A Study to Assess the Safety and Efficacy of Nemolizumab (CD14152) in Subjects With Prurigo Nodularis (PN)
Phase: PHASE2
Conditions: Prurigo Nodularis
Sponsor: Galderma R&D

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 
CONFIDENTIAL  GALDERMA 
23-Jun-2017
Internally Approved

GALDERMA R&D 
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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23-Jun-2017
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Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
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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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Protocol No.: RD.03.SPR.115828  
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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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Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
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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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Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
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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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23-Jun-2017
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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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Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
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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 
CONFIDENTIAL  GALDERMA 
23-Jun-2017
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Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
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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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FINAL version V00 dated 30 MAY 17 
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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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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. 
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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. 
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blockade of human interleukin-31 receptor A by a humanized monoclonal antibody. Exp 
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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 
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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 
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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 
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Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
Page 79 of 86 
 
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Ständer S, Augustin M, Reich A, Blome C, Ebata T, Phan NQ, Szepietowski JC. 
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Augustin M. Dynamic Pruritus Score: Evaluation of the Validity and Reliability of a New 
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receptor 1 with aprepitant: a novel antipruritic strategy. PLoS One. 2010 
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Protocol No.: RD.03.SPR.115828  
FINAL version V00 dated 30 MAY 17 
Page 80 of 86 
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GALDERMA R&D 
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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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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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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