Clinical trial NCT04562116
Conditions: Atopic Dermatitis
Sponsor: Galderma R&D
Start date: 2021-12-08; Completion date: 2023-06-07
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the effect of nemolizumab (CD14152) on the pharmacokinetics (PK) of a drug "cocktail" representative of CYP450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 sensitive index substrates) in adult participants with moderate to- severe atopic dermatitis (AD).

Detailed description:

Arms: arm 1: Participants will receive 1 single oral dose of selected, commercially available, cytochrome P450 substrates (CYP450-S) on Day 1 and after a 1-week washout period, participants will receive a 60 milligram (mg) loading dose of nemolizumab via 2 consecutive subcutaneous (SC) 30-mg injections at the Week 1 visit, followed by a single 30-mg injection once in every 4 weeks (Q4W) at Week 5 and Week 9. Participants will receive a second oral dosing of CYP450-S at Week 10.
Interventions: intervention 1: Nemolizumab intervention 2: CYP 450 Substrates
Intervention descriptions: intervention 1: Nemolizumab 30 mg will be administered as SC injections. intervention 2: CYP substrates (Caffeine, Warfarin Sodium, Midazolam, Omeprazole, and Metoprolol Tartrate) will administered orally at Week 0 (Day 1) and Week 10 as per the commercially available prescribing information.

Protocol documents:
Prot_000.pdf: 
Name
Reason for Signature
Date
Approver
15-Jul-2024 07:33:13 UTC
7FSTJPO
protocol-v5
1.0
PPD
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Protocol: RD.06.SPR.201593
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14SEPT2021
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1 CLINICAL STUDY PROTOCOL
An Open-label Drug-Drug Interaction Study to Assess the Effects of 
Nemolizumab on Cytochrome P450 Substrates in Subjects with Moderate-to-
Severe Atopic Dermatitis
Protocol Number:
RD.06.SPR.201593
EudraCT Number:
2020-000229-24
IND Number:
117122
Investigational Product:
Nemolizumab (CD14152)
Indication:
Moderate-to-severe atopic dermatitis 
Phase:
2
Sponsor:
Galderma S.A.
Avenue Gratta-Paille 2
1018 Lausanne
Switzerland
Galderma Research & Development, LLC
14501 North Freeway
Fort Worth, TX 76177
United States
Protocol Date:
14SEPT2021
Protocol Version:
5.0
CONFIDENTIAL
This document contains confidential, proprietary information, and may not be 
reproduced or communicated to a third party without the written permission of 
Galderma S.A./Galderma R&D, LLC
 
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PROTOCOL APPROVAL SIGNATURES
Protocol Title:
An Open-label Drug-Drug Interaction Study to Assess the Effects of 
Nemolizumab on Cytochrome P450 Substrates in Subjects with Moderate-
to-Severe Atopic Dermatitis
Protocol Number:
RD.06.SPR.201593
This study will be conducted in compliance with the clinical study protocol (and amendments),
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH) guidelines for current Good Clinical Practice (GCP) and applicable regulatory 
requirements.
Sponsor Signatory
Senior Medical Expert
R&D Medical Advisory
Galderma S.A.
Rue d'Entre-deux-Villes 10 
1814 La Tour-de-Peilz 
Switzerland
Signature
Date
 
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2
SYNOPSIS
Title of Study:
An Open-label Drug-Drug Interaction Study to Assess the Effects of Nemolizumab on 
Cytochrome P450 Substrates in Subjects with Moderate-to-Severe Atopic Dermatitis
Investigational 
Product:
Nemolizumab (CD14152)
Protocol 
Number:
RD.06.SPR.201593
Investigators /
Study Sites / 
Centers:
At least 2 study sites are planned.
Phase of 
Development:
Phase 2
Primary 
Objective:
The primary objective is to evaluate the effect of nemolizumab (CD14152) on the 
pharmacokinetics (PK) of a drug "cocktail" representative of Cytochrome P450 (CYP) 
1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 sensitive index substrates in adult 
subjects with moderate-to-severe atopic dermatitis (AD).
Secondary 
Objective:
The secondary objective is to assess the safety of nemolizumab.
Study 
Endpoints:
Primary endpoint: 
The primary endpoint of this study is the change of PK parameters (AUC0-inf, AUC0-last, 
Cmax) in the 5 probe drugs administered concomitantly (Caffeine, Warfarin Sodium, 
Omeprazole, Metoprolol Tartrate, and Midazolam) derived from the plasma 
concentration-time profile before and after 9-weeks of nemolizumab treatment.
Secondary endpoint:  
x
Incidence and severity of adverse events (AEs), including treatment-emergent AEs 
(TEAEs), AEs of special interest (AESIs), and serious AEs (SAEs)
 
 
Study Design:
This is an open-label, single sequence drug-drug interaction study in approximately 25 
DGXOW VXEMHFWV DJHG   \HDUV ZLWK PRGHUDWH-to-severe AD. Eligible subjects must have 
a documented history of inadequate response to topical AD medication(s) within 6 
months of screening visit. 
The study consists of a 2 to 4 week screening period, a 1-week predose period, a 12-
week nemolizumab treatment period, and an 8-week follow-up period (12 weeks after 
last study drug injection). Refer to Figure 1 below for an overview of the treatment/study 
design. 
Subjects will apply a moisturizer at least once daily, beginning at screening and 
throughout the study. Subjects using a stable regimen of low- or medium-potency topical 
corticosteroid (TCS) with or without topical calcineurin inhibitor (TCI) at the screening 
 
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visit (i.e.,  14 days prior to the baseline visit) should continue their therapy regimen in 
the study. 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.
Subjects will receive 1 single oral dose of the selected, commercially available, CYP 
substrates [Caffeine100 mg, Warfarin Sodium 10 mg, Midazolam 2 mg (diluted with 
water, a sugar or sugar substitute may be added), Omeprazole 20 mg, and Metoprolol 
Tartrate 100 mg] administered 1 at a time in sequence at Baseline/Day 1 under fasted 
conditions for at least 10 hours. 
After a 1 week wash-out period, subjects will receive nemolizumab by subcutaneous 
(SC) injection every 4 weeks (Q4W) for a treatment period of 12 weeks. Subjects will 
receive a 60 mg loading dose of nemolizumab (given via 2 consecutive SC 30 mg 
injections) at Week 1, followed by a single 30 mg dose at Week 5 and Week 9 of the 
study.
Subjects will receive a second oral dosing of CYP substrates, administered 1 at a time in 
sequence, 9 weeks after initiation of nemolizumab treatment (at Week 10) under fasted 
conditions for at least 10 hours at the anticipated peak serum concentration of 
nemolizumab (i.e., 1 week after the last nemolizumab administration).
Blood samples will be collected at Baseline and at Week 10 before and after each oral 
dosing of CYP probe substrates up to 120 hours postdose for the determination of the 
complete plasma PK profile of each CYP probe. A total of 14 blood samples will be 
collected at each visit before and after each oral dose (i.e., predose, 0.25, 0.5, 1, 2, 3, 4, 
6, 8, 12, 16, 24, 72 and 120 hours postdose) for a total of 28 samples. 
In addition, blood samples will be collected for the assessment of nemolizumab serum 
concentrations during the treatment period at Weeks 0, 5, 9, 10 and 13. 
Subjects who complete the Week 13 visit may be eligible to enroll into the long-term 
extension (LTE) study (SPR.118163). The follow-up period including 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 21 (12 
weeks after their last study drug injection).
If deemed to be medically necessary by the investigator (eg, to control intolerable AD 
signs/symptoms), rescue therapies can be prescribed to any subject at any time during 
the study, except during the screening period.
An independent data monitoring committee (IDMC) will review and monitor subject 
safety throughout the study, and an independent adjudication committee (IAC) will 
review all asthma-related events throughout the study. The IDMC and IAC charters 
provide details on the IDMC and IAC, including the plan of analysis for output, the 
composition of the committees, procedures, roles, responsibilities, and communications.
 
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Figure 1
Study Design Schematic
Abbreviations: BL=baseline; CYP450-S=cytochrome P450 substrates; SC=subcutaneous; 
W=week.
Selection of 
Subjects: 
Inclusion Criteria: 
1.
Subjects DJHG   \HDUV DW WKH WLPH RI VFUHHQLQJ
2.
Chronic AD for at least 2 years before the screening visit, and confirmed according 
to American Academy of Dermatology Consensus Criteria (Appendix 1) at the time 
of the screening visit.
3.
($6, VFRUH  16 (Appendix 2) at both the screening and baseline visits.
4.
InvestigatRU¶V *OREDO $VVHVVPHQW ,*$ VFRUH  3 (based on the IGA scale ranging 
from 0 to 4, in which 3 is moderate and 4 is severe) (Appendix 3) at both the 
screening and baseline visits.
5.
$' LQYROYHPHQW   RI ERG\ VXUIDFH DUHD %6$) at both the screening and 
baseline visits.
6.
Peak (maximum) pruritus numeric rating scale (PP NRS) score of at least 4.0 at both 
the screening and baseline visit (Appendix 4):
x
 
 
 
 
 
 
 
7.
Documented recent history (within 6 months before the screening visit) of inadequate 
response to topical medications (TCS with or without TCI). All subjects must 
demonstrate inadequate response to TCS. All subjects who have used TCI within 6 
months of the screening visit must also demonstrate inadequate response to TCI. 
Acceptable documentation includes subject records with information on TCS (with 
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or without TCI) prescription and treatment outcome, or written documentation of the 
conversation with the subject’s treating physician, if different than the investigator. 
If documentation is inadequate, subjects may be rescreened after such documentation 
is obtained.
Inadequate response to TCS treatments (with or without TCI) is defined as:
a. Failure to achieve or maintain remission or low disease activity (equivalent to IGA 
 2) despite treatment with a regimen of a medium-, high-, or very high-potency TCS 
(Class I to III according to the US classification) (Eichenfield 2014) (with or without 
TCI), applied for at least 4 weeks or for the maximum duration per prescribing 
information;
or
b. Requirement of a long-term treatment (> 4 weeks) with a high- or very high-
potency TCS (Class I to II according to the US classification) (Eichenfield 2014)
(with or without TCI) to achieve or maintain remission or low disease activity 
(equivalent to IGA  2);
or 
c. If documentation of inadequate response to topical treatments is not available, 
subjects with a documented recent course of systemic treatment or phototherapy for 
AD (within 6 months before the visit) will also be considered as inadequate 
responders to topical treatments.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Note: “Double barrier methods” refers to simultaneous use of a physical barrier 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion Criteria: 
Subjects will be excluded from the study if 1 or more of the following criteria are 
applicable:
1.
Body weight < 45 kg
2.
Subjects meeting 1 or more of the following criteria at screening or baseline:
a. Had an exacerbation of asthma requiring hospitalization in the preceding
12 months. 
b. Reporting asthma that has not been well-controlled (i.e., symptoms occurring on 
> 2 days per week, night-time awakenings 2 or more times per week, or some 
interference with normal activities) during the preceding 3 months.
F $VWKPD &RQWURO 7HVW $&7  19 (only for subjects with a history of asthma) 
(Appendix 5).
G 3HDN H[SLUDWRU\ IORZ   RI WKH SUHdicted value.
1RWH ,Q WKH HYHQW WKDW 3() LV   RI WKH SUHGLFWHG YDOXH DW WKH VFUHHQLQJ YLVLW 3()
testing can be repeated once within 48 hours:
• For subjects without a history of asthma 
• For subjects with a history of asthma but if the ACT score is >19 at screening
3.
Subjects with a current medical history of chronic obstructive pulmonary disease 
and/or chronic bronchitis.
 
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4.
Cutaneous infection within 1 week prior to the baseline visit, any infection requiring 
treatment with oral or parenteral antibiotics, antivirals, antiparasitics or antifungals 
within 2 weeks prior to the baseline visit, or any confirmed or suspected coronavirus 
disease (COVID)-19 infection within 2 weeks before the screening or baseline visit. 
Subjects may be rescreened once the infection has resolved. Resolution of COVID-
19 infection can be confirmed by recovery assessment methods, as described in 
Section 8.7.
Note: Subjects with chronic, stable use of prophylactic treatment for recurrent herpes 
viral infection can be included in this clinical study.
5.
Requiring rescue therapy for AD during the screening period or expected to require 
systemic rescue therapy during the treatment period.
6.
Positive serology results (hepatitis B surface antigen [HBsAg] or hepatitis B core 
antibody [HBcAb], hepatitis C [HCV] antibody with positive HCV RNA, or human 
immunodeficiency virus [HIV] antibody) at the screening visit. 
Note: Subjects with a positive HBcAb and a negative HBsAg can be included in this 
clinical study if hepatitis B surface antibody is positive (considered immune after a 
natural infection). Subjects who are positive for HCV antibody and negative for HCV 
RNA may be enrolled.
In the event of rescreening, the serology tests results (eg, HBV, HCV, HIV) from 
the first screening can be used by the investigator to assess the eligibility of 
rescreened subjects if those tests were performed within 6 weeks prior to the 
baseline visit.
7.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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15. Consumption of any 1 or more of the following food items and/or beverages within 
1 week prior to baseline:
x
Grapefruit or grapefruit juice, apple or apple juice, orange or orange juice, 
lemons or lemon juice, limes or lime juice, cranberries or cranberry juice
x
Vegetables from the mustard green family (eg, broccoli, kale)
x
Charbroiled meats
x
Beverages, foods, or drugs containing caffeine
 
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Subjects who are not willing to abstain from the consumption of these food items 
and/or beverages for 7 days before and 7 days after administration of CYP substrates 
will also be excluded. 
16. Subjects with international normalized ratio (INR) > 1.5. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24. Current smokers. 
 
 
 
 
 
 
 
Planned Sample 
Size:
Approximately 25 subjects are planned to be enrolled in this study.
Therapies:
Investigational therapy
Nemolizumab (CD14152) 30 mg 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) by 2 SC injections at the Week 1 visit, followed by a single 30 mg injection 
Q4W at Week 5 and Week 9.
 
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CYP Substrates
At Baseline/Day 1 and Week 10, subjects will receive a cocktail of Midazolam 2 mg, 
Omeprazole 20 mg, Warfarin Sodium 10 mg, Caffeine 100 mg, and Metoprolol Tartrate
100 mg.
All drugs contained in the cocktail are listed as sensitive substrates in the US Food and 
Drug Administration (2017) and European Medicines Agency (2012) guidances. The 
probe doses were chosen based on the clinical tolerability of these drugs and the ability 
to reliably assess their PK parameters. 
•
Caffeine (CYP1A2 substrate) 100 mg was chosen as it is approximately the amount 
found in 1 cup of coffee. 
•
Warfarin Sodium (CYP2C9 substrate) 10 mg is often used as a maintenance dose.
•
Omeprazole (CYP2C19 substrate) dose of 20 mg once daily is used in the treatment 
of symptomatic gastro-esophageal reflux disease and duodenal ulcer.
•
Metoprolol Tartrate (CYP2D6 substrate) is currently used in clinic at a daily dose of 
100 mg.
•
Midazolam (CYP3A4/5 substrate), with an DEVROXWH ELRDYDLODELOLW\ RI  D GRVH
of 0.03 mg/kg of the intravenous formulation given orally should lead to significant 
systemic exposure without major sedative effect. This dose corresponds to 
approximately a 2 mg dose in a 70 kg subject.
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
$W WKH VFUHHQLQJ YLVLW  GD\V SULRU WR EDVHOLQH Vubjects 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 will not be sourced by 
the sponsor. 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. “As needed” (PRN) use of TCS or TCI is not permitted.
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 Therapies
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 any
subject at any time during the study, except during the screening period.
Permitted rescue therapies include: 
 
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• 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. Subjects receiving any systemic rescue during 
the treatment period must permanently discontinue study drug and CYP substrate 
administration.
Treatment 
Duration: 
The expected duration of each subject’s participation in the study is up to 25 weeks, 
including an up to 4-week screening period, a 1-week predose period, a 12-week 
treatment period, and an 8-week follow-up period (12 weeks after the last study drug
injection).
The 8-week follow-up period is not required for subjects who will continue in the LTE 
study (SPR.118163).
The reduction in pruritus (as measured using the PP-NRS) after treatment with 
nemolizumab reflects the blockade of interleukin (IL)-31 receptor signaling. For this 
reason, a change in pruritus NRS can be viewed as a relevant metric for clinical efficacy 
in both AD and prurigo nodularis (PN) patient populations. In subjects with AD (Study
SPR.114322), a highly significant effect on pruritus was observed from Week 8 of 
treatment (mean percent change from baseline of - LQ QHPROL]XPDE WUHDWHG
subjects compared with - LQ WKH SODFHER JURXS >P <0.001]). Similarly in subjects 
with PN (Study SPR.115828), a highly significant effect on pruritus was also observed 
from Week 8 of treatment (percent change from baseline of - LQ QHPROL]XPDE
treated subjects compared with - LQ WKH SODFHER JURXS >P <0.001]). Based on these 
considerations, assessment of the perpetrator potential of nemolizumab on CYP enzymes 
following 9 weeks of nemolizumab treatment was considered appropriate.
Efficacy:
 
Safety:
The following safety assessments are planned according to the schedule of assessments
(Table 1): 
•
AEs, including TEAEs, AESIs, and serious AEs
•
Physical examination and vital signs
•
Clinical laboratory tests
•
Electrocardiogram
•
Respiratory examination and assessments
Pharmacokineti
cs:
The following PK assessments are planned according to the schedule of assessments
(Table 1):
•
Midazolam, Omeprazole, Warfarin Sodium, Caffeine (Jet-Alert Regular Strength 
Caffeine), and Metoprolol Tartrate plasma concentrations
•
Serum nemolizumab concentrations
 
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•
Anti-drug antibody (ADA) serum concentrations
Statistical 
Methods and 
Planned 
Analyses: 
The safety population will include all subjects who receive at least 1 dose of 
nemolizumab. All safety and efficacy data will be summarized using the safety 
population. 
The per-protocol population will consist of all subjects who complete the study without 
any major protocol deviations or any other event which could render the probe drugs 
plasma concentration-time profiles unreliable, especially (but not limited to): 
•
vomiting and diarrhea which could render the plasma concentration-time 
profiles unreliable i.e., after probe drugs intake and/or before 2 times median 
tmax  
•
other AEs which could render the plasma concentration-time profile unreliable
•
intake of concomitant medications which could render the plasma 
concentration-time profile unreliable
•
administration errors which could render the plasma concentration-time profile 
unreliable. 
The primary endpoint will be analyzed using the per-protocol population.  
For the primary endpoint analysis, a linear mixed-effect model will be used to the log-
transformed PK parameters (AUC0-inf, AUC0-last and Cmax) of each CYP substrate, with 
treatment (with or without nemolizumab) as a fixed effect and subject as a random 
effect. Some clinically important baseline characteristics may also be included in the 
model as appropriate. The geometric mean ratio between treatments (substrates with 
[test] or without [reference] nemolizumab) after back-transformation and the 
FRUUHVSRQGLQJ  FRQILGHQFH LQWHUYDO &, ZLOO EH SURYLded. 
$FFRUGLQJ WR WKH FDOFXODWHG  CI for AUC, the following will be claimed:
•
,I WKH ORZHU OLPLW RI WKH  &, LV !  QR LQWHUDFWLRQ LV SUHVHQW
•
,I WKH ORZHU OLPLW RI WKH  &, LV   DQG !  D ZHDN LQWHUDFWLRQ LV
present
•
,I WKH ORZHU OLPLW RI WKH  &, LV   DQG !  D PRGHUDWH LQWHUDFWion is 
present
•
,I WKH ORZHU OLPLW RI WKH  &, LV   D VWURQJ LQWHUDFWLRQ LV SUHVHQW
A weak interaction will not be considered clinically meaningful.
Approximately 25 subjects will be enrolled to have 15 completed subjects in the per-
protocol population to provide a reliable estimate of the magnitude and variability of the 
interaction.
 
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3
TABLE OF CONTENTS
1
CLINICAL STUDY PROTOCOL........................................................................... 1
PROTOCOL APPROVAL SIGNATURES .......................................................................... 2
STUDY PERSONNEL............................................................................................................. 3
2
SYNOPSIS.................................................................................................................. 4
3
TABLE OF CONTENTS ........................................................................................ 16
TABLE OF FIGURES ........................................................................................................... 20
TABLE OF TABLES ............................................................................................................. 20
4
LIST OF ABBREVIATIONS ................................................................................. 21
5
INTRODUCTION ................................................................................................... 23
Background and Rationale ..................................................................................... 23
Justification of Study ................................................................................ 23
Justification of Patient Population ............................................................ 24
Justification of Substrates ......................................................................... 24
Justification of Study Duration ................................................................. 24
Nonclinical Studies ................................................................................................... 25
Clinical Studies ......................................................................................................... 25
Risk/Benefit Assessment .......................................................................................... 28
Nemolizumab ............................................................................................ 28
CYP Substrates ......................................................................................... 29
Study Drug Profile ................................................................................................... 29
Dose Selection Rationale ......................................................................................... 29
6
STUDY OBJECTIVES AND ENDPOINTS ......................................................... 30
Primary Objective(s) ............................................................................................... 30
Secondary Objective ................................................................................................ 30
Primary Endpoint(s) ................................................................................................ 30
Secondary Endpoint(s) ............................................................................................ 30
7
INVESTIGATIONAL PLAN ................................................................................. 31
Overall Study Design and Plan: Description ......................................................... 31
Restrictions ............................................................................................... 32
Diet and Lifestyle ..................................................................................... 33
Discussion of Study Design ..................................................................................... 38
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Study Design ............................................................................................. 38
8
SELECTION OF STUDY POPULATION ........................................................... 38
Number of Planned Subjects .................................................................................. 38
Inclusion Criteria ..................................................................................................... 38
Exclusion Criteria .................................................................................................... 40
Rescreening .............................................................................................................. 45
Removal of Subjects From Therapy or Assessments ........................................... 45
Pregnancy ................................................................................................................. 46
COVID-19 Infection ................................................................................................ 46
Investigational Product ........................................................................................... 47
Investigational Product Administration .................................................... 47
Investigational Product Preparation and Injection .................................... 47
Identity of Investigational Products .......................................................... 48
Investigational Products Packaging and Labeling .................................... 48
Investigational Products Management ...................................................... 49
Storage ...................................................................................................... 49
Accountability ........................................................................................... 49
Dispensing and Return .............................................................................. 50
Method of Assigning Subject Numbers .................................................... 50
Selection of Doses in the Study ................................................................ 50
Dose Modification .................................................................................... 50
Treatment Compliance .............................................................................. 50
Product Technical Complaints .................................................................. 50
Probe Drugs - CYP Substrates ............................................................................... 51
Preparation and Administration of CYP Substrates ................................. 51
Contraindications, Warnings, and Risks of CYP Substrates .................... 51
Packaging, Labeling, and Storage of CYP Substrates .............................. 52
CYP Substrate Accountability and Compliance ....................................... 53
Blinding 53
Prior and Concomitant Therapy ............................................................................ 53
Permitted Concomitant Therapy ............................................................... 54
Moisturizer ................................................................................................ 54
Background Topical Therapy ................................................................... 54
Rescue Therapy ........................................................................................ 55
Prohibited Medication/Therapy ................................................................ 55
Duration of Subject Participation .......................................................................... 57
Early Termination Visit ............................................................................ 57
Unscheduled Visit ..................................................................................... 57
9
STUDY ASSESSMENTS ........................................................................................ 58
Efficacy Assessments ............................................................................................... 58
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Treatment-Emergent Adverse Events ....................................................... 76
Clinical Laboratory ................................................................................... 77
Vital Signs ................................................................................................ 77
Other Safety Data ..................................................................................... 77
Interim Analyses ...................................................................................................... 77
Handling of Missing Data ....................................................................................... 77
Determination of Sample Size ................................................................................. 77
Protocol Deviations .................................................................................................. 77
11
QUALITY ASSURANCE AND QUALITY CONTROL ..................................... 78
Audit and Inspection ............................................................................................... 78
Monitoring ................................................................................................................ 78
Personnel Training .................................................................................................. 78
Data Management .................................................................................................... 78
Clinical Study Conduct ........................................................................................... 79
Amendments ............................................................................................................. 79
Quality Management and Risk Evaluation ........................................................... 79
12
ETHICS .................................................................................................................... 79
Independent Ethics Committee or Institutional Review Board .......................... 79
Regulatory Authorities ............................................................................................ 80
Ethical Conduct of the Study .................................................................................. 80
Informed Consent .................................................................................................... 80
Subject Confidentiality ............................................................................................ 80
Financing and Insurance ......................................................................................... 81
13
REPORTING AND PUBLICATION, INCLUDING ARCHIVING .................. 81
14
REFERENCES ........................................................................................................ 82
15
APPENDICES .......................................................................................................... 84
Appendix 1: 
American Academy of Dermatology Consensus Criteria for 
AD Diagnosis ............................................................................................................ 84
 
Appendix 3:
Investigator’s Global Assessment .......................................................... 86
 
Appendix 5: 
Asthma Control Test .............................................................................. 88
Appendix 6: 
Specific Guidance for Study Conduct and Subject Safety 
during the COVID-19 Pandemic. ........................................................................... 89
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Appendix 7:  
Total Number of Samples and Blood Volume Withdrawn ................. 93 
INVESTIGATOR SIGNATURE PAGE.............................................................................. 94 
TABLE OF FIGURES
Figure 1 
Study Design Schematic ............................................................................. 6 
Figure 2 
Study Visit Schematic ............................................................................... 32 
TABLE OF TABLES
Table 1 
Schedule of Assessments .......................................................................... 34 
Table 2 
Schedule of PK and ADA Sample Collection .......................................... 37 
Table 3 
Description of Nemolizumab (CD14152) ................................................ 48 
Table 4 
Prohibited Medication/Therapy ................................................................ 56 
 
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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
AST
aspartate aminotransferase
AUC
area under the curve
BLQ
below the lower quantification limit
BSA
body surface area
COVID-19
coronavirus disease-19
CPK
creatinine phosphokinase
CRO
contract research organization
CYP
Cytochrome
CYP450
cytochrome P450
DCS
dual-chamber syringe
DDI
drug-drug interaction
EASI
Eczema Area and Severity Index
ECG
Electrocardiogram
eCRF
electronic case report form
ET
early termination 
FSH
follicle-stimulating hormone
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
IGA
Investigator’s Global Assessment
IgE
immunoglobulin E
IL
Interleukin
INR
international normalized ratio
IRB
Institutional Review Board
IRR
injection-related reaction
LTE
Long-Term Extension
NRS
numeric rating scale
PAS
Prurigo Activity Score
PDE
Phosphodiesterase
PEF
peak expiratory flow
PK
Pharmacokinetics
PN
prurigo nodularis
PP NRS
peak pruritus numeric rating scale
PTC
product technical complaint
Q4W
every 4 weeks
RA
receptor A
SAE
serious adverse event
 
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SAP
statistical analysis plan
SC
Subcutaneous
SIN
subject identification number
SNRI
serotonin-norepinephrine reuptake inhibitor
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
TMF
Trial Master File
ULN
upper limit of normal
UPT
urine pregnancy test
 
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(IL-6 receptor blocker) was associated with a significant decrease in systemic exposure to 
orally administered simvastatin, a CYP3A4 substrate (Schmitt 2011). Such interaction was 
not observed in patients with chronic moderate-to- severe psoriasis who underwent treatment 
with secukinumab (IL-17A blocker) or tildrakizumab (IL23p19 blocker) (Bruin 2019;
Khalilieh 2018). Likewise, blockade of IL-4/IL-13 signaling by dupilumab in patients with 
type 2 inflammation did not significantly affect CYP450 enzyme activity in patients with AD
(Davis 2018).
Mechanisms for biologic-small drug interactions are likely to be complex and only partially 
understood. Evaluation of disease-drug interaction from in vitro systems is difficult, so only 
clinical studies are commonly used.
Justification of Patient Population 
The proposed study design includes 3 important elements: a perpetrator (nemolizumab), 
victim drugs (small molecules), and a mediator (AD disease state). Because of the low 
immunogenicity potential of nemolizumab, immunogenicity is not considered a potential 
mediator of interaction. The inflammatory state is a key element; therefore, this study will be 
conducted in patients with moderate-to-severe AD as they have significant inflammation 
which would have the greatest potential for an effect on CYP450 activity. Although IL-31 is
an important cytokine for the regulation of PN and AD, considering the low prevalence of PN 
subjects, the study will be conducted only in patients with moderate-to-severe AD not 
adequately controlled by topical corticosteroid (TCS). 
Justification of Substrates  
CYP450 isozymes are the major drug metabolizing enzymes in the liver. Although this class 
has more than 50 enzymes, 6 of them (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, 
DQG &<3$ PHWDEROL]H DSSUR[LPDWHO\  RI DOO GUXJV Pinto 2011). Therefore, the 
patients in this study will receive single oral doses of Midazolam (primarily metabolized by 
CYP3A4/5), Omeprazole (CYP2C19), Warfarin Sodium (CYP2C9), Caffeine (CYP1A2), 
and Metoprolol Tartrate (CYP2D6) before and after nemolizumab treatment.
There are different CYP450 isoform-selective probe drug cocktails that have been reported in 
the investigation of drug-drug interaction (DDI) in vivo. The cocktail described above for the 
current study was selected because no PK interaction was evidenced between probe drugs 
when administered in combination as a cocktail when compared to the probes administered 
alone (Turpault 2009). The 5 selected probe drugs are listed as index substrates by the Food 
and Drug Administration or European Medicines Agency, i.e., they predictably exhibit 
exposure change because of regulation of a given metabolic pathway and are commonly used 
in clinical DDI studies.
Justification of Study Duration  
The reduction in pruritus (as measured using the peak pruritus numeric rating scale
[PP NRS]) after treatment with nemolizumab reflects the blockade of IL-31 receptor 
signaling. Furthermore, similar effects on PP NRS was observed in both patients with AD
and patients with PN:  
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GLIIHUHQFH ZDV VWDWLVWLFDOO\ VLJQLILFDQW  confidence interval [CI] = -30.2, -3.2; P = 0.016)
compared with placebo. The nemolizumab 10-mg dose showed marginally significant 
difference versus placebo (least squares PHDQ GLIIHUHQFH    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 PP NRS responder (PP NRS improvement  4) rate was 
statistically significant (P < 0.05) for all nemolizumab doses at all timepoints from Week 2.
All doses of nemolizumab were associated with a slightly higher incidence of treatment-
emergent adverse events (TEAEs) when compared to placebo. There was no increase in the 
incidence of skin infections in the nemolizumab group compared with the placebo group, 
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 events in subjects with pre-existing asthma (1 >@  >@  >@ DQG 
>@ LQ SODFHER; 10 mg, 30 mg, and 90 mg, respectively). Events were mostly mild (1 
severe event with highest dose), manageable, and reversible under treatment with study drug. 
Treatment for asthma was prescribed in 16 of the 24 asthma events. Further, a higher 
incidence of AD exacerbation in the placebo arm compared with the nemolizumab treatment
arms was observed. Local and systemic injection-related reactions (IRRs) occurred more 
frequently in the placebo group than in 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 1 non-related serious adverse event (SAE) with a fatal outcome (a patient aged 
82 years, treated with the 10-mg dose, died because of 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], 3 [], 2 [], 
and 2 [] in placebo; 10 mg, 30 mg, and 90 mg, respectively) but not severe TEAEs (5 
[], 3 [], 5 [], and 2 [] in placebo; 10 mg, 30 mg, and 90 mg, respectively) 
when compared with placebo.  
Incidence of ADA formation was limited. Among the 5 subjects with ADA at Week 16 and 
WKH  VXEMHFWV ZLWK $'$ DW :HHN  $'$ LQ RQO\   DQG   VXEMHFWV
respectively, was observed after nemolizumab treatment and therefore considered treatment-
emergent. None of the subjects developed neutralizing ADA at any study time point. 
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. 
Phase 2a Safety and Efficacy Study in Prurigo Nodularis
The Phase 2a study was a randomized, placebo-controlled, double-blind, parallel-group, 
multicenter study to evaluate the safety and efficacy of nemolizumab in subjects suffering 
from PN over a 12-week treatment period. 
A total of 70 subjects were randomized: 36 subjects were randomized to placebo and 
34 VXEMHFWV ZHUH UDQGRPL]HG WR QHPROL]XPDE  PJNJ 6L[W\ VXEMHFWV  FRPSOHWHG
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 
 
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PAS at baseline, which was slightly higher in the placebo group than in the nemolizumab 
group, and more subjects in the nemolizumab group had a severe Investigator Global 
Assessment (IGA) score compared with the placebo group.
The primary efficacy endpoint was percent change from baseline in PP NRS to Week 4 
(weekly average of the peak). Nemolizumab was clinically and statistically significantly 
superior to placebo in reducing the PP NRS scores at Week 4 (difference between treatment 
groups -  &, -51.0, -25.0; P <0.001).  
The proportion of subjects with IGA success, a secondary endpoint, was higher in the 
nemolizumab group than in the placebo group at Week 12 and at a follow-up visit at Week 
 DQG WKH GLIIHUHQFHV ZHUH VWDWLVWLFDOO\ VLJQLILFDQW :HHN  GLIIHUHQFH  P = 0.020; 
:HHN  GLIIHUHQFH  P = 0.001). 
Secondary endpoints also included PP NRS scores at other time points, Average Pruritus 
NRS, PP and Average Pruritus 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 
LQ WKH QHPROL]XPDE JURXS  VXEMHFWV  DQG WKH SODFHER JURXS  VXEMHFWV 
The incidence of neurodermatitis was higher in the placebo group (5 VXEMHFWV  than in 
WKH QHPROL]XPDE JURXS  VXEMHFWV  7KH LQFLGHQFH RI $' ZDV KLJKHU LQ WKH
QHPROL]XPDE JURXS  VXEMHFWV  than in the placebo group (0 subjects). The percentage 
of subjects with severe TEAEs was higher in the nemoOL]XPDE JURXS  VXEMHFWV 
than in WKH SODFHER JURXS  VXEMHFW  7KH LQFLGHQFH RI 7($(V OHDGLQJ WR SHUPDQHQW
discontinuation of the study drug was similar between the nemolizumab and placebo groups. 
The incidence of treatment-emergent serious AEs (SAEs) was similar between the 
QHPROL]XPDE JURXS  VXEMHFWV  DQG WKH SODFHER JURXS  VXEMHFWV 
Neurodermatitis was the most frequently reported treatment-emergent SAE, for which all 
VXEMHFWV ZHUH LQ WKH SODFHER JURXS  VXEMHFWV  2QH VXEMHct in the nemolizumab group 
had a treatment-emergent SAE related to study drug (dermatitis psoriasiform). There were no 
deaths reported during the study. 
A total of 2 confirmed ADA-positive subjects were reported in the study. Only 1 subject 
developed positive ADA after nemolizumab treatment, which was and therefore was 
considered as treatment-emergent. No subjects had positive ADA that included 
immunoglobulin E (IgE), and no subjects developed neutralizing antibodies. 
 
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If deemed to be medically necessary by the investigator (eg, to control intolerable AD 
signs/symptoms), rescue therapies can be prescribed to any subject at any time during the 
study, except during the screening period. See Section 8.11.4 for further details. 
An IDMC will review and monitor subject safety throughout the study, and an independent 
adjudication committee (IAC) will review all asthma-related events throughout the study. 
The IDMC and IAC charters will provide details on the IDMC and IAC, including the plan of 
analysis for output, the composition of the committees, and the procedures, roles, 
responsibilities, and communications. 
Figure 2 
Study Visit Schematic
Abbreviations: BL=baseline; CYP450-S=cytochrome P450 substrate; SC=subcutaneous; W=week.
Restrictions
During the baseline period, subjects will be confined from the evening preceding the CYP 
substrates administration (Study Day -1) until the morning of Day 2 (after the 24-hour blood 
sample collection).
During the treatment period, subjects will be confined from the evening preceding the CYP 
substrates administration (Study Day 70) until the morning of Day 72 (after the 24-hour 
blood sample collection).  
When not confined, subjects will return to the clinical facility for required study drug 
administration and scheduled assessments (Table 1).
For the 4 hours following the CYP substrates administration, when not involved in study 
activities, the subjects will remain seated or standing. They will not be allowed to lie down.
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During confinement, hazardous, strenuous, or athletic activities will not be permitted.
Diet and Lifestyle
During confinement, subjects will not take any food or drinks (except water) for at least 10 
hours (i.e., overnight) before CYP substrates administration.
A standardised low-fat dinner will be served at approximately 20:00 on Day -1 and Day 70. 
The subjects will remain fasted up to 5 hours postdose. 
Water will be allowed as desired, except for 1 hour before and 1 hour after investigational 
product administration. In order to maintain an adequate hydration, subjects will be 
encouraged to drink at least 180 mL of still mineral water every 2 hours for 5 hours postdose, 
starting at 1 hour postdose. At all other times during the study, subjects may consume water 
on an ad libitum basis. 
On Day 1 and Day 71, standardized lunch and dinner will be served at 5 hours 
(approximately at 13:00) and 12 hours (approximately at 20:00) after investigational product 
administration, respectively. No other meals will be served during the study.  
Coffee, alcohol, and other drinks and food listed in Exclusion Criteria 13 (Section 8.3) will be 
forbidden during confinement. 
Smoking will not be allowed. 
During confinement, routine ambulant daily activities will be strongly recommended.
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7. Documented recent history (within 6 months before the screening visit) of inadequate 
response to topical medications (TCS with or without TCI). All subjects must 
demonstrate inadequate response to TCS. All subjects who have used TCI within 6 
months of the screening visit must also demonstrate inadequate response to TCI. 
Acceptable documentation includes subject records with information on TCS (with or 
without TCI) prescription and treatment outcome, or written documentation of the 
conversation with the subject’s treating physician, if different than the investigator. If 
documentation is inadequate, subjects may be rescreened after such documentation is 
obtained. 
Inadequate response to TCS treatments (with or without TCI) is defined as:
a. Failure to achieve or maintain remission or low disease activity (equivalent to IGA 
2) despite treatment with a regimen of a medium-, high-, or very high-potency TCS 
(Class I to III according to the US classification) (Eichenfield 2014) (with or without 
TCI), applied for at least 4 weeks or for the maximum duration per prescribing 
information; 
or 
b. Requirement of a long-term treatment (> 4 weeks) with a high- or very high-potency 
TCS (Class I to II according to the US classification) (Eichenfield 2014) (with or 
without TCI) to achieve or maintain remission or low disease activity (equivalent to 
IGA  2); 
or  
c. If documentation of inadequate response to topical treatments is not available, 
subjects with a documented recent course of systemic treatment or phototherapy for 
AD (within 6 months before the visit) will also be considered as inadequate responders 
to topical treatments.
 
 
 
 
 
 
 
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contain 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, subjects will be 
monitored closely for any signs or symptoms of hypersensitivity reaction before being 
discharged. Subjects should remain at the study center for at least 30 minutes after the first 2 
injections during the study. 
Identity of Investigational Products
Table 3 pprovides a description and overview of open-label study drug administered under this 
protocol. 
Table 3
Description of Nemolizumab (CD14152) 
Name
Nemolizumab (CD14152)
Internal code 
CD14152
Pharmaceutical form
Lyophilized powder and water for injection for solution for injection in a 
dual-chamber syringe.
Packaging
Single-Use Dual-chamber syringe (DCS)
Storage conditionsa
Stored at room temperature; do not store above 30°C; protected from 
freezing, protected from light; until current stock is depleted. 
Then newer stock should be stored between 2 to 8°C (36 to 46°F); protected 
from freezing; protected from light, as per product label.
Dosage 
60 mg loading dose of Nemolizumab (given via 2 consecutive SC 30 mg 
injections) at baseline.
Routeb
Only Subcutaneous use by clinic staff after reconstitution
Dose schedule 
60 mg loading dose at Week 1, followed by a single 30-mg dose Q4W at 
Week 5 and Week 9 of the study; refer to Table 1 for study dosing schedule.
Treatment duration
12-week nemolizumab treatment period
a Refrigeration is not required for current stock. 
b All injections are performed at the clinic office by clinical site staff. 
Investigational Products Packaging and Labeling
All packaging and labeling operations will be performed according to Good Manufacturing 
Practice for Medicinal Products in the local language, national regulations/guidelines, and the 
relevant regulatory requirements, specifying that the drug is for use in a clinical trial. Each DCS 
will be provided as open-label study drug, packaged in an individual carton, including a 27G 
1/2” needle and a plunger rod (not assembled). Local adaptation of the kit design may be 
required; specific details for each country are provided in the pharmacy manual. 
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Investigational Products Management 
Storage 
All DCS units must be stored together in a safe and secure area with restricted access. Upon 
receipt, the DCS must be removed from the shipper, kept in the outer carton until use, and stored 
securely at room temperature complying with the following storage conditions:  
Stored at room temperature; do not store above 30°C; protected from freezing, protected from 
light; until current stock is depleted. Then the newer stock should be stored between 2 to 8°C (36 
to 46°F); protected from freezing; protected from light, as per product label.
The storage area must be monitored daily, and if a temperature excursion occurs, the designated 
personnel should promptly inform the study monitor, as specified in the current version of the 
pharmacy manual. 
Accountability
Study drug will be provided to the investigational study center and site personnel will 
acknowledge receipt of the study drug as defined in the current version of the pharmacy manual 
to confirm the shipment condition and content. Upon receipt of the investigational drug and CYP 
substrates, the designated site personnel will visually inspect the shipment and verify the
contents and condition of the items received, and confirm receipt as described in the pharmacy 
manual. If a damaged shipment is received and/or a temperature excursion has been experienced,
he/she will notify the sponsor/contract research organization (CRO) and follow the guidelines 
according to the current version of the pharmacy manual. The designated personnel will also 
maintain accurate records of the study drug throughout the clinical study, including the inventory 
delivered to the site, the use by each subject, the reconciliation of all delivered and received DCS 
units, and the return/destruction of unused study drug as specified in the current version of the 
pharmacy manual. No unauthorized use is permitted. Used DCS units will be properly 
documented in drug accountability records. Unless a product technical complaint (PTC) is 
detected, the used DCS can be disposed in an appropriate sharps container and according to 
waste regulation(s) in the country. A DCS involved in a malfunction or an investigator or subject 
complaint must be retained on site and designated personnel must proceed as defined in the 
current version of the pharmacy manual. Refer to Section 8.8.9 for PTCs.
The study monitor may check the study supplies at each study center at any time during the 
study. It is the responsibility of the study monitor to ensure that the investigator (or designee) has 
correctly documented the amount of the study drug received, dispensed, and returned/destroyed 
on the dispensing log that will be provided. A full drug accountability log will be maintained at 
the study center at all times. The study monitor will arrange collection of any unused study drug
not destroyed by the site. The study monitor will also perform an inventory of study drug at the 
close-out visit to the study center. All discrepancies must be accounted for and documented. 
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Dispensing and Return
All drug preparation must be appropriately performed and documented by the designated 
personnel as defined in the current version of the Pharmacy Manual. Any error in the preparation 
of dosing solution must be reported to the study monitor promptly and be properly documented. 
At the end of the study, the reconciliation/return/destruction processes for all unused study drug 
will be conducted according to the sites’ SOPs, local regulations, and best practices, as described 
in the current version of the pharmacy manual. If the site does not have the capability to destroy 
drug, then the unused study drug will be returned to the CRO/drug depot for destruction. 
Method of Assigning Subject Numbers 
Upon confirmation of eligibility for a given subject to participate in the study, a unique SIN for 
that subject will be assigned via an electronic data capture system.  
All study treatment will occur with open-label study drug. 
Selection of Doses in the Study
The 30-mg dose proposed for this study is supported by the results of the Nemolizumab Phase 2b 
study (Study SPR.114322). Refer to Section 7.2.1 for further details.  
Dose Modification 
Dose modification of the study drug will not be permitted during the clinical trial. 
Any inadvertent dose modifications should be reported to the sponsor/CRO.  
In the event of a missed dose (i.e., temporary discontinuation of the study drug), it will be 
documented in the eCRF that the drug has not been administered at the study visit, together with 
the reason (eg, for safety). Subjects will be asked to return to the investigational study centers for 
all remaining visits and complete all study assessments and procedures as described in 
Section 7.1.
Treatment Compliance
Treatment compliance will be assessed through the treatment records and drug dispensation logs. 
As study drug is administered in the clinic, treatment compliance will be overseen and 
documented by the investigator and study staff (using the treatment records and drug 
accountability records). At a minimum, date, time, injector (study center staff) and site of 
injection should be accurately recorded to confirm that each dose of study treatment was 
properly administered as define in the current version of the Pharmacy Manual. 
Product Technical Complaints
All DCS units, including plunger rod, must be inspected prior to preparation/injection by the 
persons performing the preparation/injection to ensure absence of visual defects that could lead 
to a DCS PTC as required by the Instruction for Use and the current version of the Pharmacy 
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3. Midazolam will be administered as a 2 mL solution (2 mg/2 mL): 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=575d8bf0-7af7-427c-a231-
966e2a5e070d  
4. Omeprazole will be administered as 20 mg tablets: 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fe0bb8c5-9965-46f6-b675-
773f2730d9f0 
5. Metoprolol Tartrate will be administered as 100 mg tablets: 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6ae551f6-b6cc-46df-b3d7-
eb2963295e0a  
Packaging, Labeling, and Storage of CYP Substrates
Commercially available CYP substrates will be supplied to the sites and stored as described 
according to their respective storage and handling information: 
1. Warfarin Sodium: Warfarin Sodium is manufactured by Exelon Pharmaceutical Inc. 10 
mg tablets will be supplied in a bottle of 100 tablets. Store at 20oC to 25oC (68oF to 
77oF). Protect from light and moisture. Do not use after the expiry date which is stated on 
the folding carton and the container after “Expiry date.” 
2. Jet-Alert Regular Strength Caffeine (Caffeine): Jet-Alert Regular Strength Caffeine is 
manufactured by Bell Pharmaceutical, Inc. 100 mg tablets will be supplied in bottles of 
120 tablets. Jet-Alert Regular Strength Caffeine 100 mg tablets are white in color. Do not 
use after the expiry date which is stated on the folding carton and the container after 
“Expiry date”. The expiry date relates to the last day of the indicated month. Store at 
room temperature between 59°-86°F (15°C-30°C). Protect from excessive moisture.
3. Midazolam: Midazolam is manufactured by Hikma Pharmaceuticals (West-Ward 
Pharmaceuticals). 2 mg/2 mL (2 mL of liquid contains 2 mg of midazolam) will be 
supplied as a clear and colorless solution in clear glass vials. Do not use this medicine 
after the expiry date which is stated on the label/carton after “EXP:”. The expiry date 
refers to the last day of that month. Store at 20°-25°C (68°-77°F) and do not freeze.  
4. Omeprazole: Omeprazole is manufactured by Sunmark; 20 mg tablets will be supplied in 
a blister with 14 tablets. Store at 20-25°C (68-77°C) and protect from moisture. The 
shelf-life of the drug is indicated on the packaging. Do not take after the expiry of the 
deadline date. Do not use this medicine after the expiry date which is stated on the 
label/carton after “EXP:”.
5. Metoprolol Tartrate: Metoprolol Tartrate is manufactured by Sun Pharmaceutical 
Industries, Inc. 100 mg tablets will be supplied in 100-tablet bottles. The deadline date is 
printed on the bottle. Do not use after this date. Store at 20°-25°C (68°-77°F); excursions 
permitted to 15°-30°C (59°-86°F). 
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Previous and concomitant therapies for drugs/therapies or for medical/surgical procedures are to 
be recorded in the appropriate eCRF. Concomitant therapies are to be recorded, reviewed, and 
updated at each visit. At each visit, investigators should also confirm concomitant therapies for 
contraception. Contraceptive counseling will occur at screening. 
Any new concomitant therapy or modification of an existing therapy may be linked to an AE. In 
such cases, a corresponding AE form should be completed to account for the new therapy or 
change in therapy, except in some cases such as dose modification for a chronic condition (see 
Section 8.8.7), in which case the medication will be linked to an item in the medical history.
Permitted Concomitant Therapy
Unless specified as prohibited therapies (see Section 8.11.5), 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, IL- 71)Į ,)1 GXULQJ FKURQLF LQIODPPDWLRQ
Although there is no known evidence suggesting that IL-31 affects the level or activity of 
CYP450 enzymes, the effect of nemolizumab (CD14152) 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 (CD14152) in subjects using other therapies that are CYP450 
substrates and have a narrow therapeutic index.  
Moisturizer
Subjects will apply a moisturizer at least once daily, and liberally as needed, to dry skin and AD 
lesions, beginning at screening/baseline, 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 clinic/office visits involving AD clinical assessments (eg, EASI).
Whenever possible, subjects should use the same moisturizer throughout the study. Moisturizer 
use and any adjustments should be documented in the eCRF.
Background Topical Therapy
At the VFUHHQLQJ YLVLW  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 will not be sourced by the sponsor. 
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. The prescribed use of 
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background therapies and any adjustments should be documented in the eCRF. “As needed” 
(PRN) use of TCS or TCI is not permitted.
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 8.11.4).
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.  
Permitted rescue therapies 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 administration should be continued unless there is a safety concern according 
to the investigator’s judgment. Subjects receiving any systemic rescue during the treatment 
period must permanently discontinue study drug and CYP substrate administration. 
Prohibited Medication/Therapy
Treatment with the following concomitant medications/therapies is prohibited during the study 
unless otherwise specified in Table 4. “As needed” (PRN) use of background topical therapy is 
not permitted.
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Table 4
Prohibited Medication/Therapy
Timeframe
Treatment(s)a
Prior to Day 1/
Baseline
Day 1 –
Week 21
Coal tar products
2 weeks
Prohibited
Topical PDE-4 inhibitor
2 weeks
Prohibited
7&, RQO\ IRU VXEMHFWV QRW XVLQJ VWDEOH 7&, WKHUDS\   GD\V SULRU WR
baseline 
2 weeks
Prohibited*
High- or very high-potency TCS (all subjects); any TCS only for subjects 
QRW XVLQJ VWDEOH 7&6 WKHUDS\  GD\V SULRU WR EDVHOLQH
2 weeks
Prohibited*
Topical medications, including TCS and TCI, with occlusive dressings (eg, 
wet wraps)
2 weeks
Prohibited
Systemic corticosteroids (corticosteroid inhalers are permitted)
4 weeks
Prohibited*
Phototherapy 
4 weeks
Prohibited*
Tanning beds
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)
8 weeks or 
5 half-lives 
(whichever is 
longer)
Prohibited*
Dupilumab
10 weeks
Prohibited
Live attenuated vaccine
12 weeks
Prohibited
Non-live vaccine
4 weeks
Prohibited
Medication that is a known inducer, inhibitor, or competitive substrate of 
one or more of the following CYP enzymes: CYP3A4/5, CYP2C19, 
CYP2C9, CYD2D6, and CYP1A2 b,c
2 weeks or 
5 half-lives 
(whichever is 
longer)
Prohibited
Midazolam, Omeprazole, Warfarin Sodium, Metoprolol Tartrate
2 weeks or 
5 half-lives 
(whichever is 
longer)
Prohibited
Caffeine (eg, coffee, tea, chocolate, energy drinks, soft drinks, 
supplements)
1 week
Prohibited
Anticoagulants or drugs that may affect INR (eg, aspirin, clopidogrel, 
ticlopidine, and dipyridamole)
2 weeks
Prohibited
Drugs with a sedative effect such as benzodiazepines, imidazopyridines, 
barbiturates, or sedative anti-depressants (eg, amitriptyline)
(Stable treatment with antihistamines with sedative effect, is allowed at a 
dose that, based on previous experience, is well tolerated by the subject.)
1 week
Prohibited
 
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CYP substrates PK samples should be collected exactly at the scheduled sampling time points
throughout the study, to the extent possible. The date and the time of each sample collection will 
be recorded in the eCRF, together with the time of study drug injection at the same visit (or 
missed injection if applicable).
CD14152 and CYP Substrates Quantification in Blood Sampling 
Concentration of nemolizumab (CD14152) in the serum will be determined by the designated 
CRO using a validated enzyme-linked immunosorbent assay method.  
Concentration of CYP substrates in plasma will be determined up to 120 hours for Warfarin 
Sodium and up to 24 hours for the other substrates using a fully validated LC-MS/MS methods. 
Details related to the processing of serum and plasma samples and the assessments of 
nemolizumab and CYP substrates will be described in the bioanalytical plans, which will be 
finalized before the beginning of sample analysis. Results will be described in a bioanalytical 
report for nemolizumab and for each CYP substrate probe, which will be included as an 
appendix in the final clinical study report. 
Pharmacokinetic Parameters
No PK parameter for nemolizumab (CD14152) will be calculated. Only trough concentrations 
will be reported as proof of exposure.
The following individual PK parameters will be measured and/or calculated for each CYP 
substrates with a Non-Compartmental Analysis (NCA), using a suitable validated software 
(actual software used and version will be stated in the final report):
Cmax
Observed maximum plasma concentration
tmax
Time to achieve Cmax 
Ȝz
Terminal elimination rate constant, calculated, if feasible, by log-linear regression using
at least 3 points excluding Cmax
t1/2
Half-OLIH FDOFXODWHG LI IHDVLEOH DV OQȜz
AUC0-last
Area under the concentration-time curve from administration to the last observed 
concentration-time t, calculated with the linear trapezoidal method
AUC0-inf
Area under the concentration-time curve extrapolated to infinity, calculated, if feasible, 
as AUC0-last + ClastȜz, where Clast is the last measurable drug concentration
$8&extra
Percentage of the residual area (Clast/Oz) extrapolated to infinity in relation to the total 
AUC0-inf, calculated, if feasible, as 100×[(Clast/Oz)/AUC0-inf] 
Cl
Systemic clearance, calculated, if feasible, as DOSE/AUC0-inf
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AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not it is related to the medicinal (investigational) product. This includes an 
exacerbation of pre-existing conditions or events, intercurrent illnesses, drug interaction, or the 
significant worsening of the indication under investigation that is not recorded elsewhere in the 
eCRF under specific efficacy assessments.  
Note(s):
x
Any new sign or symptom reported by the subject that appears after accidental or 
intentional overdose or misuse should be reported as an AE. 
x
Whenever possible, a diagnosis should be reported on the AE form, instead of signs, 
symptoms, or abnormal laboratory values.  
x
Pregnancy is not to be considered an AE; however, it must be monitored and reported as 
described in Section 9.4.1.5.
x
Each worsening of a chronic disease from the screening visit should be reported as a new 
AE.
The investigator or designee will report all AEs that occur from the time the ICF is signed until 
the end of the study. The sponsor/CRO should be informed if the investigator becomes aware of 
any safety information that appears to be drug-related, even after the subject has completed the 
clinical study.
At each post-enrollment visit, the investigator (or sub-investigator) will question the subject 
about AEs using open non-persuasive questions 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”) of the eCRF along with the date of onset, severity, relationship to the study 
drug(s), and outcome, without omitting any requested and known information. Additional 
information will be requested under certain circumstances.
AEs assessed as related to the treatment or study procedure will be monitored until they have 
resolved or reached a stable condition. Other AEs will be monitored until the last visit if they 
have not resolved or reached a stable condition.  
The investigator will obtain and maintain in the subject’s files all pertinent medical records, 
information and medical judgment from colleagues who assisted in the treatment and follow up 
of the subject. If necessary, the investigator will contact the subject’s personal physician or 
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Assessment of Severity
Each AE will be assigned a category by the investigator as follows: 
Mild:
An AE that is easily tolerated by the subject, causes minimal discomfort, and 
does not interfere with everyday activities.
Moderate:
An AE that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed.
Severe:
An AE that prevents normal everyday activities; treatment or other intervention 
usually needed.
If there is a change in severity of an AE, it must be recorded as a separate event.
Assessment of Causality
The investigator is to determine whether there is a reasonable causal relationship between the 
occurrence of the AE, and exposure to the study drug and/or study procedure (eg, injection, 
background topical 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 (i.e., suggestive 
evidence or arguments) that there is a causal relationship irrespective of the dose administered:
x
between the study drug (nemolizumab) and the AE, and/or 
x
between the clinical study protocol procedure (eg, injection, background topical 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: 
 
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x None 
x Study drug stopped 
x Study drug temporarily interrupted 
x Concomitant medication (any additions or discontinuations) 
x 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
AEs should be reported and documented in accordance with the procedures outlined below. All 
AEs occurring during the study must be documented on the relevant eCRF pages. The following 
data should be documented for each AE:
x Description of the symptom event 
x Classification of “serious” or “not serious” 
x Severity
x Date of first occurrence and date of resolution (if applicable)
x Action taken
x Causal relationship
x Outcome of event (unknown, recovered, not yet recovered, recovered with sequelae, death 
[with date and cause reported]) 
Adverse Events of Special Interest
An AESI is a noteworthy treatment-emergent event for the study drug that should be monitored 
closely and reported promptly. See Section 9.4.1.4 for reporting procedures. An AESI can be 
either serious or non-serious.  
Based on the potential risks of nemolizumab (CD14152) and the risks associated with biologics 
(and their biosimilar equivalents) in general (i.e., class effects), the following AEs will be 
considered AESIs: 
x
Injection Related Reaction (IRRs) 
o
Anaphylactic reactions 
o
Acute allergic reactions requiring treatment
o
Severe injection site reaction (i.e., lasting > 24 hours) 
x
Newly diagnosed asthma or worsening of asthma 
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o
More specifically, subjects with a medical history of asthma will be referred to 
the physician who manages their asthma when: 

$&7 VFRUH   $Q $&7 VFRUH   FRQYH\V DVWKPD WKDW PD\ QRW EH
adequately controlled. An AESI is reported based on the investigator’s 
clinical judgment, including consideration of the managing physician’s 
report.

Peak expiratory flow (PEF)   RI WKH SUHGLFWHG YDOXH: An AESI should 
be reported. 

Unexpected worsening of asthma is observed or reported. An AESI is 
reported based on the investigator’s clinical judgment.  
o
Subjects without a medical history of asthma will be referred to an appropriate 
respiratory physician/specialist when:

Signs and/or symptoms suggestive of asthma have been observed or 
reported. An AESI is reported based on the investigator’s clinical 
judgment of the specialist’s report.

Respiratory assessments (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.
x
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 
x
Peripheral edema: limbs, bilateral
x
Facial edema
x
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, 
x
Results in death.
x
Is life-threatening (an AE is life-threatening if the subject was at immediate risk of 
death from the event as it occurred, i.e., it does not include a reaction that might have 
caused death if it had occurred in a more serious form).
x
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]. The details of such 
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hospitalizations must be recorded on the medical history or physical examination
eCRF.) 
x
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.) 
x
Results in a congenital anomaly/birth defect. 
x
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 
 Safety and Pharmacovigilance 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.
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 
Safety and Pharmacovigilance group (see contact details above), within 24 hours 
of receipt of this relevant information.
4. Monitor and record the progress of the event until it resolves or reaches a stable condition, 
with or without sequelae. For all additional follow-up evaluations, complete an updated SAE 
report within 24 hours of receipt of the updated information. 
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5. Obtain and maintain in the subject files all pertinent medical records, information, and 
medical judgments from colleagues who participate in the treatment and follow-up of the 
subject. If necessary, contact the subject’s personal physician or hospital staff to obtain 
further details.
6. When the outcome of the event is known, complete an updated SAE report, if appropriate.
7. Prompt notification of SAEs by the investigator is essential so that legal obligations and 
ethical responsibilities toward the safety of subjects are met. The sponsor has a legal 
responsibility to notify both the local regulatory authority and other regulatory agencies 
about the safety of a product under clinical investigation. The sponsor or its delegate (i.e., the 
CRO) will comply with country-specific regulatory requirements relating to safety reporting 
to regulatory authorities, institutional review board (IRB)/independent ethics committee 
(IEC) and investigators. Investigator safety reports are prepared for SUSARs according to 
local regulatory requirements, and are forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor or its delegate 
(i.e., the CRO) will file it accordingly (i.e., within the Trial Master File [TMF]), and will 
notify the IRB/IEC, if appropriate according to local requirements.
8. Comply with the applicable regulatory requirement(s) related to the reporting of SAEs to the 
IRB/IEC.
Procedure for Reporting Adverse Events of Special Interest
For any AESI occurring during the clinical study, regardless of whether or not related to the 
treatment, the investigator must:
1. Take prompt and appropriate medical action, if necessary. The safety of subjects is the first 
priority.
2. Ensure that the event is evaluated as an AESI. Notify (within 3 days of receipt of the event) 
the 
 Safety and Pharmacovigilance group of an AESI report, by email. Refer to 
Section 9.4.1.3.
Note: AESI reporting is required by the investigator if it occurs during the clinical study 
following the first dose of study drug or within 12 weeks (± 5 days) of receiving the last dose 
of study drug, whether or not the event is considered to be related to the investigational 
product.
The demographics, medical history, drugs/therapies, and medical and surgical procedures 
forms must also be available for review in eCRF, at that time.
3. Send any relevant information or medical records (eg, laboratory test results) to the 
Safety and Pharmacovigilance group within 3 days of receipt of this relevant information.
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4. Monitor and record the progress of the event until it resolves or reaches a stable condition, 
with or without sequelae. For all additional follow-up evaluations, update the AESI report 
within 3 days of receipt of the updated information. 
5. Obtain and maintain in the files all pertinent medical records, information, and medical 
judgments from colleagues who participate in the treatment and follow-up of the subject. If 
necessary, contact the subject’s personal physician or hospital staff to obtain further details.
6. When the outcome of the event is known, update the AESI report, if appropriate.
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 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 along with the exit form within 24 hours of receipt of the 
information, to the 
 Safety and Pharmacovigilance group. Refer to Section 9.4.1.3.
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 to the 
Safety and Pharmacovigilance 
group within 24 hours of receipt of the information. If the subject can no longer be reached 
(i.e., lost to follow-up), documentation of the non-response/contact with 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 to the 
 Safety and Pharmacovigilance group within 24 hours of receipt of the information.
6. If the pregnancy leads to an abortion (i.e., voluntary abortion, spontaneous abortion, or 
therapeutic abortion), in utero death, or congenital anomaly, follow the procedure for 
declaration of reporting an SAE (see Section 9.4.1.3).
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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).  
The sponsor or its delegate will comply with country-specific regulatory requirements relating to 
safety reporting to regulatory authorities, IRB/IEC and investigators. Investigator safety reports 
are prepared for SUSARs according to local regulatory requirements and sponsor policy, and are 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other specific
safety information (eg, summary or listing of SAEs) from the sponsor or its delegate will file it 
accordingly (i.e., within the TMF), and will notify the IRB/IEC, if appropriate according to local 
requirements.
Clinical Laboratory Evaluation 
The hematology laboratory analyses, clinical chemistry laboratory analyses, and urinalyses will 
be performed by the sites local laboratory while the CYP metabolism genotyping we be done by 
a designated lab.  
Reference ranges will be supplied by and used by the investigator to assess the laboratory data 
for clinical significance and pathological changes.  
The investigator or medically qualified sub-investigator must review and evaluate laboratory 
values for each subject in a timely manner. Study centers should refer to the current version of 
the laboratory manual for laboratory values outside of normal limits. For each out-of-range 
laboratory result, the investigator or designee will evaluate whether he/she considers it to be 
clinically significant, defined as meeting at least 1 of the following conditions:  
x
The abnormality suggests a disease and/or organ toxicity, or 
x
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 effect the safety of the 
subject or the interpretation of the trial results. This should occur only after discussion with 
Medical Monitor. 
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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 (i.e., 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 scheduled 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 non-fasting 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).
See Sections 9.4.3, 9.4.4, and 9.4.5 for details regarding pregnancy testing, virology, and TB 
testing samples, respectively. (See Section 9.3, Appendix 7, and the clinical laboratory manual
for details regarding PK and ADA sampling.)
The following laboratory safety tests will be performed as specified in Table 1.
CYP Metabolism Genotyping
Poor metabolizers of CYP2C9, CYP2C19, or CYP2D6 will be identified based on genotype.
Hematology
Testing will include hemoglobin, hematocrit, white blood cell count (with differential including 
eosinophils), red blood cell count, platelet count, mean cell volume, and INR.  
Clinical Chemistry
Testing will include creatinine, AST, ALT, gamma glutamyltransferase, alkaline phosphatase, 
lactate dehydrogenase, total bilirubin, direct bilirubin, albumin, total protein, uric acid, sodium, 
potassium, calcium, chloride, glucose, urea, total cholesterol, triglycerides, low-density 
lipoprotein, high-density lipoprotein, and creatinine phosphokinase (CPK). CPK isoenzyme test 
will be performed only if CPK is elevated to > 2.5 × ULN. The investigator should also contact 
the Medical Monitor in such situations.
The postmenopausal status is defined as no menses for 12 consecutive months, and will be 
confirmed with a high follicle-stimulating hormone (FSH) level in the postmenopausal range at 
the screening visit.  
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Urinalysis
Testing will include pH, glucose, ketones, blood, protein, leukocytes, nitrites, bilirubin, 
urobilinogen, and specific gravity.  
A 12-panel drug test at screening will include: marijuana, opiates, PCP, cocaine, amphetamines, 
benzodiazepines, barbiturates, methadone, methaqualone, propoxyphene, ecstasy, and 
oxycodone. 
Pregnancy Testing
A serum pregnancy test is required at screening for women of childbearing potential (WOCBP).
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.  
UPTs 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. If the result of a UPT is positive, it must be confirmed with a serum pregnancy test, and 
no study drug should be administered pending the serum pregnancy test result. Subjects with a 
positive serum pregnancy test result during the trial must discontinue treatment and be 
withdrawn from the trial.
Virology 
Virology including HBsAg, HBcAb, hepatitis C, human immunodeficiency virus (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. Subjects will be screened 
for active or latent TB before entry into this study.
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 (Centers for Disease Control and Prevention [CDCP]
guidelines 2010), 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 
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disease to others and should commence a course of prophylactic antimycobacterial treatment to 
eliminate the infection and commit to completing the course of treatment.
Tuberculosis Screening
Ideally, as part of the medical history, the subject should be asked if they have presented with 
active or latent TB in the past and whether they have received a bacillus Calmette-Guérin (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. If confirmed indeterminate, the subject should then be 
managed as though he/she has a positive test result.
Vital Signs
Vital signs will be evaluated at the screening visit and at subsequent visits according to Table 1.
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.
Height and Weight
Height and weight will be measured according to Table 1.
Physical Examination
A complete physical examination will include assessments of the head, ears, eyes, nose, throat, 
neck (including thyroid), skin/integumentary system, cardiovascular system, respiratory system
(see Section 9.4.9 for additional respiratory assessments), gastrointestinal system, 
musculoskeletal system, lymph nodes, nervous system, and extremities.
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.
Respiratory Assessments 
At screening/baseline, the investigator should specifically question all subjects about any 
medical history of asthma and their respiratory health (eg, wheezing, coughing, allergies, 
infections). Subjects with a history of asthma will be questioned about the seasonality of their 
asthma and known triggers, such as allergens. Newly diagnosed asthma or worsening of asthma 
during the study will be reported as an AESI. 
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Asthma Control Test
Subjects with a medical history of asthma will take the ACT at designated visits according to 
Table 1.
Subjects with a new (de novo) diagnosis of asthma will take the ACT beginning at the visit the 
diagnosis was first confirmed and at designated visits thereafter. The ACT should be completed 
before questioning and physical examination by the investigator. 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. See Appendix 5.
Respiratory Examination 
A respiratory examination will be performed for all subjects at designated visits according to 
Table 1.
The ACT will aid the investigator’s questioning of subjects with a medical history of asthma and 
should be completed before the clinical questioning. At all designated visits, all subjects will be 
asked non-leading questions about any respiratory changes. The investigator or designee will 
then perform a respiratory examination.  
Subjects with a medical history of asthma will be referred to the physician managing their 
asthma if unexpected worsening of asthma is observed or reported. Subjects without a medical 
history of asthma who experience respiratory changes (examination findings or newly reported 
signs and/or symptoms suggestive of asthma) will be referred to a respiratory specialist. 
Peak Expiratory Flow 
PEF measurements will be performed for all subjects at screening, baseline, Week 13, and 
follow-up visits. For subjects reporting a medical history of asthma, PEF measurements will be 
conducted at additional designated visits, including Weeks 5 and 9 (see Table 1). 
Subjects with a new (de novo) diagnosis of asthma will undergo PEF testing at all designated 
visits after the diagnosis is first made.
PEF testing during the clinical study will be performed under the supervision of qualified study 
personnel. PEF 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 (Quanjer 1993; Polgar 1979).
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14 REFERENCES
US Food and Drug Administration. Drug Development and Drug Interactions: Table of 
Substrates, 
Inhibitors 
and 
Inducers. 
https://www.fda.gov/drugs/drug-interactions-
labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers 
European Medicines Agency. Guideline on the investigation of drug interactions. 21 June 
2012. CPMP/EWP/560/95/Rev. 1 Corr. 2**. Committee for Human Medicinal Products 
(CHMP). https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-
investigation-drug-interactions_en.pdf
Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387(10023):1109-1122. 
Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic 
dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. 
J Am Acad Dermatol. 2014;71(1):116-32. 
Hyde JN, Montgomery FH. A practice treatise on disease of the skin for the use of students 
and practitioners. 1909. 174-175. 
Warlich B, Fritz F, Osada N, et al. Health-related quality of life in chronic pruritus: an 
analysis related to disease etiology, clinical skin conditions and itch intensity. Dermatology.
2015;231(3):253-259. 
Silverberg JI. Public health burden and epidemiology of atopic dermatitis. Dermatol Clin.
2017;35(3):283-289. 
8.
Schmitt C, Kuhn B, Zhang X, Kivitz AJ, Grange S. Disease-drug-drug interaction involving 
tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin Pharmacol Ther.
2011;89(5):735-40. 
9.
Bruin G, Hasselberg A, Koroleva I, et al. Secukinumab treatment does not alter the 
pharmacokinetics of the cytochrome P450 3A4 substrate midazolam in patients with 
moderate to severe psoriasis. Clin Pharmacol Ther. 2019 Jun 22. 
10.
Khalilieh S, Hussain A, Montgomery D, et al. Effect of tildrakizumab (MK-3222), a high 
affinity, selective anti-IL23p19 monoclonal antibody, on cytochrome P450 metabolism in 
subjects with moderate to severe psoriasis. Br J Clin Pharmacol. 2018;84(10):2292-2302. 
11.
Davis JD, Bansal A, Hassman D, et al. Evaluation of potential disease-mediated drug-drug 
interaction in patients with moderate-to-severe atopic dermatitis receiving dupilumab. Clin 
Pharmacol Ther. 2018;104(6):1146-1154. 
12.
Pinto N, Dolan ME. Clinically relevant genetic variations in drug metabolizing enzymes. 
Curr Drug Metab. 2011 Jun;12(5):487-97. 
13.  Turpault S, Brian W, Van Horn R, et al. Pharmacokinetic assessment of a five-probe cocktail 
for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. Br J Clin Pharmacol. 2009;68(6):928-935. 
14.  Galderma S.A. Nemolizumab CD14152/CIM331 Investigator’s Brochure. 
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15.  CIM003JG Clinical study report: A phase II, randomized, double-blind, placebo-controlled, 
multiple-dose study to evaluate the safety, tolerability, and efficacy of CIM331 in atopic 
dermatitis patients who are inadequately controlled by or intolerant to topical therapy. 2017.
16.
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. 
17.
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):11-18. 
18. 
Simpson EL, 1. 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):2335-2348. 
19.  Centers for Disease Control and Prevention (CDCP). Updated guidelines for using interferon 
gamma release assays to detect mycobacterium tuberculosis infection í United States, 2010. 
MMWR Recomm Rep. 2010;59(RR05);1-25. 
20.  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. 
21.
Polgar G, Weng TR. The functional development of the respiratory system from the period 
of gestation to adulthood. Am Rev Respir Dis. 1979;120(3):625-695. 
 
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15 APPENDICES
Appendix 1:  
American Academy of Dermatology Consensus Criteria for AD Diagnosis 
Features to be considered in diagnosis of patients with atopic dermatitis: 
ESSENTIAL FEATURES; must be present: 
x
Pruritus 
x
Eczema (acute, subacute, chronic):
o
Typical morphology and age-specific patterns*  
o
Chronic or relapsing history 
*Patterns include:
1) Facial, neck, and extensor involvement in infants and children;  
2) Current or prior flexural lesions in any age group;  
3) Sparing of groin and axillary regions. 
IMPORTANT FEATURES; seen in most cases, adding support to the diagnosis: 
x
Early age of onset  
x
Atopy 
o
Personal and/or family history 
o
Immunoglobulin (IgE) reactivity 
x
Xerosis 
ASSOCIATED FEATURES; these clinical associations help to suggest the diagnosis of AD but are 
too non-specific to be used for defining or detecting AD for research and epidemiologic studies:
x
Atypical vascular responses (eg, facial pallor, white dermographism, delayed blanch response) 
x
Keratosis pilaris / pityriasis alba / hyperlinear palms / ichthyosis 
x
Ocular / periorbital changes 
x
Other regional findings (eg, perioral changes / periauricular lesions)  
x
Perifollicular accentuation / lichenification / prurigo lesions 
EXCLUSIONARY CONDITIONS; it should be noted that a diagnosis of AD depends on excluding 
conditions such as: 
x
Scabies
x
Seborrheic dermatitis
x
Contact dermatitis (irritant or allergic) 
x
Ichthyoses 
x
Cutaneous T-cell lymphoma
x
Psoriasis
x
Photosensitivity dermatoses
x
Immune deficiency diseases
x
Erythroderma of other causes 
Source: Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. 
Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116-32. 
 
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Appendix 6:  
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 5.4.1 
Risk/Benefit Assessment
During the COVID-19 pandemic, additional risks to participants may exist, including general 
environmental risks (e.g., being outside the home, possible contact with unsanitized surfaces) 
and study-related activities (e.g., interaction with study staff). Potential new subjects with known 
or suspected COVID-19 infection are ineligible for study enrolment until the infection has 
resolved. Furthermore, potential new subjects in a high-risk population for COVID-19 (e.g. 60 
years and older or with comorbidities), should be temporarily deferred until the COVID-19 risk 
has subsided at the location of the enrolling site, according to investigator judgement. Risk 
mitigation measures to be implemented for enrolled subjects and for new subjects during the 
COVID-19 pandemic are detailed in Additional Measures for Subjects Amidst COVID-19 
Pandemic below. Subjects with a known or suspected COVID-19 infection will immediately 
discontinue study drug; instructions for resuming treatment are described in Section 8.7 and 
below in Guidance for Existing Subjects. Known or suspected COVID-19 infection will also be 
followed as an AESI. 
New Subsection to Section 7.1, Overall Study Design and Plan: 
Additional Measures for Subjects Amidst COVID-19 Pandemic
All investigational sites should act according to applicable site regulations, to guidelines 
and restrictions implemented by local authorities, and to best practices for conducting 
clinical research during the COVID-19 pandemic.  
- Guidance for New Subjects:
Best practices currently in place must be followed when evaluating eligibility of subjects 
to participate in the study during the COVID-19 pandemic.
For potential subjects in a high-risk population for COVID-19 as defined by the American 
Academy of Dermatology (AAD) (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. 
 
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INVESTIGATOR SIGNATURE PAGE
Protocol Title:
An Open-label Drug-Drug Interaction Study to Assess the Effects of 
Nemolizumab on Cytochrome P450 Substrates in Subjects with 
Moderate-to-Severe Atopic Dermatitis
Protocol Number:
RD.06.SPR.201593
Confidentiality and Current GCP Compliance Statement
I, the undersigned, have reviewed this protocol (and amendments), including appendices, and 
I will conduct the study as described in compliance with this protocol (and amendments), GCP, 
and relevant ICH guidelines. 
Once the protocol has been approved by the IEC/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 ICF modifications to Galderma S.A./Galderma 
R&D, LLC and the IEC/IRB, and approval will be obtained before any amendments are 
implemented.
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 eCRFs, laboratory samples, or source 
documents forwarded to the sponsor. Clinical information may be reviewed by the sponsor or its 
agents or regulatory agencies. Agreement must be obtained from the subject before disclosure of 
subject information to a third party.
Information developed in this clinical study may be disclosed by Galderma S.A./Galderma R&D, 
LLC to other clinical investigators, regulatory agencies, or other health authority or government 
agencies as required.
Investigator Signature
Date
Printed Name
Title
Institution
Study Center Number
 
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SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System organ class 
t½ 
The apparent elimination half-life 
TB 
Tuberculosis 
TCI 
Topical calcineurin inhibitor 
TCS 
Topical corticosteroid 
TEAE 
Treatment-emergent adverse event 
Tmax 
The time from dosing at which Cmax is apparent determined by direct inspection of the 
concentration vs time data 
ULN 
Upper limit of normal 
UPT 
Urine pregnancy test 
WHO 
World health organization 
 
Terminal phase (apparent elimination) rate constant 
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REVISION HISTORY 
Version 
Number 
Effective Date 
Changes since previous version 
Final 1.0 
08 DEC 2020 
Original version, Not Applicable 
Final 2.0 
24 OCT 2023 
1)
Section 3: The LTE Criteria has been added based latest protocol 
amendment (Version 5, dated 14 September 2021). 
2)
Section 3.14.1: For the definition of TEAE the study drug 
(Nemolizumab) has been specified. 
3)
Section 7.14: The definition of Prior and Concomitant 
medication has been modified. 
4)
Section 7.18: Treatment related ADA definition added. 
5)
Section 7.19: The definition of Periods has been modified.
6)
 Section 7.19.2: Normalization criteria added. 
7)
Section 8: The Table 14.1.1.3, 14.1.7, 14.3.5.1.2, Figure 
14.3.4.1.2.5, 14.3.4.1.2.6 and Listing 16.2.1.2 are added. 
8)
Other edits  typographical or for clarity. 
Final 3.0 
06 DEC 2023 
1)
Update in per-protocol population definition 
2)
Update in caffeine NCA analysis 
3)
Typographical edits 
 
 
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TABLE OF CONTENTS 
SIGNATURES ................................................................................................................................ 2 
CLIENT SIGNATURE PAGE ....................................................................................................... 3 
LIST OF ABBREVIATIONS ......................................................................................................... 4 
REVISION HISTORY.................................................................................................................... 6 
TABLE OF CONTENTS ................................................................................................................ 7 
1. 
INTRODUCTION ................................................................................................................. 10 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................ 11 
2.1 
Objectives ....................................................................................................................... 11 
2.1.1 
Primary Objective ................................................................................................... 11 
2.1.2 
Secondary Objective ............................................................................................... 11 
2.2 
Endpoints ........................................................................................................................ 11 
3. 
STUDY DESIGN .................................................................................................................. 12 
3.1 
General ........................................................................................................................... 12 
3.2 
Study Population ............................................................................................................ 18 
3.3 
Evaluations at Screening ................................................................................................ 18 
3.4 
Randomization and Treatment Assignments.................................................................. 18 
3.5 
Determination of Sample Size........................................................................................ 18 
3.6 
Study Drug Administration ............................................................................................ 18 
3.7 
Prior and Concomitant Therapy ..................................................................................... 19 
3.8 
Drug Compliance ........................................................................................................... 20 
3.9 
Evaluation of Efficacy .................................................................................................... 20 
3.10 Evaluation Pharmacokinetic and Sampling Schedule .................................................... 21 
3.11 Evaluation of Pharmacodynamics and Sampling Schedule ........................................... 22 
3.12 Evaluation of Immunogenicity and Sampling Schedule ................................................ 22 
3.13 Evaluation of Other Parameters and Sampling Schedule............................................... 22 
3.14 Evaluation of Treatment Safety...................................................................................... 22 
3.14.1 
Adverse Events ....................................................................................................... 22 
3.14.2 
Clinical Laboratory Assessments............................................................................ 23 
3.14.3 
Vital Signs ............................................................................................................... 24 
3.14.4 
Electrocardiograms ................................................................................................. 24 
3.14.5 
Physical Examinations ............................................................................................ 25 
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3.14.6 
Other Safety Assessments ....................................................................................... 25 
3.15 Protocol Deviation Reporting......................................................................................... 26 
4. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS .............. 27 
5. 
QUALITY CONTROL AND QUALITY ASSURANCE METHODS FOR DATA 
ANALYSIS ................................................................................................................................... 28 
6. 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ....................... 29 
6.1 
Pharmacokinetic Assessment ......................................................................................... 29 
6.1.1 
Treatment of Outliers .............................................................................................. 30 
6.1.2 
Non-Quantifiable Concentrations ........................................................................... 30 
7. 
STATISTICAL METHODS.................................................................................................. 32 
7.1 
General ........................................................................................................................... 32 
7.2 
Handling of Dropouts or Missing Data .......................................................................... 33 
7.2.1 
Handling of missing/ incomplete dates for Adverse Event .................................... 33 
7.2.2 
Handling missing or partial Prior/Concomitant Medication & Medical and Surgical 
Procedure Dates ..................................................................................................................... 34 
7.3 
Multiple Comparisons and Multiplicity ......................................................................... 34 
7.4 
Adjustments for covariates ............................................................................................. 34 
7.5 
Multicenter Studies ........................................................................................................ 34 
7.6 
Examination of Subgroups ............................................................................................. 34 
7.7 
Coding dictionaries ........................................................................................................ 35 
7.8 
Analysis Populations ...................................................................................................... 35 
7.8.1 
Enrolled Population ................................................................................................ 35 
7.8.2 
Safety Population .................................................................................................... 35 
7.8.3 
Per Protocol Population .......................................................................................... 35 
7.9 
Subject Accountability ................................................................................................... 35 
7.10 Protocol Deviations ........................................................................................................ 36 
7.11 Subject Demographics and Baseline Characteristics ..................................................... 36 
7.12 Medical and Surgical History ......................................................................................... 36 
7.13 Medical and Surgical Procedures ................................................................................... 36 
7.14 Prior and Concomitant Medications............................................................................... 36 
7.15 Measurements of Treatment Compliance ...................................................................... 38 
7.16 Pharmacokinetic Analysis .............................................................................................. 38 
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7.17 Efficacy Analyses ........................................................................................................... 40 
7.18 Immunogenicity Analysis .............................................................................................. 40 
7.19 Safety Analyses .............................................................................................................. 40 
7.19.1 
Adverse Events ....................................................................................................... 40 
7.19.2 
Clinical Laboratory Assessments............................................................................ 42 
7.19.3
Vital Signs............................................................................................................... 44
7.19.4 
Electrocardiograms (ECG)...................................................................................... 45 
7.19.5 
Physical Examinations ............................................................................................ 45 
7.19.6 
Other Observations Related to Safety ..................................................................... 45 
7.20 Data Monitoring Committee .......................................................................................... 45 
7.21 Statistical Software ......................................................................................................... 45 
7.22 General Conventions for Tables, Listings and Figures .................................................. 46 
8.
LIST OF TABLES, FIGURES, AND LISTINGS ................................................................ 47 
9.
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1.
INTRODUCTION
This statistical analysis plan (SAP) is consistent with the statistical methods section of the final 
study protocol (Version 5.0, dated 14 SEPT 2021) and includes additional detail of 
pharmacokinetic (PK), Immunogenicity, efficacy analyses and safety summaries to be included in 
the clinical study report (CSR). 
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3.
STUDY DESIGN
3.1 General 
This is an open-label, single sequence drug-drug interaction study in approximately 25 adult 
subjects. Two study sites are planned in the United States and Europe. 
participation in the study will be approximately 25 
weeks, including up to a 4-week screening period, a 1-week pre-dose period, a 12-week 
nemolizumab treatment period, and an 8-week follow-up period (12 weeks after the last study 
drug injection). The 8-week follow-up period is not required for subjects who will continue in 
the LTE study (SPR.118163), a separate study. Refer to Figure 3-1 below for an overview of the 
treatment/study design. 
Blood samples will be collected at Baseline and at Week 10 before and after each oral dosing up 
to 120 hours post-dose for warfarin and 24 hours post-dose for rest of the CYP substrates for the 
determination of the complete plasma PK profile of each CYP probe. A total of 14 blood 
samples for warfarin and 12 blood samples for the rest of the CYP substrates will be collected at 
each visit before and after each oral dose making a total of 28 samples for warfarin and 24 
samples for rest of the CYP substrates. In addition, blood samples will be collected for the 
assessment of nemolizumab serum concentrations during the treatment period.  
Subjects who complete the Week 13 visit may be eligible to enroll into the long-term extension 
(LTE) study (SPR.118163). The follow-up period including 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 21 (12 weeks after their last study 
drug injection). Subjects who discontinue the study prematurely should complete an early 
termination (ET) visit and a follow-up visit 12 weeks after the last study drug injection. 
An independent data monitoring committee (IDMC) will review and monitor subject safety 
throughout the study, and an independent adjudication committee (IAC) will review all asthma-
related events throughout the study.  
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Figure 3-1: 
Study Design Schematic
Abbreviations: BL=baseline; CYP450-S=cytochrome P450 substrates; SC=subcutaneous; W=week.
Study procedures and assessments with their timing summarized in Table 3-1.
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3.2 Study Population 
-to-severe AD. Eligible subjects 
must have a documented history of inadequate response to topical AD medication(s) within 6 
months of screening visit.
3.3 Evaluations at Screening  
The study consists of a 2 to 4 week screening period. Subjects will apply a moisturizer at least 
once daily, beginning at screening and throughout the study. Refer Table 3-1 for screening 
procedures.
 
Screen failures may be allowed to rescreen up to 1 time unless the reason for screen failure is 
related to disease severity inclusion criteria (IGA, EASI, BSA, and PP NRS). The latter subjects 
are not permitted to rescreen. Subjects who are rescreened must sign a new Informed Consent 
Form and be assigned a new subject identification number. 
3.4 Randomization and Treatment Assignments 
Upon confirmation of eligibility for a given subject to participate in the study, a unique SIN for 
that subject will be assigned via an electronic data capture system. All study treatment will occur 
with open-label study drug.  
 
This is a single sequence drug-drug interaction study, hence, randomization is not required.  
3.5 Determination of Sample Size 
Approximately 25 subjects will be enrolled to have 15 completed subjects in the per-protocol 
population to provide a reliable estimate of the magnitude and variability of the interaction. 15 
completed subjects in the per-protocol population is the lower limit of reliability for ANOVA 
based tests as defined by bioequivalence guidelines. 
3.6 Study Drug Administration 
Subjects will apply a moisturizer at least once daily, beginning at screening and throughout the 
study. Subjects using a stable regimen of low- or medium-potency topical corticosteroid (TCS) 
with or without topical calcineurin inhibitor (TCI) at the screen
the baseline visit) should continue their therapy regimen in the study. 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. Moisturizer or background therapies use and 
any adjustments should be documented in the electronic case report form (eCRF). 
 
Subjects will receive 1 single oral dose of the selected, commercially available, CYP substrates 
Caffeine100 mg, Warfarin Sodium 10 mg, Midazolam 2 mg (diluted with water, a sugar or sugar 
substitute may be added), Omeprazole 20 mg, and Metoprolol Tartrate 100 mg] administered 1 at 
a time in sequence at Baseline/Day 1 under fasted conditions for at least 10 hours.  
 
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After a 1week wash-out period, subjects will receive nemolizumab by subcutaneous (SC) 
injection every 4 weeks (Q4W) for a treatment period of 12 weeks. Subjects will receive a 60 mg 
loading dose of nemolizumab (given via 2 consecutive SC 30 mg injections) at Week 1, followed 
by a single 30 mg dose at Week 5 and Week 9 of the study. 
Subjects will receive a second oral dosing of CYP substrates, administered 1 at a time in 
sequence, 9 weeks after initiation of nemolizumab treatment (at Week 10) under fasted 
conditions for at least 10 hours at the anticipated peak serum concentration of nemolizumab (i.e., 
1 week after the last nemolizumab administration). 
Dose modification of the study drug will not be permitted during the clinical trial. Any 
inadvertent dose modifications should be reported to the sponsor/CRO. In the event of a missed 
dose (i.e., temporary discontinuation of the study drug), it will be documented in the eCRF that 
the drug has not been administered at the study visit, together with the reason (eg, for safety). 
Subjects will be asked to return to the investigational study centers for all remaining visits and 
complete all study assessments and procedures as described in Table 3-1. 
3.7 Prior and Concomitant Therapy 
Previous therapies are defined as therapies that have been stopped within the 3 months before the 
screening visit, unless relevant to the inclusion/exclusion criteria. Whenever possible, previous 
therapies for AD 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 (eg, changes in dose, formulation or application 
frequency) during the course of the clinical trial 
any new therapies received by the subject since the screening visit 
Previous and concomitant therapies for drugs/therapies or for medical/surgical procedures are to 
be recorded in the appropriate eCRF. Concomitant therapies are to be recorded, reviewed, and 
updated at each visit. Information recorded will include: start and stop dates and times, dose and 
route of administration, and indication. Medications taken for a procedure should also be 
included. 
Any new concomitant therapy or modification of an existing therapy may be linked to an AE. In 
such cases, a corresponding AE form should be completed to account for the new therapy or 
change in therapy, except in some cases such as dose modification for a chronic condition 
(Section 3.6), in which case the medication will be linked to an item in the medical history. 
Permitted Concomitant Therapy 
Unless specified as prohibited therapies, all therapies are authorized including basic skin care 
(cleansing and bathing), moisturizers, bleach baths, topical anesthetics and antihistamines without 
a sedative effect. 
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3.11 Evaluation of Pharmacodynamics and Sampling Schedule 
Not Applicable
3.12 Evaluation of Immunogenicity and Sampling Schedule 
According to the schedule of assessments (Table 3-1) and the clinical laboratory manual, blood 
samples will be collected to assess anti-nemolizumab ADA, which will be determined at these 
time points by the designated CRO using a validated enzyme-linked immunosorbent assay 
screening assay. The serum concentration will be assessed using a multi-tiered approach. 
 
If serum circulating ADA is detected, presence will be confirmed and characterized (eg, for 
neutralizing potential) using a validated assay.  
3.14 Evaluation of Treatment Safety 
3.14.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a clinical study subject administered a 
medicinal product which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not it is related to the medicinal (investigational) product. This includes an 
exacerbation of pre-existing conditions or events, intercurrent illnesses, drug interaction, or the 
significant worsening of the indication under investigation that is not recorded elsewhere in the 
eCRF under specific efficacy assessments. 
AEs assessed as related to the treatment or study procedure will be monitored until they have 
resolved or reached a stable condition. Other AEs will be monitored until the last visit if they have 
not resolved or reached a stable condition. 
If there is a change in severity of an AE, it must be recorded as a separate event. 
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A TEAE is defined as an AE that occurs on or after the first date of study drug (Nemolizumab) 
administration until the date of last study visit.  
An SAE is defined as any event that results in death, is immediately life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in persistent or 
significant disability/incapacity, or is a congenital anomaly/birth defect. 
Subjects will be monitored throughout the study for AEs, from the time informed consent is 
obtained through End of Study. The following details will be collected: description of the AE, start 
date and time, stop date and time, action taken with study drug (dose not changed, drug interrupted, 
drug withdrawn, and not applicable), outcome (recovered/resolved, not recovered/not resolved, 
recovered/resolved with sequelae, recovering/resolving, fatal and unknown), severity (mild, 
moderate, severe, life threatening and fatal), seriousness (yes, no), relationship to study drug (not 
related, unlikely related, possibly related, probably related, definitely related), additional treatment 
required.  
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. An AESI can be either serious or non-serious. AESIs are injection-
related reactions, newly diagnosed asthma or worsening of asthma, infections, peripheral edema, 
facial edema, elevated ALT or AST (> 3 × ULN) in combination with elevated bilirubin (> 2 × 
ULN).
3.14.2 Clinical Laboratory Assessments 
The hematology laboratory analyses, clinical chemistry laboratory analyses, urinalyses, CYP 
metabolism genotyping, pregnancy testing, virology, and tuberculosis (TB) testing sample will 
be collected as specified in Table 3-1.  
CYP Metabolism Genotyping 
Poor metabolizers of CYP2C9, CYP2C19, or CYP2D6 will be identified based on genotype. 
Hematology 
Testing will include hemoglobin, hematocrit, white blood cell count (with differential including 
eosinophils), red blood cell count, platelet count, mean cell volume, and INR. 
Clinical Chemistry
Testing will include creatinine, aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), gamma glutamyltransferase, alkaline phosphatase, lactate dehydrogenase, total bilirubin, 
direct bilirubin, albumin, total protein, uric acid, sodium, potassium, calcium, chloride, glucose, 
urea, total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, and 
creatinine phosphokinase (CPK). CPK isoenzyme test will be performed only if CPK is elevated 
to >2.5 × ULN. The investigator should also contact the Medical Monitor in such situations. 
The postmenopausal status is defined as no menses for 12 consecutive months, and will be 
confirmed with a high follicle-stimulating hormone (FSH) level in the postmenopausal range at 
the screening visit. 
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4.
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS
All analyses specified in this SAP are consistent with the final study protocol (Version 5.0, dated 
14 SEPT 2021). Any changes in this analysis provided or any additional analysis performed will 
be documented in CSR.   
Prior/Concomitant medications is changed from the protocol to: 
Prior medications: defined as therapies that have been started and ended before first 
dosing of CYP substrate. 
Concomitant medications: defined as medications started or ongoing or ended on or after 
first dosing of CYP substrate. 
Definition of Per-
The per-protocol population (PP population) will consist 
of all subjects who complete the study without any major protocol deviations or any other event 
which could render
The per-protocol population (PP population) 
will consist of all subjects who complete the treatment period without any major protocol 
deviations or any other event which could render
completed the treatment period and utilize maximum data in summary and analysis.  
For Caffeine analyte only, additional NCA calculations for each study periods will be performed 
using actual sampling times and pre-dose corrected measured concentrations. The pre-dose 
correction will be performed subtracting, for each subject and each study period, the measured 
value of caffeine concentration at pre-doses from each correspondent post-dose concentrations. 
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5. 
QUALITY CONTROL AND QUALITY ASSURANCE METHODS FOR DATA 
ANALYSIS 
Case report forms will be monitored and collected by 
All monitored CRFs will be sent to 
the Data Management group at 
and processed according to the
 Study Specific 
Procedure SSP DM-02020051.01 Data Management Plan (DMP). The DMP describes CRF data 
processing, edit checks, data query management, medical dictionary coding, SAE reconciliation, 
data transfers, and data quality review through database lock or any necessary reopening of the 
database. After database lock, the data will be retrieved from the database using SAS® (details 
mentioned in the Section 7.21). 
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z, t1/2, AUC0-inf, %AUCextra and Cl), when considered 
unreliable, will not be reported.  
The calculations of PK parameters will be based on the actual sampling times. 
6.1.1 Treatment of Outliers 
Individual concentration-time points, if considered anomalous, may be excluded from the analysis 
at the discretion of the pharmacokinetics following a review of the available documentation. Any 
such exclusion will be discussed with the sponsor and clearly outlined in the study report. 
Entire individual study drug profiles for a subject may be excluded following review of the 
available documentation and discussion with the sponsor. Examples of reasons for exclusion could 
be (but are not limited at, see section 7.8.3 and 7.16): 
Subjects experiencing emesis or diarrhea during the course of the study if vomiting or 
diarrhea occurs at or before two times median Tmax for CYP substrates.
the lack of any measurable concentrations or only very low plasma concentrations of the 
probe drug at visit 2. A subject is considered to have very low plasma concentrations if 
his/her AUC is less than 5% of the geometric mean AUC of the probe drug at visit 2 (which 
should be calculated without inclusion of data from the outlying subject).  
In case of exclusion concentration and the PK parameter data for the given subject will be listed 
but excluded from the PK summaries. However, results of analysis with and without the excluded 
profiles may be presented in the study report as deemed appropriate. Any such exclusion will be 
clearly listed in the study report along with justification for exclusion. 
Any anomalous concentration values observed at predose will be identified and discussed in the 
CSR. For all analyte except caffeine, pharmacokinetic parameters will be computed if the predose 
concentration value is not greater than 5% of Cmax for a given subject. If the predose concentration 
value is greater than 5% of the subsequent Cmax, concentration and the PK parameter data for the 
given subject will be listed but excluded from the PK summaries and statistical analysis.  
For Caffeine analyte only, additional NCA calculations for each study periods will be performed 
using actual sampling times and pre-dose corrected measured concentrations. The pre-dose 
correction will be performed subtracting, for each subject and each study period, the measured 
value of caffeine concentration at pre-doses from each correspondent post-dose concentrations. 
6.1.2 Non-Quantifiable Concentrations 
All concentration values reported as no results (not collected or not determined) values will be 
treated as missing.  
For the calculation of the PK parameters summary statistics, plotting mean and individual 
concentration time profiles, concentrations below the lower quantification limit (BLQ) will be 
treated as follows:
BLQ plasma concentrations occurring before the first measurable concentration will be 
treated as zero; 
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BLQ plasma concentrations occurring after the first measurable concentration will be 
omitted from the calculation of PK parameters. 
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7. 
STATISTICAL METHODS 
7.1 General 
The statistical analysis will be conducted following the principles specified in the International 
Council for Harmonisation (ICH) Topic E9 Statistical Principles for Clinical Trials 
(CPMP/ICH/363/96). 
All statistical tabulations and analyses will be done using SAS GRID Linux/SAS Studio (details 
mentioned in section 7.21). PK parameters will be derived using Phoenix
 WinNonlin®, Version 
8 or higher (Certara, St. Louis, MO).   
For other than PK data, the default summary statistics for continuous variables includes number 
of contributing observations (n), mean, standard deviation (SD), median, Q1, Q3, minimum, and 
maximum. 
For categorical variables, the number and percentage (as the percentage of subjects in each 
category relative to the total number of subjects in each category) will be the default summary 
presentation.
In the data listings, study day relative to dosing date may be presented. Study day relative to dose 
will be calculated as: event date  
 First dose 
date refers to dosing of CYP substrate administration. 
For all the efficacy and safety endpoints/measures, unless otherwise specified except for PP NRS, 
Baseline
first dosing of 
Nemolizumab, as applicable (this includes unscheduled visits). For PP NRS, 
as based on the average of daily PP NRS (score ranging from 0 to 10) during the 7 days 
immediately preceding first dosing of Nemolizumab (rounding to nearest whole number is not 
permitted). A minimum of 4 daily scores out of the 7 days is required for this calculation. For 
numerical variables,  
Change from baseline will be calculated as (Post baseline value  Baseline value). 
Percent change from baseline will be calculated as [(Post baseline value  Baseline value) 
/Baseline value]*100. 
There will be no multiple comparison adjustment for various analyses.  
Concentrations and PK parameters will be summarized using descriptive statistics to include, as 
appropriate, n, mean, SD, coefficient of variation (CV), minimum, Q1, median, Q3, maximum, 
geometric mean (GM), and geometric CV%, 95% CI of mean and number of BLQs (Below Limit 
of Quantification). BLQ will be considered as missing and excluded from the descriptive summary. 
For tmax, summary statistics will be described by n, minimum, Q1, median, Q3, and maximum 
only. 
Unscheduled and repeat assessment will only be used to derive last post-baseline and maximum 
post-baseline results and will not be used in rest of the summary tables; however, all results will 
be included in the data listings. 
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All data will be summarized by visit for Overall unless otherwise specified. 
7.2 Handling of Dropouts or Missing Data 
There will be no imputations for missing data other than that implicit by ignoring missing data 
when using the trapezoidal rule for the calculation of AUCs. For all variables, only the observed 
data from the subjects will be used in the by-visit summaries. 
If the character result is reported for quantitative laboratory parameter then for summary and 
analysis it will be changed as follows into numerical value   
a) 
%. 
b) 
% will be added. 
Eg: if lab parameter is reported as >40 then it will be considered as 40.4 and if the parameter is 
reported as <40 then it will be considered as 39.6. 
7.2.1 Handling of missing/ incomplete dates for Adverse Event 
Imputation rules for missing or partial AE start date are defined below:
If only Day of Adverse Event start date is missing:  
If the start date has month and year but day is missing, the first day of the month will be imputed 
If this date is earlier than the first Nemolizumab dose date, then the first Nemolizumab 
dose date will be used instead. 
If this date is later than the stop date (possibly imputed), then the stop date will be used 
instead. 
If Day and Month of Adverse Event start date are missing: 
If the start date has year, but day and month are missing, the 1st of January will be imputed 
If this date is earlier than the first Nemolizumab dose date, then the first Nemolizumab 
dose date will be used instead. 
If this date is later than the stop date (possibly imputed), then the stop date will be used 
instead. 
If Year of Adverse Event start date is missing:
If the year of AE start is missing or AE start date is completely missing then imputation will not 
be done. 
Missing or partial Adverse Event stop date: 
a.
If only Day is missing, the earlier between the last date of the month and year
reported and the date of the final contact with the subject will be assumed.
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b. If Day and Month are both missing, the earlier between last day of the year reported
and the date of the final contact with the subject will be assumed.
c.
assigned.
If the AE end date (full or partial) is before the first dose date then the AE should be considered 
as a pre-treatment AE. Otherwise, the AE will be considered as TEAE. 
7.2.2 Handling missing or partial Prior/Concomitant Medication & Medical and Surgical 
Procedure Dates
Missing or partial medication start date: 
a.
If only Day is missing, the first day of the month will be assumed.
b. If Day and Month are both missing, the first day of the year will be assumed.
c.
If Day, Month and Year are all missing, the day before the first dose date will be
assumed.
Missing or partial medication stop date: 
d. If only Day is missing, the earlier between the last date of the month and year
reported and the date of the final contact with the subject will be assumed.
e.
If Day and Month are both missing, the earlier between last day of the year reported
and the date of the final contact with the subject will be assumed .
f.
If Day
 status to stop date will be 
assigned. 
7.3 Multiple Comparisons and Multiplicity 
No adjustment will be made for the multiple comparisons. 
7.4 Adjustments for covariates 
COVID-19, asthma, age or any co-morbidity will be considered as covariate in PK statistical 
model.  
7.5 Multicenter Studies 
2 study sites are planned, one in the United States and one in Europe. As the main objective of 
this study is to evaluate the change of PK parameters (AUC0-inf, AUC0-last, Cmax) in the 5 probe 
drugs administered concomitantly, center effect will not be considered for analysis. 
7.6 Examination of Subgroups 
No subgroup analyses are planned. 
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7.7 Coding dictionaries 
Medical history and adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA, version 23.0 or upper). Medications will be coded using the 
World Health Organization Drug Reference List (WHO Global B3 format - March 2020 or upper). 
Medical procedures will not be coded. 
7.8 Analysis Populations 
7.8.1 Enrolled Population 
All subjects who signed the informed consent form and are enrolled in the study.
7.8.2 Safety Population
The safety population will include all subjects who receive at least 1 dose of nemolizumab. All 
safety and efficacy data will be summarized using the safety population. This set will be used for 
the safety data summaries, baseline characteristic summaries and pharmacokinetic concentration 
summaries.  
7.8.3 Per Protocol Population 
The per-protocol population (PP population) will consist of all subjects who complete the 
treatment period without any major protocol deviations or any other event which could render 
the probe drugs plasma concentration-time profiles unreliable, especially (but not limited to): 
Vomiting and diarrhea which could render the plasma concentration-time profiles 
unreliable i.e., after probe drugs intake and/or before 2 times median tmax 
Other AEs which could render the plasma concentration-time profile unreliable 
Intake of concomitant medications which could render the plasma concentration time 
profile unreliable 
Administration errors which could render the plasma concentration-time profile 
unreliable 
The primary endpoint will be analyzed using the per-protocol population. 
7.9 Subject Accountability 
Subject disposition will be listed and summarized. It will include all subjects who were screened. 
Listings will be provided for subject accountability and exclusions from analysis populations.  
The table will contain following information: 
Number of subjects screened 
Number of screen failure subjects and reason for screen failure 
Number of subjects in Enrolled Population 
Number of subjects received CYP substrate 
Number and percent of subjects who were dosed with at least one dose of Nemolizumab 
(Safety Population) 
Number and percent of subjects who completed the treatment   
Number and percent of subjects who discontinued early from the treatment and reason for 
early discontinuation 
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Number and percent of subjects who completed the study 
Number and percent of subjects who discontinued early from the study and reason for 
early discontinuation 
Number and percent of subjects rolled over into LTE study 
Percentage will be calculated based on enrolled population. 
7.10 Protocol Deviations 
Major protocol deviation will be summarized for enrolled population. Separate table for major 
protocol deviation will be summarized by visit for enrolled population. 
All Protocol deviations will be listed. 
7.11 Subject Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be listed and summarized descriptively. 
The summary will 
ethnicity, weight at baseline (in kg), height (in cm), Status of Habitual Tobacco Use, EASI 
(baseline score), PP-NRS (baseline score), IGA at baseline and BSA (%). Demographics will be 
summarized for enrolled, safety and per-protocol populations. 
7.12 Medical and Surgical History 
The medical and surgical history data will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA Version 23.0 or upper), will be listed and summarized descriptively as 
number and percent of subjects reporting each system organ class (SOC) and preferred term (PT) 
and sorted alphabetically by SOC and descending frequency of PT within SOC. Summary tables 
will be presented for safety population and per-protocol populations. 
7.13 Medical and Surgical Procedures 
Medical and surgical procedures will be classified as follows: 
Prior procedure: defined as procedures that started and ended before first dosing of CYP 
substrate.
Concomitant procedure: defined as procedures started or ongoing or ended on or after
first dosing of CYP substrate. 
Prior and concomitant medical and surgical procedures will be summarized separately using the 
number and percent of subjects reporting each SOC and PT and sorted alphabetically by SOC 
and in descending frequency of PT within SOC. Summary tables will be presented for safety 
population and per-protocol populations. 
Prior and concomitant medical and surgical procedures listings will be provided. 
7.14 Prior and Concomitant Medications 
Prior/Concomitant medications will be classified as follows: 
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Lack of any measurable concentrations or only very low plasma concentrations of the 
probe drug at visit 2. A subject is considered to have very low plasma concentrations if 
his/her AUC is less than 5% of the geometric mean AUC of the probe drug at visit 2 
(which should be calculated without inclusion of the outlying subject)  
Non-zero baseline concentrations > 5% of Cmax 
 
Subjects should not be excluded from the statistical test if their individual AUC0-t covers less 
than 80% of their individual AUC0-inf. 
Concentration and PK parameters for the 5 selected CYP substrates (Caffeine, Warfarin Sodium, 
Omeprazole, Metoprolol Tartrate and Midazolam) will be summarized by timepoint for per-
protocol population. These will be listed for Per-protocol Population. 
The individual sampling and subject concentration-time for plasma (CYP substrates) 
concentrations will be displayed graphically on linear and semi-log scales (CYP substrates only). 
Linear and semi-logarithmic plots of the individual plasma concentration by actual sampling 
time for each study drug will be provided by subject (one subject per page). For all these figures, 
each drug in their own figure with all days data presented in the same figure. 
Overlay of individual concentration profiles over time will be provided by study drug. Plots of 
mean (SD) concentration profiles versus time will be presented for each study drug in the 
separate plot. Each drug in their own figure with all days data presented in the same figure. 
Concentration values will be listed and summarized for nemolizumab by condition and 
timepoints. 
For the primary endpoint analysis, a linear mixed-effect model will be used to the log-
transformed PK parameters (AUC0-inf, AUC0-last and Cmax) of each CYP substrate, with treatment 
(with or without nemolizumab) as a fixed effect and subject as a random effect. The geometric 
mean ratio between treatments (substrates with [test] or without [reference] nemolizumab) after 
back-transformation and the corresponding 90% confidence interval (CI) will be provided. 
The following example code can be used for statistical analysis. Please note that required 
modification should be made as necessary as per the data.  
PROC MIXED DATA=DATASET;  
BY ANALYTE; 
CLASS SUBJECT TREATMENT;  
MODEL LOGPK = TREATMENT / S DDFM=KR;  
RANDOM SUBJECT;  
LSMEANS TREATMENT / CL ALPHA=0.1;  
ESTIMATE 'Test VS Reference' TREATMENT -1 1 / ALPHA=0.1 CL;  
RUN;
Where ANALYTE = CYP substrate 
 
According to the calculated 90% CI for AUC, the following will be claimed: 
If the lower limit of the 90% CI is > 80%, no interaction is present 
 
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A weak interaction will not be considered clinically meaningful. 
An additional sensitivity analysis will be presented with considering COVID-19, asthma, age or 
any co-morbidity as covariate in PK statistical model. Only effects significant at 5% level of 
significance will be considered in the analysis. 
7.19 Safety Analyses 
7.19.1 Adverse Events 
All AEs including those with an onset before the first dosing of study drug will be listed. All AE 
summaries will include treatment emergent AEs.  
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The TEAEs will be summarized and tabulated at both the subject (n [%] of subjects) and event 
(number of events) level:
 
Overall summary of TEAEs  
 
Summary by SOC and PT  
 
TEAEs by SOC and PT, maximum severity
TEAEs Related to Study Drug by SOC and PT, maximum severity 
 
TEAEs Related to Study Drug by SOC and PT 
 
TEAEs Related to Protocol Procedure by SOC and PT 
 
Treatment-emergent AESIs by SOC and PT 
 
Treatment-emergent SAEs by SOC and PT 
 
TEAEs resulting in discontinuation of study by SOC and PT 
 
TEAEs resulting in discontinuation of study drug by SOC and PT 
 
Most common TEAEs (Occurred in >= 5% of Subjects) by PT 
 
Periods are defined as:
1) Cytochrome only Period: Any AE onset from first dosing of CYP substrate to prior to 
first dosing of Nemolizumab on Day 8. 
2) Nemolizumab only Period: Any AE onset from first dosing of Nemolizumab to prior to 
drug administration of second CYP substrate.
3) Cytochrome + Nemolizumab Period: Any AE onset after second CYP substrate to end of 
the study. 
 
The overall incidence of TEAEs (number and percentage of subjects) as well as the number of 
events will be summarized during Cytochrome only period, severity of TEAE; AESIs; SAE; 
related TEAE and related SAE; TEAEs leading to study discontinuation, TEAEs leading to study 
drug discontinuation; and TEAEs leading to death will be tabulated. Adverse events during 
Cytochrome only period will be summarized by SOC and PT as well. 
 
The frequency of TEAEs (AE burden) will be summarized using descriptive statistics by SOC 
and PT.  
For the incidence at the subject level by SOC and PT, if a subject experiences more than 1 event 
within the same SOC and PT, only 1 occurrence will be included in the incidence. 
For the incidence at the subject level by SOC, PT and severity, if a subject experiences more 
than 1 event within the same SOC, PT and severity, only the most severe occurrence will be 
included in the incidence. 
For the incidence at the subject level by SOC, PT and relationship to study drug; if a subject 
experiences more than 1 event within the same SOC, PT and relationship, only the most closely 
related occurrence will be included in the incidence. 
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Any SAEs, AEs with outcome of death, AESIs or AEs resulting in discontinuation of study or 
study drug will be listed separately.  
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7.20 Data Monitoring Committee 
An IDMC will review and monitor subject safety throughout the study, and an IAC will review 
all asthma-related events throughout the study. The IDMC and IAC charters provide details on 
the IDMC and IAC, including the plan of analysis for output, the composition of the committees, 
procedures, roles, responsibilities, and communications. 
7.21 Statistical Software 
All data listings, summaries, and statistical analyses will be generated using SAS GRID 
Linux/SAS Studio. 
 
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7.22 General Conventions for Tables, Listings and Figures  
 
Times new roman font size of no less than 8 point will be used for tables and listings. 
A source line will be included on the bottom of each page of all tables and listings. It will contain 
the SAS code program name and the run date and time. 
Each variable is recorded to a specific number of decimal places. If the raw data is presented 
with varying precision, then the least precise value will be considered as the data precision. 
For summary tables, unless otherwise specified, the number of decimal places provided in the 
tables and listings will be based on the precision of the least precise value in the raw data as 
follows: 
N 
integer 
Arithmetic mean 
1 decimal place more than the least precise number in the raw data 
SD 
2 decimal place more than the least precise number in the raw data 
CV(%) 
2 decimal places 
Geometric mean 
1 decimal place more than the least precise number in the raw data 
Geometric CV 
2 decimal places 
Median 
1 decimal place more than the least precise number in the raw data 
Minimum 
same number of decimal places as raw data
Maximum
same number of decimal places as raw data
Confidence interval 
same number of decimals as the associated statistic 
Percentage 
1 decimal place 
 
 
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8. 
LIST OF TABLES, FIGURES, AND LISTINGS 
Table/Figure 
Number 
Table/Figure Name 
Section 14.1 
Demographic and Subject Characteristics Data Summaries
Table 14.1.1 
Summary of Subject Disposition (All Screened Subjects) 
Table 14.1.1.2 
Subject Accounting by Visit (Enrolled Population) 
Table 14.1.2 
Summary of Analysis Populations (Enrolled Population) 
Table 14.1.3.1 
Protocol Deviations Summary (Safety Population) 
Table 14.1.3.2 
Protocol Deviations Summary by Visit (Safety Population) 
Table 14.1.4.1 
Demographic and Baseline Characteristics (Enrolled Population) 
Table 14.1.4.2 
Demographic and Baseline Characteristics (Safety Population) 
Table 14.1.4.3 
Demographic and Baseline Characteristics (Per-protocol Population) 
Table 14.1.5.1 
Medical and Surgical History Summary (Safety Population) 
Table 14.1.5.2 
Medical and Surgical History Summary (Per-protocol Population) 
Table 14.1.5.3 
Prior Medical and Surgical Procedures Summary (Safety Population) 
Table 14.1.5.4 
Prior Medical and Surgical Procedures Summary (Per-protocol 
Population) 
Table 14.1.5.5 
Concomitant Medical and Surgical Procedures Summary (Safety 
Population) 
Table 14.1.5.6 
Concomitant Medical and Surgical Procedures Summary (Per-protocol 
Population) 
Table 14.1.6.1 
Prior Medication Summary (Safety Population) 
Table 14.1.6.2 
Prior Medication Summary (Per-protocol Population) 
Table 14.1.6.3 
Concomitant Medication Summary (Safety Population) 
Table 14.1.6.4 
Concomitant Medication Summary (Per-protocol Population) 
Table 14.1.6.5 
Background Therapy Summary (Safety Population) 
Table 14.1.6.6 
Rescue Medication Summary (Safety Population) 
Table 14.1.7 
Exposure Summary (Safety Population) 
Section 14.2 
Pharmacokinetic / Efficacy/ Immunogenicity Data Summaries 
Section 14.2.1 
Pharmacokinetic Data Summaries 
Table 14.2.1.1.1 
Summary of Cytochrome Probes Plasma Concentration (Per-protocol 
Population) 
Table 14.2.1.1.2 
Summary of Nemolizumab Serum Concentration (Per-protocol 
Population) 
Table 14.2.1.2 
Summary of Cytochrome Probes Plasma Pharmacokinetic Parameters 
(Per-protocol Population) 
Note: present for plasma CYP substrates  
Table 14.2.1.3 
Statistical Analysis of Pharmacokinetic Data (Per-protocol Population) 
Note: present for plasma CYP substrates  
Table 14.2.1.4 
Sensitivity Analysis of Pharmacokinetic Data from ANCOVA model (Per-
protocol Population)
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Note: present for plasma CYP substrates  
Figure 14.2.1 
Plot of Mean (SD) Concentration (Per-protocol Population) 
Note: present for plasma CYP substrates, each analyte separately and all 
days in one plot 
Section 14.2.2 
Efficacy Data Summaries
Table 14.2.2.1 
Peak Pruritus Numeric Rating Scale Summary (Safety Population) 
Table 14.2.2.2 
Eczema Area and Severity Index Summary (Safety Population) 
Section 14.2.3 
Immunogenicity Data Summary 
Table 14.2.3.1 
Summary of Anti-drug Antibody Status (Safety population) 
Table 14.2.3.2 
Summary of Anti-drug Antibody Status (Per-protocol population) 
Section 14.3 
Safety Data Summaries 
Section 14.3.1 
Displays of Adverse Events 
Table 14.3.1.1 
Overall Summary of Adverse Events (Safety Population) 
Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class 
and Preferred Term (Safety Population) 
Table 14.3.1.3 
Summary of Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term and Maximum Severity (Safety Population)
Table 14.3.1.4.1 
Summary of Treatment-Emergent Adverse Events Related to Study Drug 
by System Organ Class and Preferred Term (Safety Population)
Table 14.3.1.4.2 
Summary of Treatment-Emergent Adverse Events Related to Protocol 
Procedure by System Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.5 
Summary of Adverse Events of Special Interest by System Organ Class 
and Preferred Term (Safety Population) 
Table 14.3.1.6 
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.7 
Treatment-Emergent Adverse Events Related to Study Drug by System 
Organ Class, Preferred Term and Maximum Severity (Safety Population) 
Table 14.3.1.8
Summary of Treatment-Emergent Adverse Events resulting in 
Discontinuation of Study by System Organ Class and Preferred Term 
(Safety Population) 
Table 14.3.1.9 
Summary of Treatment-Emergent Adverse Events resulting in 
Discontinuation of Study Drug by System Organ Class and Preferred 
Term (Safety Population)
Table 14.3.1.10 
Most common TEAEs (Occurred in >= 5% of Subjects) by Preferred Term 
(Safety Population) 
Table 14.3.1.11 
Summary of Adverse events during Cytochrome only period by System 
Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.12 
Listing of Adverse Events with Outcome of Death (Safety Population) 
Table 14.3.1.13 
Listing of Serious Adverse Events (Safety Population) 
Table 14.3.1.14 
Listing of Adverse Events Leading to Study Discontinuation (Safety 
Population) 
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Section 14.3.4 
Abnormal Laboratory Value Listing 
Table 14.3.4 
Abnormal Laboratory Value Listing (Safety Population) 
Figure 14.3.4.1.2.5 Distribution of Selected Laboratory Parameters by Visit with Maximum 
Post-baseline Values (Safety Population)
Figure 14.3.4.1.2.6 Spaghetti Plot of Selected Laboratory Parameters by Visit (Safety 
Population) 
Section 14.3.5 
Additional Safety Data Summaries 
Table 14.3.5.1.1 
Absolute and Change from Baseline of Clinical Laboratory Results (Safety 
Population) 
Table 14.3.5.1.2 
Categorical Summary of Clinical Laboratory Results - Urinalysis (Safety 
Population) 
Table 14.3.5.2 
Shift from baseline in Clinical Laboratory Results (Safety Population) 
Table 14.3.5.3 
Summary of Potentially Clinically Significant Laboratory Results (Safety 
Population) 
Table 14.3.5.4 
Absolute and Change from Baseline Vital Signs (Safety Population) 
Table 14.3.5.5 
Shift Table for Vital Signs (Safety Population) 
Table 14.3.5.6 
Summary of Potentially Clinically Significant Vital Signs Results (Safety 
Population) 
Table 14.3.5.7 
ECG Interpretation Summary (Safety Population) 
Table 14.3.5.8 
Respiratory Examination Findings Summary (Safety Population) 
Table 14.3.5.9 
Absolute and Change from Baseline for Asthma Control Test and Peak 
Expiratory Flow (Safety Population) 
Note: include Asthma control test and Actual PEF (L/min), and Actual 
PEF Rate of the predicted value (%)
Table 14.3.5.10 
Categorical Summary for Asthma Control Test and Peak Expiratory Flow 
(Safety Population)
Table 14.3.5.11 
Summary of COVID-19 Impact (Safety Population) 
Listing Number 
Listing Name 
Section 16.2.1 
Discontinued Subjects 
Listing 16.2.1.1 
Subject Disposition (All Screened Subjects) 
Listing 16.2.1.2 
Visits (Enrolled Population) 
Section 16.2.2 
Protocol Deviations 
Listing 16.2.2 
Protocol Deviations (Enrolled Population) 
Section 16.2.3 
Subjects Excluded from Analysis 
Listing 16.2.3.1 
Analysis Populations (Enrolled Population) 
Listing 16.2.3.2 
Eligibility Criteria (All Screened Subjects) 
Section 16.2.4 
Demographic Data 
Listing 16.2.4.1 
Demographics and Baseline Characteristics (Enrolled Population) 
Note: Screening Height, Weight and Smoking History
Listing 16.2.4.2 
Medical and Surgical History (Enrolled Population) 
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Listing 16.2.4.3 
Prior and Concomitant Medications (Enrolled Population) 
Listing 16.2.4.4 
Prior or Concomitant Medical and Surgical Procedures (Enrolled 
Population) 
Listing 16.2.4.5 
Investigator's Global Assessment (Enrolled Population) 
Listing 16.2.4.6 
Body Surface Area of Atopic Dermatitis Involvement (Enrolled Population) 
Section 16.2.5 
Compliance and/or Drug Concentration Data 
Listing 16.2.5.1 
Study Drug Dosing Record and Compliance (Safety Population) 
Listing 16.2.5.2 
Individual Concentrations (Safety Population) 
Note: present for plasma CYP substrates and serum nemolizumab
Listing 16.2.5.3 
Individual Pharmacokinetic Parameters (Safety Population)
Note: present for plasma CYP substrates  
Figure 16.2.5.1 
Plots of Individual Concentration (Safety Population) 
Note: present for plasma CYP substrates, each analyte separately and all 
days in one plot 
Figure 16.2.5.2 
Overlay Plots of Individual Concentration (Safety Population) 
Note: present for plasma CYP substrates, each analyte separately and all 
days in one plot 
Section 16.2.6 
Individual Efficacy/Pharmacokinetic Response Data 
Section 16.2.6.1 
Individual Efficacy Response Data 
Listing 16.2.6.1.1 Peak Pruritus Numeric Rating Scale Results (Safety population) 
Listing 16.2.6.1.2 Eczema Area and Severity Index (Safety population) 
Section 16.2.7 
Adverse Event Listings 
Listing 16.2.7 
All Adverse Events (Enrolled population) 
Section 16.2.8 
Individual Measurements by Subject 
Listing 16.2.8.1 
Clinical Laboratory Data (Enrolled population)
Listing 16.2.8.2.1 Pregnancy Test and FSH Results (Enrolled population) 
Listing 16.2.8.2.2 Child Bearing Potential (Enrolled population) 
Listing 16.2.8.3 
International Normalized Ratio Data (Enrolled population) 
Listing 16.2.8.4 
Vital Signs (Enrolled population) 
Note: Include weight
Listing 16.2.8.5 
Electrocardiogram Results (Enrolled population) 
Listing 16.2.8.6 
Physical Examination Findings (Enrolled population) 
Listing 16.2.8.7 
Anti-drug Antibody Results (Safety population) 
Listing 16.2.8.8 
Asthma Control Test (Enrolled population) 
Listing 16.2.8.9 
Respiratory Assessment (Enrolled population) 
Listing 16.2.8.10 
Peak Expiratory Flow Rate (Enrolled population) 
Listing 16.2.8.11 
Asthma Triggers (Enrolled Population) 
Listing 16.2.8.12 
QuantiFERON-TB Gold Test Results (Enrolled Population) 
Listing 16.2.8.13 
Cytochrome P450 Genotyping (Enrolled Population) 
Listing 16.2.8.14 
Alcohol Urine Test and Urine Drug Screen Results (Enrolled population) 
Listing 16.2.8.15 
COVID-19 Impact Listing (Enrolled population) 
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Listing 16.2.8.16 
Comments (Enrolled population) 
 
 
 
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9. REFERENCES
1. Chuang-Stein C. Summarizing laboratory data with different reference ranges in multi-
center clinical trials. Drug Information Journal 1992; 26(1): 77-84
2. Chuang-Stein C. Some issues concerning the normalization of laboratory data based on
reference ranges. Drug International Journal 2001; 35(1): 153-56
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