Conditions: Prurigo Nodularis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 70
Healthy volunteers: no

Brief summary:
The aim of this study is to assess the safety and efficacy of nemolizumab in subjects with prurigo nodularis.

Detailed description:
This is a randomized, placebo-controlled, double-blinded, parallel group, multicenter study to evaluate the safety and efficacy of nemolizumab over a 12-week treatment period in patients suffering from prurigo nodularis compared to its placebo.

Arms:
arm 1: Participants received 3 subcutaneous injections of placebo (matched to nemolizumab) every 4 weeks (Q4W) up to Week 8. arm 2: Participants received 3 subcutaneous injections of nemolizumab 0.5 milligram per kilogram (mg/kg) Q4W up to Week 8.

Interventions: intervention 1: CD14152 Dose A intervention 2: CD14152 placebo
Intervention descriptions: intervention 1: 3 subcutaneous injections (every 4 weeks during the 12-week treatment period) intervention 2: 3 subcutaneous injections (every 4 weeks during the 12-week treatment period)

Protocol document:
Prot_000.pdf: 
Official Title 
A  study to assess the safety and efficacy of nemolizumab (CD14152)  in subjects with prurigo nodularis (PN) 
NCT Number: NCT03181503
Date : 30 May 2017


GALDERMA R&D 
Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
Page 1 of 86 
CONFIDENTIAL 
This document contains confidential, proprietary information 
All the information provided to the Investigator and his/her staff and all data obtained through 
this GALDERMA clinical trial protocol are confidential.  The Sponsor reserves all proprietary 
rights. No information may be disclosed to any third party without prior written consent from 
GALDERMA. 
CLINICAL TRIAL PROTOCOL 
PROTOCOL NUMBER: RD.03.SPR.115828 
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Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
Page 2 of 86 
TITLE PAGE 
Title 
A  study to assess the safety and efficacy of nemolizumab (CD14152)  in subjects with prurigo 
nodularis (PN) 
Project Name or CD number: 
Project Number: 
Clinical Trial Phase: 
CD14152 
1295 
II a 
EUDRACT NUMBER: 2017-001715-36 
IND Number: 117122 
Version Number: V00 
SPONSOR: 
Name: 
GALDERMA R&D, SNC 
Address: 
Les Templiers 
2400 route des Colles 
06410 BIOT France 
Telephone: 
+33 (0)4 93 95 70 70 
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Protocol No.: RD.03.SPR.115828  
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For any safety questions, please contact the Clinical Safety Officer (CSO) using the contact 
details provided in Section 7.2.4.2.2. 
For any medical questions related to the clinical trial protocol, please contact the Medical Expert 
(see contact details in study team contact list). 
This clinical trial will be performed in compliance with applicable regulatory requirements and 
Good Clinical Practice (GCP).  This clinical trial protocol follows guidelines outlined by the 
International Conference on Harmonisation (ICH) and the GALDERMA template. 
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Table of Contents 
TITLE PAGE ............................................................................................................................................... 2 
SYNOPSIS .................................................................................................................................................... 10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................................ 18 
1 
BACKGROUND AND RATIONALE ........................................................................................... 22 
1.1 
Medical background and Short rationale for the clinical trial .............................................. 22 
1.2 
Drug profile ................................................................................................................................ 24 
1.3 
Pharmacokinetic profile ............................................................................................................ 26 
1.4 
Risk/Benefit assessment ............................................................................................................. 26 
2 
CLINICAL TRIAL OBJECTIVES AND CLINICAL HYPOTHESIS ..................................... 27 
2.1 
Clinical trial objectives .............................................................................................................. 27 
2.1.1 
Primary objective .................................................................................................................. 27 
2.1.2 
Secondary objectives ............................................................................................................. 27 
2.2 
Clinical hypothesis ..................................................................................................................... 28 
3 
OVERALL CLINICAL TRIAL DESCRIPTION ........................................................................ 28 
3.1 
Overview ..................................................................................................................................... 28 
3.2 
Rational for study design ........................................................................................................... 29 
4 
CLINICAL TRIAL DURATION AND TERMINATION .......................................................... 30 
5 
SELECTION AND DISPOSITION OF CLINICAL TRIAL POPULATION .......................... 30 
5.1 
Number of subjects .................................................................................................................... 30 
5.2 
Clinical trial population characteristics ................................................................................... 30 
5.3 
Inclusion criteria ........................................................................................................................ 31 
5.4 
Exclusion criteria ....................................................................................................................... 32 
5.5 
Specific exclusion criteria for skin biopsies ............................................................................. 35 
5.6 
Previous and concomitant therapies......................................................................................... 35 
5.6.1 
Definition ............................................................................................................................... 35 
5.6.2 
Categories .............................................................................................................................. 35 
5.6.3 
Recording ............................................................................................................................... 36 
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5.6.4 
Authorized concomitant therapies ...................................................................................... 36 
5.6.5 
Prohibited concomitant therapies........................................................................................ 36 
5.7 
Rescue therapies ......................................................................................................................... 37 
5.8 
Procedures/Reasons for subject discontinuation from the study ........................................... 37 
6 
CLINICAL SUPPLIES ................................................................................................................... 38 
6.1 
Clinical supply identification and use ...................................................................................... 38 
6.1.1 
Study drug description ......................................................................................................... 38 
6.1.2 
Subject Identification Number (SIN) .................................................................................. 38 
6.1.3 
Method of treatment assignment ......................................................................................... 39 
6.1.4 
Randomization number ........................................................................................................ 39 
6.1.5 
Instructions for use and administration .............................................................................. 39 
6.1.6 
Other supplies........................................................................................................................ 39 
6.2 
Study drugs packaging and labeling ........................................................................................ 39 
6.3 
Supplies management ................................................................................................................ 40 
6.3.1 
Accountability ....................................................................................................................... 40 
6.3.2 
Storage of study drug ............................................................................................................ 40 
6.3.3 
Dispensing and return .......................................................................................................... 40 
6.3.4 
Treatment compliance management and record ............................................................... 40 
6.4 
Dose modification ....................................................................................................................... 40 
6.5 
Study drug discontinuation ....................................................................................................... 41 
6.6 
Blinding ....................................................................................................................................... 41 
6.6.1 
Verification of blinding ......................................................................................................... 41 
6.6.2 
Un-blinding during the clinical trial .................................................................................... 42 
7 
CLINICAL TRIAL ASSESSMENT .............................................................................................. 42 
7.1 
Efficacy measurements .............................................................................................................. 42 
7.1.1 
Assessment of pruritus and quality of life by the Subject ................................................. 42 
7.1.1.1 
Pruritus Numeric Rating Scale (NRS) ........................................................................... 42 
7.1.1.2 
Verbal rating scale (VRS) ............................................................................................... 43 
7.1.1.3 
Sleep disturbance Numeric Rating Scale (NRS) ........................................................... 43 
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7.1.1.4 
Dynamic Pruritus Score (DPS) ....................................................................................... 44 
7.1.1.5 
Dermatology Life Quality Index (DLQI) ....................................................................... 44 
7.1.2 
Assessment of prurigo by the Physician .............................................................................. 44 
7.1.2.1 
Investigator Global Assessment (IGA) of Prurigo ........................................................ 44 
7.1.2.2 
Assessment of Prurigo Activity Score(PAS) .................................................................. 44 
7.1.3 
Appropriateness of efficacy measurements ........................................................................ 45 
7.2 
Safety assessment ....................................................................................................................... 45 
7.2.1 
Electrocardiograms (ECG) .................................................................................................. 45 
7.2.2 
Physical examination and vital signs ................................................................................... 46 
7.2.2.1 
Physical examination ....................................................................................................... 46 
7.2.2.2 
Vital signs ......................................................................................................................... 46 
7.2.2.3 
Height and Weight ........................................................................................................... 46 
7.2.2.4 
Respiratory assessments and PEF measurement .......................................................... 46 
7.2.3 
Laboratory safety tests ......................................................................................................... 47 
7.2.4 
Adverse Events ...................................................................................................................... 49 
7.2.4.1 
Definitions ......................................................................................................................... 49 
7.2.4.1.1 
Adverse events (AE) ...................................................................................................... 49 
7.2.4.1.2 
Serious Adverse events (SAE) ....................................................................................... 49 
7.2.4.1.3 
Adverse Events of Special Interest (AESIs) .................................................................. 50 
7.2.4.1.4 
Unexpected adverse drug reaction ............................................................................... 51 
7.2.4.1.5 
Adverse event reporting period .................................................................................... 51 
7.2.4.1.6 
Severity ......................................................................................................................... 51 
7.2.4.1.7 
Relationship to the study drug(s) and/or clinical trial procedure ................................ 51 
7.2.4.2 
Reporting procedures ...................................................................................................... 52 
7.2.4.2.1 
Procedures for reporting Adverse Events ..................................................................... 52 
7.2.4.2.2 
Procedure for reporting a Serious Adverse Event ........................................................ 53 
7.2.4.2.3 
Procedure for reporting asthma/worsening of asthma ................................................. 54 
7.2.4.2.4 
Procedures for reporting pregnancies .......................................................................... 54 
7.3 
Pharmacokinetic assessments ................................................................................................... 55 
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7.3.1 
Technical procedures for pharmacokinetic blood sampling ............................................. 55 
7.3.2 
Serum and PK analyses ........................................................................................................ 56 
7.3.3 
Anti-drug antibody analysis ................................................................................................. 57 
7.4 
Pharmacodynamic assessments ................................................................................................ 57 
7.4.1 
Blood samples for PD ............................................................................................................ 58 
7.4.2 
D-Squames samples .............................................................................................................. 58 
7.4.3 
Skin biopsies .......................................................................................................................... 58 
7.5 
Biophysical assessments ............................................................................................................. 59 
7.5.1 
Actigraphy ............................................................................................................................. 59 
7.5.2 
Whole body imaging ............................................................................................................. 59 
8 
CLINICAL TRIAL VISITS DESCRIPTIONS AND PROCEDURES ...................................... 60 
8.1 
Description of clinical trial visits .............................................................................................. 60 
8.1.1 
Screening period (Day -28 to Day -1) .................................................................................. 60 
8.1.1.1 
Visit 1 / Screening visit 1 (Day – 28 to Day -8) .............................................................. 60 
8.1.1.2 
Visit 2 / Screening visit 2 (Day –7) .................................................................................. 61 
8.1.2 
Treatment period .................................................................................................................. 61 
8.1.2.1 
Visit 3 / Baseline visit (Day 1) ......................................................................................... 61 
8.1.2.2 
Visit 4 / Day 8 Week 1 (+/-1 day) & Visit 5 / Day 15 Week 2 (+/-2 days) .................... 63 
8.1.2.3 
Visit 6 / Day 29 Week 4 (+/-2 days) & Visit 7 / Day 57 Week 8 (+/-2 days) ................ 63 
8.1.2.4 
Visit 8 / Day 85, Week 12 (+/- 5 days) ............................................................................. 64 
8.1.3 
Follow up period ................................................................................................................... 64 
8.1.3.1 
Visit 9 / Day 113, Week 16 (+/- 5 days) ........................................................................... 64 
8.1.3.2 
Visit 10 / Day 126, Week 18 (+/- 7 days) ......................................................................... 65 
8.1.4 
Early Termination visit or unscheduled visit: .................................................................... 65 
8.2 
Subject instructions (other than study drug administration) ................................................ 66 
9 
STATISTICAL METHODS PLANNED ...................................................................................... 66 
9.1 
Variables to be analyzed ............................................................................................................ 66 
9.1.1 
Efficacy endpoints ................................................................................................................. 66 
9.1.2 
Safety endpoints .................................................................................................................... 67 
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9.1.3 
PK endpoints ......................................................................................................................... 67 
9.1.4 
PD endpoints.......................................................................................................................... 67 
9.1.5 
Other endpoints ..................................................................................................................... 67 
9.2 
Statistical and analytical plans .................................................................................................. 67 
9.2.1 
Data transformations ............................................................................................................ 68 
9.2.2 
Populations analyzed, evaluability and limitation / evaluation of bias ............................ 68 
9.2.2.1 
Intent-to-treat (ITT) Efficacy Population ...................................................................... 68 
9.2.2.2 
Per-protocol (PP) Efficacy Population ........................................................................... 68 
9.2.2.3 
Safety Population ............................................................................................................. 68 
9.2.2.4 
PK analysis population .................................................................................................... 68 
9.2.2.5 
PD analysis population .................................................................................................... 68 
9.2.3 
Data presentation and graphics ........................................................................................... 69 
9.2.4 
Inferential statistical analyses .............................................................................................. 70 
9.2.5 
Pharmacokinetic parameters and ADA analyses ............................................................... 71 
9.3 
Sample size determination ......................................................................................................... 72 
9.3.1 
Historical data ....................................................................................................................... 72 
9.3.2 
Assumptions........................................................................................................................... 72 
9.3.3 
Sample size calculation ......................................................................................................... 72 
9.4 
Interim analysis at Week 4 ........................................................................................................ 72 
10 
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE ........... 73 
10.1 
Personnel training ...................................................................................................................... 73 
10.2 
Clinical monitoring .................................................................................................................... 73 
10.3 
Data management ...................................................................................................................... 73 
10.4 
Quality assurance / audit / inspection....................................................................................... 74 
10.5 
Changes in clinical trial conduct / amendments ...................................................................... 74 
10.5.1 
Clinical trial conduct ............................................................................................................ 74 
10.5.2 
Amendments .......................................................................................................................... 74 
11 
ETHICS AND GENERAL CLINICAL TRIAL CONDUCT CONSIDERATIONS ................ 75 
11.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ....................... 75 
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11.2 
Ethical conduct of the clinical trial ........................................................................................... 75 
11.3 
Subject information and consent .............................................................................................. 75 
11.4 
Contractual requirements ......................................................................................................... 75 
11.5 
Data collection and archiving .................................................................................................... 76 
11.5.1 
Data collection ....................................................................................................................... 76 
11.5.2 
Source documentation .......................................................................................................... 76 
11.5.3 
Archives ................................................................................................................................. 76 
11.6 
Insurance .................................................................................................................................... 77 
11.7 
Investigator and Administrative Structure ............................................................................. 77 
12 
LITERATURE REFERENCE LIST ............................................................................................. 77 
13 
APPENDICES ................................................................................................................................. 81 
List of Tables 
Table 1 
Clinical trial schematic ........................................................................................................... 15 
Table 2 
Schedule of Assessments ........................................................................................................ 16 
Table 3 
Forbidden therapies ................................................................................................................. 34 
Table 4 
 Description and usage of the study drug ................................................................................ 38 
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SYNOPSIS 
Clinical Trial Title: A study to assess the safety and efficacy of nemolizumab (CD14152)  in subjects with prurigo nodularis (PN) 
Clinical Trial phase: 
II a 
Clinical Trial Population:  
Adult subjects with clinical diagnosis of PN for at least 6 months with at least 20 nodules on the whole body 
Clinical Trial objectives: 
Primary objective: 
The primary objective is to assess the efficacy of nemolizumab compared to placebo in the treatment of pruritus 
in patients suffering from PN. 
Secondary objective: 
The secondary objectives are: 
Efficacy and safety: 

Evaluation of the safety of nemolizumab compared to its placebo in patients with PN.

Evaluation of the efficacy of nemolizumab compared to its placebo in the treatment of prurigo lesions
in patients with PN.

Evaluation of nemolizumab effect compared to its placebo on quality of life in patients with PN
Pharmacokinetics (PK) 

Characterization of nemolizumab PK profile and exposure response relationship in patients with PN
Pharmacodynamics (PD) 

Evaluation of the effect of nemolizumab on biomarkers in patients with PN
Biophysical (exploratory) 

Evaluation of the efficacy of nemolizumab on scratching events and sleep improvement using
actigraphy

Evaluation of the efficacy of nemolizumab on lesions improvement using whole body images device
only on equipped sites.
Clinical Trial design: 
This is a randomized, placebo-controlled, double-blinded, parallel group, multicenter study to evaluate the safety 
and efficacy of nemolizumab in patients suffering from PN.  
Approximately 70 adult patients suffering from PN for at least 6 months with severe pruritus defined by the 
mean of the worst daily intensity of the NRS score ≥ 7 over the previous week at baseline will be randomized in 
the study. 
Subjects meeting inclusion/exclusion criteria will be randomized in a 1:1 ratio to nemolizumab or placebo. Each 
subject will receive three subcutaneous injections of 0.5mg/kg of nemolizumab or matching placebo. Injections 
will be administered every 4 weeks (baseline, week 4 & week 8). 
Subjects’ participation in the study will be up to 22 weeks, including an up to 4-week screening period, a 12-
week treatment period (last study drug injection at week 8) and a 6-week follow-up period  (10 weeks after the 
last study drug injection corresponding to 5 half-lives of nemolizumab). 
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SYNOPSIS 
Clinical Trial Title: A study to assess the safety and efficacy of nemolizumab (CD14152)  in subjects with prurigo nodularis (PN) 
A total of 10 visits per subject is planned.  Schedule of assessments is summarized in Table 2. Safety and 
efficacy assessments will be conducted throughout the study. Pruritus severity will be self-evaluated by the 
subjects on a daily basis using the ePRO and following instructions provided by the Investigator. The 
Investigator will evaluate the evolution of prurigo lesions using appropriate scales. 
PK profile of nemolizumab in PN patients will be assessed according to Table 2. 
PD assessments will be performed to evaluate cytokines/chemokine profiles, IL31 and IL31 RA quantification by 
proteomics, 
genomic 
and 
histology 
analysis 
using 
three 
4-mm 
skin 
biopsies,  
D-squames and blood samples collected according to  Table 2. Skin biopsies will be optional, patients  
accepting this procedure will have to sign an additional consent. 
Exploratory biophysical assessments will be performed by measuring scratching events during the night and 
sleep duration using actigraphy. The subject will have to wear two watches from Day -7 to baseline and during 
the first four weeks of the study. In addition, photographs of the entire body will be taken in equipped sites using 
a whole-body imaging device according to Table 2 
An interim analysis may be performed once at least 40 subjects will have completed the week 4 visit or 
discontinued before (decision will be taken by the Sponsor according to the recruitment rate). This analysis will 
include efficacy data on all subjects up to that time point. In addition to efficacy, all safety data available (not 
only data up to week 4) will also be analyzed (Section 9.4). 
Total number of subjects 
(Planned):  
As a screen failure rate of approximately 30 percent is expected, approximately 100 subjects may have to be 
screened in order to get 70 randomized subjects (35 subjects per treatment group).  
Number of clinical trial 
centers (Planned): 
Approximately 20 sites 
Regions / countries 
involved (Planned): 
Austria, France, Germany, Poland & US 
Clinical trial duration: 
The planned clinical trial duration (from FSFV to LSLV) is approximately 10 months. 
Duration of subject 
participation:  
Clinical trial participation for each subject is approximately 22 weeks. 
Key Inclusion criteria 
1.  Male or female of at least 18 years at screening
2. Clinical diagnosis of PN for at least 6 months  with:

Prurigo lesions on upper limbs with or without lesions on the trunk  or lower limbs

At least 20 nodules on the entire body with a bilateral distribution
3. Severe pruritus defined as follows on a Numerical Rating Scale (NRS) 

At the Screening visit 1: Mean of the worst daily intensity of the NRS score is ≥ 7 over the previous 3 days

At the Baseline visit: Mean of the worst daily intensity of the NRS score is ≥ 7 over the previous week; 
NOTE: NRS score should be measured on at least 5 days during the week preceding the baseline visit.  
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Key Exclusion 
criteria 
1. Chronic pruritus resulting from another condition than PN  such as scabies, insect bite, lichen simplex chronicus,
psoriasis, acne, folliculitis, habitual picking, lymphomatoid papulosis, chronic actinic dermatitis, dermatitis
herpetiformis, sporotrichosis, bullous disease 
2. Unilateral lesions of prurigo (e.g only one arm affected)
3. Cutaneous bacterial or viral infection within 1 week before the baseline visit. 
4. Infection requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics or antifungals within 1 week
before the screening visit, or during the screening period, unless completely resolved at the screening/ baseline visits
respectively, 
5. Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with the
interpretation of the clinical trial results and/or put the subject at significant risk according to Investigator’s judgment
(e.g. solid cancer, AIDS, serious or uncontrolled cardiac disease…) at Screening or Baseline. 
NOTE: Patients with controlled diseases such as diabetes mellitus, thyroid disorders and psychiatric disorders
(such as depression and anxiety) are eligible 
6. Any active dermatoses that would need immediate therapy. 
7. Subject with active atopic dermatitis or known with recurrent flares of atopic dermatitis 
NOTE: patients with atopic diathesis, as diagnosed by the medical history and/or laboratory analysis (i.e. specific
IgE), are eligible for the study
8. Neuropathic and psychogenic pruritus (notalgia paresthetica, brachioradial pruritus, dilutional parasitosis,
pathomimia)
9. Positive serology results hepatitis B surface antigen [HBsAg] or hepatitis B core antibody [HBcAb], hepatitis C
antibody or Human Immunodeficiency virus [HIV] antibody) at the screening visit 
NOTE : Subject with a positive HBcAb and a negative HBsAg can be included in this trial if HBsAb is positive
(considered immune after a natural infection)
10. Subject having any of the abnormal lab criteria listed below, at the screening visit: 

Elevated ALT / AST ≥ 3 ULN 

Elevated CPK > 1.5 ULN, unless not confirmed on a repeat assessment to be performed at least 72h
after the first one 

Neutrophil count < 1.5 x 103/µl

Creatinine clearance <60ml/min/1.73m² calculated with the CKD-EPI formula (Levey et al 2009)

Any other abnormal lab result that would be considered as clinically significant by the investigator
11.
Subjects with a medical history of asthma that fulfill any or more of the conditions  below 

Had an asthma exacerbation requiring hospitalization in the last 12 months before screening visit 

Whose asthma has not been well-controlled (i.e. symptoms >2 days per week, nighttime awakenings
>1-3 times per week, or some interference with normal activities) during the last 3 months before the
screening visit 

PEF <80% of the predicted value at screening or baseline visit
12. Latent or active TB, as determined by a positive Quantiferon-based TB test result at screening visit 1. 
NOTE: In case of indeterminate result, the test should be repeated in local laboratory at screening visit 2 (only one
retest is allowed). If the test is still indeterminate, the subject will not be included. 
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Investigational 
product and its 
comparator 
Investigational product 
Comparator 
Name 
Nemolizumab 
Nemolizumab placebo 
Internal code 
CD14152 
NA 
Pharmaceutical form 
Lyophilized powder 
Lyophilized powder 
Concentration 
100mg/ml when reconstituted 
NA 
Formula number 
NA 
NA 
Packaging 
Vial 
Vial 
Storage conditions 
Stored between 2 to 8°C (36-46°F) and 
protected from light 
Stored between 2 to 8°C (36-46°F) and 
protected from light 
Dosage 
0.5 mg/kg 
Not applicable 
Route 
Subcutaneous injection 
Subcutaneous injection 
Dose regimen 
3 injections (baseline, Week 4, Week 8) 
3 injections (baseline, Week 4, Week 8) 
Treatment duration 
12 weeks 
12 weeks 
Efficacy endpoints:  Primary: The primary efficacy outcome will be the percent change from baseline in NRS to week 4 (weekly average of 
the peak). 
Secondary: 

Absolute and Percent change from baseline in weekly average of the peak and average pruritus NRS to each visit 

Change from baseline of VRS at each time point

DPS 

PAS: Distribution for item 6 (excoriation/crusts and healed lesions stages) and change from baseline for item 5 (in
lesions number)

IGA: Distribution score and success rate (defined as IGA=0[clear] or IGA=1[Almost clear] with two point
improvement from baseline).
Other enpoints: 

Quality of life (DLQI)

Objective assessments of scratching and sleep by Actigraphy

Sleep disturbance NRS
Safety 
assessments: 
The safety measures for this study are as follows: 

Adverse events

Laboratory tests

Vital signs

Physical exam and body weight

12-lead ECG

PEF
Pharmacokinetic 
assessment and 
anti-drug antibody 
(ADA) assessment: 
Blood samples will be collected at specific time points according to Table 2 for measurement of PK profile of 
nemolizumab and anti-nemolizumab antibodies . 
The nemolizumab serum exposure will be assessed at the following time-points: baseline, weeks 1, 2, 4, 8, 12, 16 and 
18 and at early termination or any unscheduled visit for safety reason. 
ADA will be assessed at baseline, weeks 4, 8, 12, 16 and 18 and in case of early termination or unscheduled visit for 
safety reason. 
Pharmacodynamics 
assessment: 
Blood and skin samples (D-Squames and skin biopsies) will be collected to investigate the effect of nemolizumab on 
biomarkers according to Table 2 
As much as possible, skin sampling will be performed in similar body areas for all samples in all patients, on a selected 
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area at baseline, such as the upper arms. Skin biopsies on prurigo lesions will be performed on lesional and non 
lesional skin at baseline, and on lesional skin at week 12 (only for patients consenting to have skin biopsies). Non-
lesional sample will be taken in areas with no scratch such as the inner part of the upper arm,  approximately 5 cm apart 
from lesional skin  
The detail of the procedure and storage conditions will be described in an Operational manual. 
All collected samples will be sent to GALDERMA R&D for analysis. After performance of the planned investigations, the 
remaining samples will be integrated into the long term research program being performed in the research department 
of Galderma R&D (Program (2) – “Physiopathological study on skin disease to identify new dermatological medications; 
Initial declaration CP ECOH : DC-2008-315, 31/01/2009).  
Principal statistical 
method: 
The primary efficacy analysis of the percent change from baseline to week 4 of the weekly average of the NRS (weekly 
average of the worst score)  will be an ANOVA including the Treatment group as factor, presence and absence of 
background of atopy and country as a cofactors. 
In addition to the per-protocol analysis, several sensitivity analyses on ITT population will be conducted for the primary 
endpoint. For ITT, NRS will be set to missing after rescue medication is used.  
 The primary imputation method for any missing data will be the LOCF (Last observation carried forward) approach. 
 Multiple Imputation (MI) using the Missing At Random (MAR) assumption will also be used. The MI procedure of the 
SAS system will be used to generate five sets of data with missing values imputed from observed data. It is expected
that the pattern of missing data will be monotonic, with slight deviations being corrected by the Markov Chain Monte
Carlo (MCMC) method of the MI procedure.  Linear regression will be employed to model the missing NRS score,
with the following covariates included in the imputation model: treatment and non-missing data from earlier
timepoints. The imputed datasets will be analyzed using the methodology described for percent change from baseline
in NRS score. The results from the analysis of the multiple imputed datasets will be combined by the MIANALYZE
procedure of the SAS system. The seed number to be used will be the protocol number (115828).
The PD parameters will be visualized by boxplots (with a logarithm base 10 Y axis where needed). The compound effect 
will be estimated by Student’s t test comparing the change at D85 from D1 for CD14152 vs the change at D85 from D1 
for placebo (or other if more appropriate). The multiple testing problem will be taken into account by the Benjamini-
Hochberg approach (1995)(or other if more appropriate). 
Summary statistics will be provided by treatment group for treatment emergent adverse events, 
Sample size: 
With an effect size of (30/35=) 0.857, a power of 90% and a type I error of 5% two-sided; at least 30 subjects are 
needed per group. In order to maintain the power of the tests, for per-protocol population, in case of drop outs/major 
deviations at Week 4, the sample size will be increased to 35 subjects per group, i.e. 70 to be randomized. 
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Table 1 
Clinical trial schematic 
Screening (approximately 100) 
↓ 
Randomization (approximately 70) 
Group 1 
Group 2 
N= approximately 35 
N= approximately 35 
Treatment 
CD14152 0.5mg/kg 
CD14152 placebo 
Treatment Frequency 
Every 4 weeks (Q4W) 
Every 4 weeks (Q4W) 
Treatment Duration 
12 weeks (last study drug injection at 
week 8) 
12 weeks (last study drug injection at 
week 8) 
Follow up 
6 weeks (10 weeks after the last study 
drug injection) 
6 weeks (10 weeks after the last 
study drug injection) 
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Table 2 
Schedule of Assessments 
Study period 
Screening period 
(Day -28 to Day-1) 
Treatment period 
Observation period/ 
Follow up 
Early 
termination 
(E/T)  or 
Unscheduled 
visit  
(if applicable) 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Week 
Screening 1 
screening 2 
Baseline 
W1 
W2 
W4 
W8 
W12 
W16 
W18 
Day 
D-28 to D-8  
Day-7 (a)  
Day 1 
Day 8 
Day 15 
Day 29 
Day 57 
Day 85 
D113 
Day 126 
Visit window 
±1 day 
±2 days 
±2 days 
±2 days 
±5 days 
±5 days 
±7 days 
ICF and when applicable country specific consent  form  
● 
Photo Consent and Biopsies consent form  (if applicable) 
● 
Demographics 
● 
Medical history/ Previous therapies and procedures 
● 
Inclusion/Exclusion criteria 
● 
● 
Concomitant therapies and procedures  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Height  
● 
Weight 
● 
● 
● 
• 
Blood sample for serology (HIV, Hepatitis B and C test)  
● 
Blood samples for specific IgE 
● 
Blood samples for TB test (b) 
● 
SAFETY ASSESSMENTS 
Vital signs 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Physical exam 
● 
● 
● 
● 
● 
● 
● 
Blood samples for hematology and biochemistry (c) 
● 
● 
● 
● 
● 
Blood sample for CPK (d) 
● 
● 
● 
● 
● 
Urinalysis  
● 
● 
● 
● 
● 
12-lead ECG 
● 
● 
● 
● 
Pregnancy test  (e)  
Serum 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Respiratory assessment (f)  
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Adverse Events 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
STUDY DRUG 
Randomization 
● 
Subcutaneous study drug injection 
● 
● 
● 
(a) Screening visit 2 must be performed at least 7 days prior to Day 1 visit. Eligible subjects according to safety assessments will be provided with the Actigraphy and ePro devices. 
(b) In case of indeterminate result for TB test, the test should be repeated at screening 2 in the local laboratory (only one retest is allowed). If the test is still indeterminate, the subject must not be included in the 
study 
(c) Blood samples for hematology and biochemistry must be performed in fasting conditions  
(d) In case elevated CPK > 1.5 ULN, the test will be repetead at screening 2. If the result is still abnormal, the subject will not be included. 
(e) Only for female of childbearing potential. Serum pregnancy test to be performed at screening visit 1 and urine pregnancy test (UPT) for all other visits. UPT should have a sensitivity threshold of less than 
25mIU/mL. There should be at least 14 days between the serum pregnancy test at screening and the UPT at baseline. 
(f) Respiratory assessments for all subjects, but PEF will be measured only for subjects with medical history of asthma 
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Study period 
Screening period 
(Day -28 to Day-1) 
Treatment period 
Observation period/ 
Follow up 
Early 
termination 
(E/T)  or 
Unscheduled 
visit  
(if applicable) 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Week 
Screening 1 
screening 2 
Baseline 
W1 
W2 
W4 
W8 
W12 
W16 
W18 
Day 
D-28 to D-8  
Day-7 (a)  
Day 1 
Day 8 
Day 15 
Day 29 
Day 57 
Day 85 
D113 
Day 126 
Visit window 
±1 day 
±2 days 
±2 days 
±2 days 
±5 days 
±5 days 
±7 days 
EFFICACY/ PATIENTS REPORTED OUTCOMES 
NRS  (g)  
● 
Once daily by the subject at home in the evening until Day 126 
● 
VRS  (g)  
Once daily by the subject at home in the evening until Day 126 
● 
Sleep disturbance NRS(h) 
Once daily by the subject at home in the evening until Day 29 
DPS  (i)  
● 
● 
DLQI  
● 
● 
● 
● 
Prurigo Assessment Scale (PAS)  
● 
● 
● 
● 
● 
● 
IGA  
● 
● 
● 
● 
● 
● 
PK AND ADA ASSESSMENTS 
Blood sample for PK 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Blood sample for ADA 
● 
● 
● 
● 
● 
● 
● 
PHARMACODYNAMIC ASSESSMENTS 
Blood sample for biomarkers  
● 
● 
● 
D-Squames samples  
● 
● 
● 
4-mm skin biopsies  (j)  
● 
● 
Control of biopsies healing(k) 
●  
● 
BIOPHYSICAL ASSESSMENTS 
Photos of whole body  (l)  
● 
● 
● 
● 
● 
Actigraphy 
Every day until Day 29 
Exit Form 
● 
(a) NRS and VRS must be performed by the subject at home using the device provided by the site once daily in the evening from screening  2 to the last visit. 
(b) NRS for sleep disturbance must be performed by the subject at home using the device provided by the site once daily in the morning from screening  2 to Day 29 
(c) DPS must be performed by the subject at home following instruction provided by the Nurse on site and then subject should record DPS 24, 48 & 72 hrs after the 1st injection and at week 4 
before the injection. 
(d) Skin biopsies will be performed on lesional and non lesional skin at baseline and on lesional skin at week 12 only for patients consenting to have skin biopsies.  
(e) When applicable, biopsies healing should be checked 2 weeks after skin biopsies  
(f) Only for selected equipped sites – at least a Baseline & Week 12; Week 4, week 8 & week 18 if possible.
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
°C 
Degrees Celsius 
°F 
Degrees Fahrenheit 
ADA 
Anti-drug antibodies  
AD 
Atopic Dermatitis 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT/ALAT (SGPT) 
Alanine Aminotransferase (Serum Glutamic Pyruvic Transaminase) 
Approx. 
Approximately 
AST/ASAT (SGOT) 
Aspartate Aminotransferase (Serum Glutamic Oxaloacetic Transaminase) 
AUC 
Area under Curve 
CA 
Competent Authorities 
CI 
Coordinating Investigator 
Cmax 
Maximum Concentration 
CPK 
creatinine phosphokinase 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CS 
Clinical Significant 
CSO 
Clinical Safety Officer 
CV 
Coefficient of Variation 
DLQI 
Dermatology Life Quality Index 
DMP 
Data Management Plan 
DPS 
Dynamic Pruritus Score 
EASI 
Eczema Area and Severity Index 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
e.g 
For Example (Latin: exempli gratia) 
E/T 
Early Termination 
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etc 
Et cetera 
EU 
European Union 
Eur. Ph. or EP 
European Pharmacopoeia 
FDA 
Food and Drug Administration 
FSFV 
First Subject First Visit  
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
Hb 
Hemoglobin   
HBcAb 
Hepatitis B Core Antibody 
HBsAg 
Hepatitis B Surface Antigen 
Hct 
Hematocrit 
HCV 
Hepatitis C Virus 
HDL 
High density lipoprotein 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent Form 
ICH 
International Conference on Harmonisation 
i.e. 
That is (Latin: id est) 
IEC 
Independent Ethics Committee 
IGA 
Investigator’s Global Assessment 
IgE 
Imunoglobulin E 
IL 
Interleukin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRR 
Injection related Reaction 
IRT 
Interactive Response Technology 
ITT  
Intent-to-treat 
IU 
International Units 
LDL 
Low density lipoprotein 
LOCF 
Last Observation Carried Forward 
LOQ 
Limit of Quantification 
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LSFV 
Last Subject First Visit  
LSLV 
Last Subject Last Visit 
MCMC 
Markov Chain Monte Carlo 
MCV 
Mean Cell Volume 
MCVmax 
Maximum Mean Cell Volume 
MD 
Medical Doctor 
ME 
Medical Expert 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
N or n 
Number 
N/A 
Not Applicable 
NCS 
Non clinically significant 
NRS 
Numeric rating scale 
NSAID 
Non steroidal Anti-inflammatory drug  
p 
Page(s) 
PAS 
Prurigo Activity Score 
PD 
Pharmacodynamics 
PDE-4 
Phosphodiesterase-4 
PE 
Physical Exmination 
PEF 
Peak  Expiratory Flow 
PN 
Prurigo nodularis 
PK 
Pharmacokinetics 
Plt 
Platelets 
PP 
Per-Protocol 
PR 
Pulse Rate 
QoL 
Quality of Life 
RBC 
Red blood cell 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCORAD 
Scoring Atopic Dermatitis 
SD 
Standard Deviation 
SOC 
System Organ Class 
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SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t½ 
Half-life 
TB 
Tuberculosis  
TCS 
Topical corticosteroids 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to maximum concentration 
TOC 
Table of contents 
ULN 
Upper Limit of Normal 
UP 
Uremic Pruritus 
UPT 
Urine Pregnancy Test 
US 
United States 
VAS 
 Visual Analogue Scale 
VRS 
Visual rating scale 
WBC 
White Blood Cell 
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1 
BACKGROUND AND RATIONALE 
1.1 
Medical background and Short rationale for the clinical trial 
Prurigo nodularis (PN) is characterized by the presence of symmetrically distributed multiple (up 
to hundreds), highly pruritic, hyperkeratotic, erosive or crusted nodules and papules (Hyde JN et 
al., 1909). This leads to an impaired quality of life and high burden due not only to the severe 
itch but also the chronic, skin lesions and lack of treatment options (Warlich B., et al 2015). 
No reliable data exist about incidence and prevalence of PN in the general population, but it 
seems to be more frequent and intense in females and elderly (Iking A., et al., 2013). 
The physiopathology of PN is still not fully understood; however, the interactions between 
cutaneous nerve fibres, neuropeptides and immune cells seem to play an important role in the 
onset of PN (Zeidler C et al. 2016).  It was assumed that PN is a subclinical small fibre 
neuropathy based on the observed reduction of intraepidermal nerve fibre density in patients’ 
biopsies (Bharati et al 2007, Schuhknecht B et al., 2011) and observations with positive response 
to gabapentin and pregabalin commonly utilized in the treatment of pain and neuropathy 
[(Fostini et al., 2013). Changes in the morphology of skin nerve fibers with increased dermal 
neural hyperplasia and  inflammation caused by T lymphocytes, eosinophilic, granulocytes and 
mast cells were described in the development and chronification of PN (Zeidler C et al., 2016). 
Recent findings suggest that PN might be a consequence of chronic itch inducing neural 
sensitization followed by lesion appearance and development of a chronic itch-scratch cycle. A 
large spectrum of underlying conditions were considered as the origin of chronic pruritus 
classified in dermatological (e.g. atopic dermatitis), systemic (e.g. chronic kidney failure), 
neurological (e.g. brachioradial pruritus), psychiatric and mixed origin (Ständer S et al., 2007). 
Only few studies have described the incidence and the strength of association of different co-
morbidities in representative cohort of patients with PN (Iking  et al., 2013). An atopic 
predisposition seemed to be most commonly associated to PN patients in nearly half of the 
subjects. The atopic diathesis was also found to predict a significantly earlier age of onset 
(median age 19 years) compared to non-atopic patients (median age 48 years) (Tanaka et 
al.1995). 
Psychosocial disorders are also significantly associated with PN. These disorders can be a 
primary association or secondary to the itch in PN, presence of visible scratch-related nodules 
and inadequate response to currently available therapies. Rowland Payne et al., found that more 
than 50% of their PN patients had a history of depression or anxiety requiring medical 
intervention. 
The goal of PN treatment is to break the itch-scratch cycle and allow the skin to heal. Treatment 
of chronic pruritus is still notoriously challenging and frustrating for both dermatologists and 
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patients as in the majority of cases, the response is either limited or associated with severe 
adverse events with the current therapy options. There is no standardized or approved therapy for 
PN up-to-date and evidence from controlled studies is limited (Fostini AC et al., 2013). The 
difficulty in treating this disease is reflected in the wide range of treatments proposed in the 
literature. 
The current recommendations include identification and  treatment of any underlying disease, 
moisturizers and antipruritics, topical therapies (corticosteroids, calcineurin inhibitors) associated 
to non-sedating and sedating antihistamines  as first-line agents (Weisshaar E et al., 2012). 
Phototherapy, oral or intra-lesional steroids, topical vitamin D3 (calcipotriol), capsaicin, 
cryotherapy and antidepressants (amitriptyline, selective serotinine re-uptake inhibitors) are used 
as second-line therapies with variable efficacy. In third-line, systemic treatments such as 
cyclosporine (Berth-Jones J et al., 1995), antiepileptic drugs (gabapentin, pregabalin) (Mazza M 
et al 2013) and thalidomide (Andersen TP et al.2011) showed moderate-to-good response in 
pruritus reduction after several months of administration, but their use is limited by their 
unfavorable safety profile. Other off label therapeutic options proposed for pruritus in 
uncontrolled series referred to opioid receptor agonists and antagonists (naltrexone) (Brune A et 
al; 2004), NKR1-antagonists (aprepitant) (Ständer S et al., 2010), antibiotics (roxitromycine, 
erythromicine) (Horiuchi Y et al 2006). 
Nemolizumab (CD14152) is a humanized anti-human IL-31 receptor A (RA) monoclonal 
antibody that inhibits the binding of IL-31 to IL-31RA and subsequent signal transduction. 
The T-cell-derived cytokine interleukin-31 (IL-31) has been suggested to be a key player in the 
development of pruritus, inducing severe pruritus and dermatitis in mouse models (Dillon et al. 
2004, Arai et al., 2013). IL-31 binds to a heterodimeric receptor at TRPV1 (+)/TRPA1 (+)-C-
fibres, keratinocytes, macrophages and eosinophils, and thus may be involved in transmission of 
pruritus and promotion of inflammation. Not limited to the skin, the densest area of this receptor 
seems to be at the dorsal horn of spinal cord where the cell bodies of cutaneous sensory neurons 
reside (Sonkoly et al., 2006). Therefore, IL-31 may be a link between the immune and the neural 
system.  
In dogs with atopic dermatitis, lokivetmab, a caninized, anti-canine IL-31 antibody has been 
shown to reduce pruritus in a dose-dependent manner with a rapid onset of effect and to decrease 
the dermatitis score compared to placebo (Michels et al. 2016) and in cynomolgus monkeys, 
nemolizumab suppressed IL-31 induced scratching (Oyama et al. 2016). Also recent clinical 
studies of nemolizumab in patients with atopic dermatitis showed a rapid onset of pruritus 
reduction within one week followed by disease improvement (Ruzicka T et al 2017). 
Interestingly, skin biopsies from PN patients with an atopic background, in comparison to 
healthy skin from healthy individuals, showed a 50-fold upregulation of IL-31 mRNA and 4.5 
fold upregulation compared to atopic dermatitis patients (Sonkoly et al., 2006).  A significant 
higher level of IL-31 mRNA was also observed by Park K et al. in PN patients with unknown 
AD background compared to normal skin. 
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Taken all together, IL-31 seems to be an important cytokine for the regulation of PN and a 
potential therapy target. 
In conclusion, nemolizumab may present a new treatment option for PN in patients that usually 
present with severe pruritus, which leads to extensive scratching further aggravating the disease. 
The main objective of this study is to evaluate the efficacy, safety and pharmacokinetics (PK) of 
multiple subcutaneous doses of nemolizumab in the treatment of pruritus and lesions associated 
to PN. 
1.2 
Drug profile 
Nemolizumab is a humanized monoclonal modified immunoglobulin G (IgG) 2 antibody 
comprising a structure of two H-chains (445 amino acid residues) and two L-chains (214 amino 
acid residues) connected by 16 disulfide bonds.  
Please refer to the Investigator’s Brochure (IB) for detailed information on non-clinical and 
clinical studies. Two clinical studies have been completed and reported for nemolizumab (Phase 
1: CIM001JP; and Phase 2a: CIM003JG). In addition, one Phase 2 clinical study in uremic 
pruritus has been recently completed, but its clinical study report is not yet available (Phase 2: 
CIM106JP). Final data from studies CIM001JP and CIM003JG and preliminary data from study 
CIM106JP are summarized below. 
The safety, tolerability, and pharmacokinetics of a single subcutaneous dose of nemolizumab 
were evaluated in a randomized, double-blind, placebo-controlled phase 1 study including 80 
healthy volunteers and 36 Japanese AD subjects (CIM001JP) (Nemoto et al.  2016). There were 
no deaths or serious adverse events (SAE) reported in the study, and no dose-dependent increase 
in the incidence of AEs was observed. In healthy volunteers, the incidence of AEs was 
comparable between the nemolizumab groups and the placebo group, with similar results for 
Caucasians and Japanese volunteers. Among the healthy Caucasian adult males, increased 
creatinine phosphokinase (CPK) was more common in the nemolizumab groups, but the CPK 
increase in most subjects could be explained by excessive exercise.  
Efficacy results were also obtained in this phase 1 study with 36 moderate-to-severe Japanese 
AD subjects receiving a single dose of nemolizumab (0.3mg/kg, 1mg/kg or 3mg/kg) or placebo 
with concomitant topical hydrocortisone butyrate. Intensity of pruritus decreased as early as 
week 1 in the nemolizumab groups, by a similar degree with all three doses. Treatment with 
nemolizumab also increased sleep efficiency as measured by actigraphy and decreased the use of 
TCS in the study. Incidence of AE in AD subjects was similar between nemolizumab groups and 
placebo group, and was not dose-dependent. The most common AEs reported with nemolizumab 
included aggravated atopic dermatitis, folliculitis and nasopharyngitis. One subject in the group 
of 3 mg/kg was diagnosed with asthma: the subject experienced some degree of breathlessness 
from day 9 after nemolizumab administration and symptoms had resolved by day 22. The subject 
experienced no further respiratory symptoms until the last observation.  
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In the completed phase 2a study, the safety, tolerability and efficacy of nemolizumab 
monotherapy were evaluated in 264 moderate-to-severe AD subjects who were inadequately 
controlled by or intolerant to topical therapy (CIM003JG). The study included a 12-week 
randomized, double-blind, placebo-controlled period (Part A), a 52-week extension (Part B), and 
a 12-week follow-up period without treatment. At week 12, all doses of nemolizumab (0.1mg/kg, 
0.5mg/kg or 2.0mg/kg) administered subcutaneously every 4 weeks (Q4W) were statistically 
significantly more effective than placebo in reducing pruritus visual analogue scale (VAS), with 
0.5mg/kg and 2.0mg/kg doses being more effective than 0.1mg/kg. No additional benefit was 
observed with the 2mg/kg Q4W or Q8W compared with 0.5mg/kg Q4W. The mean percent 
changes in Eczema Area and Severity Index (EASI), Body Surface Area (BSA) of AD, SCORing 
Atopic Dermatitis (SCORAD), Investigator’s Global Assessment (IGA) and sleep disturbance 
VAS were also numerically greater in all treatment groups than in the placebo group.  The 
greatest improvements were generally observed in the nemolizumab 0.5 mg/kg and 2.0 mg/kg 
Q4W groups. Subjects who received placebo in Part A were randomized to receive 0.1mg/kg, 
0.5mg/kg or 2.0mg/kg Q4W in Part B. There was evidence of a progressive improvement in all 
efficacy parameters with prolonged treatment.  
During Part A, incidence of AEs was slightly higher in the nemolizumab groups (all groups 
pooled) than in the placebo group. AEs that occurred in 5% or more of nemolizumab-treated 
patients (all groups pooled) were (worsening of) atopic dermatitis, nasopharyngitis, upper 
respiratory tract infection, peripheral edema, and blood CPK increased.   
Atopic dermatitis ,peripheral  edema , and headache were observed more often in Nemolizumab 
groups pooled compared to the placebo group, with generally no dose-dependency, except for 
peripheral edema (which was more frequent in Nemolizumab 2.0mg/kg Q4W group compared to 
lower dose groups of nemolizumab). However, most of cases of peripheral edema occurred 
during part A, were transient, of mild or moderate intensity and none led to treatment 
discontinuation.  
Lastly, various AEs that could be grouped as “injection-related reactions (IRRs)” or “skin 
infection” were also observed with a higher frequency with nemolizumab than with placebo.  
Severe AEs were reported more frequently in nemolizumab groups than in placebo group (in Part 
A), but there was no evidence that the incidence increased with higher dose.  
During the entire study (Part A and B), AEs that occurred in 5% or more of  nemolizumab-
treated patients (all groups pooled) were nasopharyngitis, atopic dermatitis , blood CPK 
increased, upper respiratory tract infection, headache, peripheral edema , and impetigo. The 
majority of AEs were mild or moderate in intensity.  
No clinically relevant findings were observed during the study for laboratory tests, vital signs, 
physical examination or electrocardiogram (ECG).  
Treatment-emergent antibodies to Nemolizumab were observed in 7.1% of the patients in the 
pooled nemolizumab groups. In addition one patient in the 0.1 mg/kg Q4W group with anti- drug 
antibodies (ADA) present from baseline developed neutralizing antibodies at 64 weeks.  
 
A randomized, double-blind, placebo-controlled, parallel group Phase 2 study recently completed 
evaluated the efficacy and safety of a single subcutaneous dose of nemolizumab (0.125mg/kg, 
0.5mg/kg or 2mg/kg) compared to placebo in 69 Japanese hemodialysis patients with uremic 
pruritus during 12 weeks (CIM106JP). The study included an open-label reference product group 
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(nalfurafine hydrochloride).   Preliminary data show that there were no death, no drug-related 
SAE, no dose-dependent increase in the incidence of AEs and no new safety concern reported in 
the study. In terms of efficacy, the absolute change in pruritus VAS score from baseline to 4 
weeks after administration was selected as the primary outcome measure.  Improvement was 
observed in all nemolizumab groups and placebo. Although there was no statistical significance, 
a trend was observed in pruritus reduction for 0.5-mg/kg group.  also noticed in post-hoc analysis  
with a higher proportion of patients achieving  less than 30 in the VAS, corresponding to a mild 
severity of pruritus. 
1.3 
Pharmacokinetic profile 
PK profile of Nemolizumab was investigated in two clinical studies (Phase 1: CIM001JP; and 
Phase 2a in AD patient: CIM003 J Gin which single doses from 0.1 to 3 mg/kg, or repeated 
doses of 0.1 mg/kg, 0.5 mg/kg or 2.0 mg/kg Q4W, or 2 mg/kg Q8W were studied. PK 
assessment after subcutaneous injections of mg/kg doses showed a dose proportional increase of 
nemolizumab serum concentrations after single and repeated dose administrations. The terminal 
elimination half-life of nemolizumab was around 2 weeks after single and repeated 
administrations. Steady state concentrations were achieved from week 16 of treatment and 
limited systemic accumulation was observed after repeated administrations. The systemic 
exposure to nemolizumab appeared to be slightly lower in AD subjects compared to healthy 
volunteers (AUC ratios ranging from 0.63 to 0.92). 
1.4 
Risk/Benefit assessment 
Pruritus is the cardinal symptom in PN, often difficult to be treated with current therapies. 
Chronic itching is believed to induce and maintain the characteristic PN skin lesions through an 
itch-scratch cycle.  Therefore the goal of PN treatments target pruritus remission in order to 
allow the skin healing and patients’ quality of life improvement. 
Results from previous clinical studies with nemolizumab demonstrated a marked effect on 
pruritus and pruritus-related sleep loss in diseases associating moderate to severe pruritus such as 
atopic dermatitis and uremic pruritus. The decrease in itching sensation was rapid in both 
indications, usually within the first week following the first injection and improved with 
subsequent administrations. 
This improvement in the signs and symptoms of AD and UP was consistent with the observed 
improvement in sleep quality (evaluated both subjectively and by using the objective 
measurement of Actigraphy) and QoL (evaluated using dermatology life quality index [DLQI]).  
Also, continuous treatment led to improvement in overall severity of AD, evaluated with various 
validated scales (i.e. EASI, SCORAD and IGA).  
Based on the safety data from the three completed studies there are no identified risks for 
nemolizumab.  
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However, based on the currently available information on nemolizumab and the risks associated 
with biologic agents in general, the important potential risks for Nemolizumab so far include 
injection –related reactions(IRR), asthma, skin infection and AD exacerbation. Peripheral edema 
and headache are considered as non-important potential risks. There is no anticipated additional 
potential risk in this study conducted in patients with PN.  
Exclusion criteria of this clinical trial will prevent high-risk patients from receiving 
nemolizumab. Subjects will not be eligible if they have a recent history of a current bacterial or 
viral infection, or a not well-controlled asthma, or active lesions of AD/recurrent flares of AD. 
As no data are available in pregnant or breastfeeding women, or in patients receiving live 
vaccines, they are not eligible from this study. 
Safety will be evaluated closely throughout the study to minimize the risk, until 10 weeks after 
the last study drug administration.  
The following adverse events have been defined as Adverse Events of Special Interest (AESI) 
for the study: elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
combined with elevated bilirubin, elevated CPK, newly diagnosed asthma or worsening of 
asthma (to be reported within 24 hours), IRRs, peripheral edema, skin or systemic infection, 
headache, and exarcerbation of AD (for patients with medical history of AD). 
Additional information regarding these events will be collected, when applicable. 
Medical interview of signs and symptoms of asthma will be conducted in all subjects at each 
study visit, and a peak expiratory flow [PEF] measurement will be performed at each study visit 
on all subjects with a history of asthma.  
In conclusion, when taking into consideration the potential benefit of nemolizumab in patients 
with PN, and the risk-minimization approaches implemented in the study, the benefit risk ratio of 
nemolizumab is considered favorable in this study.     
2 
CLINICAL TRIAL OBJECTIVES AND CLINICAL HYPOTHESIS 
2.1 
Clinical trial objectives 
2.1.1 
Primary objective 
The primary objective is to assess the efficacy of nemolizumab compared to placebo in the 
treatment of pruritus in patients suffering from PN. 
2.1.2 
Secondary objectives  
The secondary objectives are:  
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Efficacy and safety: 
 Evaluation of the safety of nemolizumab compared to its placebo in patients with PN. 
 Evaluation of the efficacy of nemolizumab compared to its placebo in the treatment of prurigo 
lesions in patients with PN. 
 Evaluation of nemolizumab effect compared to its placebo on quality of life in patients with 
PN  
 
Pharmacokinetics (PK) 
 Characterization of nemolizumab PK profile and exposure response relationship in patients 
with PN 
 
Pharmacodynamics (PD) 
 Evaluation of the effect of nemolizumab on biomarkers in patients  with PN 
 
Biophysical (exploratory) 
 Evaluation of the efficacy of nemolizumab on scratching events  and sleep improvement using 
actigraphy 
  Evaluation of the efficacy of nemolizumab on lesions improvement using whole body images 
device only on equipped sites. 
2.2 
Clinical hypothesis 
The clinical hypothesis is that nemolizumab is more effective than placebo in reducing the 
pruritus as the major symptom of PN based on the results observed from the previous studies. 
3 
OVERALL CLINICAL TRIAL DESCRIPTION 
3.1 
Overview 
This is a randomized, placebo-controlled, double-blinded, parallel group, multicenter study to 
evaluate the safety and efficacy of nemolizumab in patients suffering from PN.  
Approximately 70 adult patients suffering from PN for at least 6 months with severe pruritus 
defined by the mean of the worst daily intensity of the NRS score ≥ 7 over the previous week at 
baseline will be randomized in the study. 
Subjects meeting inclusion/exclusion criteria will be randomized in a 1:1 ratio to nemolizumab 
or placebo. Each subject will receive three subcutaneous injections of 0.5mg/kg of nemolizumab 
or matching placebo. Injections will be administered every 4 weeks (at baseline, week 4 & week 
8). 
Subjects’ participation in the study will be up to 22 weeks, including an up to 4-week screening 
period, a 12-week treatment period (last study drug injection at week 8) and a 6-week follow-up 
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period  (10 weeks after the last study drug injection corresponding to 5 half-lives of 
nemolizumab). 
A total of 10 visits per subject is planned.  Schedule of assessments is summarized in Table 2. 
Safety and efficacy assessments will be conducted throughout the study. Pruritus severity will be 
self-evaluated by the subjects on a daily basis using the ePRO and following instructions 
provided by the Investigator. The Investigator will evaluate the evolution of prurigo lesions using 
appropriate scales. 
PK profile of nemolizumab in PN patients will be assessed according to Table 2.  
PD assessments will be performed to evaluate cytokines/chemokine profiles, IL31 and IL31 RA 
quantification by proteomics, genomic and histology analysis using three 4-mm skin biopsies,  
D-squames and blood samples collected according to Table 2. Skin biopsies will be optional, 
patients  accepting this procedure will have to sign an additional consent. 
Exploratory biophysical assessments will be performed by measuring scratching events during 
the night and sleep duration using actigraphy. The subject will have to wear two watches from 
Day -7 to baseline and during the first four weeks of the study. In addition, photographs of the 
entire body will be taken in equipped sites using a whole-body imaging device. 
An interim analysis may be performed once at least 40 subjects will have completed the week 4 
visit or discontinued before (decision will be taken by the Sponsor according to the recruitment 
rate). This analysis will include efficacy data on all subjects up to that time point. In addition to 
efficacy, all safety data available (not only data up to week 4) will also be analyzed (Section 9.4). 
 
3.2 
Rational for study design 
Rational for study population: 
The selected study population in this study should have a moderate to severe disease that would 
justify a systemic treatment. As no validated scales are available today to define this condition 
severity, eligible patients for this clinical trial will present with chronic disease for at least 6 
months, severe pruritus and more than 20 nodules on the whole body. Prurigo Activity Score 
(PAS) (Schedel et al 2013) was recently validated for clinical assessments including descriptive 
items such as lesions type, number and distribution. Thresholds of 20 and 100 lesions are 
indicated that could correspond to moderate and severe disease respectively, according to this 
scale. The lesions distribution should be bilateral, in order to help avoid underlying conditions 
such as neuropathic disorders. Also for consenting subjects, it is required for the patients to have 
lesions on the upper arms, in order to perform the biopsies on the same area of the body.  
Only patients with controlled underlying disease will be enrolled. Randomization will be 
stratified according to presence or absence of atopy background as it is considered as a 
prognostic factor. 
 
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Rational for dose and regimen: 
The results of previous phase 2a study in AD showed similar efficacy with 0.5 mg/kg and 2 
mg/kg doses Q4W and Q8W. Also in the recent phase 2a study in UP preliminary results 
showed, that  0.5 mg/kg dose presented a trend to  better pruritus improvement at 4 weeks 
following one injection compared to 0.125 mg/kg and 2 mg/kg doses.  Thus, the dose of 0.5 
mg/kg was selected for the current phase 2a study in PN patients. Patients will be treated with 3 
injections of 0,5mg/kg Q4W in order to demonstrate the efficacy or Nemolizumab in lesions of 
this chronic condition. 
 
Rational for primary endpoint: 
Nemolizumab has demontrated its efficacy  in terms of  pruritus improvement in previous non 
clinical and clinical studies with a rapid onset of action observed in the first week following 
administration in clinical studies. Based on the observations that itch is the cardinal symptom of 
PN, believed to precede lesion occurrence and associated with a high impact on QoL of patients, 
the effect on pruritus was chosen as the primary endpoint in this study with an effect to be 
demonstrated in the first month after treatment administration, as in uremic pruritus patients. 
  
4 
CLINICAL TRIAL DURATION AND TERMINATION 
The planned clinical trial duration (from FSFV to LSLV) is approximately 10 months. The date 
of end of the clinical trial is defined as the date of the last visit of the last subject. 
Clinical trial participation for each subject is approximately 22 weeks from the first screening 
visit to the last visit. 
GALDERMA may decide to prematurely terminate or suspend the participation of a particular 
clinical trial center (for example, for lack of subject enrollment or non-compliance with clinical 
trial protocol, regulation, or GCP) or prematurely suspend the clinical trial (for example, for 
safety, study drug quality, regulatory, efficacy, or logistical reasons) at any time with appropriate 
notification. 
5 
SELECTION AND DISPOSITION OF CLINICAL TRIAL POPULATION 
5.1 
Number of subjects 
As a screen failure rate of approximately 30 percent is expected, approximately 100 subjects may 
have to be screened in order to get 70 randomized subjects (35 subjects per treatment group).  
5.2 
Clinical trial population characteristics 
In order to be eligible for the clinical trial, subjects must present with a clinical diagnosis of PN 
for at least 6 months before screening visit, with at least 20 nodules with a bilateral distribution, 
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on upper limbs with or without lesions on the trunk and/or lower limbs and who must meet the 
following inclusion and exclusion criteria described in section 5.3 and 5.4 below. 
 
Multiple coexisting and underlying diseases ranging from dermatological, systemic, neurological 
or even psychiatric disorders are known to be associated to PN (Iking et al. 2013). Therefore, 
eligible PN patients for the clinical trial, who fulfill all the inclusion and exclusion criteria and 
presenting with controlled underlying disease(s) or conditions such as atopic diathesis, diabetes, 
thyroid disorders, or psychiatric disorders (such as depression and anxiety) can be included in the 
study. 
In order to be eligible for the clinical trial, subjects must fulfill all of the following criteria (when 
applicable), both at screening and at baseline unless specified.  
5.3 
Inclusion criteria 
1. 
Male or female of at least 18 years at screening 
2. 
Clinical diagnosis of PN for at least 6 months  with: 
 Prurigo lesions on upper limbs with or without lesions on the trunk  or lower limbs 
 At least 20 nodules on the entire body with a bilateral distribution   
3. 
Severe pruritus defined as follows on a Numerical Rating Scale (NRS)  
 At the Screening visit 1: Mean of the worst daily intensity of the NRS score is ≥ 7 over 
the previous 3 days 
 At the Baseline visit: Mean of the worst daily intensity of the NRS score is ≥ 7 over the 
previous week;  
NOTE: NRS score should be measured on at least 5 days during the week preceding the 
baseline visit.  
4. 
Female subjects must fulfill one of the criteria below: 
 Female subjects of non-childbearing potential (postmenopausal [absence of menstrual 
bleeding for 1 year prior to screening, without any other medical reason], hysterectomy 
or bilateral oophorectomy); 
 Female subjects of childbearing potential who agree to a true abstinence (when in line 
with the preferred and usual lifestyle of the subject), or to use an effective method of 
contraception throughout the clinical trial and for 120 days after the last study drug 
administration:  
NOTE: Effective and highly effective methods of contraception are defined below: 
 Effective methods of contraception include: 
o Progestogen-only oral hormonal contraception 
o Male or female condom 
o Cap, diaphragm or sponge with spermicide 
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o Combination of male or female condom with cap, diaphragm or sponge with 
spermicide 
 Highly effective methods of contraception include: 
o Combined (estrogen and progestogen containing) hormonal contraception, oral, or 
intra-vaginal, or transdermal 
o Injectable or implants hormonal contraception 
o Intra-uterine devices 
o Bilateral tubal ligation, or tube insert (such as Essure system) provided it has been 
inserted at least 3 months before the study 
o Vasectomized partner (for at least 3 months) 
5. 
Willing and able to comply with all the time commitments and procedural requirements of 
the clinical trial protocol   
6. 
Willing and able to use electronic devices for Patient reported outcomes and actigraphy 
devices during the study or living with someone who can ensure that the electronic devices 
will be properly used. 
7. 
Apprised of the Health Insurance Portability and Accountability Act (HIPAA), if in the 
US., as verified by signing a written authorization 
8. 
Understand and sign an Informed Consent Form (ICF) prior to any investigational 
procedures being performed. 
9. 
Subject agrees that his/her samples (blood and skin) collected for PD analysis will be kept 
at GALDERMA R&D after analysis as part of a long-term research (Program (2) – 
“Physiopathological study on skin disease to identify new dermatological medications; 
Initial declaration CP ECOH : DC-2008-315, 31/01/2009) 
5.4 
Exclusion criteria 
1. Chronic pruritus resulting from another condition than PN  such as scabies, insect bite, 
lichen simplex chronicus, psoriasis, acne, folliculitis, habitual picking, lymphomatoid 
papulosis, chronic actinic dermatitis, dermatitis herpetiformis, sporotrichosis, bullous 
disease 
2. Unilateral lesions of prurigo (e.g only one arm affected) 
3. Cutaneous bacterial or viral infection within 1 week before the baseline visit.  
4. Infection requiring treatment with oral or parenteral antibiotics, antivirals, antiparasitics or 
antifungals within 1 week before the screening visit, or during the screening period, unless 
completely resolved at the screening/ baseline visits respectively,  
5. Any uncontrolled or serious disease, or any medical or surgical condition, that may either 
interfere with the interpretation of the clinical trial results and/or put the subject at 
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significant risk according to Investigator’s judgment (e.g. solid cancer, AIDS, serious or 
uncontrolled cardiac disease…) at Screening or Baseline.  
NOTE: Patients with controlled diseases such as diabetes mellitus, thyroid disorders and 
psychiatric disorders (such as depression and anxiety) are eligible 
6. Any active dermatoses that would need immediate therapy.  
7. Subject with active atopic dermatitis or known with recurrent flares of atopic dermatitis 
NOTE: patients with atopic diathesis, as diagnosed by the medical history and/or 
laboratory analysis (i.e. specific IgE), are eligible for the study 
8. Neuropathic and psychogenic pruritus (notalgia paresthetica, brachioradial pruritus, 
dilutional parasitosis, pathomimia) 
9. Positive serology results hepatitis B surface antigen [HBsAg] or hepatitis B core antibody 
[HBcAb], hepatitis C antibody or Human Immunodeficiency virus [HIV] antibody) at the 
screening visit 
NOTE : Subject with a positive HBcAb and a negative HBsAg can be included in this trial if 
HBsAb is positive (considered immune after a natural infection) 
10. Subject having any of the abnormal lab criteria listed below, at the screening visit: 
 Elevated ALT / AST ≥ 3 ULN  
 Elevated CPK > 1.5 ULN, unless not confirmed on a repeat assessment to be 
performed at least 72h after the first one  
 Neutrophil count < 1.5 x 103/µl  
 Creatinine clearance <60ml/min/1.73m² calculated with the CKD-EPI formula 
(Levey et al 2009) 
 Any other abnormal lab result that would be considered as clinically significant by 
the investigator 
11. Subjects with a medical history of asthma that fulfill any or more of the conditions  below  
 Had an asthma exacerbation requiring hospitalization in the last 12 months before 
screening visit  
 Whose asthma has not been well-controlled (i.e. symptoms >2 days per week, 
nighttime awakenings >1-3 times per week, or some interference with normal 
activities) during the last 3 months before the screening visit 
 PEF <80% of the predicted value at screening or baseline visit 
12. Latent or active TB, as determined by a positive Quantiferon-based TB test result at 
screening visit.  
NOTE: In case of indeterminate result, the test should be repeated in local laboratory at 
screening 2(only one retest is allowed). If the test is still indeterminate, the subject will not 
be included.  
13. Having received any of the following treatments within the specified time frame prior to the 
baseline visit: 
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Table 3 
Forbidden therapies 
Topical treatments 
Wash-out periods 
Calcineurin inhibitors (tacrolimus, pimecrolimus), TCS, vitamin D analogs , PDE-4 inhibitors 
2 weeks  
Any topical treatment other than  moisturizer ( e.g capsaicin, cryotherapy)  
2 weeks  
Emollients or moisturizer with menthol, capsaicine, polidocanol or other having “anti-itch” claim 
1 week 
Systemic treatments 
 
Wash-out periods 
Corticosteroids oral, injectable 
4 weeks 
immunosuppressive or immunomodulatory drugs (e.g, azathioprine, methotrexate, thalidomide, 
cyclosporine 
8 weeks or 5 half-lives 
(whichever is longer) 
Antihistamines 
1 week 
Phototherapy 
4 weeks 
Roxitromycin, erythromycin 
1 week 
Opiods (naltrexone, naloxone, nalbuphine etc), NK1 receptor antagonists (aprepitant),  antiepileptics 
(gabapentin, pregabalin) 
4 weeks or 5 half-lives 
(whichever is longer) 
Biologics, Retinoids  
8 weeks or 5 half-lives 
(whichever is longer) 
Live vaccine  
4 weeks 
Drugs with sedative effect such as benzodiazepines, imidazopyridines, hydroxizine barbiturates, or 
sedative anti-depressants such as amitryptiline,  paroxetine, except if these treatments were taken at 
a stable dose for at least 3 months before screening 
3 months 
14. Subject planning to change emollients or moisturizer including over the counter (OTC) 
preparations, or have bath oil treatment for relief of pruritus during the course of the trial. 
15. Pregnant women (positive serum pregnancy test result at the screening visit, or positive 
UPT at baseline visit), or women planning to become pregnant during the clinical trial 
16. Lactating women 
17. Prior treatment with nemolizumab 
18. History of lymphoproliferative disease or history of malignancy of any organ system within 
the last 5 years before screening visit, except for 
 basal cell carcinoma, actinic keratoses or squamous cell carcinoma in situ (including 
Bowen’s disease) that have been treated and have no evidence of recurrence in the last 12 
weeks before the screening visit 
  carcinoma in situ of the cervix, or non-invasive malignant colon polyps that have been 
removed 
19. History of hypersensitivity (including anaphylaxis) to an immunoglobulin product (plasma-
derived or recombinant, e.g. monoclonal antibody) 
20. Known or suspected immunosuppression 
21. Any social or medical condition such as drug or alcohol abuse, drug dependency, mental 
disorder that, in the Investigator’s judgment might interfere with the subject’s ability to 
comply with the requirement of the protocol 
22. Planned or expect to have a major surgical procedure during the clinical trial 
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23. Subjects unwilling to refrain from using prohibited medications during the clinical trial (see 
Section 5.4 item 13 ) 
24. Currently participating in any other clinical trial of a drug or device, participated in a 
clinical trial within the past 3 months prior to screening visit, or is in an exclusion period (if 
verifiable) from a previous clinical trial 
25. Vulnerable subject as defined in ICH/GCP 
5.5 
Specific exclusion criteria for skin biopsies 
The following criteria not allowing the biopsy samples (at baseline and week 12) will be checked 
at screening, only for subjects who accept skin biopsies (by signing an additional consent) :  
1. The subject has history of coagulation disorders  
2. The subject has known sensitivity to local anesthetics. 
3. The subject is using platelet aggregation inhibitors, or anticoagulants (of note, sporadic 
intake or continuous low-dose intake of aspirin or other NSAIDS is allowed). 
4. The subject has history or physical evidence of keloids or hypertrophic scarring resulting 
from skin trauma. The clinical examination will include the observation of the possible scars 
of the subject. 
5.6 
Previous and concomitant therapies 
5.6.1 
Definition 
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 PN and underlying disease(s) if any, should be documented.  
Concomitant therapies are defined as follows: 
• any existing therapies ongoing at the time of the screening visit, 
• any changes to existing therapies (such as changes in dose or formulation) during the 
course of the clinical trial, or 
• any new therapies received by the subject since the screening visit   
5.6.2 
Categories 
The following two categories are to be considered for previous and concomitant therapies:  
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• Drugs/therapies including but not limited to, prescription, over-the-counter (OTC), birth 
control pills/patches/hormonal devices, vitamins, moisturizers, sunscreens, herbal 
medicines/supplements, and homeopathic preparations. 
• Medical and surgical procedures including, but not limited to, laser/radiation procedures, 
dermal fillers, X-rays, etc. 
5.6.3 
Recording 
Previous and concomitant therapies are to be recorded on the Drugs/Therapies form 
(for drugs/therapies) or on the Medical and Surgical Procedures form (for medical/surgical 
procedures) in the electronic case report form (eCRF).  
Concomitant therapies are to be recorded, reviewed, and updated at each visit. Any new 
concomitant therapy or modification of an existing therapy may be linked to an AE. 
A corresponding AE form should be completed to account for the change in therapy, except in 
some cases such as dose modification for a chronic condition (see section 7.2.4), in which case 
the medication will be linked to an item in the medical history. 
5.6.4 
Authorized concomitant therapies 
Unless listed under the exclusion criteria (Section 5.4) or in prohibited concomitant therapies 
(see Section 5.6.5), all therapies are authorized. 
Sedatives and antidepressants as described in Table 3 are allowed if they have been 
administrated for at least 3 months at a stable dose before screening baseline and dose changes 
are not planned during the study. 
Starting from the screening visit, subjects will be instructed to use their daily moisturizer, if it is 
not containing any compound with known anti-itch effect (such as menthol, polidocanol; etc.). It 
is not authorized changing emollients or moisturizers or applying products for itching relief 
during the course of the study. 
5.6.5 
Prohibited concomitant therapies 
The therapies listed in Section 5.4 item 13 are prohibited because they may interfere with the 
efficacy and/or safety assessment of the study drug.  If prohibited therapies become a necessary 
treatment for the safety or best interest of the subject, GALDERMA or its designee (i.e. Contract 
Research Organization (CRO)) should be notified to discuss possible alternatives prior to 
administration of a prohibited therapy and the pertinence and the modalities for the subject to 
continue in the clinical trial. 
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5.7 
Rescue therapies 
If deemed to be medically necessary by the Investigator, rescue treatments for pruritus could be 
added to the study drug from Day 29. In that case, all efficacy and safety assessments should be 
completed before starting the rescue treatments.  
Rescue therapies should prioritize the use of antihistamines, which are commonly used and are 
not associated with significant side effects. If the investigator considers it necessary, occasional 
local treatment with TCS of mid-potency might be also combined with antihistamines. 
In case of the above mentioned rescue therapies, the administration of study drug can be 
continued.  
If the subject receives another rescue treatment for PN than the ones listed above (e.g. 
cyclosporine, thalidomide, gabapentin, phototherapy), the study medication must be stopped. 
5.8 
Procedures/Reasons for subject discontinuation from the study 
Subjects may discontinue from the study or only discontinue the study treatment (as described in 
Section 6.5)  
The reasons and procedures for subject discontinuation from the study are described below..  
Although the importance of completing the entire clinical trial will be explained to the subjects, 
any subject is free to discontinue his/her participation in the study at any time and for whatever 
reason, specified or unspecified, and without any prejudice. No constraints are to be imposed on 
the subject, and when appropriate, a subject may be treated with other conventional therapy 
when clinically indicated. Investigators or the sponsor can also withdraw subjects from the 
clinical trial if deemed to be necessary. 
When a subject discontinues from the clinical trial, he/she will be fully assessed whenever 
possible. Subjects discontinued before the week 4 visit (visit for the primary endpoint) should 
attend an early termination visit and a final visit 10 weeks after the last study drug injection for 
safety follow-up. Subjects discontinued after the week 4 visit should attend a final visit 10 weeks 
after the last study drug injection. 
Potential reasons for study discontinuation include pregnancy, consent withdrawal by the subject, 
lost to follow-up, lack of efficacy, AEs, protocol deviations and others. If the reason is “consent 
withdrawal by the subject” or “others”, the subject will be questioned to rule out the possibility 
of an AE. If an AE leads to study discontinuation, AE should be chosen as the reason instead of 
“withdrawal by the subject” or “other”. If a subject discontinues study treatment and study 
participation at the same time, the reasons for those two discontinuations should be the same. 
A subject who has been randomized and assigned a randomization number cannot be replaced by 
another subject. 
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All discontinuations and the reason for discontinuation are to be documented by the Investigator 
on the Exit Form. 
For discontinuation due to an AE, the Adverse Event Form is to be completed. The Investigator 
should also ensure that the subject receives suitable therapy for the AE. 
GALDERMA may also decide to prematurely terminate or suspend a subject’s participation in 
the clinical trial. 
6 
CLINICAL SUPPLIES 
6.1 
Clinical supply identification and use 
6.1.1 
Study drug description 
Table 4 
 Description and usage of the study drug 
 
Investigational product 
Comparator 
Name 
Nemolizumab 
Nemolizumab placebo 
Internal code 
CD14152 
NA 
Pharmaceutical form 
Lyophilized powder 
Lyophilized powder 
Concentration 
100mg/ml when reconstituted 
NA 
Formula number 
NA 
NA 
Packaging  
Vial 
Vial 
Storage conditions 
Stored between 2 to 8°C (36-46°F) and 
protected from light 
Stored between 2 to 8°C (36-46°F) and 
protected from light 
Dosage 
0.5 mg/kg 
Not applicable 
Route 
Subcutaneous injection 
Subcutaneous injection 
Dose regimen  
3 injections (baseline, Week 4, Week 8) 
3 injections (baseline, Week 4, Week 8) 
Treatment duration 
12 weeks 
12 weeks 
 
6.1.2 
Subject Identification Number (SIN)  
Upon signature of the ICF, each subject will be assigned a subject identification number (SIN). 
The SIN will be allocated in ascending sequential order to each subject. 
For the duration of the entire clinical trial, the subject will be identified using the SIN in 
all documentations and discussion.  
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6.1.3 
Method of treatment assignment 
Treatment will be assigned centrally via Interactive Response Technology (IRT). All eligible 
subjects will be randomly assigned to one of the two treatment groups (0,5mg/kg or placebo) in a 
1:1 ratio at baseline. Details of the IRT procedure will be described in the IRT manual.  
Randomization will be stratified according to presence or absence of background of atopy. 
6.1.4 
Randomization number 
A randomization number will be allocated to each eligible subject at baseline by IRT system.  
6.1.5 
Instructions for use and administration 
Nemolizumab and placebo will be supplied in single-use vials in the form of lyophilized powder. 
When the drug product is reconstituted by adding 1.3mL distilled water for injection, the 
resulting solution contains 100mg/mL nemolizumab. Although the reconstituted solution has 
been shown to be stable for up to 24 hours at room temperature (25°C or 77°F), it is 
recommended to use it immediately after preparation, as it does not contain any preservative.  
The pharmacist (or other qualified personnel) will prepare dosing solution, by mixing appropriate 
amounts of nemolizumab and placebo, according to the “instruction for use” in the pharmacy 
manual and the specific instruction provided by the IRT system, which takes into consideration 
the randomization scheme and the visit. The pharmacist (or other qualified personnel) is 
unblinded, which means that he/she will be aware of the exact treatment to be administered to the 
subjects.  
Once the dosing solution is prepared, the pharmacist is to calculate the amount of solution to be 
injected to the subject, taking into account their weight (a dose of 0.5mg/kg is to be administered 
to the subject). The needed amount of solution will be drawn into a syringe, which will be carried 
to the investigator or other qualified person, who will administer the study drug subcutaneously 
in the abdomen of the subjects.   
6.1.6 
Other supplies 
Syringes, needles, water for injection, peak flow meters,  urine pregnancy tests [UPTs, with a 
sensitivity < 25IU/L]),and urine test strips  will be provided to the investigational sites to be used 
in this clinical trial. 
6.2 
Study drugs packaging and labeling 
The vials will be packaged and labeled in local language according to Good Manufacturing 
Practice and national regulations/guidelines, specifying that the drug is for use in a clinical trial. 
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6.3 
Supplies management 
6.3.1 
Accountability 
Study drug sent to the unblinded pharmacist (or other qualified personnel) at the investigational 
site will be accounted for and no unauthorized use is permitted. The designed personnel will 
acknowledge receipt of the study drug using IRT to confirm the shipment condition and content. 
If a damaged shipment is received, he/she will notify the Sponsor/ CRO, quarantine the shipment 
in a specific storage area, and document the event as specified in the pharmacy manual.  
The designed personnel will also maintain accurate records of the study drug throughout the 
clinical trial, including the inventory delivered to the site, the use by each subject, 
the reconciliation of all delivered and received vials of  study drug, and the return of used and 
unused study drug as specified in the pharmacy manual. 
6.3.2 
Storage of study drug 
All vials of study drug must be stored together in a safe and secure area with restricted access. 
Upon receipt, the study drug must be removed from the shipping cooler, stored in a refrigerator 
between 2 and 8°C (36-46°F) and protected from light. The refrigerator must be monitored daily, 
and if temperature excursion occurs, the designed personnel should promptly inform the Clinical 
Research Associate (CRA) as specified in the pharmacy manual.   
6.3.3 
Dispensing and return 
All drug preparation must be appropriately performed and documented by the designated 
personnel (unblinded pharmacist or other qualified personnel). Any error in the preparation of 
dosing solution must be reported to the CRA promptly and properly documented. At the end of 
the study, all unused study drug will be returned to the CRO/drug depot for destruction.  
6.3.4 
Treatment compliance management and record 
Treatment compliance will be assessed through the drug dispensation and accountability logs. 
6.4 
Dose modification  
Dose modification of the study drug will not be permitted throughout the clinical trial. Any 
inadvertent dose modification should be discussed with sponsor.  
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6.5 
Study drug discontinuation 
The study drug must be permanently discontinued when any of the following conditions is 
reported for a subject during the clinical trial: 
  
• Serious immediate-type allergic manifestations including anaphylactic reaction  
• Diagnosis of a malignancy  (except curatively treated in situ cervical carcinoma or basal 
cell carcinoma) 
• Pregnancy 
• Any opportunistic infection (such as active TB and other infections whose nature or course 
suggest an immune-compromised status) 
• Other systemic rescue therapies for PN (such as cyclosporine, thalidomide, gabapentin, 
phototherapy)  
• Asthma/ worsening of asthma reported as a serious adverse event 
In the event that the study drug is discontinued, the subjects should remain in the study and will 
be asked to return for all remaining visits and all assessments (including daily assessments of 
pruritus and sleep disturbance) according to Table 2, except those who withdraw their consent 
for study participation or in case of pregnancy.  
 
In the event of a missed dose (i.e. temporary discontinuation of the study drug), it will be 
documented in the eCRF that the drug has not been administered at the study visit, together with 
the reason (e.g. for safety reason). Subjects will be asked to return to the investigational sites for 
all remaining visits and complete all study assessments and procedures as described in Table 2. 
6.6 
Blinding 
6.6.1 
Verification of blinding 
This is a double-blind clinical trial, which means that neither the subject nor the 
investigator/evaluator have access to the treatment received by the subject. With the exception of 
the unblinded pharmacist (or other qualified personnel) who will handle study drug preparation, 
and  the unblinded CRA who will monitor the drug records only, this study will remain blinded 
to all study individuals until the pre-specified unblinding at the end of the study. 
All study personnel must follow the procedures described below to avoid compromising the 
blinding: 
1. 
The randomization list will be managed through the IRT system with restricted access to 
designated personnel only; 
2. 
Study drug management and preparation (including reconstitution and dilution) will be 
performed by the unblinded pharmacist (or other qualified personnel) only, while the 
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evaluator will have no contact with the study drug. The person who will administer the 
study drug will receive only filled syringe(s) with required volume of dosing solution ready 
for injection; 
3. 
The unblinded pharmacist (or other qualified personnel) will be instructed to not discuss 
the study drug with the investigator/evaluator and the subjects; 
4. 
An unblinded CRA will be responsible for monitoring the record of study drug only, and 
will have no access to other data collected during the study or to the eCRF. The unblinded 
CRA will also be instructed to not discuss trial-related matters with the 
investigator/evaluators, the subjects or with the blinded CRA involved in the monitoring of 
study data; 
6.6.2 
Un-blinding during the clinical trial 
Emergency unblinding during the clinical trial may be required for therapeutic or for regulatory 
reasons (e.g. for expedited safety reporting). If unblinding is necessary, the investigator should 
unblind the study treatment for the specific subject only. If possible, the investigator should 
discuss with Galderma or its designee before breaking the blind. If not possible to discuss before, 
investigator must document the date, time and reason for the unblinding and notify Galderma or 
its designee immediately afterwards. 
To allow the analysis to be done on the data, up to 4 weeks after the initial injection, a database 
lock will be done after at least 40 subjects have completed their Week 4 visit or discontinued 
before. An unblinding of the database will be performed for the study statistician. The Data 
manager and CRAs will remain blinded during the course of the study. 
After this analysis, all efforts will be done to maintain the whole data blinded for other team 
members (except statistician). 
7 
CLINICAL TRIAL ASSESSMENT 
7.1 
Efficacy measurements  
Efficacy assessments should be conducted by the investigators (or trained designees) and 
subjects (for patient-reported efficacy measurements) according to Table 2. Whenever possible, 
the same evaluator should make the assessment throughout the study. 
7.1.1 
Assessment of pruritus and quality of life by the Subject 
7.1.1.1 
Pruritus Numeric Rating Scale (NRS) 
Pruritus NRS (Appendix 2) is a scale to be used by the subjects to report the intensity of their 
pruritus (itch) during the last 24 hours all along the study from first screening visit to the follow 
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up visit.  Subjects will receive instructions on how to record their pruritus NRS scores on an 
electronic device, and will complete the assessment once daily at home in the evening throughout 
the clinical trial (including the follow-up period). 
Subjects will be asked the following questions in their local language: 
•
For average itch intensity: “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being
‘worst itch imaginable’, how would you rate your itch overall during the previous 24
hours?”
•
For maximum itch intensity: “On a scale of 0 to 10, with 0 being ‘no itch’ and 10 being
‘worst itch imaginable’, how would you rate your itch at the worst moment during the
previous 24 hours?”
7.1.1.2 
Verbal rating scale (VRS) 
The VRS (Appendix 3) consists of a list of adjectives describing different levels of symptom 
intensity (Phan et al., 2012), to be used by the subjects to report the intensity of their pruritus 
(itch) over the last 24 hours.  Subjects will receive instructions on how to record their pruritus 
VRS scores on an electronic device, and will complete the assessment once daily in the evening 
from Screening visit 2 and throughout the clinical trial (including the follow-up period).  In the 
eDiary, patients will mark on a 5-point VRS (Ständer et al. 2013), the response that best 
describes their pruritus intensity in the last 24 hours.  
Subjects will be asked the following questions in their local language: 
For average itch intensity: “On a scale of 0 to 4, with 0 being ‘no itch’ and 4 being ‘very
severe itch’, how would you rate your itch overall during the previous 24 hours?”
For maximum itch intensity: “On a scale of 0 to 4, with 0 being ‘no itch’ and 4 being ‘very
severe itch’, how would you rate your worst itch during the previous 24 hours?”
7.1.1.3 
Sleep disturbance Numeric Rating Scale (NRS) 
The sleep disturbance NRS is a scale to be used by the subjects to report the degree of their sleep 
loss related to PN (see Appendix 4). Subjects will receive instructions on how to record their 
sleep disturbance NRS scores on an electronic device, and will complete the assessment once 
daily in the morning from screening 2 (Day -7) to Week 4 visit (Day 29). 
Subjects will be asked the following questions in their local language: 
On a scale of 0 to 10, with 0 being ‘no sleep loss related to signs/symptoms of PN’ and 
10 being ‘I cannot sleep at all due to the signs/symptoms of PN’, how would you rate your 
sleep last night?” 
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7.1.1.4 
Dynamic Pruritus Score (DPS) 
The 9-point DPS (Appendix 5) is a dynamic scale to be used by subjects to evaluate the change 
of their pruritus compared with an earlier time point (i.e. before injection on Day 1). The scale 
ranges from 0 (strongly worsened pruritus) to 8 ([almost] no pruritus anymore), including 
intermediate marks for slightly improved/worsened, moderately improved/worsened, and rather 
improved/worsened (Ständer et al. 2017). Subjects will receive instructions on how to record 
their DPS score on an electronic device displaying the scale in their local language, and will 
complete the assessment 24, 48h and 72h after the 1st injection at baseline and at W4 before the 
second injection. This assessment will be performed by the subject based on his itch perception 
over the 24h hours preceding the baseline injection. 
7.1.1.5 
Dermatology Life Quality Index (DLQI) 
DLQI (Appendix 6) is a validated 10-item questionnaire, covering domains including 
symptoms/feelings, daily activities, leisure, work/school, personal relationships and treatment. 
Subject will rate each question ranging from 0 (not at all) to 3 (very much), and the total score 
ranges from 0 to 30, with a higher score indicating a poorer QoL. DLQI will be given only to the 
subset of subjects who fluently speak a language in which the questionnaire is presented (based 
on availability of validated translations in participating countries).  
This assessment will be performed by the subject on the provided electronic device at baseline, 
week 4 and week 12 and in case of Early termination visit / Unscheduled visit, if applicable. 
7.1.2 
Assessment of prurigo by the Physician 
7.1.2.1 
Investigator Global Assessment (IGA) of Prurigo 
IGA (see Appendix 7) is a 5-point scale ranging from 0 (clear) to 4 (severe) used by the 
investigator or trained designee to evaluate the severity of the disease. IGA corresponds to the 
overall assessment of the severity of prurigo including presence of crust and nodules or skin 
bleeding that will be evaluated at Baseline, Week 4, Week 8, Week 12, Week 18 & in case of 
Early termination visit / Unscheduled visit, if applicable.  
7.1.2.2 
Assessment of Prurigo Activity Score(PAS) 
The evaluation of the disease will be performed by the Investigator using the Prurigo Assessment 
Scale (PAS) (see Appendix 8) at baseline and Week 12 using the entire scale and at week 4, 8,18  
and in case of Early termination visit / Unscheduled visit, if applicable using item 5 (number of 
lesions only) and 6 (excoriation/crusts and healed lesions) (Schedel et al. 2013).  
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7.1.3 
Appropriateness of efficacy measurements 
All the above mentioned patient-reported outcomes and investigator evaluations will be used to 
assess pruritus, lesions severity and the impact on the subject’s QoL. 
Efficacy on pruritus will be evaluated using pruritus NRS and VRS. NRS initially validated in 
pain, (Williamson A et al 2005) showed a good correlation with the commonly used Visual 
Analog  Scale (VAS) when assessed in pruritus (Phan et al 2012), with the advantage of an easier 
usage.  The current recommendation for chronic pruritus assessment in clinical trials is to 
associate NRS in combination with VRS (Ständer et al 2013). 
No validated scale defining PN  severity is available today. Prurigo  Activity score (PAS) ( 
Schedel et al 2013) recently validated for clinical assessments includes descriptive items such as 
lesions type, number and distribution. An IGA (not validated) will also be used in the current 
trial to determine the global severity of the disease and the clinical response to the treatment.   
.   
Several instruments  have been proposed over time to evaluate the impact of pruritus on patients’ 
QoL (Ständer et al 2013, Erturk et al 2012). DLQI questionnaire being the most frequently used 
instrument.   Many patients with chronic pruritus also report problems with falling asleep or 
waking up frequently during night impacting the QoL. Thus, a measurement of sleeping 
disturbance may be a valuable aid in the valid assessment of pruritus.  This will be evaluated by 
the subject using NRS and by objective measurements such as actigraphy (Section 7.5.1) .   
7.2 
Safety assessment 
Safety assessments will be conducted for all subjects at the screening visit (upon the signature of 
the ICF) and at subsequent visits as defined in Table 2. Safety assessments include:  
 AE, SAE, AESI 
 12-lead Electrocardiogram (ECG),  
 Physical examination, vital signs, and body weight 
 Respiratory assessments for all subjects, and PEF measurement only for subjects with a 
medical history of asthma 
 Laboratory safety tests 
7.2.1 
Electrocardiograms (ECG) 
A 12-lead ECG will be performed according to Table 2. ECGs for each subject should be 
obtained using the same electrocardiograph machine whenever possible. To minimize variability, 
subjects must remain in a resting position for at least 10 minutes prior to each ECG recording. 
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Environmental distraction should be avoided during the pre-ECG resting period and during ECG 
recording. 
For safety monitoring, the investigator or qualified designee must review, sign and date all ECG 
tracings. Paper ECG recordings will be kept as part of the subject file at the site.  
All abnormal ECG findings considered to be clinically significant by the investigator at the 
screening visit will be recorded in the Medical History form.  
Any clinically significant changes from the screening visit will be reported as AEs in the eCRF.  
7.2.2 
Physical examination and vital signs 
7.2.2.1 
Physical examination 
Physical examination should be performed according to Table 2. The investigator should assess 
all abnormal findings for clinical significance.   
All clinically significant abnormal findings at the screening visit will be recorded in the Medical 
History form.  
Any clinically significant changes from the screening visit will be recorded as an AE. 
7.2.2.2 
Vital signs 
Vital signs assessment should be performed according to Table 2. Vital signs will include pulse 
rate, systolic and diastolic blood pressure (after the subject has been siting for at least 5 minutes).  
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. 
7.2.2.3 
Height and Weight 
Height  and weight measurement should be performed according to Table 2. Any clinically 
significant weight changes from the screening visit will be recorded as an AE. 
7.2.2.4 
Respiratory assessments and PEF measurement 
At each visit, investigator or designee will perform a respiratory medical examination and ask all 
subjects whether they have experienced any signs/symptoms of asthma, such as shortness of 
breath, attack or recurrence of wheezing (described by subjects as a continuous, coarse, whistling 
sound while breathing), troublesome cough, and wheeze or cough after exercise.  
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In addition, for subjects reporting a medical history of asthma, PEF will be performed at each 
visit during the clinical trial using a peak flow meter under the supervision of qualified study 
personnel. PEF measurements should consist of 3 good efforts, with the best result documented. 
It is preferable that PEF measurement be performed before noon or at the same time during each 
study visit whenever possible.  
Subjects with a medical history of asthma must be referred to the physician who manages his/her 
asthma when: 
 
PEF decreased by ≥20% from baseline value, and/or 
 
Unexpected worsening of asthma (in particular if the subject has symptoms >2 days 
per week, nighttime awakening >1-3 times per week, or interference with normal 
activities) 
Subjects without a medical history of asthma must be referred to an appropriate specialist 
physician if signs/symptoms of asthma have been newly reported during the study. 
The procedures to be followed for reporting asthma/worsening of asthma are described in 
Section 7.2.4.2.3. 
7.2.3 
Laboratory safety tests 
The following laboratory safety tests will be performed according to Table 2; whenever possible, 
the tests will be performed in fasting conditions: 
 Hematology: WBC count with differential count (including eosinophils), red blood cell 
(RBC) count, hemoglobin (Hb), hematocrit (hct), mean cell volume (MCV), and platelet 
count (Plt) 
 Blood chemistry: sodium, potassium, calcium, chloride, glucose, urea, creatinine, 
AST/ALT, alkaline phosphatase (ALP), total and direct bilirubin, CPK, high sensitivity 
C-reactive protein (hsCRP), fibrinogen, gamma-glutamyl transpeptidase (GGT), lactate 
dehydrogenase (LDH), total protein, albumin, uric acid, total cholesterol, low-density 
lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides   
 CPK isoenzyme test will be performed only if CPK is elevated to >2.5X ULN. 
 Urinalysis (semi-quantitative analysis): blood, proteins, leukocytes, glucose, ketones, 
nitrites, bilirubin, urobilinogen, pH, and specific gravity  
 Pregnancy test: All women of childbearing potential will have a serum pregnancy test at 
the screening visit 1, and UPTs monthly at all subsequent visits (including baseline 
visit) until the end of the study and in case of Early termination visit / Unscheduled 
visit, if applicable. If the result of UPT is positive, it must be confirmed with a serum 
pregnancy test. 
 Virology, including HBsAg, HBsAb, HBcAb, hepatitis C, HIV-1 and -2 antibody 
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 TB test (using QuantiFERON-based TB test) 
 IgE  
The screening visit laboratory values must be available prior to the Baseline visit. 
The Investigator or a medically qualified Sub-Investigator must review and evaluate laboratory 
values for each subject in a timely manner.  The Investigator or designee will check all 
laboratory reports by affixing his initials and date and note directly on the report whether or not 
each out-of-range laboratory value is clinically significant. An out of range laboratory value 
should be considered as clinically significant if either of the following conditions is met: 
− The abnormality suggests a disease and/or organ toxicity 
− The abnormality is of a degree that requires additional active management, e.g., 
discontinuation of the study drug, close observation, more frequent follow-up 
assessments, or further diagnostic investigation 
For each out-of-range laboratory result, the Investigator or designee will enter directly in the 
eCRF the Investigator judgment on the presence or the absence of a clinical significance. 
All clinically significant out-of-range laboratory values for blood and/or urine samples collected 
at screening  will be recorded in the medical history (report a diagnosis rather than an individual 
laboratory parameter abnormality whenever possible). 
All clinically significant out-of-range laboratory values for blood and/or urine samples 
collected after screening, 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., there is a 
significant change from screening).  
If the Investigator observes a clinically relevant laboratory test value, the laboratory tests will be 
repeated as soon as possible and monitored until the values have returned to normal and/or an 
adequate explanation for the abnormality is found. This does not apply to screening laboratory 
test values, except for TB test and CPK, which will be assessed at Screening 1 visit, and for 
which one retest is allowed at the Screening 2 visit (see Table 2).   
In instances when a laboratory abnormality is reported as an AE or AESI, whenever possible, the 
Investigator is to provide a diagnosis rather than reporting individual laboratory abnormalities. 
The following out-of-range laboratory values should be reported as an AESI (see Section 
7.2.4.2.1):  
− Elevated ALT or AST (>3 ULN) in combination with elevated bilirubin (>2 ULN), 
whether or not considered as related to the study drug by the investigator; 
− Elevated CPK (≥2.5 ULN) if considered as related to the study drug by the investigator. 
 
A summary of sample volumes and the number of blood samples is detailed in Appendix 1. 
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7.2.4 
Adverse Events 
Adverse events (AEs) are to be monitored throughout the course of the clinical trial.  All AEs are 
to be reported on the Adverse Event Form of the eCRF with complete information as required.  If 
AEs occur, the main concern will be the safety of the subjects.  At the time of the ICF signature, 
each subject must be provided with the name and phone number of clinical trial center personnel 
for reporting AEs and medical emergencies. 
7.2.4.1 
Definitions 
7.2.4.1.1 
Adverse events (AE) 
According to ICH E2A, an AE is any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and 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 value), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product. 
Thus any new sign, symptom or disease, or any clinically significant worsening of an existing 
sign, symptom or disease compared to the condition at the first visit (including disease treated), 
should be considered as an AE.  Lack of efficacy is not considered as an AE. 
Notes: 
• Any new sign or symptom reported by the subject that appears after accidental or 
intentional overdose or misuse should also be reported as an AE. 
• There should be an attempt to report a diagnosis rather than the signs, symptoms or 
abnormal laboratory values associated with the report of an AE.  However, a diagnosis 
should be reported only if, in the Investigator’s judgment, it is relatively certain.  
Otherwise, symptoms, signs, or laboratory values should be used to describe the AE. 
• Pregnancy is not to be considered as an AE; however, is an important medical event that 
must be monitored as described in Section 7.2.4.2.4. 
• Each new episode of a chronic disease (e.g. hay fever, allergy, etc.) from the screening visit 
should be reported as a new AE. 
7.2.4.1.2 
Serious Adverse events (SAE) 
A SAE is any untoward medical occurrence that meets any of the following criteria : 
• Results in death, 
• Is life-threatening, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
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• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a SAE when, based upon appropriate medical judgment, they 
may jeopardize the safety of the subject, and may require medical or surgical intervention to 
prevent one of the outcomes listed 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. 
Note: 
The term “life-threatening” refers to an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event that hypothetically might have caused death if it was 
more severe. 
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 enrolment in the clinical trial, 
admission to a day-care facility, social admission (e.g., if the subject has no place to sleep), or 
administrative admission (e.g., for a yearly examination). 
7.2.4.1.3 
Adverse Events of Special Interest (AESIs) 
An AESI is a noteworthy event for the particular study drug that can be appropriate to monitor 
closely.  It could be serious or non-serious. 
The AESIs for this clinical trial have been defined as follows: 
• Elevated ALT or AST (> 3 ULN) in combination with elevated bilirubin > 2 ULN, whether 
or not considered as related to the study drug by the investigator 
• Elevated CPK (≥ 2.5 ULN), if considered as related to the study drug by the investigator 
• Asthma or worsening of asthma ; this AESI will have to be reported within 24 hours, see 
Section 7.2.4.2.3  
• IRR (local and systemic reactions, including hypersensitivity) 
• Peripheral edema 
• Skin or systemic infection 
• Headache 
• Exacerbation of AD, in subjects with medical history of AD 
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Study treatment should be permanently discontinued if asthma/worsening of asthma is reported 
as a serious adverse event, and may be temporarily discontinued for non-serious cases based on 
the judgment of the investigator, until return to the baseline condition. Refer to Section 7.2.4.2.3 
for the procedures to be followed in case of new occurrence or worsening of asthma. 
If applicable, additional information may be required (e.g. photo documentation of the AE) to 
allow a better evaluation and understanding of the above listed AEs. 
7.2.4.1.4 
Unexpected adverse drug reaction 
According to ICH E6, an unexpected adverse drug reaction is defined as an adverse reaction, the 
nature or severity of which is not consistent with the applicable study drug information 
(e.g. Investigator’s Brochure for an unapproved investigational product or the package 
insert/summary of product characteristics for an approved product). 
7.2.4.1.5 
Adverse event reporting period 
The clinical trial period during which AEs must be reported is starting  from the subject’s 
signature of the Informed Consent Form to the end of the subject’s participation. 
The Sponsor should be informed if the Investigator becomes aware of any unusual safety 
information or any safety information that appears to be drug-related involving a subject who has 
participated in a clinical trial, even after the subject has completed the clinical trial.  The 
Investigator should be diligent in looking for possible latent safety effects that do not appear until 
a medication has been discontinued. 
7.2.4.1.6 
Severity 
Severity is a clinical determination of the intensity of an AE and not of a disease. 
The Investigator is to classify the intensity of AEs using the following definitions:  
Mild 
Awareness of signs or symptom, but easily tolerated. 
Moderate 
Discomfort, enough to cause interference with usual activity 
Severe 
Incapacitating with inability to work or perform usual activity 
7.2.4.1.7 
Relationship to the study drug(s) and/or clinical trial procedure 
The Investigator is to determine whether there is a reasonable causal relationship between the 
occurrence of the AE and exposure to the study drug(s) (i.e. nemolizumab or placebo) and/or 
study procedure (e.g. injection, blood sample collection).  Medical judgment should be used to 
determine the relationship, considering all relevant factors including the pattern of reaction, 
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temporal relationships, positive dechallenge or rechallenge, relevant medical history, and 
confounding factors such as co-medication or concurrent diseases. 
The expression “reasonable causal relationship” is meant to convey in general that there are facts 
or arguments to suggest a causal relationship (ICH E2A, Section IIIA 1). 
The relationship assessment for an AE is to be completed using the following definitions: 
Reasonable possibility: 
According to the reporting Investigator, there is a reasonable possibility (i.e., suggestive 
evidence or arguments) that there is a causal relationship irrespective of the dose administered: 
• Between the study drug (nemolizumab or its placebo) and the AE, and/or  
• Between a clinical trial protocol procedure (e.g. injection, blood sample collection) and the 
AE  
No Reasonable Possibility: 
No suggestive evidence or arguments can be identified regarding a causal relationship between 
the study drug or a clinical trial protocol procedure and the AE. 
7.2.4.2 
Reporting procedures 
7.2.4.2.1 
Procedures for reporting Adverse Events 
The collection of AEs is from the time that a subject signs the ICF to their final visit. 
At each post-enrolment visit, the Investigator (or sub-Investigator) will question the subject 
about AEs using an open non-persuasive question to elicit reporting of AEs, for example “Have 
you noticed any change in your health since the last visit?”  Directed questioning and 
examination will then be performed as appropriate.  
Any AE occurring during the AE reporting period, whether it is related to the study drug(s) 
and/or study procedure(s) or not, will be recorded immediately in the source document, and 
described on the Adverse Event Form of the eCRF along with the date of onset, severity, 
relationship to the study drug(s) and/or study procedure(s), and outcome, without omitting any 
requested and known information.  Additional information will be requested under certain 
circumstances (e.g. for AESI).   
Adverse Events (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.  
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Reporting procedures for SAEs (see Section7.2.4.2.2),  AESI to be reported within 24 hours (see 
Section7.2.4.2.3) , and pregnancies (see Section7.2.4.2.4) must be followed. 
7.2.4.2.2 
Procedure for reporting a Serious Adverse Event 
For a SAE occurring during the clinical trial, regardless of whether it is related to the study drug 
and/or study procedure or not, 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 classified as an SAE. Immediately complete the AE and SAE form 
in the eCRF. This will generate an automatic email alert to Galderma Pharmacovigilance 
and to the Global Medical Services (GMS) within the CRO. The demographics, medical 
history, drugs/therapies form, and medical and surgical procedures form must also be 
completed and available for review in the eCRF at that time. (Of note, in case there is no 
access to the eCRF, please refer to the instructions in your Investigator Site File for 
reporting an SAE). 
3. 
If required, contact  the GMS within the CRO to discuss further actions to be taken; see 
contact details below: 
Investigator contact: 
Clinical Safety Officer 
CRO Safety mailbox:  NEM0-SRP115828-SAE@PAREXEL.com 
4. 
Send any relevant information or anonymized medical records (e.g. laboratory test results) 
to the GMS within the CRO (see contact details above), within 24 hours of receipt of this 
relevant information. 
5. 
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 form in the eCRF within 24 hours of receipt of the updated information.  
6. 
Obtain and maintain in 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. 
7. 
When the outcome of the event is known, complete an updated SAE form, if appropriate.  
8. 
Prompt notification of SAEs by the investigator to GALDERMA is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. 
GALDERMA has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a product under clinical investigation. 
GALDERMA 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 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
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according to local regulatory requirements and GALDERMA policy, and are forwarded to 
investigators as necessary. An investigator who receives an investigator safety report 
describing an SAE(s) or other specific safety information (e.g., summary or listing of 
SAEs) from GALDERMA or its delegate (i.e. the CRO) will file it with the IB and will 
notify the IRB/IEC, if appropriate according to local requirements. 
Comply with the applicable regulatory requirement(s) related to the reporting of SAEs to the 
IRB/IEC. 
7.2.4.2.3 
Procedure for reporting asthma/worsening of asthma  
In this study, AESIs have been defined as described in Section 7.2.4.1.3. Among these AESIs, 
new occurrence of asthma/worsening of asthma will have to be reported within 24 hours 
according to the procedure described below. 
Whether new occurrence of asthma or worsening of asthma is assessed as related to the treatment 
or not, the Investigator is to do the following: 
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. Immediately complete the AE form in the 
eCRF.  This will generate an automatic email alert to the GMS within the CRO. The 
demographics, medical history, drugs/therapies form, and medical and surgical procedures 
form must also be completed and available for review at that time. (Of note, in case there is 
no access to the eCRF, please refer to the instructions in the Investigator Site File for 
reporting an AESI). 
3. 
Send any relevant information or medical records (e.g. laboratory test results) to the GMS 
within the CRO (see contact details in Section 7.2.4.2.2), 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, update the AE form in 
the eCRF within 24 hours of receipt of the updated information.  
5. 
Obtain and maintain in 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 AE form in the eCRF, if appropriate. 
7.2.4.2.4 
Procedures for reporting pregnancies 
Any pregnancy occurring during clinical trials, 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. 
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If a subject becomes pregnant, the Investigator is to do the following: 
7. 
Withdraw the subject from the clinical trial. The subject must not receive any further 
injection of the study drug. 
8. 
Complete as fully as possible the Pregnancy Surveillance Form – Part I: History and Start 
of Pregnancy, available in the eCRF. Print and send it by e-mail along with the exit form 
within 24 hours of receipt of the information, to the GMS within the CRO (contact see 
Section 7.2.4.2.2). (Of note, in case there is no access to the eCRF, please refer to the 
instructions in the Investigator Site File for reporting a pregnancy). 
9. 
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. 
10. 
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, print and send the form by e-mail to the GMS within the 
CRO within 24 hours of receipt of the information. If the subject can no longer be reached 
(lost to follow-up), documentation of the non-response/contact with two phone calls and a 
letter (certified with return receipt) is required. 
11. 
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 e-mail to 
the GMS within the CRO within 24 hours of receipt of the information. 
12. 
If the pregnancy leads to an abortion (voluntary abortion, spontaneous abortion or 
therapeutic abortion), in utero death or congenital anomaly, follow the procedure for 
declaration of an SAE (see Section 7.2.4.2.2).  
7.3 
Pharmacokinetic assessments 
Blood samples will be collected at specific time points according to Table 2 for measurement of 
PK profile of nemolizumab and Antibodies anti-nemolizumab (ADA). 
The nemolizumab serum exposure will be assessed at the following time-points: baseline, weeks 
1, 2, 4, 8, 12, 16 and 18 and in case of early termination or any unscheduled visit for safety 
reason. 
ADA will be assessed at baseline, weeks 4, 8, 12, 16 and 18 and or in case of early termination 
or unscheduled visit for safety reason.  
7.3.1 
Technical procedures for pharmacokinetic blood sampling 
At each sampling time for PK assessment, 2 mL of blood will be collected for the assessment of 
nemolizumab concentrations in serum samples.  
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For ADA assessment, 2 mL of blood will be collected at the same time as PK sampling. 
PK samples are to be collected before drug injection (pre-dose samples) at Baseline, weeks 4, 8; 
the maximum allowed time windows for PK blood sampling is 30 minutes before drug injection. 
At weeks 1, 2, 12, 16 and 18 blood samples will be collected at the corresponding usual time of 
drug injection with an allowed time window of ±1h. 
The date and time of collection for each sample along with the time of the last study drug 
injection and missed injections have to be recorded on the eCRF. 
Processing of blood samples for PK and ADA assessments will be described in a specific 
manual. 
Volumes of blood to be obtained for PK, ADA tests are summarized in Appendix 1.  
7.3.2 
Serum and PK analyses  
Nemolizumab serum concentrations will be determined using validated ELISA method by a 
sponsor representative. A bioanalytical plan describing the details of the bioanalytical work 
related to serum samples of nemolizumab assessment will be written before the beginning of the 
sample analysis. 
The results will be described in a bioanalytical report, which will be included as an appendix in 
the final clinical study report. 
The PK analyses will be performed by a Sponsor representative. The results will be described in 
a PK report, which will be included in the final study report. 
The PK parameters will be determined by a model independent approach (non-compartmental 
method) using individual serum concentration. Data from subjects with missing concentration 
values (missing samples) may be used if pharmacokinetic parameters can be estimated using the 
remaining data points. 
When appropriate, the following PK parameters will be determined for each subject: 
From baseline to week 4: 
• Cmax: The observed peak drug concentration 
• Tmax: The time at which Cmax occurs 
• AUC0-t: area under the concentration time curve calculated by the mixed linear 
logarithmic trapezoidal method from T0 up to the sampling time corresponding to the last 
quantifiable concentration (Clast) 
• AUC0-28d: Area under the concentration time curve from pre dose through 28 days post 
dosing. AUC0-28d will be calculated by mixed linear logarithmic trapezoidal method 
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From week 12 to week 18 (or Early termination or Unscheduled visit if applicable): 
• t1/2: the terminal half-life value (t1/2) will be calculated using the equation ln2/k after the 
last drug injection (week 8). 
• AUC0-t: area under the concentration time curve calculated by the mixed linear 
logarithmic trapezoidal method from T0 up to the sampling time corresponding to the 
last quantifiable concentration (Clast). 
• AUC0-inf: Area under the plasma concentration-time curve calculated by the mixed 
linear- logarithmic trapezoidal method from T0 and extrapolated to time infinity as: 
AUC0-inf=AUC0-t+ Clast / kel. When the extrapolation represents more than 20%, AUC0-inf 
and t1/2 will not be reported. 
At weeks 4, 8, 12, 16, 18 (or Early termination or Unscheduled visit if applicable): 
• Ctrough: The residual drug concentration  
7.3.3 
Anti-drug antibody analysis 
ADA will be evaluated by a Sponsor representative using a validated ELISA screening assay. If 
serum circulating ADA is detected, they will be characterized using a validated assay. Incidence 
of positive ADA results will be summarized by treatment group (absolute occurrence and percent 
of subjects). 
7.4 
Pharmacodynamic assessments 
Blood and skin samples (D-Squames and skin biopsies) will be collected to investigate the effect 
of nemolizumab on biomarkers.  
As much as possible, skin sampling will be performed in similar body areas for all samples in all 
patients, on a selected area at baseline, such as the upper arms. Biopsies on prurigo lesions will 
be performed at baseline and post-treatment only for consenting subjects. Non-lesional sample 
will be taken at baseline in areas with no scratch such as the inner part of the upper arm  
approximately 5cm, apart from lesional skin. 
The detail of the procedures for PD samples and storage conditions will be described in an 
Operational manual.  
All collected samples will be sent to GALDERMA R&D for analysis. After performance of the 
planned investigations, the remaining samples will be integrated into the long term research 
program being performed in the research department of Galderma R&D (Program (2) – 
“Physiopathological study on skin disease to identify new dermatological medications; Initial 
declaration CP ECOH : DC-2008-315, 31/01/2009).  
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Volumes of blood to be obtained for PD tests are summarized in Appendix 1.  
7.4.1 
Blood samples for PD 
Blood samples for speficic IgE will be collected at baseline only for all subjects. These samples 
will be analysed by the central laboratory. 
Plasma samples will be collected at baseline, week 4 and week 12 for analysis of IL-31 protein 
expression levels for all randomized subjects. 
7.4.2 D-Squames samples  
Stratum Corneum (SC) samples will be collected for all randomized subjects using D-Squames 
to evaluate the microbiome, and cytokine and chemokine expression levels. SC samples will be 
collected for all randomized subjects at baseline visit, at Day 29 (week 4) and at Day 85 (week 
12) as described below: 
 Baseline visit (proteomic and microbiome analyses) 
− Non lesional skin 
− Lesional skin at baseline 
 Week 4, day 29 (proteomic analysis only): 
- Lesional skin 
 Week 12, day 85 (proteomic and microbiome analyses) : 
− Lesional skin  
For proteomic analysis, 10 large rectangle D-squames (D100 Monaderm) will be used for 
consecutive tape stripping. Cytokine/chemokine profile including IL-31 will be performed using 
ELISA-like technologies. The 3 lesional samplings of D-squames at baseline, week 4 and week 
12 will be taken on exactly the same anatomical location, no matter if the lesion regressed or not. 
For microbiome analysis, one D-squame will be used (DS100 Monaderm, 2.2 mm diameter) 
being successively applied in the targeted area at least 20 times.  
D-squames sampling should be performed as far as possible in a similar body location for every 
patient (e.g.upper arms) on selected areas and recorded in the CRF. 
7.4.3 
Skin biopsies  
Three 4-mm skin biopsies will be performed (only for subjects who accept skin biopsies by 
signing the additional consent form) for 
IL-31 
and 
IL-31RA quantification by 
immunohistochemistry techniques and IL-31 and IL-31RA mRNA by genomics analysis, if 
sufficient biological material is available. 
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Body location for biopsy sampling should be performed as far as possible in a similar body 
location for every patient (e.g. upper arms) and recorded in the eCRF. 
The samples will be collected as much as possible on the same anatomical area than D-squames, 
in an adjacent lesion with as much as possible a similar clinical presentation. 
 
Skin biopsies will be performed as it follows: 
 
 Baseline visit: 
− One biopsy on lesional skin (nodule) 
− One biopsy on non lesional skin (e.g. inner arm): approx. 5 cm apart from lesion skin 
 
 
 Week 12 (day 85) visit: 
− One biopsy on lesional skin after treatment  (on a nodule selected at baseline) 
7.5 
Biophysical assessments 
7.5.1 
Actigraphy 
High resolution actigraphy will be used in this study to evaluate scratching events and duration 
of sleep during the night. This is a non-invasive, ambulatory, wrist-mounted device designed to 
capture, record, and store all wrist movements, which is an indicator of whole body movement. 
The High resolution actigraphy provides an objective method for measuring scratching events 
during the night and other parameters such as sleep quality (Almazan et al  2016).   
Philips will, in accordance with procedures, centrally analyze assessment data for scratching 
events and sleep parameters obtained from the  actigraphy device and submit data to the CRO. 
Patients will wear two devices, one on each wrist, from D-7 and every day during the first 4 
weeks of the study, by following  the instructions provided by the CRO. 
7.5.2 
Whole body imaging 
This device will be used in equipped sites only and the photographs of the entire body will be 
taken according to the operational manual provided by the Sponsor at least at baseline and Week 
12 (Day 85)  and if it is possible at Week 4 (Day 29), Week 8 (Day 57) , and Week 18 (Day 126.   
It is for illustration and as exploratory evaluation of the lesions improvement. 
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8 
CLINICAL TRIAL VISITS DESCRIPTIONS AND PROCEDURES 
8.1 
Description of clinical trial visits 
Please refer to the Schedule of Assessments table in the Synopsis (Table 2). 
A written, signed ICF must be obtained prior to performing any clinical trial-related evaluations 
and/or procedures. The subject must be provided with a fully completed, dated and signed copy. 
At each visit, assessments/procedures should be performed in the following order: 
1. 
Patient-reported outcomes 
2. 
Investigator assessments (including efficacy and safety) 
3. 
Blood sample collection for laboratory assessments, PK and PD assessments 
4. 
Administration of study drug 
8.1.1 
Screening period (Day -28 to Day -1) 
8.1.1.1 
Visit 1 / Screening visit 1 (Day – 28 to Day -8) 
Screening visit 1 must be performed between Day -28 and -8 prior to Day 1 visit.  
At this Screening visit, the Investigator or designee will: 
1. Review and explain the nature of the study to the subject, particularly the prohibited 
activities and constraints. 
2. Obtain the signed and dated ICF (and country-specific, photo and biopsy consent form if 
applicable) and provide a fully completed, dated and signed copy to the subject.  
3. Collect information regarding demographics, relevant medical history, previous therapies 
and procedures, and concomitant therapies and procedures. 
4. Assign the subject a SIN.  
5. Perform a physical examination, vital signs measurements and ECG.  
6. Conduct respiratory medical assessments, including PEF for subjects with a history of 
asthma.  
7. Confirm that the subject meets inclusion/exclusion criteria for screening visit. 
8. Complete serum pregnancy test if the subject is a female of childbearing potential. 
9. Collect and record any AEs starting from the time of Informed Consent signature. 
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10. Collect blood sample for CPK, TB test, IgE analysis and viral serology 
11. Ask the subject  about the mean worst itch daily intensity over the previous 3 days 
according  to NRS and record the information and record the information on the 
electronic device. 
12. Schedule the Visit 2/Screening visit 2 and instruct the subject about the precautions to be 
taken for visit 2 (Avoid intensive sport, fasting condition for biochemistry analysis)  
8.1.1.2 
Visit 2 / Screening visit 2 (Day –7) 
At this Screening visit, the Investigator or designee will: 
1. Collect information regarding concomitant therapies and procedures and AEs. 
2. Conduct respiratory medical assessments, including PEF for subjects with a history of 
asthma. 
3. Check  TB result previously performed. In case of inderterminate results, collect blood 
sample to retest this parameter.  
4. Check IgE & virology results 
5. Collect blood sample for hematology, blood biochemistry.  
6.  Collect urine for urinalysis. 
7. Instruct the subject on how to use the electronic device for the daily evaluation of pruritus 
NRS, VRS, sleep disturbance NRS. Remind the subject to report the assessments on a 
daily basis on the ePRO according to the protocol. 
8. Provide the subject with electronic devices for pruritus assessments. 
9. Instruct the subject on the use of the watches for Actigraphy 
10. Provide the subject with the watches for Actigraphy assessments 
11. Schedule the Visit 3/Day 1. 
8.1.2 
Treatment period 
8.1.2.1 
Visit 3 / Baseline visit (Day 1) 
At the Baseline visit, the Investigator or designee will: 
1. Ask the subject about AEs using an open-ended question, such as “Have you noticed any 
change in your health since the last visit?” Record all events, as appropriate, on the 
corresponding eCRF form(s). 
2. Check laboratory results (hematology, biochemistry, virology, urinalysis, IgE, TB tests) 
from the Screening visits. 
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3. Complete urine pregnancy test if the subject is a female of childbearing potential. 
4. Ask the subject about any changes in his/her concomitant therapies/procedures (added, 
removed or changed) since the previous visit. Record all changes in the source document 
and the eCRF. 
5. Perform a physical examination (including height and weight), vital signs measurements 
and ECG.  
6. Conduct respiratory medical assessments, including PEF for subjects with a history of 
asthma 
7. Check subject’s record for pruritus NRS and VRS and sleep disturbance NRS. 
8. Confirm the eligibility of the subject according to inclusion and exclusion criteria. Enroll 
the subject in the clinical trial and record the corresponding SIN in the eCRF 
9. Complete the evaluation of PAS and IGA.  
10. Take whole body photographs (selected centers only). 
11. Ask subject to complete the DLQI. 
12. Check subject’s use of watches for Actigraphy 
13. Collect urine for urinalysis. 
14. Collect blood sample for hematology, and entire blood biochemistry 
15. Perform D-Squames. 
16. Perform 4-mm biopsies  for subjects who consented by signing the additional ICF 
17. Collect blood samples for PK, ADA & biomarkers before drug injection. 
18. The pharmacist (or other qualified personnel) will: 
a. Prepare the syringe of dosing solution of appropriate volume of nemolizumab or 
placebo according to the pharmacy manual and the specific instruction provided 
by the IRT system; 
b. Provide the prefilled syringe to the blinded investigator or qualified personnel for 
injection. 
19. Blinded investigator or qualified personnel will administer the study drug subcutaneously 
to the subject, who will remain under medical observation for at least 30 minutes before 
been  discharged. 
20. Instruct the subject on how to use the electronic device to evaluate DPS 24, 48, and 72 
hours after study drug administration, and remind subject about the daily evaluation of 
pruritus NRS, VRS and sleep disturbance NRS.  
21. Complete the Subject Enrollment Log. 
22. Schedule the next visit V4 Day 8. 
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8.1.2.2 
Visit 4 / Day 8 Week 1 (+/-1 day) & Visit 5 / Day 15 Week 2 (+/-2 days) 
The Investigator or designee will: 
1. Collect information regarding AE (including review of laboratory values) and 
concomitant therapies/procedures. 
2. Perform vital signs measurements. 
3. Conduct respiratory medical assessments, including PEF for subjects with a history of 
asthma 
4. When applicable check biopsy healing (for subjects who have consented).  
5. Collect PK blood samples.  
6. Check subject's record for pruritus NRS and VRS and sleep disturbance NRS  
Remind the subject to evaluate NRS and VRS and sleep disturbance NRS daily by  
completing their device  
7. Check subject’s use of watches for Actigraphy 
8. Schedule the next visit. 
8.1.2.3 
Visit 6 / Day 29 Week 4 (+/-2 days) & Visit 7 / Day 57 Week 8 (+/-2 days) 
The Investigator or designee will: 
1. Collect information regarding AE (including review of laboratory values) and 
concomitant therapies/procedures. 
2. Perform physical examination & vital signs measurements (including weight). 
3. Conduct respiratory medical assessments, including PEF for subjects with a history of 
asthma.  
4. Perform ECG at visit 7/Day 57 only 
5. Complete urine pregnancy test for female of childbearing potential only. 
6. Complete the evaluation of PAS and IGA.  
7. Check subject’s record for pruritus NRS and VRS & sleep disturbance NRS  
8. Ask subject to complete the DPS & DLQI before injection at Visit 6/Day 29 only 
9. Collect the watches for Actigraphy analysis at Visit 6/Day29 only 
10. Collect urine for urinalysis at Visit 6/Day29 only. 
11. Collect blood sample for hematology and entire blood biochemistry, at Visit 6/Day29 
only 
12. Collect blood samples for biomarkers at Visit 6/Day29 only. 
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13. Collect PK blood samples for PK and ADA before drug injection.  
14. Perform D-Squames sampling at Visit 6/Day29 only. 
15. Take whole body photographs  (selected centers only) if possible  
16. Perform subcutaneous study drug injection and observe for at least 30 minutes before 
discharging the subject. 
9. Remind the subject to complete the device daily 
10. Schedule the next visit 
8.1.2.4 
Visit 8 / Day 85, Week 12 (+/- 5 days) 
The Investigator or designee will: 
1. Collect information regarding AE (including review of laboratory values) and 
concomitant therapies/procedures. 
2. Perform physical examination (including weight) & vital signs measurements. 
3. Collect blood samples for hematology & entire biochemistry. 
4. Collect urine to perform urinalysis test. 
5. Complete urine pregnancy test for female of childbearing potential only. 
6. Conduct respiratory medical assessments, including PEF for subjects with a history of 
asthma.  
7. Check subject’s record for pruritus NRS and VRS  and  remind subject  to complete them  
daily 
8. Ask subject to complete the DLQI. 
9. Complete the evaluation of PAS and IGA.  
10. Collect blood samples for PK, ADA & biomarkers. 
11. Perform D Squames. 
12. Perform 4-mm biopsies for subjects who consented. 
13. Take whole body photographs when applicable. 
14. Schedule the next visit for Visit 9. 
8.1.3 
Follow up period 
8.1.3.1 
Visit 9 / Day 113, Week 16 (+/- 5 days) 
The Investigator or designee will: 
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1. Collect information regarding AE (including review of laboratory values) and 
concomitant therapies/procedures. 
2. Perform vital signs measurements. 
3. Complete urine pregnancy test for female of childbearing potential only. 
4. Conduct respiratory medical assessments, including PEF for subjects with a history of 
asthma.  
5. Collect blood samples for PK, ADA  
6. Control the good healing of biopsies when applicable. 
7. Check subject’s record for pruritus NRS and VRS  and  remind subject  to complete them  
daily 
8. Schedule the next visit for Visit 10. 
8.1.3.2 
Visit 10 / Day 126, Week 18 (+/- 7 days) 
The Investigator or designee will: 
1. Collect information regarding AE (including review of laboratory values) and 
concomitant therapies/procedures. 
2. Check subject’s record for pruritus NRS and VRS. 
3. Perform physical examination & vital signs measurements. 
4. Complete urine pregnancy test for female of childbearing potential only. 
5. Conduct respiratory medical assessments, including PEF for subjects with a history of 
asthma.  
6. Complete the evaluation of PAS and IGA.  
7. Collect blood samples for PK, ADA  
8. Take whole body  photographs (selected centers only). 
9. Collect the device used for Pruritus assessments 
10. Complete the exit form. 
8.1.4 
Early Termination visit or unscheduled visit: 
The Investigator or designee will: 
1. Collect information regarding AE (including review of laboratory values) and 
concomitant therapies/procedures. 
2. Check subject’s record for pruritus NRS and VRS. 
3. Ask subject to complete the DLQI. 
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4. Complete the evaluation of PAS and IGA.  
5. Perform physical examination & vital signs measurements and ECG. 
6. Conduct respiratory medical assessments, including PEF for subjects with a history of 
asthma.  
7. Complete urinalysis. 
8. Complete urine pregnancy test for female of childbearing potential only. 
9. Collect blood samples for hematology & biochemistry 
10. Collect blood samples for PK and ADA.  
11. Complete the exit form in case of early termination and collect e-devices. 
8.2 
Subject instructions (other than study drug administration) 
Throughout the study duration, subjects should be instructed to use their own moisturizer 
emollient including OTC preparations or bath oil. They will be instructed to avoid any topical 
product for pruritus relief containing capsaicin, menthol or other during the course of the study  
Subjects will be instructed to avoid intensive physical exercise before blood sampling for 
biochemistry (CPK) to limit false positive and to come on site for Screening visit 2 in fasting 
conditions. 
9 
STATISTICAL METHODS PLANNED 
9.1 
Variables to be analyzed 
9.1.1 
Efficacy endpoints 
The primary efficacy endpoint will be the percent change from baseline in NRS to week 4 
(weekly average of the peak). 
 
The secondary efficacy endpoints will be: 
 Absolute and Percent change from baseline in weekly average of the peak and average 
pruritus NRS to each visit 
 Change from baseline of VRS at each time point 
 DPS  
 PAS: Distribution for item 6 (excoriation/crusts and healed lesions stages) and change from 
baseline for item 5 (in lesions number) 
 IGA: Distribution score and success rate (defined as IGA=0[clear] or IGA=1[Almost clear] 
with two point improvement from baseline). 
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9.1.2 
Safety endpoints 
The safety endpoint measures for this study are as follows: 
 Adverse events 
 Laboratory tests 
 Vital signs  
 Physical exam and body weight 
 12-lead ECG 
 PEF 
9.1.3 
PK endpoints 
The PK endpoints measures for this study are as follows: 
 Serum IL-31 concentration  
 Anti-CD14152 antibodies 
9.1.4 
PD endpoints 
The pharmacodynamic endpoints measures for this study are as follows: 
 Serum: IL-31 concentration 
 Dsquames : IL-31, IL-31RA expression level and Cytokine/chemokine profiling in Dsquames 
 Skin biopsies : IL-31 and IL-31 RA quantification by immunohistochemistry techniques and 
IL-31 and IL-31RA mRNA quantification by genomics analyses. 
9.1.5 
Other endpoints 
 Quality of life (DLQI) 
 Objective assessment of scratching and sleep with Actigraphy 
 The sleep disturbance NRS  
9.2 
Statistical and analytical plans 
A Statistical Analysis Plan (SAP) will be developed as a separate document. The SAP will 
contain detailed and technical description of specific data conventions, calculations and of 
statistical procedures for executing the analyses that are specified in the sections of the clinical 
trial protocol below.   
Any changes made to analysis after finalization of SAP will be documented in the clinical study 
report. 
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9.2.1 
Data transformations 
9.2.2 
Populations analyzed, evaluability and limitation / evaluation of bias 
The statistical analyses will be performed based on the following subject populations. 
9.2.2.1 
Intent-to-treat (ITT) Efficacy Population 
The ITT Population is defined as comprising all subjects who are randomized.  All primary 
efficacy variables and secondary efficacy variables will be analyzed based on the ITT 
Population.  
9.2.2.2 
Per-protocol (PP) Efficacy Population 
The PP Population is defined as comprising the ITT subjects who have no major protocol 
deviations. This will be the primary population for this study.  
Major deviations are categorized into 4 categories: 
1) Entrance criteria deviations, 
2) Non compliance, 
3) Concomitant therapies taken during the study, interfering with efficacy, 
4) Administrative errors such as unblinding or study drug dispensing errors. 
PP analysis will be conducted only up to Week 4. 
9.2.2.3 
Safety Population 
The Safety Population is defined as comprising the ITT Population subjects who receive the 
study drug at least once. Randomized subjects will only be excluded if there is a clear 
documented evidence that the subject did not receive any study drug injection.  All safety data 
will be summarized based on the Safety Population. 
9.2.2.4 
PK analysis population 
The PK analysis population will include all subjects in the safety population who provide at least 
one post-baseline evaluable drug concentration value. 
9.2.2.5 
PD analysis population 
The PD statistical analyses will be performed based on the PP population, and after exclusion of 
samples unable to produce reliable quantifications of cytokines, and/or immunohistological 
markers and/ or transcriptomic biomarkers, due to the material quantity and/or quality. 
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9.2.3 
Data presentation and graphics 
Subject disposition, demographics, baseline characteristics, previous therapies, concomitant 
therapies, and treatment duration by treatment will be summarized by descriptive statistics. 
All efficacy variables will be summarized by treatment at each visit.  The categorical variables 
[VRS, IGA, PAS (Item 6)] will be summarized by frequency and percentage for each response 
category (N, %).  The continuous variables [weekly average NRS peak and mean, PAS (Item 5)] 
will be summarized using means, medians, minimum, maximum, and standard deviations for the 
data collected at each visit. 
Quality of life questionnaire (DLQI) at each visit and the change from baseline will be 
summarized by treatment using descriptive statistics. Categorization of the score will also be 
summarized. (Hongbo Y, et al.,2005)  
 
Treatment-emergent Adverse Events (TEAEs) will be tabulated in frequency tables by System 
Organ Class and Preferred Term based on the Medical Dictionary for Regulatory Activities 
(MedDRA).  Additional summary tables will be provided for AEs that are considered serious 
(SAEs), related to the study drug(s), by severity, AESIs, and AEs leading to discontinuation.  For 
a given AE, a subject will be counted once even if he/she has experienced multiple episodes of 
that particular AE.  
In addition, AEs with an onset prior to baseline will be listed separately. 
Therapies and procedures ongoing at the baseline visit or starting after the baseline visit will be 
summarized separately from those ending at baseline or before. 
PEF measurements (absolute values and change from baseline) will be summarized by visit and 
treatment group. 
Vital sign measurements and the changes from baseline (Day 1/pre-dose) to the each post 
baseline timepoint will be summarized using descriptive statistics (n, means, standard deviation, 
median, minimum and maximum value).  
For each vital sign a shift table with the number and percentage of subjects who are normal, 
abnormal (CS) and abnormal (NCS) will be displayed with the last pre-treatment value versus 
the post baseline  scheduled on-treatment. Subjects with missing pair of data will not be counted 
in the percentages. 
For physical exams, the number and percentage of subjects who are normal, abnormal (CS) and 
abnormal (NCS) will be displayed with the last pre-treatment value versus the post baseline 
scheduled on-treatment. 
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9.2.4 
Inferential statistical analyses 
The primary efficacy analysis of the percent change from baseline to week 4 of the weekly 
average of the peaks  pruritus NRS, will be an ANOVA including the Treatment group as factor, 
presence and absence of background of atopy and country as a cofactors. 
In addition to the per-protocol analysis, several sensitivity analyses on ITT population will be 
conducted for the primary endpoint. For ITT, NRS will be set to missing after rescue medication 
is used.  
 The primary imputation method for any missing data will be the LOCF (Last observation 
carried forward) approach.  
 Multiple Imputation (MI) using the Missing At Random (MAR) assumption will also be used. 
The MI procedure of the SAS system will be used to generate five sets of data with missing 
values imputed from observed data. It is expected that the pattern of missing data will be 
monotonic, with slight deviations being corrected by the Markov Chain Monte Carlo 
(MCMC) method of the MI procedure.  Linear regression will be employed to model the 
missing NRS score, with the following covariates included in the imputation model: treatment 
and non-missing data from earlier timepoints. The imputed datasets will be analyzed using the 
methodology described for percent change from baseline in NRS score. The results from the 
analysis of the multiple imputed datasets will be combined by the MIANALYZE procedure of 
the SAS system. The seed number to be used will be the protocol number (115828). 
For secondary endpoints: 
The percent change from baseline to any visits of the weekly average of the peak and of the 
average pruritus NRS, will be analyzed separately via an ANOVA including the Treatment group 
as factor, presence and absence of background of atopy and country as a cofactors. The absolute 
change will be analyzed via an ANCOVA, same factors as the percent change but with including 
baseline NRS as a covariate. 
IGA, DPS and PAS will be analyzed at any visits by the CMH test stratified by background of 
atopy and by country with the ridit transformation and the row mean difference statistic (FREQ 
procedure from SAS). 
Proportion of subjects achieving success (IGA=0[clear] or IGA=1[Almost clear] with two point 
improvement from baseline)  will be analyzed at each evaluation visit using the Cochran-Mantel-
Haenszel (CMH) test stratified by background of atopy and  by country with the ridit 
transformation and the general association statistic (FREQ procedure from SAS). 
PP and ITT (Criteria will be set to missing after rescue medication is used and imputed to LOCF, 
for continuous outcomes and to failure for binary outcomes) will be conducted on secondary 
endpoints. 
DLQI data will be analyzed on observed cases by CMH test test stratified by background of 
atopy and  by country with the ridit transformation and the row mean difference statistic (FREQ 
procedure from SAS)on the data in categories and also in terms change from baseline via an 
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ANCOVA including treatment, baseline DLQI as a covariate, background of atopy and  country 
as cofactors 
The absolute and the percent change in weekly average sleep disturbance NRS from baseline up 
to week 4 will be analyzed by CMH test stratified by background of atopy and  by country with 
the ridit transformation and the row mean difference statistic (FREQ procedure from SAS) 
The PD parameters will be visualized by boxplots (with a logarithm base 10 Y axis where 
needed). The compound effect will be estimated by Student’s t test comparing the change at D85 
from D1 for CD14152 vs the change at D85 from D1 for placebo (or other if more appropriate). 
The multiple testing problem will be taken into account by the Benjamini-Hochberg approach 
(1995)(or other if more appropriate). 
9.2.5 
Pharmacokinetic parameters and ADA analyses 
The PK parameters derived using non-compartmental techniques will be regarded as primary 
endpoints for the pharmacokinetic analyses. Primary inference for all the PK parameters will be 
based on the pharmacokinetic analysis population. 
The concentration at each time point will be summarized as arithmetic mean, standard deviation, 
median, minimum, and maximum, number of BLQs (Below the Limit of Quantification).  
Pharmacokinetic parameters using geometric means will be compared to determine when steady 
state conditions are achieved during the treatment period. Geometric means and between-subject 
coefficients of variation (CVb) will be calculated for loge-transformed AUC0-28d, Ctrough and Cmax 
where: 
 
Geometric mean = exp(mean on log scale) 
 
CVb (%) = sqrt[exp(SD2) - 1] x 100 
– where SD is the standard deviation of the loge-transformed data. 
Following loge-transformation, Ctrough will be analyzed using analysis of variance (ANOVA), the 
model will include time and subject as a fixed effect.  The residual variance from the model will 
be used to calculate point estimates and 90% CIs for the least squares means for each treatment 
formulation on the loge scale.  These estimates will be back transformed to give point estimates 
and 90% CIs on the original scale. 
The potential relationship between plasma concentrations of nemolizumab and change in pruritus 
NRS, biomarkers or other indicators of disease activity will be explored using PK/PD modeling, 
as appropriate. 
Incidence of positive ADA results will be summarized by treatment group (absolute occurrence 
and percent of subjects). Individual PK profiles of subjects with our without ADA will be plotted 
to explore ADA impact on systemic exposure levels. 
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9.3 
Sample size determination 
9.3.1 
Historical data 
Two recent studies comparing several doses (among them, 0.5 mg/kg)  of Nemolizumab to the 
placebo conducted in two different indications were evaluating the weekly average of the worst 
itching score over the past 24 hours at week 4 on a VAS (CIM003JG and CIM106JP). The 
following results were observed: 
Indication 
N(0.5 mg/kg ; Placebo) 
Mean Effect versus Placebo (in 
terms of percent change from 
baseline) 
SD 
Uremic pruritus 
14;14 
18% 
35 
Atopic Dermatitis 
51;45 
40% 
30 
9.3.2 
Assumptions 
VAS and NRS are considered highly correlated (Reich et al 2012 ), thus all estimators for VAS 
are assumed to be the same for NRS.  
For the current study, it is assumed that the common standard deviation is 35 and that the true 
difference between Nemolizumab and the placebo is 30% in terms of percent change from 
baseline in worst ichting score on a NRS at Week 4. 
9.3.3 
Sample size calculation 
With an effect size of (30/35=) 0.857, a power of 90% and a type I error of 5% two-sided; at 
least 30 subjects are needed per group. In order to maintain the power of the tests, for per-
protocol population, in case of drop outs/major deviations at Week 4, the sample size will be 
increased to 35 subjects per group, i.e. 70 to be randomized. 
9.4 
Interim analysis at Week 4 
An interim analysis may be performed once at least 40 subjects will have completed the week 4 
visit or discontinued before (decision will be taken by the Sponsor according to the recruitment 
rate). This analysis will include efficacy data on all subjects up to that time point. In addition to 
efficacy, all safety data available (not only data up to week 4) will also be analyzed. This interim 
analysis may be performed to inform the Sponsor for the subsequent clinical program. Blind will 
be broken for a limited Galderma R&D Staff involved in this trial according to the 
communication plan. The study will remain blinded to Investigators, CRO clinical team and sites 
staffs, as no results will be sent out. Furthermore, only summary statistics (by treatment) and 
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individual listings (without treatment identity) will be provided for this analysis. This will avoid 
individual unblinding. No discontinuation rules have been defined for this study based on the 
outcome of  this interim analysis. 
10 
TRAINING / MONITORING / DATA MANAGEMENT / QUALITY ASSURANCE 
10.1 
Personnel training 
CRA and all relevant personnel will be trained prior to study initiation on the condition to be 
treated, the Standard Operating Procedures (SOPs) to be used in this clinical trial, the protocol, 
and all study-specific procedures. Team organization, communication, and operational issues 
will also be discussed and agreed upon. 
Investigators, evaluators, study coordinators, pharmacists and other applicable personnel are 
recommended to attend an investigator/initiation meeting. During the meeting, participants will 
be trained on the protocol, ICH-GCP, study-specific procedures (including efficacy assessment 
scales and instruction for use of the study drug), IRT and eCRF completion.  
A study initiation visit will be conducted for each study center prior to the enrolment of any 
subjects. All personnel involved in the study conduct will receive on-site training prior to 
participating in any procedure and/or evaluation. Each study center will have a training record as 
part of the site file and Trial Master File 
10.2 
Clinical monitoring 
The conduct of the clinical trial will be closely monitored by representatives of GALDERMA to 
verify adherence to the clinical trial protocol, ICH-GCP guidelines, and applicable SOPs.   
The Investigator will allow the CRO/Sponsor’s representatives, to have direct access to all 
clinical trial records, CRFs, corresponding subject medical records, study drug(s) dispensing 
records, and any other documents considered source documentation.  Additionally, the 
CRO/Sponsor representative is to have access to the study drug(s) storage area and clinical trial 
facilities. 
The Investigator also agrees to assist the representative if required. 
10.3 
Data management 
All data management procedures will be detailed in a data management plan (DMP).  
The DMP will describe the clinical data management system that will be used to collect data, and 
who is responsible for performing the data management activities. Computerized edit checks and 
review processes will be performed on an ongoing basis as outlined in the DMP until all data 
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clarifications are resolved. The data will be exported to be stored in SAS datasets. After all data 
clarifications are resolved, coding is approved, SAE/pregnancy reconciliation has been 
completed and subject’s evaluability is determined, the database will be locked. 
Pruritus NRS, VRS, DPS, sleep disturbance NRS, DLQI, Actigraphy will be collected using 
separate electronic devices provided to the subject. Data collected from Pruritus NRS, VRS, 
DPS,  sleep disturbance NRS, DLQI will be exported to be stored in datasets. 
10.4 
 Quality assurance / audit / inspection 
The clinical trial is conducted under the sponsorship of GALDERMA in compliance with the 
applicable international and local regulatory requirements as well as applicable ICH guidelines 
and in accordance with the SOPs for clinical trial conduct and monitoring from GALDERMA 
and/or the Contract Research Organization (CRO). 
Audits of clinical trial centers may be conducted by the Sponsor/CRO representatives, and 
inspection may be performed by Regulatory Authority inspectorates or IRBs/IECs before, 
during, or after the clinical trial.   
The Investigator will allow and assist the CRO/Sponsor’s representatives, IRBs/IECs and any 
regulatory agency to have direct access to all requested clinical trial-related records. For the 
audits performed by, or on behalf of GALDERMA auditors, audit certificate(s) will be provided 
by Quality Assurance. 
10.5 
Changes in clinical trial conduct / amendments 
10.5.1 
Clinical trial conduct 
With the exception of eliminating an immediate hazard to a subject, the Investigator should not 
deviate from the clinical trial protocol or implement any changes without written approval from 
the Sponsor and prior review and documented approval/favorable opinion from the IRB/IEC of a 
protocol amendment. 
Changes that involve only logistical or administrative changes to the clinical trial protocol are 
authorized.  The Investigator should document and explain any deviation from the clinical trial 
protocol. 
10.5.2 
Amendments 
The Sponsor may modify the clinical trial protocol at any time for ethical, medical, or scientific 
reasons. Any amendments will be handled according to applicable local regulations. 
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The Sponsor does not have to notify non-substantial amendments to the competent authorities or 
the Ethics Committees. However, non-substantial amendments should be recorded and detailed 
in subsequent submissions e.g., in the subsequent notification of a substantial amendment. 
11 
ETHICS AND GENERAL CLINICAL TRIAL CONDUCT CONSIDERATIONS 
11.1 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
This clinical trial protocol and all amendments will be reviewed and approved by the appropriate 
IECs/IRBs. 
11.2 
Ethical conduct of the clinical trial 
This clinical trial will be conducted in accordance with the protocol, the HELSINKI declaration 
(1964) and subsequent amendments, and the ICH GCP, and in compliance with applicable 
regulatory requirements.  
11.3 
Subject information and consent 
All subjects who participate in this clinical trial are required to be fully informed about the 
clinical trial in accordance with GCPs guidelines, federal regulations, HIPAA (for the U.S), and 
guidelines and in accordance with local requirements.   
The ICF approved by an IRB/IEC will be fully explained to the subject. Prior to enrolment into 
the clinical trial, the subject will sign and date the consent form. The investigator is responsible 
for maintaining each subject’s consent form in the site file and providing each subject with a 
copy of the signed and dated consent form. 
11.4 
Contractual requirements 
A 
contractual 
agreement 
will 
be 
signed 
between 
the 
CRO/Sponsor 
and 
each 
Investigator/Institution.  This document will contain supplementary information, including 
financial terms, confidentiality, the clinical trial schedule, third party responsibility, and 
publication rights. 
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11.5 
Data collection and archiving 
11.5.1 
Data collection 
The investigator must maintain all required records for all subjects. Data for this clinical trial will 
be recorded in the subject’s source documents (including electronic device) and in the eCRF 
provided by the sponsor/CRO. All data should be recorded in the eCRF completely and 
promptly.  
11.5.2 
Source documentation 
The investigator must keep accurate separate records (except those defined below for which 
eCRF could be considered as source documentation) of all subject visits, and ensure that they 
include all pertinent clinical trial-related information. A statement should be made indicating that 
the subjects have been included in this clinical trial and have provided signed written ICF. 
All AEs must be thoroughly documented. 
Specifically, source documentation include medical records (including pharmacy records) and 
documented conversation between the investigator and other healthcare provided. Information 
based on subject’s medical interview with no other supporting evidence cannot be accepted.  
Results of any laboratory tests conducted during the clinical trial should also be included in the 
source documentation. Scores of NRS, VRS will be calculated automatically in the eCRF and 
will therefore be considered as e-source data; however, the components of PAS must be 
documented on a separate source document. Data documented on electronic devices directly 
(pruritus NRS, VRS, PCS, sleep disturbace NRS, DLQI and Actigraphy) will also be considered 
as e-source data. 
11.5.3 
Archives 
All pertinent data, samples, photographs, correspondence, and reports, the original or amended 
clinical trial protocol, and all other material relating to the clinical trial will be maintained 
securely in Sponsor/CRO/Investigator/Institution archives for the legally required duration for 
archiving. 
The Investigator/Institution should maintain the essential clinical trial documents as specified in 
Section 8 of ICH-GCP, and according to the applicable regulatory requirements. 
The Investigator/Institution should take measures to prevent accidental or premature destruction 
of these documents. 
If the Principal Investigator retires, relocates, or withdraws from the responsibility of keeping the 
clinical trial records for any other reasons, custody must be transferred to a person who will 
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accept the responsibility.  The Sponsor/CRO must be notified in writing of the name and address 
of the new custodian. 
11.6 
Insurance 
A certificate attesting Third Party coverage of CRO/Sponsor will be provided upon request. 
11.7 
Investigator and Administrative Structure  
Designation of a Coordinating Investigator (CI) will be done pursuant to the European Agency 
for the Evaluation of Medicinal Products (EMA) guidance on “Coordinating Investigator 
Signature of Clinical Study Reports”. 
12 
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2. 
Andersen TP, Fogh K. Thalidomide in 42 patients with prurigo nodularis Hyde. 
Dermatology. 2011;223:107–112. 
3. 
Arai, I., Tsuji, M., Takeda, H., Akiyama, N., Saito, S. (2013). A single dose of interleukin-
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Berth-Jones J, Smith SG, Graham-Brown RAC. Nodular prurigo responds to cyclosporine. 
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Bharati A, Wilson NJE. Peripheral neuropathy associated with nodular prurigo. Clin Exp 
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Fostini AC, Girolomoni G, Tessari G. Prurigo nodularis : an update on etiopathogenesis 
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10. 
Hyde JN, Montgomery FHA. Practical treatise on diseases of the skin for the use of 
students and practitioners. Lea & Febiger, Philadelphia, 1909. 174-175 
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Hongbo Y, Thomas CL, Harrison MA, Salek MS and Finlay AY. Translating the science 
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Invest Dermatol 2005; 125:659-64 
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Horiuchi Y, Bae S, Katayama I. Uncontrollable prurigo nodularis effectively treated by 
roxithromycin and tranilast. J Drugs Dermatol.2006;5:363–365. 
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Iking A, Grundmann S, Chatzigeorgakidis E, Phan NQ, Klein D, Ständer S. Prurigo as a 
symptom of atopic and non-atopic diseases: aetiological survey in a consecutive cohort of 
108 patients. J Eur Acad Dermatol Venereol. 2013;27:550–557. 
14. 
Levey AS, MD; Stevens LA., MD, MS; Schmid CH., PhD; Zhang Y(L), MS; Castro III AF., 
MPH; Feldman HI., MD, MSCE; Kusek JW., PhD; Eggers P, PhD; Van Lente F, PhD; Greene 
T, PhD; and Coresh J, MD, PhD, MHS. A New Equation to Estimate Glomerular Filtration 
Rate, Annals of Internal Medicine 2009;150(9):604-613 
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Mazza M, Guerriero G, Marano G, Janiri L, Bria P, Mazza S. Treatment of prurigo 
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Michels GM et al. A blinded, randomized, placebo-controlled, dose determination trial of 
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client owned dogs with atopic dermatitis. Vet Dermatol 2016; 27: 478-e129. 
17. 
Nemoto O, Furue M, Nakagawa H, Shiramoto M, Hanada R, Matsuki S, Imayama S, Kato 
M, Hasebe I, Taira K, Yamamoto M, Mihara R, Kabashima K, Ruzicka T, Hanifin J, 
Kumagai Y. The first trial of CIM331, a humanized antihuman interleukin-31 receptor A 
antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, 
tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-
controlled study.Br J Dermatol. 2016 Feb;174(2):296-304 
18. 
Oyama S et al. Cynomolgus monkey model of interleukin-31-induced scratching depicts 
blockade of human interleukin-31 receptor A by a humanized monoclonal antibody. Exp 
Dermatol 2016 Oct 7 
19. 
Park K, Mori T, Nakamura M, Tokura Y. Increased expression of mRNAs for IL-4, IL-
17, IL-22 and IL-31 in skin lesions of subacute and chronic forms of prurigo. Eur J 
Dermatol. 2011 Jan-Feb;21(1):135-6 
20. 
Phan NQ, Blome C, Fritz F, Gerss J, Reich A, Ebata T, Augustin M, Szepietowski 
JC, Ständer S Assessment of pruritus intensity: prospective study on validity and reliability 
of the visual analogue scale, numerical rating scale and verbal rating scale in 471 patients 
with chronic pruritus. Acta Derm Venereol. 2012 Sep;92(5):502-7 
21. 
Reich A, Heisig M, Phan NQ, Taneda K, Takamori K, Takeuchi S, Furue M, Blome 
C, Augustin M, Ständer S, Szepietowski JC. Visual Analogue Scale: Evaluation of the 
Instrument for the Assessment of Pruritus. Acta Derm Venereol. 2012 Sep;92(5):497-501 
CONFIDENTIAL  GALDERMA 
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Internally Approved


GALDERMA R&D 
Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
Page 79 of 86 
 
22. 
Rowland PayneCM, Wilkinson JD, McKee PH, Jurecka W et al. Nodular prurigo – a 
clinicopathological study of 46 patients. Br J Dermatol 1985; 113: 431–439. 
23. 
Ruzicka T, Hanifin JM, Furue M, Pulka G, Mlynarczyk I, Wollenberg A, Galus R, Etoh T, 
Mihara R, Yoshida H, Stewart J, Kabashima K; XCIMA Study Group.. Anti-Interleukin-31 
Receptor A Antibody for Atopic Dermatitis. N Engl J Med. 2017 Mar 2;376(9):826-835 
24. 
Schedel F, Schürmann C, Augustin M et al (2013) Prurigo nodularis: introduction of a re-
defined classification and Prurigo Activity Score (PAS). Acta Derm Venereol 93:610 (7th 
World Conference on Itch (WCI), Boston) 
25. 
Schuhknecht B, Marziniak M, Wissel A, Phan NQ, Pappai D, Dangelmaier J, et al. 
Reduced intraepidermal nerve fibre density in lesional and nonlesional prurigo nodularis 
skin as a potential sign of subclinical cutaneous neuropathy. Br J Dermatol. 2011;165:85–
91. 
26. 
Sonkoly E, Muller A, Lauerma AI, Pivarcsi A et al. IL-31: a new link between T cells and 
pruritus in atopic skin inflammation. J Allergy Clin Immunol 2006; 117: 411–417. 
27. 
Ständer S, Augustin M, Reich A, Blome C, Ebata T, Phan NQ, Szepietowski JC. 
Pruritus assessment in clinical trials: consensus recommendations from the International 
Forum for the Study of Itch (IFSI) Special Interest Group Scoring Itch in Clinical Trials. 
Acta Derm Venereol. 2013 Sep 4;93(5):509-14 
28. 
Ständer S, Blome C, Anastasiadou Z, Zeidler C, Jung KA, Tsianakas A, Neufang G, 
Augustin M. Dynamic Pruritus Score: Evaluation of the Validity and Reliability of a New 
Instrument to Assess the Course of Pruritus. Acta Derm Venereol. 2017 Feb 8;97(2):230-
234 
29. 
Ständer S, Weisshaar E, Mettang T, Szepietowski JC et al. Clinical classification of itch: a 
position paper of the International Forum for the Study of Itch. Acta Derm Venereol 2007; 
87: 291–294. 
30. 
Ständer S, Siepmann D, Herrgott I, Sunderkötter C, Luger TA. Targeting the neurokinin 
receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One. 2010 
31. 
Tanaka M, Aiba S, Matsumura N, Aoyama H, et al. Prurigo nodularis consists of two 
distinct forms: early-onset atopic and late-onset nonatopic. Dermatology 1995; 190: 269–
276. 
32. 
Tan WS, Tey HL. 
Extensive prurigo nodularis: 
characterization 
and 
etiology. 
Dermatology. 2014;228(3):276-80 
33. 
Warlich B, Osada N, Bruland P, Stumpf A, Schneider G, Dugas M, Pfleiderer B, Ständer 
S. Health-Related Quality of Life in Chronic Pruritus: An Analysis Related to Disease 
Etiology, Clinical Skin Conditions and Itch Intensity. Dermatology. 2015;231(3):253-9 
34. 
Weisshaar E, Szepietowski JC, Darsow U, Misery L, Wallengren J, Mettang T, Gieler U, 
Lotti T, Lambert J, Maisel P, Streit M, Greaves MW, Carmichael AJ, Tschachler E, Ring J, 
Ständer S. European guideline on chronic pruritus. Acta Derm Venereol. 2012 
Sep;92(5):563-81 
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GALDERMA R&D 
Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
Page 80 of 86 
35.
Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J.
Clin Nurs 2005; 14 798-804
36.
Zeidler C., Ständer S.. The pathogenesis of Prurigo nodularis – ‘Super-Itch’in exploration
Eur J Pain 20 (2016): 37-40
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Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
Page 81 of 86 
13 
APPENDICES 
Appendix 1 Volume of blood sample (ml) during the study 
Study period 
Screening period 
Treatment period 
Observation period/Follow 
up 
Unscheduled 
visit or Early 
termination 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Week 
Screening 1 
screening 
2 
Baseline 
W1 
W2 
W4 
W8 
W12 
W16 
W18 
Day 
D-28 to D-8 
Day-7 
Day 1 
Day 8 
Day 15 
Day 29 
Day 57 
D113 
Day 85 
Day 126 
TB test 
4 
Virology (HIV, hepatitis B and C) 
8,5 
Hematology 
2 
2 
2 
2 
2 
2 
Chemistry 
2 
2 
2 
2 
2 
2 
IgE 
1 
Pregnancy 
1 
CPK 
3,5 
3,5 
3,5 
3,5 
3,5 
2 
Fibrinogen 
2,7 
2,7 
2,7 
2,7 
2,7 
2 
Pregnancy 
PD 
10 
10 
10 
PK with or without ADA 
5* 
3,5 
3,5 
5* 
5* 
5* 
5* 
5* 
5 
Total blood samples per visit 
18 
6,7 
25,2 
3,5 
3,5 
25,2 
15,2 
25,2 
5 
5 
13 
Total volume 132,5 ml 
*PK and ADA samples are included in the same tube
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Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
Page 82 of 86 
Appendix 2  Numerical Rating Scale (NRS) 
Appendix 3 Verbal Rating Scale (VRS) 
Appendix 4 Sleep disturbance Numeric Rating Scale (NRS) 
On a scale of 0 to 10, with 0 being ‘no sleep loss related to signs/symptoms of PN’ and 10 being 
‘I cannot sleep at all due to the signs/symptoms of PN’, how would you rate your sleep last 
night?” 
           No sleep loss
0 
1 
2 
3 
4
5 
6 
7 
8 
9 
10 
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Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
Page 83 of 86 
Appendix 5 Dynamic Pruritus Score (DPS) 
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Appendix 6  DLQI 
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Appendix 7 Investigator Global Assessment (IGA) on PN 
Status 
Score 
Clear 
0 
Almost clear 
1 
Mild 
2 
Moderate 
3 
Severe 
4 
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Page 86 of 86 
Appendix 8  Prurigo Activity Score (PAS) 
1. Type
a) Which efflorescences do you see?
□ papules
□nodules
□plaques
□umbilicated ulcers
□ulcers
□hypo-/hyperpigmented maculae
b) Which type of prurigo is predominant?
□Prurigo papular type
□Prurigo nodular type
□Prurigo plaques type
□Prurigo ulcerated type
□Prurigo umbilicated “Kyrle” type
□completely healed
4. Please mark the affected area(s)
(for definition of trunk see image). 
whole body except head           □     
whole body head included        □ 
or 
forearm:
□left
□right
 
upper arm: 
□left
□right
lower leg: 
□left
□right
 
upper leg: 
□ left
□right
 
trunk   
□ventral
□dorsal
head 
□capillitium □ face
6. Activity. Please mark the stage.
stage 0 
stage 1 
stage 2 
stage 3 
stage 4 
Prurigo 
lesions 
with 
excoriations/crusts compared 
to all prurigo lesions 
0 % 
1- 25 % 
26 - 50 % 
51 - 75 % 
76 - 100 % 
Healed 
prurigolesions 
compared to all prurigo lesions 
100 % 
75-99 % 
50 - 74 % 
25 - 49 % 
0 - 24 % 
 
1. Type
a) Which efflorescences do you see?
□papules  
  
ap
a
□nodules  
  
□plaques  
  
□umbilicated ulcers
□ulcers
□hypo-/hyperpigmented maculae
b) Which type of prurigo is predominant?
□Prurigo papular type     
□Prurigo nodular type  
□Prurigo plaques type
□ Prurigo ulcerated type
□Prurigo umbilicated “Kyrle” type
□completely healed
2. Number
a) How many Prurigo lesions do you see on
the whole body? (estimate; do not count; 
do not consider scars)  
□0
□1 - 19
□20 – 100
□> 100
3. Distribution:
□disseminated
□localized (only 1 or 2 areas affected)
□neither of them
4. Please mark the affected area(s)
(for definition of trunk see image).
whole body except head           □
whole body head included       □
or 
forearm:
□left
□ right    
upper arm: 
 
□left        
□ right    
lower leg:
□left        
□ right    
upper leg: 
 
□left        
□ right    
trunk   
 
□ventral
□ dorsal 
head
□capillitium
□face
 
 
5. Please choose a representative area:
forearm:
□left     □ right
upper arm: 
□left       □ right
lower leg: 
□left
□right
upper leg: 
□left
□right
trunk  
□ventral □ dorsal
m: 
□left      □rig
e).
 
Number of prurigo lesions in the selected 
representative 
area 
(do 
not 
count 
scars):______ 
 
7. Take photos of the patient (optional using your own device): Overview front and back,
area(s) of marked monitor lesions to recognize on next visit 
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SAP_001.pdf: 
Official Title
A Study to Assess the Safety and Efficacy of Nemolizumab (CD14152) in Subjects With Prurigo Nodularis (PN)
NCT Number: NCT03181503
Date: 21 May 2019


GALDERMA R&D 
CLINICAL STUDY REPORT APPENDICES 
RD.03.SRE.115828 
16.1.9 
Documentation of statistical methods and interim analysis plans 
Document included: 
Statistical Analysis Plan Version 2.0, Dated 21 May 2019 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
P AREXEL International 
Note to File 
CRF Version and Formatting Issues Found in 16-May-2019 Audit Report 
#14121 for SAP V2.0 
Summary: 
CRF version: The SAP section 2 refers to version 4 of the CRF dated 08 Feb 2018, while it 
looks that the final CRF was version 6 ( cf. above fmding). This was corrected to version 6 dated 
11 June 2018. 
Following Formatting issues have been corrected in the SAP attachment to this NTF. 
Formatting issues: 
o Pages numbers in the ToC do not match the actual pages 
o Schedule of assessment included in the SAP appendix 1 is cut (follow-up & early 
termination visits are not displayed - format issue) and not in line with protocol latest 
version 02- schedule for CPK blood sampling: to be taken at V7/week 8 while 
required by the CSP (only for France). 
This document has been signed electronically on the rmal page by the following: 
Author Signatory 
TP-GDO-WW-016-07 
Effective Date: 05 Sep 2018 
Related to: SOP-GDO-WW-019 
 
 
Author of the SAP 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
P AREXEL International 
GALDERMA R&D, SNC 
Protocol Number: RD.03.SPR 115828 
A randomized, placebo-controlled, double-blinded, parallel group, multicenter study to assess the 
safety and efficacy ofnemolizumab (CD141S2) in subjeds with 
TP-GDO-WW-016-07 
Effective Date: 05 Sep 2018 
Related to: SOP-GDO-WW-019 
prurigo nodularis (PN) 
Statistical Analysis Plan 
Versionl.O 
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Effective Date: 05 Sep 2018 
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Statistical Analysis Plan 
P AREXEL Project Number: 235088 
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SPONSOR SIGNATURE PAGE 
Approved by: 
Statiltical Analysis Plan 
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Effective Dam: 05 Sep 2018 
Related to: S()p.(JJlO..WW.Ol9 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
PAREXEL SIGNATURE PAGE 
Signature below confums that the Statistical Analysis Plan was developed in accordance with SOP-GDO-
WW-0 19 and that it is approved for release. 
This do~ument has been approved and signed eledronically on the final page by the following: 
Author 
Reviewer 
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Signatory 
 
 
 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
TABLE OF CONTENTS 
1 
AMENDMENTS FROM PREVIOUS VERSION(S) ............................................. 11 
2 
INTR.ODUCTION ................................................................................................. 11 
3 
STUDY OBJECTIVES .......................................................................................... 12 
3.1 Primary Objective ............................................................................................ 12 
3.2 Secondary Objectives ...................................................................................... 12 
4 
INVESTIGATIONAL PLAN ................................................................................. 13 
4.1 Overall Study Design and Plan ........................................................................ 13 
4.2 Efficacy and Safety Variables .......................................................................... 14 
4.2.1 Efficacy Variables .................................................................................. 14 
4.2.1.1 Pruritus Numeric Rating Scale (NRS) ........................................ 14 
4.2.1.2 Verbal Rating Scale (VRS) ........................................................ 14 
4.2.1.3 Dynamic Pruritus Score (DPS) .................................................. 15 
4.2.1.4 Investigator Global Assessment ofPrurigo (IGA) ...................... 15 
4.2.1.5 Assessment ofPrurigo Activity Score (PAS) ............................. 15 
4.2.1.6 Sleep Disturbance Numeric Rating Scale (NRS) ........................ 15 
4.2.1. 7 Dermatology Life Quality Index (DLQI) ................................... 16 
4.2.2 Efficacy endpoints .................................................................................. 16 
4.2.2.1 Primary endpoint ....................................................................... 16 
4.2.2.2 Secondary efficacy endpoints .................................................... 16 
4.2.2.3 Other efficacy endpoints ............................................................ 17 
4.2.3 Safety Variables ..................................................................................... 17 
4.2.3.1 Electrocardiograms (ECG) ........................................................ 17 
4.2.3.2 Physical examination and vital signs ......................................... 17 
4.2.3 .3 Respiratory Assessments ........................................................... 18 
4.2.3.4 Laboratory safety tests ............................................................... 18 
4.2.3.5 Adverse events .......................................................................... 19 
4.2.4 Pharmacokinetic and Anti-drug Antibody Assessments .......................... 21 
4.2.5 Pharmacodynanlic Assessments ............................................................. 21 
4.2.6 Biophysical Assessments ........................................................................ 22 
4.2.6.1 Actigraphy ................................................................................ 22 
4.2.6.2 Whole Body Imaging ................................................................ 22 
5 
STATISTICAL METHODS ................................................................................... 22 
5.1 Data Quality Assurance ................................................................................... 22 
5.2 General Presentation Considerations ................................................................ 22 
5.3 Study Subjects ................................................................................................. 25 
5.3 .1 Disposition of Subjects ........................................................................... 25 
5.3 .2 Protocol Deviations ................................................................................ 26 
5.4 Analysis Populations ....................................................................................... 27 
5.5 Demographic and Other Baseline Characteristics ............................................. 28 
5.5.1 Demographic and Baseline Characteristics ............................................. 28 
5.5.2 Medical History ...................................................................................... 29 
5.5.3 Prior and Concomitant Therapies ........................................................... 30 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
5.5.3.1 Prior and concomitant medications ............................................ 32 
5.5.3.2 Prior and concomitant medical and surgical procedures ............. 32 
5.5.3.3 Rescue therapies ........................................................................ 33 
5.6 Treat:Inent Compliance ..................................................................................... 33 
5.7 Efficacy Evaluation ......................................................................................... 33 
5. 7.1 Analysis and Data Conventions .............................................................. 34 
5. 7 .1.1 Multi-center Studies .................................................................. 34 
5.7.1.2 Adjustments for Covariates ....................................................... 34 
5.7.1.3 Handling ofMissing Data .......................................................... 34 
5. 7 .1.4 Multiple Comparisons/Multiplicity ............................................ 36 
5.7.1.5 Planned Analyses ...................................................................... 36 
5.7.1.6 Examination ofSubgroups ........................................................ 36 
5. 7.2 Primary Efficacy Endpoint ..................................................................... 3 7 
5. 7.3 Secondary Efficacy Endpoints ................................................................ 3 8 
5. 7.3 .1 Assessment of pruritus and diary data by the Subject ................. 3 8 
5.7.3.2 Assessment of Prurigo by Physician .......................................... 39 
5.7.4 Other Efficacy Endpoints ....................................................................... 40 
5.8 Safety Evaluation ............................................................................................. 41 
5.8.1 Extent ofEx:posure ................................................................................. 42 
5.8.2 Adverse Events ...................................................................................... 42 
5.8.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
............................................................................................................... 43 
5.8.4 Clinical Laboratory Evaluation ............................................................... 44 
5.8.5 Vital Signs, Weight, Physical Findings and Other Observations Related to Safety 
............................................................................................................... 44 
5.8.5.1 Vital Signs and Weight. ............................................................. 44 
5.8.5.2 Peak Expiratory Flow (PEF) ..................................................... .44 
5.8.5.3 ElectrocardiogranJ. ..................................................................... 45 
5.9 Pharmacokinetic and PharmacodynanJ.ics Evaluations ...................................... 45 
5.9.1 Pharmacokinetic Parameter Calculation Methods ................................. .45 
5.9.2 Pharmacokinetic Parameters and Anti-drug Antibody Analyses ............. .47 
5.9.3 Pharmacodynamic Analyses ................................................................... 48 
5.1 0 
Determination of Sample Size ................................................................ 49 
5.11 
Changes in the Conduct of the Study or Planned Analysis ...................... 49 
6 
REFERENCES ...................................................................................................... 49 
Appendix 1 Schedule ofassessments ............................................................................. 51 
Appendix 2 Criteria for potentially clinically significant vital signs and weight ............. 53 
Appendix 3 Dermatology Life Quality Index (DLQI) .................................................... 54 
Appendix 4 Validation of the NRS responder analysis ................................................... 57 
Appendix 5 Potentially clinically significant values (PCSV) for clinical laboratory tests58 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
LIST OF ABBREVIATIONS 
Abbreviation 
ADA 
AE 
AESI 
ALP 
ALT 
ANCOVA 
ANOVA 
AST 
ATC 
AUC 
BLQ 
BMI 
bpm 
CI 
Cmax 
CMH 
CPK 
CRO 
CSR 
dL 
DLQI 
DPS 
ECG 
eCRF 
EMA 
FDA 
GGT 
HDL 
TP-GDO-WW-016-07 
Effective Date: 05 Sep 2018 
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Term 
Anti-Drug Antibody 
Adverse Event 
Adverse Event of Special Interest 
Alkaline Phosphatase 
Alanine Aminotransferase 
Analysis of Covariance 
Analysis of Variance 
Aspartate Aminotransferase 
Anatomical Therapeutic Chemical 
Area under the Curve 
Below the Limit of Quantification 
Body Mass Index 
Beats per Minute 
Confidence Interval 
Maximum Concentration 
Cochran-Mantel-Haenszel 
Creatinine Phosphokinase 
Contract Research Organization 
Clinical Study Report 
Deciliter 
Dermatology Life Quality Index 
Dynamic Pruritus Scale 
Electrocardiogram 
electronic Case Report Forms 
European Medicines Agency 
Food and Drug Administration 
Gamma-Glutamyl Transpeptidase 
High-Density Lipoprotein 
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GALDERMA R&D, SNC 
Abbreviation 
hsCRP 
ICF 
ICH 
IGA 
IgE 
IL 
IRR 
ITT 
IVRS 
IWRS 
KM 
LDH 
LDL 
LOCF 
LSmean 
MCV 
MedDRA 
MI 
mL 
NCA 
NRS 
oc 
PAS 
PCSV 
PD 
PDAP 
PEF 
PK 
PKAP 
PN 
TP-GDO-WW-016-07 
Effective Date: 05 Sep 2018 
Related to: SOP-GDO-WW-019 
Term 
High Sensitivity C-Reactive Protein 
Informed Consent Form 
Statistical Analysis Plan 
International Conference on Harmonisation 
Investigator's Global Assessment 
Immunoglobulin E 
lnterleukin 
Injection-related Reaction 
Intent-to-treat; intention-to-treat 
Interactive Voice Response System 
Interactive Web Response System 
Kaplan-Meier 
Lactate Dehydrogenase 
Low-Density Lipoprotein 
Last Observation Carried Forward 
Least Squares Mean 
Mean Cell Volume 
Medical Dictionary for Regulatory Activities 
Multiple Imputation 
Milliliter 
Non-Compartmental Analysis 
Numeric Rating Scale 
Observed Case 
Prurigo Activity Score 
Potentially Clinically Significant Value 
Pharmacodynamics 
PD Analysis Population 
Peak Expiratory Flow 
Pharmacokinetics 
PK Analysis Population 
Prurigo nodularis 
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GALDERMA R&D, SNC 
Abbreviation 
pp 
PT 
Ql 
Q3 
Q4W 
QoL 
RA 
RBC 
ROC 
SAE 
SAF 
SAP 
SD 
soc 
TARC 
TCS 
TEAE 
TESAE 
TLF 
ULN 
VRS 
WBC 
WHODD 
TP-GDO-WW-016-07 
Effective Date: 05 Sep 2018 
Related to: SOP-GDO-WW-019 
Term 
Per-Protocol 
Preferred Term 
Lower quartile 
Upper quartile 
Every 4 weeks 
Quality ofLife 
receptor A 
Red Blood Cell 
Receiver Operating Characteristic 
Serious Adverse Event 
Safety (analysis population) 
Statistical Analysis Plan 
Standard Deviation 
System Organ Class 
Statistical Analysis Plan 
thymus and activation-regulated chemokine 
Topical Corticosteroids 
Treatment-emergent Adverse Event 
Treatment-emergent Serious Adverse Event 
Tables, Listings, and Figures 
Upper Limit of Normal 
Verbal Rating Scale 
White Blood Cell 
World Health Organization Drug Dictionary 
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CONFIDENTIAL  GALDERMA 
02-Jul-2019
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
1 
AMENDMENTS FROM PREVIOUS VERSION(S) 
The following is a change from the Statistical Analysis Plan (SAP) dated 17 Aug20 18: 
• 
Added details of how to calculate pharmacokinetic parameters to the section 3 .2.4 of the Version 
1.0 of the SAP. The new section is 5.9.1 of this Amendment of the SAP (Version 2.0). 
2 
INTRODUCTION 
This SAP describes the planned analysis and reporting for GALDERMA R&D, SNC, protocol 
RD.03.SPR115828, entitled "A study to assess the safety and efficacy of nemolizwnab 
(CD14152) in subjects with prurigo nodularis (PN)", All Countries Amendment Version 2.0 
dated Apr 09, 2018. 
Prurigo nodularis (PN) is characterized by the presence of symmetrically distributed multiple (up to 
hundreds), highly pruritic, hyperkeratotic, erosive or crusted nodules and papules (Hyde JN et al., 1909). 
This leads to an impaired quality of life and high burden due not only to the severe itch but also the 
chronic, skin lesions and lack of treatment options (Warlich B., et al2015). 
The goal ofPN treatment is to break the itch-scratch cycle and allow the skin to heal. Treatment of 
chronic pruritus is still notoriously challenging and frustrating for both dermatologists and patients as in 
the majority of cases, the response is either limited or associated with severe adverse events with the 
current therapy options. There is no standardized or approved therapy for PN up-to-date and evidence 
from controlled studies is limited (Fostini ACetal., 2013). The difficulty in treating this disease is 
reflected in the wide range of treatments proposed in the literature. 
Nemolizumab (CD14152) is a humanized anti-human IL-31 receptor A (RA) monoclonal antibody that 
inhibits the binding ofll..-31 to IL-31RA and subsequent signal transduction. IT..-31 has been suggested to 
be a key player in the development of pruritus. Recent clinical studies of nemolizumab in patients with 
atopic dermatitis showed a rapid onset of pruritus reduction within one week followed by disease 
improvement (Ruzicka T et al2017). 
The main objective of this study is to evaluate the efficacy, safety and pharmacokinetics (PK) of multiple 
subcutaneous doses of nemolizumab in the treatment of pruritus and lesions associated to PN. 
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Statistical Analysis Plan 
The planned analyses identified in this SAP may be included in the clinical study report (CSR), regulatoty 
submissions, or future manuscripts. Also, post hoc exploratory analyses not necessarily identified in this 
SAP may be performed to further examine study data. Any post hoc, or unplanned, exploratory analyses 
performed, if included, will be clearly identified as such in the fmal CSR. 
This SAP is based upon the following study documents: 
• 
Study protocol, All Countries Amendment Version 2.0 (09 Apr 2018) 
• 
Electronic Case Report Form (eCRF), Version 6.0 (11-June-2018). 
The structure and content of this SAP provides sufficient detail to meet the requirements identified by the 
Food and Drug Administration (FDA), European Medicines Agency (EMA), and International 
Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for 
Human Use: Guidance on Statistical Principles in Clinical Trials. All work planned and reported for this 
SAP will follow internationally accepted guidelines, e.g., Ethical Guidelines for Statistical Practice 
published by the American Statistical Association and Code of Conduct published by the Royal Statistical 
Society, for statistical practice. 
The reader of this SAP is encouraged to also read the clinical protocol, and other relevant documents for 
details on the planned conduct of this study. Other than the schedule of assessments which is provided in 
Appendix 1, operational aspects related to collection and timing of planned clinical assessments are not 
repeated in this SAP unless relevant to the planned analyses. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to assess the efficacy of nem.olizwnab compared to placebo in the 
treatment of pruritus in patients suffering from PN. 
3.2 
Secondary Objectives 
The secondary objectives are: 
Efficacy and safety: 
• 
Evaluation of the safety ofnemolizumab compared to its placebo in patients with PN. 
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• 
Evaluation of the efficacy of nemolizumab compared to its placebo in the treatment of prurigo 
lesions in patients with PN. 
• 
Evaluation of nemolizumab effect compared to its placebo on quality of life in patients with PN 
Pharmacokinetics (PK) 
• 
Characterization of nemolizumab PK profile and exposure response relationship in patients with 
PN 
Pharmacodynamics (PD) 
• 
Evaluation of the effect of nemolizumab on biomarkers in patients with PN 
Biophysical 
• 
Evaluation of the efficacy of nemolizumab on scratching events and sleep improvement using 
actigraphy 
• 
Evaluation of the efficacy of nemolizumab on lesions improvement using whole body images 
device only on equipped sites. This will be evaluated based on the availability of the data. 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a randomized, placebo-controlled, double-blinded, parallel group, multicenter study to evaluate the 
safety and efficacy of nemolizumab in patients suffering from PN. Approximately 70 adult patients 
suffering from PN for at least 6 months with severe pruritus defined by the mean of the worst daily 
intensity of the NRS score~ 7 over the previous week at baseline will be randomized in the study. 
Subjects meeting inclusion/exclusion criteria will be randomized in a 1: 1 ratio to nemolizumab or 
placebo. Each subject will receive three subcutaneous injections of O.Smglkg of nemolizumab or 
matching placebo. Injections will be administered evecy 4 weeks (at baseline, week 4 & week 8). 
Subjects' participation in the study will be up to 22 weeks, including an up to 4-week screening 
period, a 12-week treatment period (last study drug injection at week 8) and a 6-week follow-up 
period (10 weeks after the last study drug injection corresponding to 5 half-lives of 
nemolizumab ). 
Assessments of efficacy, safety, PK, PD, and biophysical will be conducted throughout this 
clinical trial. Refer to Appendix 1 for the complete schedule of assessments. 
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4.2 
Efficacy and Safety Variables 
4.2.1 Efficacy Variables 
4.2.1.1 Pruritus Numeric Rating Scale (NRS) 
Pruritus NRS is a scale to be used by the subjects to report the intensity of their pruritus (itch) during the 
last 24 hours all along the study from first screening visit to the follow-up visit. Subjects will receive 
instructions on how to record their pruritus NRS scores on an electronic device and will complete the 
assessment once daily at home in the evening throughout the clinical trial (including the follow-up 
period). 
Subjects will be asked the following questions in their local language: 
• 
For average itch intensity: "On a scale ofO to 10, with 0 being 'no itch' and 10 being 'worst itch 
imaginable', how would you rate your itch overall during the previous 24 hours?" 
• 
For maximum (Peak) itch intensity: "On a scale ofO to 10, with 0 being 'no itch' and 10 being 
'worst itch imaginable', how would you rate your itch at the worst moment during the previous 
24 hours?" 
Weekly prorated average score will be calculated and used in the analysis. If a subject has less 
than 5 diary entries in a week, the weekly average scores will be set to missing. Refer to Section 
5.2 for classification of diary data into analysis week/visit. 
4.2.1.2 Verbal Rating Scale (VRS) 
The VRS consists of a list of adjectives describing different levels of symptom intensity, to be used by the 
subjects to report the intensity of their pruritus (itch) over the last 24 hours. Subjects will receive 
instructions on how to record their pruritus VRS scores on an electronic device and will complete the 
assessment once daily in the evening from Screening visit 2 and throughout the clinical trial (including 
the follow-up period). In the eDiary, patients will mark on a 5-point VRS, the response that best describes 
their pruritus intensity in the last 24 hours. 
Subjects will be asked the following questions in their local language: 
• 
For average itch intensity: "On a scale of 0 to 4, with 0 being 'no itch' and 4 being 'very severe 
itch', how would you rate your itch overall during the previous 24 hours?" 
• 
For maximum (Peak) itch intensity: "On a scale ofO to 4, with 0 being 'no itch' and 4 being 'very 
severe itch', how would you rate your worst itch during the previous 24 hours?" 
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Weekly prorated average score will be calculated and used in the analysis. If a subject has less 
than 5 diary entries in a week, the weekly average scores will be set to missing. Refer to Section 
5.2 for classification of diary data into analysis week/visit. 
4.2.1.3 Dynamic Pruritus Score (DPS) 
The 9-point DPS is a dynamic scale to be used by subjects to evaluate the change of their 
pruritus compared with an earlier time point (ie. before injection on Day 1). The scale ranges 
from 0 (strongly worsened pruritus) to 8 ([almost] no pruritus anymore), including intermediate 
marks 
for 
slightly 
improved/worsened, 
moderately 
improved/worsened, 
and rather 
improved/worsened. Subjects will receive instructions on how to record their DPS score on an 
electronic device displaying the scale in their local language, and will complete the assessment 
24, 48h and 72h after the 1st injection at baseline and at W4 before the second injection. This 
assessment will be performed by the subject based on his itch perception over the 24h hours 
preceding the baseline injection. 
4.2.1.4 Investigator Global Assessment of Prurigo (IGA) 
IGA is a 5-point scale ranging from 0 (clear) to 4 (severe) used by the investigator or trained 
designee to evaluate the severity ofthe disease. IGA corresponds to the overall assessment of the 
severity of prurigo including presence of crust and nodules or skin bleeding that will be 
evaluated at Baseline, Week 4, Week 8, Week 12, Week 18 & in case ofEarly termination visit I 
Unscheduled visit, if applicable. 
4.2.1.5 Assessment ofPrurigo Activity Score (PAS) 
The evaluation of the disease will be performed by the Investigator using the Prurigo Assessment Scale 
(PAS) at baseline and Week 12 using the entire scale and at Weeks 4, 8, 18 and in case ofEarly 
termination visit I Unscheduled visit, if applicable using item 5 (number oflesions only) and 6 
(excoriation/crusts and healed lesions). 
4.2.1.6 Sleep Disturbance Numeric Rating Scale (NRS) 
The sleep disturbance NRS is a scale to be used by the subjects to report the degree of their sleep loss 
related to PN. Subjects will receive instructions on how to record their sleep disturbance NRS scores on 
an electronic device and will complete the assessment once daily in the morning from Screening 2 (Day -
7) to Week 4 visit (Day 29). 
Subjects will be asked the following question in their local language: 
On a scale ofO to 10, with 0 being 'no sleep loss related to signs/symptoms ofPN' and 10 being 
'I cannot sleep at all due to the signs/symptoms of PN', how would you rate your sleep last 
night?" 
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Weekly prorated average score will be calculated and used in the analysis. If a subject has less than 5 
diary entries in a week, the weekly average scores will be set to missing. Refer to Section 5.2 for 
classification of diary data into analysis week/visit. 
4.2.1. 7 Dermatology Life Quality Index (DLQI) 
DLQI is a validated 1 0-item questionnaire, covering domains including symptoms/feelings, daily 
activities, leisure, work/school, personal relationships and treatment. Subject will rate each question 
ranging from 0 (not at all) to 3 (very much), and the total score ranges from 0 to 30, with a higher score 
indicating a poorer quality of life. Please note that ''Not relevant" is scored as 0, and Question 7 'Yes-
prevented working or studying' is scored as 3. DLQI will be given only to the subset of subjects who 
fluently speak a language in which the questionnaire is presented (based on availability of validated 
translations in participating countries). This assessment will be performed by the subject on the provided 
electronic device at baseline, Week 4, and Week 12, and in case of Early termination visit I Unscheduled 
visit, if applicable. 
For general inflammatory skin conditions, a change in DLQI score of at least 4 points is considered 
clinically important. Refer to Appendix 3 for details on scoring, data handling rules, and analysis on 
DLQI. 
4.2.2 Efficacy endpoints 
4.2.2.1 Primary endpoint 
Percent change from baseline in NRS to week 4 (weekly average of the peak). 
4.2.2.2 Secondary efficacy endpoints 
• 
Absolute and percent change from baseline in weekly average of the peak and average pruritus 
NRS to each visit 
• 
Absolute and percent change from baseline in weekly average of the peak and average VRS to 
each visit 
• 
DPS at hours 24, 48, and 72 for baseline and Week 4 visits 
• 
Absolute change from baseline in PAS Item 5 (number oflesions) to each visit 
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Statistical Analysis Plan 
• 
PAS Item 6 (excoriation/crusts and healed lesions stages) at each visit 
• 
IGA at each visit 
• 
Proportion of subjects achieving IGA success (defined as IGA=O[clear] or IGA=l[Almost clear] 
with two-point improvement from baseline) at Week 12 
4.2.2.3 Other efficacy endpoints 
• 
Absolute change and shift from baseline in Dermatology Life Quality Index (DLQI) to each 
visitAbsolute and percent change from baseline in weekly average Sleep Disturbance Numeric 
Rating scale (NRS) up to Week 4 
• 
Objective assessment of scratching events during the night and sleep duration using Actigraphy. 
Ratio 'scratching duration/duration' and 'scratching events/duration' up to week 4 are the study 
endpoints. 
4.2.3 Safety Variables 
Safety assessments will be conducted for all subjects at the screening visit (upon the signature of the 
informed consent form [ICF]) and at every subsequent visit. 
Safety assessments include electrocardiogram (ECG), physical examination, vital signs, body weight, 
respiratory assessments (peak expiratory flow [PEF] measurement only for subjects with a medical 
history of asthma), laboratory safety tests, and AE recording (including serious AEs [SAE] and AEs of 
Special Interest [ AESI]). 
4.2.3.1 Electrocardiograms (ECG) 
A 12-lead ECG will be performed at screening 1, baseline and Week 8, or early termination 
and/or unscheduled visits when applicable. 
All abnormal ECG fmdings considered to be clinically significant by the investigator at the screening visit 
will be recorded in the Medical History form. Any clinically significant changes from the screening visit 
will be reported as AEs in the eCRF. 
4 .2.3 .2 Physical examination and vital signs 
Physical examination: The physical examination will be performed at screening 1, baseline, weeks 4, 8, 
12, 18, or early termination and/or unscheduled visits when applicable. 
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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. 
Vital signs: The vital signs will be evaluated at screening 1, baseline, weeks 1, 2, 4, 8, 12, 16, 18, or early 
termination and/or unscheduled visits when applicable. 
Vital signs will include pulse rate, systolic and diastolic blood pressure (after the subject has been siting 
for at least 5 minutes). 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 will be measured at the baseline visit only, and weight will be measured at 
baseline, weeks 4, 8, and 12. 
Any clinically significant weight changes from the screening visit will be recorded as an AE. 
Blood pressure (systolic and diastolic), pulse rate, and weight values meeting criteria for 
potentially clinically significant values (PCSV) will be reported. 
Criteria for PCSV for vital signs and weight are listed in Appendix 2. 
4.2.3.3 Respiratory Assessments 
At each visit, investigator or designee will perform a respiratory physical examination and ask all subjects 
whether they have experienced any signs/symptoms of asthma. In addition, for subjects reporting a 
medical history of asthma, PEF will be performed. PEF measurements should consist of 3 good efforts, 
with the best result documented. 
Newly diagnosed asthma or worsening of asthma during the study will be reported as AESI. 
4.2.3.4 Laboratory safety tests 
The following laboratory safety tests will be performed: 
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• 
Hematology: white blood cell (WBC) count with differential count (including eosinophils), red 
blood cell (RBC) count. hemoglobin (Hb), hematocrit (hct), mean cell volume (MCV), and 
platelet count (Plt) 
• 
Blood chemistry: sodium, potassium, calcium, chloride, glucose, urea, creatinine, aspartate 
aminotransferase (AS1)/ alanine aminotransferase (ALT), alkaline phosphatase (ALP), total and 
direct bilirubin, creatinine phosphokinase (CPK), high sensitivity C-reactive protein (hsCRP), 
fibrinogen, gamma-glutamyl transpeptidase (001), lactate dehydrogenase (LDH), total protein, 
albumin, uric acid, total cholesterol. low-density lipoprotein (LDL), high-density lipoprotein 
(HDL) and triglycerides 
• 
CPK isoenzyme test will be performed only ifCPK is elevated to >2.5X Upper Limit ofNormal 
(ULN). 
• 
Urinalysis: blood, proteins, leukocytes, glucose, ketones, nitrites, bilirubin, urobilinogen, pH, and 
specific gravity 
All clinically significant out-of-range laboratory values at the screening visit will be recorded in the 
medical history form. 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). 
4.2.3.5 Adverse events 
Adverse events (AE) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 19.0. 
An AE will be considered a treatment-emergent AE (TEAE) if it started after the date of the first dose of 
study drug or it started before the date of the :frrst dose of study drug and worsened after the date of the 
frrst dose. AEs occurring on the date of the first dose of study drug will be considered a TEAE if the 
onset of the AE is on or after the time of injection on that day. Where dates are missing or partially 
missing, AEs will be assumed to be treatment-emergent. unless there is clear evidence (through 
comparison of partial dates) to suggest that the AE started prior to the frrst dose of study treatment. 
The investigator will have to assess if there is a reasonable possibility of a causal relationship between the 
study drug and/or a study procedure (e.g. injection, blood sample collection) and an AE. Related AEs will 
be defined as study drug related AEs or study procedure related AEs. 
The AESis for this clinical trial have been defined as follows: 
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• 
Elevated AL Tor AST (> 3 ULN) in combination with elevated bilirubin> 2 ULN, whether or not 
considered as related to the study drug by the investigator 
• 
Elevated CPK ~ 2.5 ULN), if considered as related to the study drug by the investigator 
• 
Asthma or worsening of asthma 
• 
IRR (local and systemic reactions, including hypersensitivity) 
• 
Peripheral edema 
• 
Skin or systemic infection 
• 
Headache 
• 
Exacerbation of AD, in subjects with medical history of AD 
Missing date information for AEs 
The following imputation rules only apply to cases in which the start date for AEs is incomplete (i.e., 
partial missing): 
Missin~ Month and Day 
• 
If the year of the incomplete start date is the same as the year of the first administration of the 
study drug, then the month and day of the ftrst administration of the study drug will be assigned 
to the missing fields. 
• 
If the year of the incomplete start date is before the year of the frrst administration of the study 
drug, December 31 will be assigned to the missing fields. 
• 
If the year of the incomplete start date is after the year of the frrst dose of double-blind IP, 
January 1 will be assigned to the missing fields. 
Missing Month Only 
• 
If only the month is missing, then the day will be treated as missing and both the month and the 
day will be replaced according to the procedure above. 
Missing Day Only 
• 
If the month and year of the incomplete start date are the same as the month and year of the ftrst 
administration of the study drug, then the day of the frrst administration of the study drug will be 
assigned to the missing day. 
• 
If either the year of the incomplete start date is before the year of the date of the frrst 
administration of the study drug or if both years are the same but the month of the incomplete 
start date is before the month of the date of the frrst administration of the study drug, then the last 
day of the month will be assigned to the missing day. 
• 
If either the year of the incomplete start date is after the year of the date of the ftrst administration 
of the study drug or if both years are the same but the month of the incomplete start date is after 
the month of the date of the frrst administration of the study drug, then the ftrst day of the month 
will be assigned to the missing day. 
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If the stop date is complete and the imputed start date as above is after the stop date, then the start date 
will be imputed by the stop date. 
If the start date is completely missing and the stop date is complete, then the following algorithm will be 
used to impute the start date: 
• 
If the stop date is after the date of the frrst administration of the study drug, then the date of the 
first administration of the study drug will be assigned to the missing start date. 
• 
If the stop date is before the date of the first administration of the study drug, then the stop date 
will be assigned to the missing start date. 
4.2.4 Pharmacokinetic and Anti-drug Antibody Assessments 
Blood samples will be collected to determine the PK profile ofnemolizumab and to assess anti-drug 
antibodies (ADA). The serum concentration ofnemolizumab will be assessed at baseline, weeks 1, 2, 4, 
8, 12, 16, 18, and in case of early termination or unscheduled visit for safety reasons. ADA will be 
assessed at baseline, weeks 4, 8, 12, 16 and 18, and in case of early termination or unscheduled visit for 
safety reason. 
Results will be described in the bioanalytical report, which will be included as an appendix in the final 
clinical study report. 
Nemolizumab serum concentrations will be determined using validated ELISA method by a sponsor 
representative. A bioanalytical plan describing the details of the bioanalytical work related to serum 
samples of nemolizumab assessment will be written before the beginning of the sample analysis. 
4.2.5 Pharmacodynamic Assessments 
Blood and skin samples (D-Squames and skin biopsies) will be collected according to schedule of 
assessments to investigate the effect of nemolizumab on selected biomarkers, including but not limited to 
microbiome, cytokine, chemokine IL-31, IL31-RA. 
The PD analyses will be performed by a Sponsor representative. The results will be described in a PD 
report, which will be included in the fmal study report. 
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4.2.6 Biophysical Assessments 
4.2.6.1 Actigraphy 
High resolution actigraphy will be used in this study to evaluate scratching events and duration of sleep 
during the night. Philips will, in accordance with procedures, centrally analyze assessment data for 
scratching events and sleep parameters obtained from the actigraphy device and submit data to the CRO. 
Patients will wear two devices, one on each wrist, from D-7 and every day during the first 4 weeks of the 
study, by following the instructions provided by the CRO. 
Sleep assessment evaluation will include but not be limited to the parameter 'sleep efficiency'. 
Scratching assessment evaluation will include but not be limited to the 2 ratio 'scratching 
duration/duration' and 'scratching events/duration'. 
4.2.6.2 Whole Body Imaging 
This device will be used in equipped sites only and the photographs of the entire body will be taken 
according to the operational manual provided by the Sponsor at least at baseline and Week 12 (Day 85) 
and if it is possible at Week 4 (Day 29), Week 8 (Day 57), and Week 18 (Day 126).1t is for illustration 
and as exploratory evaluation of the lesions improvement. 
5 
STATISTICAL METHODS 
5.1 
Data Quality Assurance 
All tables, figures and data listings (TI.Fs) to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard P AREXEL procedures. 
5.2 
General Presentation Considerations 
Unless otherwise stated, descriptive summaries will be presented by treatment group. In all 
tables the treatment groups will be presented in the order of Placebo, Nemolizumab. 
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, 
minimum, maximum, lower quartile (Ql), upper quartile (Q3), and number of observations, 
unless otherwise stated. Where data are collected over time, both the observed data, change from 
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baseline and percent change from baseline when appropriate will be summarized at each time 
point. The minimum and maximum will be reported to the same number of decimal places as the 
raw data recorded in the database. The mean, median, Ql, and Q3 will be reported to one more 
decimal place than the raw data recorded in the database. The SD will be reported to 2 more 
decimal places than the raw data recorded in the database. In general, the maximum number of 
decimal places reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at the 
relevant time point (n), frequency counts and percentages. Percentages will be presented to one 
decimal place. A percentage of 1 00% will be reported as 100%. Percentages will not be 
presented for zero counts. Percentages will be calculated using n as the denominator. If sample 
sizes are smal~ the data displays will show the percentages, but any textual report will describe 
frequencies only. Changes from baseline in categorical data will be summarized using shift 
tables where appropriate. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places. 
However, if a p-value is only presented to four decimal places (by SAS) it will not be rounded 
again, but will be presented to four decimal places. P-values less than 0.001 will be presented as 
"<0.001 ",and p-values greater than 0.999 will be presented as ''>0.999". 
Confidence intervals (Cis) will be presented to one more decimal place than the raw data. 
All report outputs will be produced using SAS® version 9.3 or a later version in a secure and 
validated environment. The outputs will be provided as individual TLFs in RTF as well as PDF 
formats and all TLFs in one PDF bundle. 
All statistical tests will be two-sided and will be performed at the 5% level of significance, 
unless otherwise stated. 
Baseline 
'Baseline' is defined as the last available assessment prior to the frrst planned study drug. The date of the 
frrst planned study drug refers to date of the first actual administration of study drug at visit 
V3/Baseline/Day 1 if exists; otherwise, date of randomization. 
For diary data (pruritus NRS, VRS, Sleep disturbance NRS), the baseline values will be derived from data 
collected during the 7 days prior to the frrst planned study drug. Baseline score will be the weekly 
prorated average of non-missing subject diary scores reported during the 7 days. A minimum of 5 daily 
scores out of the 7 days is required to calculate the weekly prorated average score. 
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Statistical Analysis Plan 
Analysis Visit 
Study day is relative to date of randomization. Day -1 is the day before randomization, and day 
1 is date of randomization. 
Assessments at early termination and unscheduled visits will be slotted based on the following 
visit window. 
Period 
Analysis Visit 
Target day 
Day ranges 
(relative to 
randomization) 
Screening 
Screening 1 
-28 
-28 to -8 
Period 
Screening 2 
-7 
-7to-1 
Treatment 
Baseline 
1 
<1 
Week1 
8 
2-11 
Week2 
15 
12-22 
Week4 
29 
23-43 
Week8 
57 
44-71 
Week 12 
85 
72-99 
Follow-up 
Week 16 
113 
100-119 
Week 18 
126 
>119 
The diary reported during study will be classified into analysis visits as follows (i.e., during the 7 
days prior to the target day of analysis visit. In this case, the target day of analysis visit is relative 
to date of the frrst planned study drug.): 
• 
Day -7 to -1 = Baseline 
• 
Day 1 to 7 = Week 1 
• 
Day 8 to 14 = Week 2 
• 
Day 22 to 28 = Week 4 
• 
Day 50 to 56 =Week 8 
• 
Day 78 to 84 =Week 12 
• 
Day 106 to 112 =Week 16 
• 
Day 120 to 126 =Week 18 
These analysis visits will be used in the calculations for all week-based parameters collected on subject's 
diary (e.g., pruritus NRS, VRS, Sleep disturbance NRS, PAS, DPS, DLQI) Other non-diary data, such as , 
IGA, vital signs, body weight, clinical laboratory assessments, respiratory assessment/PEF, will be 
analyzed according to actual scheduled visits. 
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Statistical Analysis Plan 
For efficacy and safety data (except clinical laboratory assessments), where two or more assessments 
(include both scheduled and unscheduled assessments) are available for the same visit interval, the one 
closest to the target visit date will be used for the summary and analyses. For clinical laboratory 
assessments, if repeated measurements are taken for either time point (scheduled visit), then the last 
measurement will be used for the value for that time point. Unscheduled labs will be included in listings, 
but not summaries of the data. All post baseline assessments, including repeated or unscheduled visits, 
will be used for potentially clinically significant value (PCSV) determinations. 
5.3 
Study Subjects 
5.3.1 Disposition of Subjects 
A clear accounting of the disposition of all subjects who enter the study will be provided, from screening 
to study completion. 
The following subject disposition summaries will be produced: 
• 
The number of subjects screened (Analysis population: Screened Subjects) 
• 
Screen failures (Analysis population: Screened Subjects) 
• 
Subjects Randomized by clinical site and overall (Analysis population: All Randomized Subjects) 
The following summaries will be produced for ITI population: 
• 
The number of subjects randomized 
• 
The number and percentage of subjects treated (with at least one dose of study drug) 
• 
The number and percentage of subjects randomized but not treated (not taken any dose of study 
drug) 
• 
The number and percentage of subjects who temporarily discontinued the study treatment and 
reasons for discontinuation 
• 
The number and percentage of subjects who permanently discontinued the study treatment and 
reasons for discontinuation 
• 
The number of subjects who completed study treatment period (defmed as completing week 12 
visit) 
• 
The number of subjects who completed the study 
• 
The number of subjects who discontinued from the study and reason of discontinuation 
• 
A Kaplan-Meier plot of the time to permanent study treatment discontinuation will be provided. 
Subjects who did not discontinue from the study treatment will be censored at their last dose of 
study drug (Analysis population: ITT). 
• 
A Kaplan-Meier plot of the time to study discontinuation will be provided. Subjects who did not 
discontinue from the study will be censored at the date of study completion or the last visit date 
on the study (Analysis population: ITI). 
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Statistical Analysis Plan 
• 
Time (days) to permanent discontinuation of study treatment by reasons for discontinuation will 
be displayed graphically in subjects having permanently discontinued study treatment 
• 
Time (days) to study discontinuation by reasons for discontinuation from study will be displayed 
graphically in subjects having discontinued study. 
By-subject listings of eligibility details, randomization details, visit dates and withdrawa1/study 
completion details (including reason for discontinuation and duration of treatment prior to 
discontinuation) will be provided. 
5.3.2 Protocol Deviations 
Deviations from the protocol including violations of inclusion/exclusion criteria will be assessed as 
'minor' or 'major'. Major PDs are defined as those deviations from the protocol that are likely to have an 
impact on the subject's right, safety, well-being, and/or the validity of the data for analysis. Minor 
deviations include all deviations from the protocol excluding those considered as major. The impact of 
major protocol deviations on the efficacy and/or safety results will be investigated by assessing the 
robustness of the study results and conclusions to the choice of analysis population (see Section 5.4), both 
including and excluding data potentially affected by major protocol deviations. Major PDs that will lead 
to the exclusion of a subject from the per-protocol (PP) population will be identified. The fmal 
determination of major protocol deviations and the exclusion of subjects from each of the analysis 
populations will be made prior to database lock. 
Refer to the study protocol deviation specification for more information. 
The following protocol deviation summaries will be provided: 
• 
Number and percentage of subjects with a major protocol deviation by type of deviation 
(Analysis population: ITT) 
• 
Number and percentage of subjects with a major protocol deviation resulting in exclusion of 
subjects from PP analysis by type of deviation (Analysis population: ITT) 
A by-subject listing of protocol deviations will be provided. 
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Statistical Analysis Plan 
5.4 
Analysis Populations 
The following analysis populations will be used to analyze the data. 
Intent-to-Treat Population (ITT): 
The ITT population will consist of all randomized subjects. 
Per Protocol Population (PP): 
The PP Population is defined as comprising the liT subjects who have no major protocol deviations that 
would have a significant effect on the efficacy of the study treatment. 
The PP population will be finalized prior to the final database lock. 
Safety Population (SAF): 
The safety (SAF) population will comprise all subjects in ITT population who receive at least 
one dose of study drug. 
PK Analysis Population (PKAP): 
The PK analysis population will include all subjects in the SAF population who provide at least 
one post-baseline evaluable drug concentration value. 
PD Analysis Population (PDAP): 
The PD statistical analyses will be performed based on the PP population, and after exclusion of samples 
unable to produce reliable quantifications of cytokines, and/or immunohistological markers and/ or 
transcriptomic biomarkers, due to the material quantity and/or quality. 
The efficacy summaries and analyses will be based on the ITT population, which is based upon 
the Intention-to-Treat (ITT) principle. In the event that a subject is allocated the incorrect study 
treatment as per the study randomization list, subjects will be summarized and analyzed 'as 
randomized' (i.e., by randomized treatment group). In the event that a subject is stratified 
incorrectly, 'randomized stratum' will be used rather than 'actual stratum'. 
For the primary and selected secondary efficacy endpoints, a sensitivity analysis will be 
performed on the PP population to assess the robustness of the study conclusions to the choice of 
analysis population. Subjects will be included in the analysis according to the treatment 'as 
randomized'. 
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Statistical Analysis Plan 
The safety summaries and analyses will be based on the SAF population. Randomized subjects 
will only be excluded if there is clear, documented evidence that the subject did not receive any 
study drug injection. In the event that a subject is allocated the incorrect study treatment as per 
the study randomization list, subjects will be summarized and analyzed 'as treated' (i.e., by 
allocated treatment group). 
Upon database release, protocol deviation and analysis population outputs will be produced and 
will be reviewed by Sponsor. An analysis population classification meeting will be arranged to 
discuss the outputs and to decide which subjects and/or subject data will be excluded from 
certain analyses. Decisions made regarding the exclusion of subjects and/or subject data from 
analyses will be made prior to database lock and unblinding and will be documented and 
approved by Sponsor. 
The following analysis population summaries will be provided: 
• 
The number and percentage of subjects in each study population will be presented by 
study treatment group including total (Analysis population: ITT). 
A by-subject listing of analysis population details will be provided. This listing will be presented 
by treatment group and will include: subject identifier, inclusion/exclusion flag for each 
population and reason for exclusion from each population. All randomized subjects will appear 
on this listing. 
The fi 11 
o oWing d . d 
d 
enve an 
d 
. bl 
van a 
compute 
·u b 
esWI 
d 
d 
epro uce : 
Variable Description 
Computation Methods, Notes, or Equation(s) 
Flag ofiTT subjects 
'Y' if subjects randomized into the study; otherwise 'N' 
Flag ofSAF subjects 
'Y' if subjects in ITT and date and/or time of the first dose injection on 
Study Drug Administration form is non-missing; otherwise 'N' 
Flag ofPP subjects 
'Y' if subjects in ITT who complete 12-week Treatment Period with the 
exception of major protocol violators who have significant effect on the 
efficacy; otherwise 'N' 
Flag ofPKAP subjects 
'Y' if subjects in the safety population who provided at least one post-
baseline evaluable drug concentration value; otherwise 'N' 
Flag ofPDAP subjects 
'Y' if subjects in the PP, and after exclusion of samples unable to produce 
reliable quantifications of cytokines, and/or immunohistological markers 
and/ or transcriptomic biomarkers, due to the material quantity and/or 
quality; otherwise 'N' 
5.5 
Demographic and Other Baseline Characteristics 
5.5.1 Demographic and Baseline Characteristics 
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Statistical Analysis Plan 
The following demographic and baseline characteristics will be summarized by descriptive 
statistics (Analysis population: ITT): 
• 
Age at time of informed consent (in years, as a continuous variable) 
• 
Age category (:S65, >65 years) 
• 
Gender (Male, Female) 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Hawaiian Native or Other Pacific Islander, Other) 
• 
Country 
• 
Weight at baseline (in kilograms) 
• 
Height at screening (in centimeters) 
• 
BMI (kg/m2) calculated using weight and height at screening 
BMI (kg/m2) = weight (kg) I height (m)2 
• 
Presence or absence of background of atopy 
• 
Baseline average and peak pruritus NRS (weekly average during the 7 days prior to day 1, as a 
continuous variable) 
• 
Purigo baseline Assessment (PAS) 
• 
IGA 
• 
Number of nodules on the entire body 
Stratification factors include country and presence or absence of background of atopy. 
A 
summary table for presence or absence of background of atopy will be provided to show any 
discrepancies between what was reported through Interactive Voice Response System (IVRS)/ 
Interactive Web Response System (IWRS) versus eCRF data (at baseline visit). Country and 
background of atopy will be used as a cofactor in the primary and secondary efficacy endpoint 
analyses. 
By-subject listings of demographic data and other baseline characteristics (as summarized above) 
will be provided. 
5.5.2 Medical History 
Medical history from the screening visit will be summarized by treatment group and overall. 
Medical history will be coded using the MedDRA version 19.0. The number and percentage of 
subjects experiencing at least one such diagnosis will be summarized by the MedDRA system 
organ class (SOC) and preferred term cPn (Analysis population: ITT). 
Summary (n, %) may be presented according to MedDRA groups for specific MH analyses (such as 
asthma, food allergy, allergic conjunctivitis, etc.). 
By-subject listings of medical history will be provided. 
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Statistical Analysis Plan 
5.5.3 Prior and Concomitant Therapies 
Start and stop dates of medications or medical and surgical procedures will be compared to the 
date of first dose of study drug to allow them to be classified as either Prior or Concomitant. 
Medications or medical and surgical procedures that start and stop prior to the date of first dose 
of study drug will be classified as Prior. 
If start and/or stop dates of medications or medical and surgical procedures are missing or 
partial. the dates will be compared as far as possible with the date of first dose of study drug. 
Medications or medical and surgical procedures will be assumed to be Concomitant, unless there 
is clear evidence (through comparison of partial dates) to suggest that they started and stopped 
prior to the first dose of study treatment. If there is clear evidence to suggest that the medication 
or medical and surgical procedure started and stopped prior to the first dose of study drug, they 
will be assumed to be Prior. 
Missing date information for prior and concomitant medications 
For prior and concomitant medications, incomplete (i.e., partial missing) start dates and/or stop dates will 
be imputed. When the start date and the stop date are both incomplete for a subject, the start date will be 
imputed first 
Incomplete start date 
The following rules will be applied to impute the missing numeric fields for an incomplete prior or 
concomitant medication start date. If the stop date is complete (or imputed) and the imputed start 
date is after the stop date, then the start date will be imputed using the stop date. 
Missing Month and Day 
• 
If the year of the incomplete start date is the same as the year of the first administration of the 
study drug, then the month and day of the first administration of the study drug will be assigned 
to the missing fields. 
• 
If the year of the incomplete start date is before the year of the first administration of the study 
drug, December 31 will be assigned to the missing fields. 
• 
If the year of the incomplete start date is after the year of the first administration of the study 
drug, January 1 will be assigned to the missing fields. 
Missing Month Only 
• 
If only the month is missing, then the day will be treated as missing and both the month and the 
day will be replaced according to the procedure above. 
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Statistical Analysis Plan 
Missing Day Only 
• 
If the month and year of the incomplete start date are the same as the month and year of the first 
administration of the study drug, then the day of the :frrst administration of the study drug will be 
assigned to the missing day. 
• 
If either the year of the incomplete start date is before the year of the date of the frrst 
administration of the study drug or if both years are the same but the month of the incomplete 
start date is before the month of the date of the first administration of the study drug, then the last 
day of the month will be assigned to the missing day. 
• 
If either the year of the incomplete start date is after the year of the date of the first administration 
of the study drug or if both years are the same but the month of the incomplete start date is after 
the month of the date of the frrst administration of the study drug, then the first day of the month 
will be assigned to the missing day. 
If the stop date is complete and the imputed start date as above is after the stop date, then the start date 
will be imputed by the stop date. 
Incomplete stop date 
The following rules will be applied to impute the missing numeric fields for an incomplete prior or 
concomitant medication stop date. If the date of the last administration of the study drug is missing, then 
replace it with the last visit date in the imputations described below. If the imputed stop date is before the 
start date (imputed or non-imputed start date), then the imputed stop date will be equal to the start date. 
Missing Month and Day 
• 
If the year of the incomplete stop date is the same as the year of the last administration of the 
study drug, then the month and day of the last administration of the study drug will be assigned to 
the missing fields. 
• 
If the year of the incomplete stop date is before the year of the last administration of the study 
drug, December 31 will be assigned to the missing fields. 
• 
If the year of the incomplete stop date is after the year of the last administration of the study drug, 
January 1 will be assigned to the missing fields. 
Missing Month Only 
• 
If only the month is missing, then the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure. 
Missing Day Only 
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Statistical Analysis Plan 
• 
If the month and year of the incomplete stop date are the same as the month and year of the last 
administration of the study drug, then the day of the last administration of the study drug will be 
assigned to the missing day. 
• 
If either the year of the incomplete stop date is before the year of the date of the last 
administration of the study drug or if both years are the same but the month of the incomplete 
stop date is before the month of the date of the last administration of the study drug, then the last 
day of the month will be assigned to the missing day. 
• 
If either the year of the incomplete stop date is after the year of the date of the last administration 
of the study drug or if both years are the same but the month of the incomplete stop date is after 
the month of the date of the last administration of the study drug, then the first day of the month 
will be assigned to the missing day. 
5.5.3.1 Prior and concomitant medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODD), version March 2016 E B2. 
Prior and Concomitant medications will be summarized separately by Anatomical Therapeutic 
Chemical (ATC) level2, level 3, and preferred name in frequency tables (Analysis population: 
ITn. Subjects with more than one medication in a given ATC level and preferred name will be 
counted only once in that category. The following summaries will be produced: 
• 
Number and percentage of subjects who had Prior medications by ATC level2, level3, 
and preferred name 
• 
Number and percentage of subjects who had Concomitant medications by ATC level 2, 
level 3, and preferred name 
A by-subject listing of all prior and concomitant medications will be provided. 
5.5.3.2 Prior and concomitant medical and surgical procedures 
Medical and surgical procedures will be coded using the MedORA version 19.0. 
Prior and Concomitant medical and surgical procedures will be summarized separately by SOC and PT in 
frequency tables (Analysis population: ITT}. Subjects with more than one procedure in a given SOC and 
PT will be counted only once in that category. The following summaries will be produced: 
• 
Number and percentage of subjects who had Prior medical/surgical procedures by SOC 
andPT 
• 
Number and percentage of subjects who had Concomitant medical/surgical procedures by 
SOCandPT 
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Statistical Analysis Plan 
A by-subject listing of all prior and concomitant medical and surgical procedures will be 
provided. 
5.5.3.3 Rescue therapies 
Rescue treatments for pruritus could be added to the study drug from Day 29. In that case, all 
efficacy and safety assessments should be completed before starting the rescue treatments. The 
number and percentage of subjects initiating use of rescue therapies will be summarized overall 
and by preferred name (for rescue medications) or preferred term (for rescue procedures) for all 
subjects in the ITT population. Rescue medication will be summarized by topical and systemic 
groups. Subjects with more than one rescue therapy in a given preferred name or preferred term 
will be counted only once in that category. 
By-subject listings of all rescue therapies will be provided. 
5.6 
Treatment Compliance 
Subject compliance with study treatment will be assessed via relative injections volume(%) of study 
drug. Refer to Section 5.8.1 for more analyses. 
Actual Total Volume (mL) is defmed as the sum of the real volume injected according to the 
case report form records. 
Prescribed Total Volume (mL) is defmed as number of total injections Type equation here.x 
(Weight of the subject in kg x 0.02 ml/Kg)). 
Compliance Rate (%) is defmed as 
(Volume(mL) of actual injections I Volume of planned injections) x 100 
A Subject is study medication compliance if the compliance rate in between 80% and 120% .. 
5. 7 
Efficacy Evaluation 
Primary inference for efficacy analysis will be the percent change from baseline in NRS to week 4 
(weekly average of the peak). This analysis will be based on the ITT population. and repeated using the 
PP population. Primary imputation method for any missing data including those who took rescue 
medication as failure will be the LOCF (last observation carried forward) approach. In addition, Multiple 
Imputation (Ml) using the missing at random assumption will be conducted on ITT population: 
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Statistical Analysis Plan 
5. 7.1 
Analysis and Data Conventions 
This study is designed to test for superiority. Appropriate statistical tests to assess the superiority of 
nemolizumab should be performed, with the null hypothesis being: there is no difference between 
nemolizumab and placebo treatments and the alternative hypothesis: there is a difference between 
treatments in reducing the pruritus as major symptom ofPN at week 4. 
5. 7 .1.1 Multi-center Studies 
For the purpose of the summaries and analyses, the term 'Center' will be used to define each investigator 
site. All sites within the country (France, Germany, Poland and Austria) will be pooled together in the 
efficacy analyses. If the country is found to be a significant factor in ANOVA or ANCOVA models the 
evaluation of the consistency of treatment effects across countries will be performed via subgroup 
analysis (see Section 5.7.1.6). 
5.7.1.2 Adjustments for Covariates 
The primary and secondary efficacy analyses will be adjusted for the following baseline covariates: 
• 
Presence or absence of background of atopy (the stratification factor for randomization to the 
treatments), 
• 
Country 
Additional covariates will be used as follows: 
• 
Absolute change from baseline to any visits of the weekly average of the peak and of the average 
pruritus NRS will use the same factors as the percent change but will also include baseline NRS 
as a covariate. 
• 
Absolute change and shift from baseline to each visit in Dermatology Life Quality Index (DLQI) 
will include baseline DLQI, background of atopy, and country as covariates. 
5. 7 .1.3 Handling of Missing Data 
Use of rescue therapy: For the purpose of efficacy analysis, subjects receiving any rescue therapies will 
be considered as treatment failures. All efficacy data, except Observed Case (OC), will be set to missing 
after rescue medication is used. In OC analysis, observed data after subject has received rescue treatment 
will be included. 
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Statistical Analysis Plan 
Diary data: If a subject has less than 5 diary entries in a week, the weekly prorated average scores will be 
set to missing. Otherwise the method of computing weekly score when data are missing will be mean 
replacement approach. i.e. calculation of the overall weekly score a given week as 7 times average of non-
missing average of that week. 
The following methods will be used to impute the missing values: 
Continuous endpoints: To impute the missing values for the primary and secondary endpoints, the 
following imputation approaches will be carried out to assess the robustness of study conclusions with 
choice of imputation method. 
For sensitivity analyses, continuous endpoints will be analysed using analysis of covariance (ANCOVA) 
including terms of treatment group, country, presence or absence of background of atopy (the 
stratification factor for randomization to the treatments) and the corresponding baseline value. 
1. Last Observation Carried Forward (LOCF): The primary imputation method for any missing 
data will be the WCF approach. The last observed post-baseline value will be used to replace 
missing values for continuous variables. For questionnaire-based variables, LOCF will be applied 
to missing individual questions first, and the value of the total (or sub-scale) score will be derived 
based on the imputed individual questions. 
2. Observed Case (OC): No data will be imputed. The observed values are used in analysis, 
including assessments post rescue medication. 
3. Multiple imputation (MI) method under assumption missing at random (MAR): 
Multiple Imputation (MI) using the Missing At Random (MAR) assumption will also be 
used. The MI procedure of the SAS system will be used to generate five sets of data with 
missing values imputed from observed data. It is expected that the pattern of missing data 
will be monotonic, with slight deviations being corrected by the Markov Chain Monte 
Carlo (MCMC) method of the MI procedure. Linear regression will be employed to 
model the missing NRS score, with the following covariates included in the imputation 
model: treatment and non-missing data from earlier timepoints. 
o 
Analysis phase: The imputed datasets will be analyzed using the methodology described 
for percent change from baseline in NRS score. 
o 
Pooling phase: The results from the analysis of the multiple imputed datasets will be 
combined by the MIANALYZE procedure of the SAS system. 
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Statistical Analysis Plan 
Binary endpoints: 
All missing values will be treated as a Non-Responder for the binary endpoints. If a subject withdraws 
from the study, all assessments after withdrawal will be considered as Non-Responder. 
• 
LOCF, OC, MI under missing not at random assumption approaches will be used as sensitivity 
analysis to impute the missing values for the selected secondary endpoints as appropriate. For 
sensitivity analyses, binary endpoints will be analysed using a Cochran-Mantel-Haenszel (CMH) 
test stratified by, presence or absence of background of atopy and country (Australia, France, 
Germany, Poland, and US) 
There will be no imputation for missing laboratory and vital sign data. 
5. 7 .1.4 Multiple Comparisons/Multiplicity 
There will be no adjustment for multiplicity. 
5. 7 .1.5 Planned Analyses 
Interim Analysis: No interim analyses are planned. 
5. 7 .1.6 Examination of Subgroups 
To evaluate the consistency of treatment effects, subgroup analyses will be explored for the 
primary and selected secondary efficacy endpoints based on: 
• 
Age (18-65 or >65) 
• 
Gender (Male, Female) 
• 
Country (Austria, France, Germany, and Poland) 
• 
Presence or absence of background of atopy (the stratification factor for randomization to the 
treatments) 
• 
Baseline number of prurigo nodularis nodule (< median vs;::: median), if exact counts are not 
available in the database then use (20-1 00 vs. > 1 00) categories as classes. 
Subgroup analyses will be explored for safety endpoints (e.g., AEs) based on: 
• 
Age (18-65 or >65) 
• 
Gender (Male, Female) 
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Statistical Analysis Plan 
• 
Country (Austria, France, Germany, and Poland) 
• 
Presence or absence of background of atopy (the stratification factor for randomization to the 
treatments) 
If the number of subjects in a subgroup is too small, subgroups may be pooled for analyses. 
Decisions regarding merging subgroups or eliminating some subgroups will be made at the blinded 
review before treatment unblinding and database lock. 
Summary statistics will be provided for each of the subgroups by time points. The estimated mean change 
of treatment groups and 95% CI will be calculated and displayed graphically using forest plots for 
subgroup. 
5. 7.2 Primary Efficacy Endpoint 
Pruritus Numeric Rating Score (NRS) is a scale to be used by the subjects to report the intensity of their 
pruritus (itch) during the last 24 hours all along the study from the first screening visit to the follow up 
visit. 
The primary variable for the assessment of efficacy is the percent change from baseline in NRS at week 4 
of average of the peak pruritus. 
An analysis of variance (ANOVA) model will be used to test the difference between the nemolizumab 
and placebo treatments with percent change from baseline in NRS scores at week 4 being the dependent 
variable, and treatment, presence or absence of atopy and country terms as factors. 
A 95% Confidence for the difference in LSmeans of treatments and p-value will be calculated based on 
contrast test statistics. 
Other covariates may be explored and will be added into the model, if appropriate. 
Sensitivity analysis: The robustness of the primary analysis will be investigated by perfonning 
the sensitivity analyses, as described in 5.7.1.3. 
Subgroup analysis: The homogeneity of the treatment effect for a number of important 
subgroups will be investigated, as described in 5.7.1.6. 
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Statistical Analysis Plan 
A by-subject listing of the primary efficacy data will be provided. In addition, a boxplot and line 
plots showing the mean percent change and 95% CI from baseline in NRS over time within each 
treatment group will be produced for ITT and PP populations. 
S. 7.3 Secondary Efficacy Endpoints 
5. 7.3 .1 Assessment of pruritus and diary data by the Subject 
Pruritus Numeric Rating Scale (NRS) 
Absolute and percent change from baseline (Day 1) in weekly average of the peak and average pruritus 
NRS at each visit (Weeks: 1. 2, 4, 8, 12, 16, 18, Elf or unscheduled visit, if applicable) up to week 18. 
The descriptive statistics for each time point and absolute change and percent change from baseline will 
be presented by each treatment group. Least square means, difference from baseline and 95% CI for that 
will also be provided at each assessment time point. 
The percent and absolute change from baseline of peak and average NRS will be analyzed separately at 
each assessment timepoint using the ANOV A model described for the primaJy analysis above. For 
absolute change endpoint, the ANCOV A model, with the same factors as in the percent change model, 
will be performed, but with baseline NRS as a covariate. 
A 95% CI for the treatment difference will be calculated for both absolute change and percent change of 
NRS from baseline and will be plotted by treatment group for ITI population. 
Sensitivity analysis: Sensitivity analyses will be performed as described in 5.7.1.3. 
Subgroup analysis: Subgroup analyses will be investigated as described in 5.7.1.6. 
Verbal rating scale (VRS) 
The VRS consists of a list of adjectives describing different levels of symptom intensity to be 
used by the subjects to report the intensity of their pruritus (itch) over the last 24 hours. 
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Statistical Analysis Plan 
The intensity of subject's pruritus (itch) will be measured daily using the five-point scale, where 
0 = no itch, 1 = mild itch, 2 = moderate itch, 3 = severe itch, 4 = very severe itch. 
The efficacy endpoint for the VRS will be the absolute and percent change from baseline in weekly 
average of the peak and average VRS to each visit (Day 1, baseline, Week 1, 2, 4, 8, 12, 16, 18, Err or 
unscheduled visit, if applicable). These endpoints will be compared with nemolizumab and placebo 
treatments using ANOV A model for the primary analysis described above separately at each assessment 
visit. For absolute change endpoint the ANOVA model will be performed, but with baseline VRS as an 
additional covariate. 
A 95% CI for the treatment difference will be calculated for both absolute change and percent change of 
VRS from baseline and will be plotted by treatment group for ITT population. 
Dynamic Pruritus Score (DPS) 
The 9-point DPS is a dynamic scale to be used by subjects to evaluate the change of their pruritus 
compared with an earlier time point (i.e. before injection on Day 1 ). 
The details of measuring scale and assessment time are given in section 4.2.1.3. The data will be analyzed 
using a Cochran-Mantel-Haenszel (CMH) test with ridit scores between nemolizumab and placebo, 
stratified by by background of atopy (presence or absence) and country. 
5. 7.3 .2 Assessment of Prurigo by Physician 
Investigator Global Assessment (IGA) of Prurigo 
IGA is a 5-point scale ranging from 0 (clear) to 4 (severe) used by the investigator or trained designee to 
evaluate the severity of the disease. The details of measuring scale and assessment time are given in 
section 4.2 .1.4. 
IGA evaluation of the severity of at each post-treatment timepoint will be summarized as a continuous 
variable and as a categorical variable, given its ordinal nature by treatment group. The data will be 
analyzed using a Cochran-Mantel-Haenszel (CMH) test with ridit scores between nemolizumab and 
placebo, stratified by by background of atopy (presence or absence) and country. 
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Statistical Analysis Plan 
The shift table will also be provided for overall investigator-rated evaluation change from baseline to 
Week 18 for each treatment group and overall. 
Assessment of Prurigo Activity Score (PAS) 
The evaluation of the disease will be performed by the Investigator using the Prurigo Assessment 
Scale (PAS) at baseline and Week 12 using the entire scale and at week 4, 8,18 and in case ofEarly 
termination visit I Unscheduled visit, if applicable, using item 5 (number of lesions only) and 6 
(excoriation/crusts and healed lesions). 
PAS evaluation of the severity of at each post-treatment timepoint will be summarized as a continuous 
variable and as a categorical variable, given its ordinal nature by treatment group. The data will be 
analyzed using a Cochran-Mantel-Haenszel (CMH) test with ridit scores between nemolizumab and 
placebo, stratified by by background of atopy (presence or absence) and country. The shift table will also 
be provided for overall investigator-rated evaluation change from baseline to Week 18 for each treatment 
group and overall. 
5. 7.4 Other Efficacy Endpoints 
Dermatology Life Quality Index (DLQI) 
DLQI will be assessed at baseline, weeks 4, 12, or early termination visit when applicable. 
The DLQI score will be categorized as follows: 
• 
0-1 =no effect at all on subject's life 
• 
2-5 =small effect on subject's life 
• 
6-10 =moderate effect on subject's life 
• 
11-20 =very large effect on subject's life 
• 
21-30 =extremely large effect on subject's life 
The DLQI can be analyzed under 6 sub-scales, namely, symptoms and feelings (question 1 and 
2), daily activities (question 3 and 4), leisure (question 5 and 6), work and school (question 7), 
personal relationships (question 8 and 9), and treatment (question 10). For general inflammatory skin 
conditions, a change in DLQI score of at least 4 points is considered clinically important. 
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Statistical Analysis Plan 
The primary study population for all QoL and productivity data will be the ITI Population. DLQI will be 
summarized by treatment group and visit. By-subject listings of these data should be provided. 
Change from baseline in DLQI at each visit will be analyzed using ANCOV A with treatment group, 
baseline DLQI as a covariate, back ground of atopy and country as cofactors. In addition, the following 
analyses will be performed: 
• 
A shift table (by visit) will be generated using the categories described above. Change from 
baseline in each sub-scale at each visit will be analyzed as the efficacy endpoint using ANCOV A. 
• 
Proportion of subjects achieving a change in DLQI score of at least 4 points at each 
Visit up to week 12 will be analyzed using a CMH test with ridit scores between nemolizumab 
and placebo, stratified by by background of atopy (presence or absence) and country. 
Number and percentage of subjects will also be provided for the following DLQI score categories at each 
visit for the above categories and analyze using CMH test stratified by background of atopy and by 
country with the redit scores. 
Sleep disturbance Numeric Rating Scale (NRS) 
The efficacy endpoint for the Sleep disturbance NRS will be the Absolute and Percent change from 
baseline in weekly average of Sleep disturbance NRS (Day 1, baseline), Week 1, Week 2, Week 4, and 
Eff or unscheduled visit, if applicable). These endpoints will be compared across nemolizumab and 
placebo treatment groups using ANOV A model for the primary analysis above separately at each 
assessment visit. For absolute change endpoint, the same ANOVA model, with the same factors as in the 
percent change model will be performed, but with baseline NRS as a covariate. 
Summary statistics of objective assessment of scratching events during the night and sleep duration the 
two Ratios 'scratching duration/duration' and 'scratching events/duration' up to week 4 will be 
summarized. 
A 95% CI for the treatment difference will be calculated for both absolute change and percent change of 
NRS from baseline and will be plotted by treatment group for ITI population. 
5.8 
Safety Evaluation 
All safety summaries and analyses will be based upon the SAF population as defmed in Section 5.4. 
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Statistical Analysis Plan 
5.8.1 Extent of Exposure 
The extent of treatment will be summarized by treatment group as follows: 
• 
Duration of study drug (days) 
• 
Cumulative dose ofnemolizumab (mg/kg) received 
• 
Relative dose volwne (%) of nemolizumab 
• 
Proportion of subjects compliant with study drug at each study drug administration visit by 
treatment group 
5.8.2 Adverse Events 
Analysis of severity: The severity of each AE will be summarized as assessed by the investigator (Mild. 
Moderate, Severe). Within the same MedDRA PT, only the most severe AE for each subject will be 
counted in tabulations by severity. Within a MedDRA SOC, subjects with more than one MedORA PT 
will be counted only once for the most severe AE reported. AEs for which the severity is missing will be 
imputed to be Severe; this imputation will take place prior to determining the most severe AE within a 
SOC or PT for a given subject. 
Analysis of causality: The relationship of each AE to the study drug and/or study procedure will be 
summarized as assessed by the investigator (Reasonable Possibility, No Reasonable Possibility). Within 
the same MedDRA PT, only the AE with the highest ranked relationship to study drug and/or study 
procedure for each subject will be counted in tabulations by causality. Within a MedDRA SOC, subjects 
with more than one MedDRA PT will be counted only once for the AE that is most related to study drug 
and/or study procedure. AEs for which the relationship to study drug is missing will be considered as 
Reasonable Possibility related. The imputation for a missing relationship will take place prior to 
determining the most related AE within a SOC or PT for a given subject. 
High-level summary ofTEAEs will be presented based on 1) all causalities, 2) study drug related, and 3) 
study procedure (including TCS) related. The table will include the nwnber and percentage of subjects 
for the following categories: 
• 
NumberofTEAEs 
• 
Subjects with TEAEs 
• 
Subjects with treatment-emergent SAEs (TESAEs) 
• 
Subjects with severe TEAEs 
• 
TEAE with fatal outcome 
• 
Subjects temporarily discontinued from study treatment due to TEAEs 
• 
Subjects permanently discontinued from study treatment due to TEAEs 
• 
Subjects discontinued from study due to TEAEs 
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Statistical Analysis Plan 
The number and percentage of subjects reporting any TEAE will be summarized by SOC and PT. 
• 
Summary ofTEAEs by MedDRA SOC and PT based on 1) all causalities; 2) study drug related. 
and 3) study procedure (including TCS) related 
• 
Summary of Severe TEAEs by MedDRA SOC and PT based on 1) all causalities; 2) study drug 
related, and 3) study procedure (including TCS) related 
• 
Summary of the most common TEAEs (>=5%) by MedDRA SOC and PT based on all causalities 
• 
Summary of TEAEs by Med.DRA SOC and PT based on all causalities for subgroups as 
described in Section 5.7.1.6 
AE summaries will be ordered in terms of decreasing frequency for SOC, and PT within SOC, in the 
treatment group (combined, nemolizumab, then placebo), and then alphabetically for SOC, and PT within 
SOC. If deemed as appropriate, a different order may be applied. 
All AEs will be provided in a by-subject listing which will include both the term reported on the eCRF 
(verbatim term) and the PT and SOC to which it is coded. Relative start and stop days will be included 
along with the actual onset and resolution dates. Pre-treatment AEs will be listed separately. 
5.8.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
Other significant TEAEs are those TEAEs reported as leading to permanent or temporary discontinuation 
of study treatment, leading to discontinuation of study, AESis. 
The following summaries will be produced: 
• 
Summary of TESAEs by MedDRA SOC and PT based on 1) all causalities; 2) study drug related, 
and 3) study procedure (including TCS) related 
• 
Summary of TEAEs associated with permanent discontinuation of study treatment by MedDRA 
SOC and PT based on 1) all causalities; 2) study drug related, and 3) study procedure (including 
TCS) related 
• 
Summary of AEs associated with discontinuation of study participation by MedDRA SOC and 
PT based on 1) all causalities; 2) study drug related, and 3) study procedure (including TCS) 
related 
• 
Summary of AESis based on 1) all causalities; 2) study drug related 
In addition, separate listings will be provided for the following: 
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Statistical Analysis Plan 
• 
Deaths and other SAEs 
• 
Permanent discontinuations of study treatment due to AEs 
• 
Discontinuations of study participation due to AEs 
• 
Temporary discontinuations of study treatment due to AEs 
• 
AESis 
5.8.4 Clinical Laboratory Evaluation 
All laboratory values will be reported in SI units. 
Laboratory data (absolute values and change from baseline) will be summarized descriptively by visit and 
treatment group. 
In addition, the number and percent of subjects below, within, and above the laboratory reference ranges 
and the number and percentage of subjects who met criteria of PCSV (see Appendix 5) will be 
summarized by treatment group. Shift tables will be generated using the reference ranges. The shift will 
also be illustrated by the spagetthi plots. 
A by-subject listing of all laboratory data will be provided by treatment group, with abnormal values 
flagged. Laboratory reference ranges should also be listed. 
5.8.5 Vital Signs, Weight, Physical Findings and Other Observations Related to Safety 
5.8.5.1 Vital Signs and Weight 
All vital signs and weight data (absolute values and change from baseline) will be summarized 
by visit and treatment group. 
In addition, the number and percent of subjects with blood pressure (systolic and diastolic), pulse 
rate, and weight values meeting criteria for PCSV will be summarized by treatment group. 
A by-subject listing of vital signs data will be provided, with potentially clinically significant 
values flagged. 
5.8.5.2 Peak Expiratory Flow (PEF) 
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Statistical Analysis Plan 
For subject with medical history of asthma, PEF measurements (absolute values and change from 
baseline for actual PEF and %predicted PEF) will be summarized by visit and treatment group. 
Number and percentage of subjects who met the following criteria will be summarized. 
• 
With %predicted PEF less than 80% 
• 
With >=20% change (decrease} from baseline in PEF 
A by-subject listing of respiratory assessments/PEP will be provided. 
5.8.5.3 Electrocardiogram 
A by-subject listing ofECG overall interpretation will be provided. 
5.9 
Phannacokinetic and Pharmacodynamics Evaluations 
5.9.1 
Pharmacokinetic Parameter Calculation Methods 
Derivation of PK parameters will be the responsibility of Quantitative Clinical Development 
(QCD}, P AREXEL International. 
PK parameters will be calculated by non-compartmental 
analysis methods from the concentration-time data using Phoenix® WinNonlin® (WNL} 
Professional (Version 6.3 or higher}. The following guidelines will be applied: 
• 
Actual sampling times relative to dosing will be used in the calculation of all derived PK 
parameters. If the dosing time is not available for the calculation of actual sample time or 
the sample collection time is not available, the nominal time as recorded in the database 
will be used in the calculation. The listing of serum concentrations will note any instance 
in which a nominal time is presented in place of an actual sample time. 
• 
BLQs at the beginning of a subject profile (i.e., before the ftrst incidence of a measurable 
concentration} will be assigned to zero. 
• 
BLQs at the end of a subject profile (i.e., after the last incidence of a measurable 
concentration) will be set to missing. 
• 
Single BLQs which fall between two measurable concentrations will be set to missing. 
• 
Consecutive BLQs which fall between measureable concentrations will be set to missing. 
• 
Data from subjects with missing concentration values (missing samples) may be used if 
pharmacokinetic parameters can be estimated using the remaining data points. 
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Statistical Analysis Plan 
Derivation of the phannacokinetic parameters for nemolizumab will be performed using the 
following guidelines: 
• 
Cmax will be obtained directly from the concentration-time data. 
• 
Tmax is the time at which Cmaxis observed. 
• 
T~astis the time ofthe last quantifiable concentration. 
• 
Az will be estimated at terminal phase by linear regression after log-transformation of the 
concentrations: 
-
Only those data points that are judged to describe the terminal log-linear decline will be 
used in the regression. 
-
A minimum number of three data points in the terminal phase will be used in calculating 
~with the line of regression starting at any post-Cmax data point (Cmax should not be part 
of the regression slope). The adjusted correlation coefficient (R2 adjusted) in general 
should be greater than 0.80. Any value< 0.80 will be excluded from the analysis. 
-
The interval used to determine A.z should be equal or greater than 1.5-fold the estimated 
half-life or otherwise flagged and excluded from the analysis. 
• 
ty. will be calculated as ln21A.z. 
• 
AUC is calculated by the linear up/log down method (linear method will be employed for all 
incremental trapezoids arising from increasing concentrations and the logarithmic method 
will be used for those arising from decreasing concentrations. 
AUCo-t= f
0
1 C(t)dt 
AUCo-inf = fot C(t)dt + ft"' C ( t )dt = AUCo-t + CJI..r.. 
• 
Clast is the last observed quantifiable concentration. 
• 
o/oAUCex will be calculated as (1 - [AUCo-JAUCo.inf])xlOO. The %AUCex should not exceed 
20% for each individual profile. If the %AUCex is more than 20%, the individual result 
should be flagged and mentioned in the report as well as all parameters depending on AUCo. 
inf. If the %AUCex is greater than 30%, the value and all dependent parameters may be 
flagged and excluded, at the discretion of the PK scientist. 
When appropriate, the following PK parameters will be determined for each subject: 
From baseline to week 4: 
• 
Clll8l[: The observed peak drug concentration 
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Statistical Analysis Plan 
• 
T max: The time at which Cmax occurs 
• 
T~ut: Time of last quantifiable concentration 
• 
AUCo-4w: Area under the concentration time curve from pre dose through 28 (4 weeks) days post 
dosing. AUCo-4w will be calculated by mixed linear logarithmic trapezoidal method 
From baseline to week 12: 
• 
AUC0-12w: Area under the concentration time curve from pre dose through 12 weeks post 
dosing. AUC0-12w will be calculated by mixed linear logarithmic trapezoidal method. AUC0-
12w included the serum drug concentration up to week 12 (i.e. the serum concentration collected 
at baseline, week 1, 2, 4, 8 and 12) 
From baseline to week 18: 
• 
AUC0-18w: Area under the concentration time curve from pre dose through 24 weeks post 
dosing. AUC0-18w will be calculated by mixed linear logarithmic trapezoidal method. AUC0-
18w included the serum drug concentration up to week 18 (i.e. the serum concentration collected 
at baseline, week 1, 2, 4, 8, 12, 16 and 18) 
• 
From baseline to week 18 (Early termination or Unscheduled visit, if applicable) 
• 
AUCO-t: area under the concentration time curve calculated by the mixed linear logarithmic 
trapezoidal method from TO up to the sampling time corresponding to the last quantifiable 
concentration (Clast) 
From week 12 to week 18 (or Early termination or Unscheduled visit, if applicable): 
• 
t112: the terminal half-life value (t112) will be calculated using the equation ln2/k after the last drug 
injection (week 8). 
• 
AUCo-t: area under the concentration time curve calculated by the mixed linear logarithmic 
trapezoidal method from TO up to the sampling time corresponding to the last quantifiable 
concentration (CJut). 
• 
AUCo-inf: Area under the plasma concentration-time curve calculated by the mixed linear-
logarithmic trapezoidal method from TO and extrapolated to time infinity as: AUCo-inf=AUCo-t + 
Clast I ke!. When the extrapolation represents more than 20%, AUCo-inf and t112 will not be reported. 
At weeks 4, 8, 12, 16, 18 (or Early termination or Unscheduled visit if applicable): 
• 
Ctrough: The residual drug concentration 
• 
Accumulation index: calculated with the serum nemolizumab trough concentration obtained 4 
weeks after the first dose (week 4) and 4 weeks after last drug injection (week 18). 
5.9.2 Pharmacokinetic Parameters and Anti-drug Antibody Analyses 
The PK parameters derived using non-compartmental techniques will be regarded as primary endpoints 
for the PK analyses (see Section 5.9.1). Primary inference for all the PK parameters will be based on the 
PKAP population. 
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Statistical Analysis Plan 
The concentration at each time point will be summarized as arithmetic mean, standard deviation, median, 
minimum, and maximum. number ofBLQs (Below the Limit of Quantification). Phannacokinetic 
parameters using geometric means will be compared to determine when steady state conditions are 
achieved during the treatment period. Geometric means and between-subject coefficients of variation 
(CVb) will be calculated for loBe-transformed AUC0_28d, Ctrough and Cmax where: 
Geometric mean = exp(mean on log scale) 
cvb (%) = sqrt[exp(SD2)- 1] X 100 
- where SD is the standard deviation of the loBe-transformed data. 
Following loBe-transformation, Cttoll8h will be analyzed using analysis of variance (ANOVA). the model 
will include time and subject as a fixed effect. The residual variance from the model will be used to 
calculate point estimates and 90% Cis for the least squares means for each treatment formulation on the 
loBe scale. These estimates will be back transformed to give point estimates and 90% Cis on the original 
scale. 
The potential relationship between plasma concentrations of nemolizumab and change in pruritus NRS. 
biomarkers or other indicators of disease activity will be explored using PK/PD modeling, as appropriate. 
Incidence of positive ADA results will be summarized by treatment group (absolute occurrence and 
percent of subjects). Individual PK profiles of subjects with or without ADA will be plotted to explore 
ADA impact on systemic exposure levels. 
S.9.3 Pharmacodynamic Analyses 
Primary inference for all biomarker analyses based on blood and skin samples (D-Squames and skin 
biopsies) will be based on the observed cases. All biomarker variables (using logarithm transformation) 
will be summarized across treatments at each time point. 
Any observations in trends within the Biomarker data may be explored with PK/PD correlations/models. 
All of this analysis will be considered exploratory. The outputs will be in a separate report. 
The detailed analysis will be carried out by Biomarker group in GALDERMA, and will be reported 
separately. 
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Statistical Analysis Plan 
5.10 Determination of Sample Size 
For the current study, it is assumed that the common standard deviation is 35 and that the true difference 
between Nemolizumab and the placebo is 30% in terms of percent change from baseline in worst itching 
score on a NRS at Week 4. 
With an effect size of(30/35=) 0.857, a power of90% and a type I error of5% two-sided; at least 30 
subjects are needed per group. In order to maintain the power of the tests, for per-protocol population, in 
case of drop outs/major deviations at Week 4, the sample size will be increased to 35 subjects per group, 
i.e. 70 to be randomized. 
5.11 Changes in the Conduct of the Study or Planned Analysis 
Changes in the conduct of the study may be instituted through a protocol amendment. Planned 
analyses will be revised as appropriate. Similarly, planned analyses may be changed as a result 
of planned blinded data reviews. Changes will be finalized prior to database lock. 
The ridit score is calculated combining data in the atopy and country stratum due to small sample 
size in each strata. The Placebo group is used as the reference group to calculate mean redit 
score of the nemolizumab group using the method describies in Uwawunkonye et. al. paper. 
6 
REFERENCES 
Basra MK et al. Determining the minimal clinically important difference and responsiveness of the 
Dermatology Life Quality Index (DLQI): further data. Dermatology, 2015; 230(1):27-33. 
Fostini AC, Girolomoni G, Tessari G. Prurigo nodularis : an update on etiopathogenesis and 
therapy. J. Dennatolg treat. 2013. 24(6):458-62. 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
Hyde JN, Montgomery FHA. Practical treatise on diseases of the skin for the use of students and 
practitioners. Lea & Febiger, Philadelphia, 1909. 174-175. 
Ruzicka T, Hanifin JM, Furue M, Pulka G, Mlynarczyk I, Wollenberg A, Galus R, Etoh T, 
Mihara R, Yoshida H, Stewart J, Kabashima K; XCIMA Study Group. Anti-lnterleukin-31 
Receptor A Antibody for Atopic Dermatitis. N Engl J Med. 2017 Mar 2;376(9):826-835. 
Warlich 8, Osada N, 8ru1and P, Stumpf A, Schneider G, Dugas M, Pfleiderer 8, Stander S. 
Health-Related Quality of Life in Chronic Pruritus: An Analysis Related to Disease Etiology, 
Clinical Skin Conditions and Itch Intensity. Dermatology. 2015;231(3):253-9. 
Uwawunkonye, EO and Anaene, OIC. A comparative study between ridit and modified ridit 
analysis. American Journal ofTheretical and Applied Statistics. 2013; 2(6):248-254. 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
Appendix 1 Schedule of assessments 
T able 2 
Schedule of A ssessments 
Study period 
Screening period 
Treatment period 
Observation period! 
Earty 
(Day ·28 to Day-1) 
Follow up 
temlinalion 
Visit 
V1 
V2 
V3 
V4 
V5 
I 
V6 
V7 
V8 
V9 
I 
V10 
(EfT) or 
Week 
Screening 1 
screening2 
Baseline 
W1 
W2 
W4 
W8 
W12 
W16 
W18 
Unscheduled 
Day 
Day8 
Day 15 
Day29 
Day 57 
Day85 
D113 
Day 126 
visit 
'flsit window 
0-28 to 0-8 
Day-7 t•l 
Day 1 
±1 day 
±2 days 
±2 days 
±2 days 
±5 days 
±5 days 
±7 days 
[rt applicable) 
tCF and when applicable country specific consent form 
• 
Photo Consent and Bbpsies consemt form (~ applicable) 
• 
Demographics 
. 
Me<fiC<II history! Pll!vious therapies and procedull!s 
. 
lnclusion/Exdusion criteria 
• 
. 
Concomitant therapies and proced~ll!s 
. 
• 
. 
• 
• 
• 
• 
• 
• 
• 
• 
Heigh! 
. 
Weight 
. 
. . 
. 
Blood sample for serology (HIV, Hepatitis Band C test) 
• 
Blood samples for spedlic lgE 
. 
Blood samples for TB test ~~ 
. 
SAFETY ASSESSMENTS 
Vital signs 
• 
• 
. 
• 
• 
• 
• 
• 
• 
• 
Physics! exam 
. 
. 
• 
. . 
. 
• 
Blood samples for hematology and biochemistry''' 
. 
. 
. 
. 
. 
Blood sample for CPK I~ 
• 
• 
• 
. 
• 
• 
Urinalysis 
. 
. 
. 
. 
. 
12-lead ECG 
. 
. 
• 
• 
Pregnancy test t•t 
Serum 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Respiratory assessment~ 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Adverse Events 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
STUDY DRUG 
RandomiZation 
I 
• 
I 
I 
I 
SubCtJtaneous study drug injection 
I 
• 
• 
I 
• 
I 
I 
(a) Screening visit 2 must be performed at least 7 days prior to Day 1 visit. Eligible subjects according to safety assessments will be provided with the Actigraphy and ePro devices. 
(b) In case of indeterminate result for TB test, the test should be repeated at Scr 2 in the local laboratory (only one retest is allowed). If the test is still indeterminate, the subject must not be included in the study 
(c) Blood samples for hematology and biochemistry must be performed in fasting condftions 
(d) In case elevated CPK > 1.5 ULN at screening 1, the test will be repetead at screening 2. If the result is still abnormal, the subject will not be included. V7/W8 CPK applicable only to France 
(e) Only for female of childbearing potentia>/. Serum pregnancy test to be performed at screening visit 1 and urine pregnancy test (UPT) for all other visffs. UPT should have a sensitivity threshold of less than 
25m/UimL There should be at least 14 days between the serum pregnancy test at screening and the UPT at baseline. 
(f) Respiratory assessments for all subjects, but PEF wit/ be measured only for subjects with medical history of asthma 
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GALDERMAR&D, SNC 
Statistical ADalysis Plan 
Study period 
Screening period 
Treabnent period 
Observation period/ 
Earty 
(Day -28 to Day-1) 
Follow up 
termination 
Visit 
V1 
V2 
V3 
V4 
V5 ! 
V6 
V7 
va 
V9 ! V10 
{EfT) or 
Week 
Screening 1 
screening 2 
Baseline 
W1 
W2 I W4 
wa 
W12 
W16 I W18 
Unscheduled 
Day 
DayS 
Day 15 I Day 29 
Day 57 
Day85 
D113 I Day 126 
visit 
Visit window 
D-28to 0-S 
Day-7 t•l 
Day1 
±1 day 
±2 days 
±2daya 
±2 daya 
±5 daya 
±5daya 
±7 daya (if applicable) 
EFFICACY/ PATlENTS REPORTED OUTCOMES 
NRS (9l 
• 
Once daily by the subject at home in the evening until Day 126 
• 
VRS ul 
Once daily by the subject at home in the evening until Day 126 
• 
Sleep distJJrbance NRSihl 
Once daily by the subject a1 home in the-morning until Day 29 
DPS fl 
• 
• 
Dl QI 
• 
• 
• 
• 
Prurigo Assessment Scale (PAS) 
. 
• 
. . 
. 
. 
IGA 
• 
• 
• 
• 
• 
• 
PK AND ADA ASSESSMENTS 
Blood sample for PK 
I 
I . . . I 
• 
I . I . I 
• 
. I . 
Blood sample for ADA 
I 
I 
• 
I 
• 
I 
• 
I 
• 
I 
• 
• 
I 
• 
PHARMACODYNAMIC ASSESSMENTS 
Blood sample for biomarkers 
• 
• 
• 
D-Squames samples 
• 
• 
• 
4-mm skin biopsies (i) 
• 
• 
Control of biopsies healitlg:>l 
• 
• 
BIOPHYSICAl ASSESSMENTS 
Photos of Whole body ll 
I 
I 
• 
I 
• 
I 
• 
I 
• 
I 
• 
Acography 
Every day until Day 29 
Extt Form 
• 
(g) NRS and VRS must be performed by the subject at home using the device provided by the site once daily in the evening from screening 2 to the last visit. 
(h) NRS for sleep disturbance must be performed by the subject at home using the device provided by the site once daily in the morning from screening 2 to Day 29 
(i) DPS must be performed by the subject at home following instruction provided by the Nurse on site and then subject should record DPS 24, 48 & 72 hrs after the 1" injection and at week 4 
before the injection. 
(j) Skin biopsies will be performed on lesional and non lesional skin at baseline and on lesional skin at week 12 only for patients consenting to have skin biopsies. 
(k} When applicable, biopsies healing should be checked 2 weeks after skin biopsies 
(I) Only for selected equipped sites - at least a Baseline & Week 12; Week 4, week 8 & week 18 if possible. 
I 
TP-GOO-WW-016-{YJ 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
Appendix 2 Criteria for potentially clinically significant vital signs and weight 
Pulse rate 
:550 bpm and decrease from baseline ;:::20 bpm 
~120 bpm and increase from baseline;:::20 bpm 
To be applied for all positions (including missing). 
SBP 
~5 mmHg and decrease from baseline ;:::20mmHg 
~160 mmHg and increase from baseline ;:::20 mmHg 
To be applied for all positions (including missing). 
DBP 
::;.45 mmHg and decrease from baseline ~10 mmHg 
~11 0 mmHg and increase from baseline ~10 mmHg 
To be applied for all positions (including missing). 
Weight 
~5% increase from baseline 
~5% decrease from baseline 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
Appendix 3 Dermatology Life Quality Index (DLQI) 
The DLQI questionnaire is designed for use in adults, i.e. subjects over the age of 16. It is 
self-explanatory and can be simply handed to the subject who is asked to fill it in without the need for 
detailed explanation. It is usually completed in one to two minutes. 
Scoring 
The scoring of each question is as follows: 
Response 
Score 
Very much 
scored 3 
A lot 
scored2 
A little 
scored 1 
Not at all 
scoredO 
Not relevant 
scoredO 
Question unanswered 
scoredO 
Question 7: ''prevented work or studying" 
scored3 
The DLQI is calculated by summing the score of each question resulting in a maximum of 30 and a 
minimum ofO. The higher the score, the more quality of life is impaired. The DLQI can also be expressed 
as a percentage of the maximum possible score of30. 
**Please Note: That the scores associated with the different answers should not be printed on the DLQI 
itself, as this might cause bias** 
Meaning ofDLQI Scores 
0-1 =no effect at all on subject's life 
2-5 =small effect on subject's life 
6-10 =moderate effect on subject's life 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
11-20 =very large effect on subject's life 
21-30 =extremely large effect on subject's life 
Detailed analysis of the DLQI 
The DLQI can be analyzed under six headings as follows: 
Section 
Questions 
Symptoms and feelings 
Questions 1 and 2 
Daily activities 
Questions 3 and 4 
Leisure 
Questions 5 and 6 
Work and School 
Question 7 
Personal relationships 
Questions 8 and 9 
Treatment 
Question 10 
Score 
Score maximum 6 
Score maximum 6 
Score maximum 6 
Score maximum 3 
Score maximum 6 
Score maximum 3 
The scores for each of these sections can also be expressed as a percentage of either 6 or 3. 
Interpretation of incorrectly completed questionnaires 
There is a very high success rate of accurate completion of the DLQI. However, sometimes subjects do 
make mistakes. 
• 
If one question is left unanswered this is scored 0 and the scores are summed and expressed as usual 
out of a maximum of 30. 
• 
If two or more questions are left unanswered the questionnaire is not scored. 
• 
If question 7 is answered 'yes' this is scored 3. If question 7 is answered 'no' but then either 'a lot' or 
'a little' is ticked this is then scored 2 or 1. If"Not relevant" is ticked, the score for Question 7 is 0. If 
it is answered 'no', but the second half is left incomplete, the score will remain 0. 
• 
If two or more response options are ticked, the response option with the highest score should be 
recorded. 
• 
If there is a response between two tick boxes, the lower of the two score options should be recorded. 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
• 
The DLQI can be analyzed by calculating the score for each of its six sub-scales (see above). When 
using sub-scales, if the answer to one question in a sub-scale is missing, that sub-scale should not be 
scored. 
Minimal Clinically Important Difference of the DLQI 
For general inflammatory skin conditions a change in DLQI score of at least 4 points is considered 
clinically important (Basra et al, 2015). This means that a subject's DLQI score has to either increase or 
decrease by at least 4 points in order to suggest that there has actually been a meaningful change in that 
subject's quality oflife since the prior measurement of his/her DLQI scores (Refer to Basra MK et al. 
paper). 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
Appendix 4 Validation of the NRS responder analysis 
To assess the appropriateness of responder thresholds in the NRS responder analysis (an improvement of 
weekly average pruritus peak NRS ;?:4), an approach combines an anchor-based approach and ROC 
curves will be performed to identify the responder thresholds that best predict classification based on an 
external criterion. First, an external anchor or another external criterion that is appropriate to identify 
responders (e.g., Pruritus PCS) is used to classify all subjects into responder (at least 1 grade 
improvement from baseline in PCS) or non-responder groups. Then, to check for appropriateness, the 
relationship between the PCS criterion and the NRS measure (change from baseline in weekly average 
pruritus peak NRS) is examined through correlation analyses. Finally, the predictive accuracy of how well 
the specific NRS change scores relate to the classifications is evaluated using logistic regression analyses 
and graphically displayed as an ROC curve. Each point on the curve provides the sensitivity (true 
positives) versus one minus the specificity (false positives) trade-off for identifying responders for a 
specific unit of change on the NRS measure. The entire range of change scores and the likelihood 
classifications are provided within the one curve. A diagonal line is included in the figure as a reference. 
Evaluations that produce curves close to the diagonal line should be viewed with caution because the 
diagonal line represents chance classification. 
The area under curve (AUC) and its 95% CI will be presented, along with percent concordant and 
discordant. 
The analyses described above will be performed using all data across all visits and the data at week 24. 
The following cumulative distribution function (CDF) plots will be produced to illustrate the between 
treatment group differences and within-subject change from baseline to Week 24. 
• 
CDF plot illustrating the treatment differences from baseline to Week 24 
• 
CDF plot of peak pruritus change score from baseline to Week 24 for all subjects by the 
different PCS response options at Week 24 
• 
CDF plot of peak pruritus change score from baseline to Week 24 for all subjects by the PCS 
change scores (differences) between baseline and Week 24 (e.g. ± 3, ± 2, ± 1, and 0 point 
change) 
In addition, the mean change in peak pruritus NRS from baseline to Week 24 will be calculated in the 
following subjects: 
• 
An improvement of;::: 1 in PCS from baseline to week 24 
• 
50-7 4%, 75-89%, or 90-100% improvement in BASI from baseline to week 24 
• 
An improvement of;::: 2 in IGA scale from baseline to Week 24 
• 
An IGA ofO or 1 at Week 24 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
Appendix 5 Potentially clinically significant values (PCSV) for clinical laboratory tests 
Parameter 
SI 
Conventional PCSV 
Units 
Units 
<3.0 Giga/L & ~.OG/L at Baseline (non-Black) 
WBC 
x10e9/L 
x10e3/J.1L 
<2.0 Giga/L & ~.OG/L at Baseline (Black) 
> 16.0 GIL & <16G/L at Baseline 
Neutrophils 
<1.5 Giga/L & ~1.5G/L at Baseline (non-Black) 
ABS 
x10e9/L 
x10e3/J.1L 
<1.0 Giga/L & ~l.OG/L at Baseline (Black) 
Eosinophils 
x10e9/L 
x10e3/J.1L 
(>0.5 Giga/L and >ULN) and (~.5 Giga/L or gJLN at Baseline) 
ABS 
Basophils 
ABS 
Monocytes 
ABS 
Lymphocytes 
ABS 
x10e9/L 
x10e3/J.1L 
Hemoglobin 
*Female 
giL 
g/dL 
*Male 
Platelets 
x10e9/L 
x10e3/J.1L 
Sodium 
mmol/L 
mmol/L 
Potassium 
mmol/L 
mmol/L 
Calcium 
(Total) 
Corrected 
mmol/L 
mgldL 
serum 
calcium 
Glucose 
mmol/L 
mgldL 
TP-GDQ-WW-016-07 
Project Document Version No. 2.0 
Effective Date: 05 Sep 20 18 
>0.1 Giga/L and ~.1 Giga/L at Baseline 
>0.7 Giga/L and ~.7 Giga/L at Baseline 
>4.0 Giga/L and ~.0 Giga/L at Baseline 
<0.5 Giga/L and ~.5 Giga/L at baseline 
~1 00 giL and Baseline > 100 giL for Male ; 
~ 90 giL and Baseline >90 giL for Female 
~00 giL and baseline <200 giL for Male; 
~180 giL and Baseline <180 giL for Female 
<100 Giga/L and ~100G/L at Baseline 
~700 GIL & <7000/L at Baseline 
~130mmol/L and Baseline> 130 
>155 mmol/L and Baseline <155 
<3mmol/L and Baseline~ 
>6.0 mmol/L and Baseline ~.0 
<7 mg/dL and Baseline ~7 mg/dL 
> 12.5 mgldL and Baseline ~12.5 mgldL 
<2.2mmol/L and ~.2 mmol/L at Baseline 
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GALDERMA R&D, SNC 
Statistical Analysis Plan 
Parameter 
SI 
Conventional 
Units 
Units 
Creatinine 
~mo1/L 
mg/dL 
AST 
U/L 
ALT 
U/L 
Alkaline 
phosphatase 
U/L 
Bilirubin 
~mo1/L 
mg/dL 
total 
CPK 
U/L 
Fibrinogen 
giL 
mg/dL 
GGT 
U/L 
Albumin 
giL 
g/dL 
Uric acid 
*Male16-59 
*Female>16 
mmo1/L 
mg/dL 
*Male>60 
Cholesterol 
mmo1/L 
mg/dL 
total 
Triglycerides 
mmo1/L 
mg/dL 
TP-GDQ-WW-016-07 
Project Document Version No. 2.0 
Effective Date: 05 Sep 20 18 
PCSV 
>13.9mmo1/L and~l3.9mmo1/L at Baseline 
~150Jllllo1/L (Adults) and Baseline <150Jllllo1IL 
>3 ULN and Baseline 9 ULN 
>3 ULN and baseline 9 ULN 
>2.5 ULN and Baseline ~.5 ULN 
>2.0 ULN and Baseline ~.0 ULN 
>3.0 ULN and Baseline 9.0 ULN 
Not provided 
>2.5 ULN and Baseline ~.5 ULN 
90 giL and Baseline >30g/L 
>600 Jllll01!L and g)OO ~mo1/L at Baseline for Male; 
>500 f1ID011L and ~00 Jllll01!L at Baseline for Female 
>10.34 mmo1/L and ~10.34 mmo1/L at Baseline 
>5.7 mmo1/L and ~.7 mmo1/L at Baseline 
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