibiotics, and anti-itch creams are 
not considered to be rescue therapy because they do not directly treat AD.
Whenever possible, investigators should first use topical medications as rescue therapy 
before escalating to systemic therapies. If subjects receive topical treatments or 
phototherapy as rescue therapy, study drug and vaccine administration should be 
continued unless there is a safety concern according to the investigator’s judgment. If 
subjects receive systemic rescue therapy, they should permanently discontinue study
treatment. 
Prohibited Medication/Therapy
Treatment with the following concomitant medications/therapies is prohibited during the 
study unless otherwise specified in Table 3. “As needed” (PRN) use of TCS or TCI is not 
permitted.
 
              
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Table 3:
Prohibited Medication/Therapy and Timeframe Prior to Baseline
Treatment(s)
Timeframe
Before 
Baseline/Day 1
Day 1 –
Week 24
Coal tar products
2 weeks
Prohibited
Topical PDE-4 inhibitor
2 weeks
Prohibited
TCI, only for subjects not using stable TCI therapy ≥14 days prior 
to baseline
2 weeks
Prohibited*
High- or very high-potency TCS (Class I-II according to the US 
classification)2 (applies to all subjects); any TCS only for subjects 
not using stable TCS therapy ≥ 14 days prior to baseline
2 weeks
Prohibited*
Topical medications, including TCS/TCI, with occlusive dressings 
(eg, wet wraps)
2 weeks
Prohibited
Systemic corticosteroids (corticosteroid inhalers are permitted)
4 weeks 
Prohibited
Phototherapy
4 weeks
Prohibited*
Tanning bed use
4 weeks
Prohibited 
Immunosuppressive or immunomodulatory drugs (eg, cyclosporine 
A, oral tacrolimus, cyclophosphamide, azathioprine, methotrexate, 
mycophenolate mofetil)
4 weeks or 5 half-
lives (whichever 
is longer)
Prohibited
Biologics and their biosimilars (eg, dupilumab, etanercept, 
adalimumab, infliximab, omalizumab, etc)
8 weeks or 5 half-
lives (whichever 
is longer)
Prohibited
Investigational topical and systemic medication (eg, topical or oral 
JAK inhibitors)
8 weeks or 5 half-
lives (whichever 
is longer)
Prohibited
Drugs with a sedative effect such as benzodiazepines, 
imidazopyridines, barbiturates, or sedative anti-depressants (eg, 
amitriptyline), except if these treatments were taken at a stable 
dose for at least 3 months before screening
(Stable treatment with antihistamines with sedative effect, SSRIs, 
or SNRIs is allowed.)
1 week
Prohibited
Gabapentinoids (eg, gabapentin, pregabalin)
4 weeks
Prohibited
Cannabinoids
2 weeks
Prohibited
Alternative medicine for AD (eg, traditional Chinese medicine)
2 weeks
Prohibited
Live (attenuated) vaccines
12 weeks
Prohibited
Non-live vaccines, except vaccines specifically administered in the 
study (exceptions apply; see Section 9.6.1)
12 weeks
Prohibited 
 
              
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Abbreviation(s): AD=atopic dermatitis; JAK=Janus kinase; PDE-4=phosphodiesterase-4; SNRI=serotonin-
norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor; TCI=topical calcineurin 
inhibitor; TCS=topical corticosteroid.
* Unless used as rescue therapy
Note: These treatments should not be discontinued for reasons related to this clinical 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.
Vaccinations during the study and follow-up period are not permitted, except for use of 
vaccines specifically administered in this study (ie, Tdap, MCV4) and non-live vaccines 
specified in Section 9.6.1.
Product Technical Complaints
All DCS and vaccine units must be inspected prior to preparation/injection by the persons 
performing the preparation/injection to ensure absence of visual defects that could lead to 
a DCS or vaccine PTC. This also includes the DCS plunger rod. In case of doubt, the 
DCS or vaccine 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. 
Refer to the current version of the pharmacy manual for further details.
9.7
Duration of Subject Participation
The expected duration for each subject’s participation in the study is up to 28 weeks,
including a 2- to 4-week screening period, a 16-week treatment period, and an 8-week 
follow-up period (12 weeks after the last study medication injection).
 
              
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The 12-week follow-up visit is not required for subjects who will continue in the LTE
study (Protocol 118163).
Early Termination Visit
Subjects may discontinue from the study or discontinue the study treatment only and 
continue to participate in the study.
Subjects who prematurely discontinue from the study should undergo final study 
assessments according to the following guidelines:

Subjects discontinued from the study during the treatment period on/before the 
Week 16 visit should attend an early termination visit. 

A follow-up/final visit is required 12 weeks after the last study drug 
administration.
Subjects who prematurely discontinue the study drug will be asked to continue 
participation in the study; however, subjects who discontinue the study drug prior to 
Week 12 should not be vaccinated. Subjects will be asked to return for all remaining 
visits and assessments (including daily assessment of pruritus, sleep disturbance, etc). 
Participation will continue until the subject completes the final study visit or otherwise 
discontinues study participation.
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 4 may be conducted, but not all 
are required. However, blood sample collection for 
 are required 
during unscheduled visits that are conducted for safety reasons.
 
              
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10
STUDY PROCEDURES
A written, signed ICF, assent form, and Health Insurance Portability and Accountability 
Act (HIPAA) authorization is required before any study-related procedures are 
performed. 
Upon provision of the signed ICF/assent form, each subject will be assigned a unique 
SIN. For the duration of the entire clinical study, the subject will be identified using the 
SIN in all documentations and discussion.
The planned study assessments are in Table 4. At each visit, assessments/procedures 
should be performed in the following order: 
1. Patient-reported safety measurements
2. Investigator assessments (including efficacy and safety)

Electrocardiogram (ECG) should be done before vital signs measurements and 
blood draws (see Section 13.7).
3. Sample collections for laboratory assessments
4. Sample collections for correlative assessments (PK, 
vaccine response)
5. Administration of study drug injections and vaccines
 
              
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11
IMMUNOGENICITY ASSESSMENTS
11.1
Vaccine Response
Humoral immune responses to tetanus and meningococcal vaccination will be determined 
using serum samples collected from all subjects according to Table 4.
Tetanus Toxoid IgG Antibody Concentration
Serum concentrations of anti-tetanus IgG will be assessed. The detection and 
characterization of antibodies to tetanus toxoid will be performed using a validated 
immunoassay.
Meningococcal Serogroup C SBA Reciprocal Titer
Immune response to meningococcal vaccination will be determined by measuring 
functional antibody responses using an SBA assay. 
 
              
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12
EFFICACY ASSESSMENTS
Efficacy measurements should be conducted by the investigators (or trained designees) 
and subjects (for patient-reported efficacy measurements) according to Table 4. 
Whenever possible, the same evaluator should make the assessment throughout the study.
 
              
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13
SAFETY ASSESSMENTS
Safety assessments will be conducted for all subjects at the screening visit (upon signing 
of the ICF) and at every subsequent visit.
13.1
Adverse Events
Adverse Event Definition
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 preexisting 
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 13.1.5.

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.
 
              
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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. 
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.
 
              
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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, topical background therapy, blood sample 
collection). Medical judgment should be used to determine the relationship, considering 
all relevant factors including the pattern of the reaction, temporal relationships, relevant 
medical history, and confounding factors such as co-medication or concurrent diseases.
The expression “reasonable causal relationship” is meant to convey in general that there 
are facts or arguments to suggest a causal relationship (International Council for 
Harmonisation [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, topical background 
therapy, blood sample collection) and the AE
No Reasonable Possibility:
No suggestive evidence or arguments can be identified regarding a causal relationship 
between the study drug or the clinical study protocol procedure and the AE.
Action Taken
The investigator will describe the action taken in the appropriate section of the eCRF, as 
follows:

None
 
              
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
Study drug stopped

Study drug temporarily interrupted

Concomitant medication (any additions or discontinuations)

Other, specify
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])
 
              
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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 13.1.4 for reporting procedure. An 
AESI can be either serious or non-serious.
Based on the potential risks of nemolizumab and the risks associated with biologics (and 
their biosimilar equivalents) in general (ie, class effects), the following AEs will be 
considered AESIs: 

Injection-related reactions
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.
 
              
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-
Respiratory assessments (eg, 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

Elevated ALT or AST (> 3 × ULN) in combination with elevated bilirubin (> 2 × 
ULN)
Serious Adverse Events
An SAE is any untoward medical occurrence or effect that, at any dose,

Results in death.

Is life-threatening (an AE is life-threatening if the subject was at immediate risk 
of death from the event as it occurred, ie, it does not include a reaction that might 
have caused death if it had occurred in a more serious form).

Requires or prolongs inpatient hospitalization. (Complications occurring during 
hospitalization are AEs and SAEs if they cause prolongation of the current 
hospitalization. Inpatient hospitalization is considered to have occurred if the 
subject has had to stay for a night at the hospital. The criterion for prolongation of 
hospitalization is also defined as an extra night at the hospital. Hospitalization 
may not constitute sufficient grounds to be considered as an SAE if it is solely for 
the purpose of diagnostic tests [even if related to an AE], elective hospitalization 
for an intervention that was already planned before subject enrollment in the 
clinical study, admission to a day care facility, social admission [eg, if the subject 
has no place to sleep], or administrative admission [eg, for a yearly examination]. 
 
              
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The details of such hospitalizations must be recorded on the medical history or 
physical examination eCRF.)

Results in persistent or significant disability/incapacity. (An AE is incapacitating 
or disabling if it results in a substantial and/or permanent disruption of the 
subject’s ability to carry out normal life functions.)

Results in a congenital anomaly/birth defect.

An important medical event that may not result in death, be life-threatening, or 
require hospitalization, may be considered an SAE when, based upon appropriate 
medical judgment, the event may jeopardize the safety of the subject, and may 
require medical or surgical intervention to prevent 1 of the outcomes listed above 
in this definition. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasia, or 
convulsions that do not result in hospitalization.
Procedure for Reporting a Serious Adverse Event
For any SAE occurring during the clinical study, regardless of whether or not related to 
the study drug and/or procedure, the investigator must:
1. Take prompt and appropriate medical action, if necessary. The safety of the 
subject is the first priority.
2. Ensure that the event is evaluated as an SAE. Immediately notify (within 24 
hours of receipt of the event) the 
 
group of an SAE report, by email or fax:
 
 
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.
 
              
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The demographics, medical history, drugs/therapies, and medical and surgical 
procedures forms must also be available for review in eCRF, at that time.
3. Send any relevant information or anonymized medical records (eg, laboratory test 
results) to the 
(see contact 
details above), within 24 hours of receipt of this relevant information.
4. Monitor and record the progress of the event until it resolves or reaches a stable 
condition, with or without sequelae. For all additional follow-up evaluations, 
complete an updated SAE report within 24 hours of receipt of the updated 
information.
5. Obtain and maintain in the subject files all pertinent medical records, information, 
and medical judgments from colleagues who participate in the treatment and 
follow-up of the subject. If necessary, contact the subject’s personal physician or 
hospital staff to obtain further details.
6. When the outcome of the event is known, complete an updated SAE report, if 
appropriate.
7. Prompt notification of SAEs by the investigator is essential so that legal 
obligations and ethical responsibilities toward the safety of subjects are met. The 
sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical 
investigation. The sponsor or its delegate (ie, the CRO) will comply with country-
specific regulatory requirements relating to safety reporting to regulatory 
authorities, IRB/IEC and investigators. Investigator safety reports are prepared for 
SUSARs according to local regulatory requirements, and are forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing an 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 [TMF]), and will notify the IRB/IEC, if appropriate according to local 
requirements.
 
              
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8. Comply with the applicable regulatory requirement(s) related to the reporting of 
SAEs to the IRB/IEC.
Procedure for Reporting an Adverse Event 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 
 of an AESI 
report, by email or fax. Refer to Section 13.1.1. 
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.
3. Send any relevant information or medical records (eg, laboratory test results) to the 
 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 form 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 form, if appropriate.
 
              
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Procedure for Reporting Pregnancies
Any pregnancy occurring during clinical studies where the fetus could have been exposed 
to the study drug must be monitored until its outcome in order to ensure the complete 
collection of safety data. If a subject becomes pregnant, the investigator must:
1. Withdraw the subject from the clinical study. The subject must not receive any 
further injection of the study drug.
2. Complete as fully as possible the Pregnancy Surveillance Form – Part I: History 
and Start of Pregnancy. Send by email or fax along with the exit form within 24 
hours of receipt of the information, to the 
 
 Refer to Section 13.1.5. 
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 
within 24 hours of 
receipt of the 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 
 
 within 24 hours of receipt of the information.
 
              
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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 13.1.3).
Unexpected Adverse Reactions
Unexpected Adverse Reaction Definition
An unexpected adverse reaction is any untoward and unintended response that is related 
to the administration of the study drug at any dose, the nature or severity of which is not 
consistent with the applicable product information (eg, reference safety information in the 
IB for nemolizumab, study protocol, etc).
The sponsor or its delegate (ie, 
 will comply with country-specific 
regulatory requirements relating to safety reporting to regulatory authorities, IRB/IEC 
and investigators. Investigator safety reports are prepared for SUSARs according to local 
regulatory requirements and sponsor policy, and are forwarded to investigators as 
necessary.
An investigator who receives an investigator safety report describing an SAE(s) or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor or its 
delegate (ie, 
 will file it accordingly (ie, with the TMF), and will notify the 
IRB/IEC, if appropriate according to local requirements.
13.2
Clinical Laboratory Assessments
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 
 
              
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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. 
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 which may impact 
the safety of the subject or the interpretation of the trial results; 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.
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). 
 
              
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See Sections 13.2.4, 13.2.5, and 13.2.6 for details regarding pregnancy testing, virology, 
and TB testing samples, respectively. 
The following laboratory safety tests will be performed as specified in.
Hematology
Hemoglobin, hematocrit, white blood cell count (with differential including eosinophils), 
red blood cell count, platelet count, and mean cell volume. 
Clinical Chemistry
Subjects should fast for at least 8 hours before the visits when blood chemistry is 
planned, except the screening visit.
Creatinine, ALT, AST, 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), and CPK 
isoenzyme. 
Urinalysis
Glucose, pH, 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 urine pregnancy tests (UPTs) at subsequent visits according to Table 4. 
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 or vaccine 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, HIV-1, and HIV-2 antibody will be 
assessed at the screening visit. Subjects with a positive HBcAb and a negative HBsAg 
will also be assessed for hepatitis B surface antibody. 
Tuberculosis Testing
Immunosuppressant biologic treatments have been shown to increase the risk of TB 
infection or to cause conversion from latent to active TB in some circumstances. Because 
of this, subjects will be screened for active or latent TB before entry into this study.
13.2.6.1 Active/Latent 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 Assay, 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.
13.2.6.2 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-
 
              
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Guérin (or 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. 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.
13.3
Vital Signs
Vital signs will be evaluated at the screening visit and at each subsequent visit according 
to Table 4. 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 will be recorded as an AE.
13.4
Height and Weight
Height and weight will be measured, according to Table 4. 
Subjects must be at least 30 kg at both screening and baseline visits in order to be 
enrolled into this clinical study.
After the screening visit, additional height assessments will only be conducted for 
adolescent subjects (aged 12 to 17).
13.5
Physical Examination
Complete physical examination should be performed at the screening, and certain 
subsequent scheduled visits, according to Table 4. A complete physical examination will 
include assessments of the head, ears, eyes, nose, throat, neck (including thyroid), 
 
              
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skin/integumentary system, cardiovascular system, respiratory system (for additional 
respiratory assessments), gastrointestinal system, musculoskeletal system, lymph nodes, 
extremities, and nervous system. 
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.
13.6
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 Table 4
before questioning and physical examination by the investigator. Subjects with a new (de 
novo) diagnosis of asthma will take the ACT beginning at the visit the diagnosis was first 
confirmed and at all subsequent study visits thereafter. Subjects with an ACT score ≤ 19 
will be referred to the physician managing their asthma. 
The ACT is an assessment to determine if a subject’s asthma symptoms are well-
controlled. The ACT is designed for adults and adolescents 12 years or older, and is 
composed of 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 (Appendix 9).
 
              
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Respiratory Examination
A respiratory examination will be required to be performed for all subjects at all 
scheduled visits, according to Table 4. The ACT will aid the investigator’s questioning of 
subjects with a medical history of asthma and should be completed before the clinical 
questioning. After the screening visit, all subjects will be asked non-leading questions 
about any respiratory changes. The investigator or designee will then perform a 
respiratory examination of all subjects at all visits. 
Subjects with a medical history of asthma will be referred to the physician managing their 
asthma if unexpected worsening of asthma is observed or reported. Subjects without a 
medical history of asthma who experience respiratory changes (examination findings or 
newly reported signs and/or symptoms suggestive of asthma) should be referred to a 
respiratory specialist. 
Peak Expiratory Flow
All subjects will undergo PEF testing at screening, baseline, and specified visits 
according to Table 4. For subjects reporting a medical history of asthma, PEF will be 
conducted at all visits. 
Subjects with a new (de novo) diagnosis of asthma will be evaluated by PEF at all visits 
after the diagnosis is first made according to Table 4. 
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. 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.27,28
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, to 
avoid interference with PEF measurements. 
 
              
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Subjects with a medical history of asthma will be referred to the physician managing their 
asthma if PEF < 80% of the predicted value.
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 (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 assessment suggests a decline in the subject’s respiratory health.
13.7
Electrocardiogram
A 12-lead Electrocardiogram (ECG) will be performed and read centrally according to 
visits specified in Table 4 using the ECG machine provided. 
ECGs will be performed in the supine position at the time points described in the 
schedule of assessments 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.
 
              
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15
OTHER ASSESSMENTS
15.1
Independent Data Monitoring Committee 
An IDMC will review and monitor subject safety throughout the study. The IDMC will 
provide recommendations on the safety of subjects. Details on the IDMC, including the 
plan of analysis for IDMC outputs, the composition of the IDMC, the procedures, roles, 
responsibilities, and their communications are provided in the IDMC charter.
15.2
Independent Adjudication Committee
An IAC will review all asthma-related AEs throughout the study. Details on the IAC, 
including the plan of analysis for IAC outputs, the composition of the IAC, the 
procedures, roles, responsibilities, and their communications are provided in the IAC
charter.
 
              
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16
STATISTICAL ANALYSIS
A statistical analysis plan (SAP) will be created and finalized before database lock. 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-database lock) 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, 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 other than the primary vaccine response 
endpoint will be 2-sided and conducted at the 5% level. All presented confidence 
intervals will be 2-sided 95% confidence intervals.
A full discussion of inclusion/exclusion of subjects into the analysis populations
described here will be provided close to database lock, including any decisions on data 
handling and other topics, and will be documented in the Blind Data Review Meeting
(BDRM) Plan and subsequently in the BDRM Report. No Per-Protocol population is 
included in this study.
 
              
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16.1
Analysis Populations
Screened Population
The Screened population comprises all subjects who signed the ICF. This population
includes screen failures, and randomized subjects. For clarity, screen failed subjects are 
defined as are those subjects who fail to meet inclusion criteria or meet exclusion criteria 
and discontinued 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.
Modified Intent-to-Treat Population (mITT)
The mITT population will consist of all randomized subjects who received at least one 
administration of study drug and vaccine injection, have an evaluable vaccine response
and did not receive any systemic rescue therapy prior to the post-vaccination vaccine 
response assessment. The mITT will be the primary population for vaccine response. All 
analyses under the mITT will be analyzed under the treatment group actually received.
Safety Population (SAF)
The SAF will consist of all randomized subjects who received at least one 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 (PKAP)
The PK analysis population (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 analyses of PK.
 
              
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16.2
Subject Disposition
The number of subjects included in each analysis population and the reasons for 
discontinuation will be summarized. In addition, subjects’ status with regard to study 
treatment and follow-up will also be summarized.
16.3
Demographics and Other Baseline Characteristics
Demographic and other baseline characteristics (e.g., age, sex, race, height, body weight, 
body mass index, and applicable baseline data for primary and key secondary efficacy 
assessments) will be summarized for the ITT, mITT, and SAF populations. Medical 
history, plus prior and concomitant therapies (including prohibited therapies) will be 
summarized for the ITT, mITT, and SAF populations.
16.4
Vaccine Response Analysis
Unless otherwise stated, vaccine response analyses will be performed on the mITT 
population, and where appropriate on the ITT.
Definition of Primary Vaccine Response Endpoint
The primary endpoint for this study is the proportion of subjects with a positive serum 
IgG response to tetanus toxoid at Week 16 (4 weeks post-vaccination), defined as:
1. ≥ 4-fold increase in anti-tetanus IgG concentration from baseline in subjects with 
pre-vaccination anti-tetanus IgG concentrations ≥ 0.1 IU/mL, OR
2. ≥ 0.2 IU/mL anti-tetanus IgG concentrations in subjects with pre-vaccination anti-
tetanus IgG concentrations < 0.1 IU/mL.
Subjects in receipt of systemic rescue medication will not be vaccinated, and so will thus 
not be included in the mITT. Thus, for the primary analysis of the primary vaccine 
response endpoint, no imputation is required as all subjects included in the mITT are 
required to have an evaluable vaccine (IgG) response.
 
              
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Analysis of Primary Vaccine Response Endpoint
The estimate of the corresponding proportion for the endpoint will be adjusted for the 
randomization strata baseline 
 using the Cochran-
Mantel-Haenszel (CMH) estimate of the risk difference and corresponding 2-sided 90% 
CI. This primary analysis will be conducted on the mITT population.
Sensitivity Analyses of the Primary Vaccine Response Endpoint
Sensitivity analyses for the primary analysis of the primary endpoint will also be 
conducted in order to test for the robustness of the primary analysis. The primary analysis 
above will be repeated on the ITT population as sensitivity, whereby any subjects without 
an evaluable vaccine response will be regarded as a Non-Responder. Further to this, an 
observed case analysis on the ITT population will also be performed, with no imputation 
for missing data at Week 16.
Secondary Vaccine Response Endpoints
The following secondary vaccine response endpoints are to be analyzed, in any order:

Proportion of subjects with a positive serum IgG response to tetanus toxoid at 
Week 16 (≥2-fold increase in anti-tetanus IgG concentration from baseline in 
subjects with pre-vaccination anti-tetanus IgG concentration ≥ 0.1 IU/mL OR
≥0.2 IU/mL anti-tetanus IgG concentrations in subjects with pre-vaccination anti-
tetanus IgG concentrations < 0.1 IU/mL) 

Proportion of subjects with serum anti-tetanus IgG concentrations of ≥ 0.1 IU/mL 
at Week 16

Proportion of subjects with serum anti-tetanus IgG concentrations of ≥ 1.0 IU/mL 
at Week 16

Proportion of subjects with a positive serum bactericidal antibody response to 
meningococcal serogroup C polysaccharide at Week 16 (4 weeks post-
vaccination) defined as ≥ 4-fold increase in SBA reciprocal titer from baseline
 
              
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
Proportion of subjects with a positive serum bactericidal antibody response to 
meningococcal serogroup C polysaccharide at Week 16 defined as SBA 
reciprocal titer ≥ 8 
All secondary vaccine response endpoints will be analyzed on the mITT population.
For all secondary vaccine response endpoints, the same analysis methods as for the 
primary vaccine response endpoint will be utilized.
Subgroup analyses may be conducted based on selected demographic variables of 
interest, and by vaccine response for the endpoints described in Section 16.4, if needed.
Further details on all vaccine response endpoints and analyses will be included in the 
SAP.
 
              
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Discrete binary secondary efficacy endpoints will be analyzed in the same manner as the 
primary vaccine response endpoint, using a CMH method to estimate the risk difference 
and two-sided 95% CI, stratified by baseline 
Given that the population for 
efficacy is the ITT population, the analysis will be conducted with any missing data at the 
time point imputed as Non-Responder.
Continuous secondary endpoints will be analyzed primarily as observed (ie, non-
imputed) using a mixed-effect model for repeated measures approach, including baseline 
as factor and baseline result for the endpoint as 
covariate. The estimated treatment difference for each endpoint at each visit will be 
displayed in the summary of statistical analysis together with the two-sided 95% 
confidence interval and associated p-value. An unstructured covariance matrix will be
used to model the correlation among repeated measurements, and the Kenward-Roger 
adjustment will be used with restricted maximum likelihood for statistical inference. 
Additionally, an analysis of covariance approach, including baseline 
as 
factor and baseline result as covariate will be conducted for the specific secondary
endpoint, based on data as observed.
Further to the above efficacy analyses, for all secondary efficacy endpoints, any missing 
data at any post-baseline visit (including Week 16) will be imputed utilizing multiple 
imputation (MI) using missing not at random (MNAR) with a controlled-based pattern 
mixture approach.
 
              
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The MI will be carried out as follows: 
1) Fifty (50) imputed datasets with a monotone missing pattern will be multiply 
created using SAS MI procedure based on the observed data (Markov-Chain-
Monte-Carlo method). The seed to be used is 118380 (the protocol number).
2) Each of the imputed datasets will be used to generate 50 complete datasets, using 
a regression method and the profiles from placebo subjects to impute the missing 
data of subsequent visits, including factors for treatment and randomization strata, 
and any applicable baseline as covariate. 
3) The complete datasets will be modelled for the endpoint as specified above for 
discrete binary or continuous endpoints
4) The results from the analysis of the multiple imputed datasets will be combined 
by the MIANALYZE procedure of the SAS system.
Further details will be provided in the SAP.
For subjects in receipt of rescue medication at any point during the study, their data 
collected post-rescue intake will be set to missing, and analyzed in the manner above as 
observed and/or imputed. An additional analysis including all collected data as observed 
will also be conducted, with no adjustment for data collected post-rescue medication 
intake.
 
              
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event stopped prior to study treatment start) will be included as treatment-emergent. 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 be provided for 12-Lead ECG, Physical Examination (Full and 
Symptom-oriented), ACT, PEF, and Respiratory Exam, by treatment group and visit 
where appropriate. Listings will also be provided.
 
              
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16.9
Determination of Sample Size
Approximately 245 subjects will be randomized (~123 per arm) to show that the 90% 
confidence interval of the proportion difference between treatment groups will exclude a 
difference of more than 10%.
16.10
Protocol Deviations
Protocol deviations may be categorized into the following main categories (not 
exhaustive):

Inclusion or Exclusion Criteria

Investigational Product (Incorrect kit, Dosing, Storage issues etc.)

Randomization

Study Procedure compliance
 
              
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
Concomitant Medication / Administration of prohibited medication

Visit Window (adherence)
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 occurring during the study will be listed. 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.
16.11
Interim Analysis 
No interim analysis will be performed.
 
              
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17
STUDY MANAGEMENT
17.1
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 US 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 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.
17.2
Data Management
The designated CRO will be responsible for activities associated with the data 
management of this study. This will include, but is not limited to, setting up a relevant 
database and data transfer mechanisms, along with appropriate validation of data and 
 
              
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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 electronic data capture (EDC) system by 
completing the eCRF via a secure internet connection. Data entered into the eCRF must 
be verifiable against source documents at the study center. Data to be recorded directly on 
the eCRF will be identified and the eCRF will be considered the source document. Any 
changes to the data entered into the EDC system will be recorded in the audit trail.
17.3
Source Documents
Source documents are considered to be all information in original records and certified 
copies of original records of clinical findings, observations, data, or other activities in a 
clinical study necessary for the reconstruction and evaluation of the study. The 
investigator will provide direct access to source documents and/or source data in the 
facilitation of trial-related monitoring, audits, review by IECs/IRBs, and regulatory 
inspections.
The investigator/institution should maintain adequate and accurate source documents and 
trial records that include all pertinent observations on each of the site’s trial subjects. 
Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, not obscure the original entry, and 
be explained if necessary.
Sponsor monitors, auditors and regulatory inspectors should have direct access to source 
data.
17.4
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 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 (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 and in a form satisfactory to the sponsor.
17.5
Monitoring
The study will be monitored according to the monitoring plan to ensure that it is 
conducted and documented properly according to the protocol, GCP, and all applicable 
regulatory requirements.
Monitoring visits and contacts will be made at appropriate times during the study. The 
principal investigator will assure he/she and adequate site personnel are available 
throughout the study to collaborate with clinical monitors. Clinical monitors must have 
direct access to source documentation in order to check the completeness, clarity, and 
consistency of the data recorded in the eCRFs for each subject.
The investigator will make available to the clinical monitor all source documents and 
medical records necessary to review protocol adherence and eCRFs. In addition, the 
investigator will work closely with the clinical monitor and, as needed, provide them 
appropriate evidence that the study is being conducted in accordance with the protocol, 
applicable regulations, and GCP guidelines.
17.6
Quality Control and Quality Assurance
The sponsor or its designee will perform the quality assurance and quality control 
activities of this study; however, responsibility for the accuracy, completeness, security, 
and reliability of the study data presented to the sponsor lies with the investigator 
generating the data.
The sponsor will arrange audits as part of the implementation of quality assurance to 
ensure that the study is being conducted in compliance with the protocol, standard 
operating procedures, GCP, and all applicable regulatory requirements. Audits will be 
 
              
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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.
17.7
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
Should a protocol deviation occur, the sponsor must be informed as soon as possible.
Protocol deviations and/or violations and the reasons they occurred will be included in 
the clinical study report. Protocol deviations will be reported to the IRB/IEC and in 
accordance with applicable regulatory authority mandates.
17.8
Ethical Considerations
This study will be conducted in accordance with this protocol, the accepted version of the 
Declaration of Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 
312, Subpart D, of Title 21 of the CFR; EU 536/2014, Annex 1, D, 17 (a); and in 
compliance with GCP guidelines.
IECs/IRBs will review and approve this protocol and the ICF. All subjects are required to 
give written informed consent before participation in the study.
 
              
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17.9
Financing and Insurance
Before the study commences, the sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study. This 
agreement will be documented in a financial agreement that will be signed by the 
investigator (or the institution signatory) and the sponsor (or its designee).
The investigator is required to have adequate current insurance to cover claims for 
negligence and/or malpractice. The sponsor will provide no-exclusion insurance coverage 
for the clinical study as required by national regulations.
17.10
Publication Policy/Disclosure of Data
Both the use of data and the publication policy are detailed within the clinical study 
agreement. Intellectual property rights (and related matters) generated by the investigator 
and others performing the clinical study will be subject to the terms of a clinical study 
agreement that will be agreed between the institution and the sponsor or their designee.
With respect to such rights, the sponsor or its designee will solely own all rights and 
interests in any materials, data, and intellectual property rights developed by investigators 
and others performing the clinical study described in this protocol, subject to the terms of 
any such agreement. In order to facilitate such ownership, investigators will be required 
to assign all such inventions either to their institution or directly to the sponsor or its 
designee, as will be set forth in the clinical study agreement.
 
              
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18
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11. Neis MM, Peters B, Dreuw A, et al. Enhanced expression levels of IL-31 correlate 
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expressing the interleukin-31 receptor. Allergy Asthma Clin Immunol. 2017;13:23.
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17. Sidbury R, Davis DM, Cohen DE, et al; American Academy of Dermatology.
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18. TOX12-0076 Clinical Study Report: A 26-week intermittent subcutaneous dose (once 
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Baker CJ, Messonnier NE; Centers for Disease Control and Prevention (CDC). 
Prevention and control of meningococcal disease: recommendations of the Advisory 
 
              
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Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013;62(RR-
2):1-28. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6202a1.htm. Accessed 
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Report Series, No. 980. Annex 5: Recommendations to assure the quality, safety and 
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https://www.who.int/biologicals/WHO_TRS_980_WEB.pdf?ua=1. Accessed October 
11, 2019.
24. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, 
a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment 
of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 
2016;75(3):494-503.e6.
25. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The Eczema 
Area and Severity Index (EASI): assessment of reliability in atopic dermatitis. EASI 
Evaluator Group. Exp Dermatol. 2001;10(1):11-8.
26. Simpson EL, Bieber T, Guttman-Yassky E, et al; SOLO 1 and SOLO 2 Investigators. 
Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 
2016;375(24):2335-48.
27. 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.
28. Polgar G, Weng TR. The functional development of the respiratory system from the 
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Appendix 4
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
Clinical Risks/Benefits
During the COVID-19 pandemic, additional risks to participants may exist, including 
generic 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 enrollment 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.
 
              
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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 
comorbidities) or local guidelines, deferring participation in the study should be 
considered. Deferment of enrollment is based on the potential risk posed by 
generic 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 enrollment. 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) and 
applicable local guidelines for assessment of subjects’ COVID-19 
status.
 
              
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-
Following the same guidelines, implement and document in the 
subject records an additional communication to the subject just before 
the scheduled visit. 
-
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 13.1.3). 

if it occurs during the clinical study following the first 
dose of study drug administration, also report as AESI (see 
Section 13.1.4). 
-
Implement preventive infection control measures against COVID-19 
infection following local guidelines (i.e. 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
 
              
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
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. 
Specific efforts should be made to administer vaccines and collect all 
immunogenicity assessments at the scheduled visits. Subject-reported 
assessments that would usually be collected on the site tablet (e.g., ACT) may be 
collected remotely (e.g., completed over the phone), as available.
Taking into account the local situation and risk of exposure to COVID-19, 
subjects can be dosed with study drug and vaccines only if 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.
-
Vaccine injections can be performed and vaccine response samples 
collected at the investigational site according to the instructions in the 
protocol, pharmacy manual and instruction for use  

In the event a subject cannot receive the vaccinations or 
provide vaccine response samples according to the Schedule 
of Assessments (protocol Section 10, Table 4), contact the 
Sponsor
-
ACT (for subjects with a medical history of asthma) and PEF (for all 
subjects) can be performed according to the protocol. 
-
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.
 
              
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If the local situation does not allow for subjects to reach the investigational site:
-
See New Subsection to Section 9.4, Dosage 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 a history of asthma)

Concomitant therapies used, 

Moisturizer use/background topical therapy 

UPT results (for WOCBP),
-
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 judgment. 
-
Subject-reported assessments that would usually be collected on the 
site tablet (e.g., ACT), may be completed over the phone, as available.
All missing assessments should be appropriately documented with COVID-19 recorded 
as the reason, where applicable.
New Subsection to Section 9.4, Dosage Modification:
Management of Subjects with Missed Doses of Study Drug due to COVID-19 
Pandemic
If a subject misses a dose of study drug due to the COVID-19 pandemic, study drug 
administration may be continued. 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 
 
              
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Measures for Subjects Amidst COVID-19 Pandemic. If a subject misses a dose of 
study drug or cannot receive the vaccinations or provide vaccine response samples 
according to the Schedule of Assessments (protocol Section 10, Table 4), the investigator 
must contact the Sponsor for further guidance. 
Subjects with missed doses of study drug may still be eligible to enter the LTE study 
SPR.118163 after the Week 16 visit has been completed, even if done remotely. 
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.
9.6.1 Permitted Concomitant Therapy
COVID-19 vaccination and study vaccinations should be administered according to
current CDC guidelines for co-administration of COVID-19 vaccines with other vaccines
(https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html).
17.5 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.
1https://assets.ctfassets.net/1ny4yoiyrqia/PicgNuD0IpYd9MSOwab47/2461e6c12cd8895
3632a13cd68952b71/Guidance on medications
10-12-20.pdf
 
              
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