Clinical trial NCT04202679
Conditions: Neurodermatitis
Sponsor: Sanofi
Start date: 2020-01-16; Completion date: 2021-11-22
Enrollment: 160 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To demonstrate the efficacy of dupilumab on itch response in participants with prurigo nodularis (PN), inadequately controlled on topical prescription therapy or when those therapies are not advisable.

Secondary Objectives:

To demonstrate the efficacy of dupilumab on additional itch endpoints in participants with PN, inadequately controlled on topical prescription therapy or when those therapies are not advisable.

To demonstrate efficacy of dupilumab on skin lesions of PN. To demonstrate the improvement in health-related quality of life. To evaluate safety outcome measures. To evaluate immunogenicity of dupilumab.

Detailed description:
The duration of study for each participant included 2-4 weeks of screening period, 24 weeks of treatment period and 12 weeks of post treatment period.

Arms: arm 1: Participants received placebo matched to dupilumab 600 milligrams (mg) (loading dose), subcutaneously (SC) on Day 1 followed by placebo matched to dupilumab 300 mg once every 2 weeks (q2w) for 24 weeks added to background therapy of topical corticosteroids/topical calcineurin inhibitors (TCS/TCI) at stable dose. arm 2: Participants received dupilumab at a loading dose of 600 mg, SC on Day 1 followed by dupilumab 300 mg q2w for 24 weeks added to background therapy of TCS/TCI at stable dose.
Interventions: intervention 1: Dupilumab SAR231893 intervention 2: Placebo intervention 3: Moisturizers intervention 4: Low to medium potent topical corticosteroids intervention 5: Topical calcineurin inhibitors
Intervention descriptions: intervention 1: Pharmaceutical form:Injection solution Route of administration: Subcutaneous intervention 2: Pharmaceutical form:Injection solution Route of administration: Subcutaneous intervention 3: Pharmaceutical form:

Route of administration: Topical intervention 4: Pharmaceutical form:

Route of administration: Topical intervention 5: Pharmaceutical form:

Route of administration: Topical

Protocol documents:
Prot_000.pdf: 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: RDSD-002540 VERSION N° 3.0 (19-FEB-2019) based on TransCelerate CPT version 5 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01  
Protocol title: 
A randomized, double blind, placebo-controlled, 
multi-center, parallel group study to evaluate the 
efficacy and safety of dupilumab in patients with 
prurigo nodularis who are inadequately controlled on 
topical prescription therapies or when those therapies 
are not advisable 
Protocol number: 
EFC16460 
Amendment number: 
01 
Compound number 
(INN/Trademark): 
SAR231893/REGN668 
dupilumab/Dupixent 
Study phase: 
Phase 3 
Short title: 
Study of dupilumab for the treatment of patients with 
prurigo nodularis, inadequately controlled on topical 
prescription therapies or when those therapies are not 
advisable 
LIBERTY-PN PRIME2  
Sponsor name: 
  
Legal registered 
address: 
  
Monitoring Team’s 
Representative Name 
and Contact Information 
  
Regulatory agency identifier number(s): 
IND: 
IND107969 
EudraCT: 
2019-003801-90 
NCT: 
NCT04202679 
WHO: 
U1111-1241-8174 
Other: 
Not applicable 
Approval Date: 
20-May-2020 
Total number of pages: 106 
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Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 01  All 
20 May 2020, version 1 (electronic 1.0) 
Original Protocol 
 
30 October 2019, version 1 (electronic 2.0) 
Amended protocol 01 (20 May 2020) 
This amended protocol (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
The proportion of participants with Investigator’s Global Assessment 0 or 1 score for PN-Stage 
(IGA PN-S) at Week 24 has been indicated as an additional key secondary endpoint. This is to 
include a lesion-related key secondary endpoint based on the recommendations from health 
authorities. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis: Objectives and endpoints 
3 Objectives and Endpoints 
3.1 Appropriateness of measurements 
9.4.1 Efficacy analyses 
To add “proportion of participants with 
Investigator’s Global Assessment 0 or 
1 score for PN-Stage (IGA PN-S) at 
Week 24” as another key secondary endpoint 
To include a lesion-related key 
secondary endpoint according to 
the health authority’s 
recommendations 
1.3 Schedule of activities  
To correct rescue medication use start date 
to Day 1 (Visit 2) 
To correct an error on the rescue 
medication use 
3 Objectives and Endpoints 
To remove the endpoint “Change from 
baseline in PAS total score at Week 4, 
Week 8, Week 12, and Week 24” in the 
exploratory endpoint and modify the 
exploratory endpoint regarding the healed 
lesions from PAS questionnaire analysis 
To clarify the analysis on efficacy 
evaluation of dupilumab on skin 
lesions using a modified prurigo 
activity score (PAS) 5-item 
questionnaire 
1.1 Synopsis (Objectives and 
endpoints) 
3 Objectives and Endpoints 
9.4.1 Efficacy analyses 
To break out the secondary endpoints with 
multiple measuring timepoints into individual 
endpoints 
To clearly define the timepoints of 
each endpoint according to health 
authority’s recommendation 
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Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion Criteria 
Change of I05 “medium-to-high potency TCS” 
to “medium-to-superpotent TCS” 
To enroll patients on medium to 
superpotent topical corticosteroids 
(TCS) according to health 
authority’s recommendations 
1.1 Synopsis: Noninvestigational 
medicinal products 
5.1 Inclusion Criteria 
6.1.1 Noninvestigational medicinal 
products 
Change of topical emollient (moisturizer) 
application in Synopsis and I06 from “once or 
twice daily for at least the 7 consecutive days 
immediately before Day 1” to “once or twice 
daily for at least 5 out of the 7 consecutive 
days immediately before Day 1” 
To allow some flexibility in 
adherence to the moisturizer usage 
by the patient during screening 
5.2 Exclusion Criteria 
To update E04 to “within 6 months before the 
screening visit, or documented diagnosis of 
moderate to severe AD from screening visit 
to randomization visit” 
To specify the exclusion criteria of 
patients with documented atopic 
dermatitis severity moderate to 
severe  
5.2 Exclusion Criteria 
1.3 Schedule of Activities 
10.2 Appendix 2: Clinical laboratory 
tests 
To update E05 “hemoglobin A1c ≥9%” to 
“hemoglobin A1c ≥9% according to the 
laboratory results within 3 months before 
screening visit” 
To clarify the exclusion criteria for 
patients with diabetes history is 
according to the hemoglobin A1c 
results within 3 months before 
screening visit  
5.2 Exclusion Criteria 
To update E10 from “within 2 weeks before 
the screening visit” to “within 2 weeks before 
screening visit and during the screening 
period” 
To exclude the patients with active 
chronic or acute infection (except 
HIV infection) requiring treatment 
with systemic antibiotics, antivirals, 
antiprotozoals, or antifungals 
during screening period 
5.2 Exclusion Criteria 
To modify E18 to allow prurigo nodularis (PN) 
patients to use stable dose of some 
anti-depressant medicines for at least 
3 months prior to screening 
To enroll PN patients with stable 
dose of anti-depressant 
5.2 Exclusion Criteria 
To add menthol and polidocanol as one of 
the moisturizer additives in E20 
To clarify that the patients who 
initiate treatment with moisturizers 
containing menthol and polidocanol 
will be excluded 
5.2 Exclusion Criteria 
6.1.1 Noninvestigational medicinal 
products 
To add to E22 a stable regimen of TCS/TCI 
"maintain same medicine, same dose from 
2 weeks prior to screening visit" 
To clarify the definition of stable 
regimen of TCS/TCI 
5.2 Exclusion Criteria 
To add “treated in the past with dupilumab” in 
E25 
To exclude the patients previously 
treated with dupilumab 
5.2 Exclusion Criteria 
To describe the participants with or without 
history of HIV infection in E26 
To clarify the exclusion criteria 
about HIV infection and HIV viral 
load, and that the CD4+ test will 
only be done in the patient with 
existing HIV history 
5.2 Exclusion Criteria 
1.3 Schedule of Activities: footnote c 
10.2 Appendix 2: Clinical laboratory 
tests: Table 9 footnote c 
To clarify to E27 the positive HBc Ab and 
HCV Ab confirmation method 
To clarify that the positive HBc Ab 
and HCV Ab will be confirmed by 
HBV DNA and HCV RNA, 
respectively 
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Section # and Name 
Description of Change 
Brief Rationale 
6.1.1 Noninvestigational medicinal 
products 
To clarify the use of noninvestigational 
medicinal products  
To prohibit topical medications that 
have anti-itch properties 
6.5 Concomitant Therapy 
To clarify the permitted and prohibited 
concomitant medications 
To clarify the requirement of 
antihistamine used concomitantly, 
and antidepressant dose should 
also remain stable (can be reduced 
or discontinued if medically 
indicated), but should not be 
initiated or increased throughout 
the study 
6.5.1 Rescue Medicine 
To clarify the use of rescue medicine 
To add criteria for rescue therapy 
6.5.1 Rescue Medicine 
To add that a pre-specified algorithm will be 
used to classify rescue and a blinded review 
of all post-baseline medications, based on 
medical judgment, will be performed to 
adjudicate rescue 
To clarify the review of adjudicate 
rescue treatment 
7.1.1 Definitive discontinuation 
7.1.2 Temporary discontinuation 
To clarify the treatment discontinuation 
criteria regarding the missing doses 
To clarify that patients with missing 
more than 2 consecutive IMP 
doses should be permanently 
withdrawn from the study treatment 
8 Study assessments and procedures 
The following wording was added: “In light of 
the public health emergency related to 
Coronavirus disease 2019 (COVID-19) (or in 
case of any other pandemic requiring public 
health emergency), the continuity of clinical 
study conduct and oversight may require 
implementation of temporary or alternative 
mechanisms eg, phone contact, virtual visits, 
online meetings, use of local clinic or 
laboratory locations, and home visits by skilled 
staff. Implementation of such mechanisms 
may differ country by country, depending on 
country regulations and local business 
continuity plans. Additionally, no waivers to 
deviate from protocol enrollment criteria due to 
COVID-19 (or any other pandemic) will be 
granted. All temporary mechanisms utilized, 
and deviations from planned study procedures 
are to be documented as being related to 
COVID-19 (or any other pandemic) and will 
remain in effect only for the duration of the 
public health emergency.” 
To describe alternative temporary 
mechanism that can be 
implemented in the study conduct 
in case of pandemic requiring 
public health emergency 
eg, COVID-19 
8.3 Adverse events and serious 
adverse events 
To update the adverse event of special 
interest (AESI) “any type of conjunctivitis or 
blepharitis (severe or serious)” to “any severe 
type of conjunctivitis or blepharitis” 
To update the AESI list to 
harmonize with the most recent list 
9.4.1 Efficacy analyses 
To add the sensitivity analysis for secondary 
endpoints information, and to separate key 
secondary endpoints in a different row 
To evaluate the robustness of the 
missing data imputation assumption 
by sensitivity analyses, and to clarify 
the endpoints analyses 
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Section # and Name 
Description of Change 
Brief Rationale 
9.4.1 Efficacy analyses 
1.1 Synopsis (Statistical considerations) 
To add the covariate “baseline anti-
depressant use (yes or no)” to primary and 
secondary endpoint analyses 
To adjust for potential impact of 
anti-depressant use on the 
treatment effect in primary and 
secondary efficacy analyses 
9.4.3 Other analyses 
The following wording was added: “Data 
collected regarding the impact of the 
COVID-19 or other pandemics, on the 
patients will be summarized (eg, 
discontinuation due to COVID-19). Any 
additional analyses and methods required to 
investigate the impact of COVID-19 or other 
pandemics requiring public health emergency 
on the efficacy (eg, missing data due to 
COVID-19) and safety will be detailed in the 
SAP”. 
To describe alternative temporary 
mechanism that can be 
implemented in the study conduct 
in case of pandemic requiring 
public health emergency 
eg COVID-19 
9.5.2 Unblinding plan 
To update the unblinding plan to “Unblinding 
plan is not applicable for this study” 
Unblinding plan is not applicable for 
this study. 
1.3 Schedule of activities 
10.2 Appendix 2: Clinical laboratory 
tests 
To remove the description about false 
positivity   
To clarify that the testing will be 
performed if considered that the 
patient is immune after a natural 
infection 
1.3 Schedule of activities 
10.2 Appendix 2: Clinical laboratory 
tests 
To add “tetranor PGDM” into urinalysis 
Tetranor PGDM will be tested in 
urinalysis since it is a Type 2 
inflammation biomarker.   
10.3 Appendix 3: Adverse events: 
Definitions and procedures for 
recording, evaluating, follow-up, and 
reporting 
To update the AE and SAE recording 
To minimize the transfer of 
personal data to be compliant with 
the General Data Protection 
Regulation (GDPR) and harmonize 
processes across countries. 
10.4 Appendix 4: Contraceptive 
guidance and collection of pregnancy 
information 
To remove the “Acceptable methods” in 
contraception guidance 
To clarify the contraceptive 
methods can be used during the 
study. 
10.7.2 Investigator’s global assessment 
of prurigo nodularis (IGA PN) 
10.7.3 Prurigo activity score (PAS) 
To add the copyright information 
To add copyright provided by the 
author for the IGA PN, PAS 
baseline and PAS Follow-up 
versions 
 
Minor editorial and formatting changes were 
done throughout the document. 
To correct minor errors or 
formatting issues.  
 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 01 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 6 
LIST OF TABLES ......................................................................................................................................... 10 
1 
PROTOCOL SUMMARY ............................................................................................................... 11 
1.1 
SYNOPSIS ..................................................................................................................................... 11 
1.2 
SCHEMA ........................................................................................................................................ 17 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 18 
2 
INTRODUCTION ............................................................................................................................ 23 
2.1 
STUDY RATIONALE...................................................................................................................... 23 
2.2 
BACKGROUND ............................................................................................................................. 23 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 25 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 28 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 29 
4 
STUDY DESIGN ............................................................................................................................ 31 
4.1 
OVERALL DESIGN ........................................................................................................................ 31 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 31 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 32 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 32 
5 
STUDY POPULATION .................................................................................................................. 33 
5.1 
INCLUSION CRITERIA .................................................................................................................. 33 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 35 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 39 
5.4 
SCREEN FAILURES...................................................................................................................... 39 
6 
STUDY INTERVENTION ............................................................................................................... 40 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 40 
6.1.1 
Noninvestigational medicinal products........................................................................................... 41 
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6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 42 
6.2.1 
Storage and handling ..................................................................................................................... 42 
6.2.2 
Responsibilities .............................................................................................................................. 42 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 42 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 44 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 44 
6.5.1 
Rescue medicine ............................................................................................................................ 45 
6.6 
DOSE MODIFICATION .................................................................................................................. 46 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 46 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 47 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 47 
7.1.1 
Definitive discontinuation ............................................................................................................... 47 
7.1.2 
Temporary discontinuation ............................................................................................................. 48 
7.1.2.1 
Rechallenge ................................................................................................................................... 49 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 49 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 50 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 51 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 51 
8.1.1 
Worst-itch numeric rating scale ...................................................................................................... 52 
8.1.2 
Investigator’s global assessment for prurigo nodularis .................................................................. 52 
8.1.3 
Prurigo activity score ...................................................................................................................... 52 
8.1.4 
Dermatology life quality index ........................................................................................................ 53 
8.1.5 
Pain and sleep numeric rating scales ............................................................................................ 53 
8.1.6 
Hospital anxiety and depression scale........................................................................................... 53 
8.1.7 
Patient Global Impression of Change of disease and Patient Global Impression of Severity ....... 54 
8.1.8 
Euroqol 5 dimensions questionnaire .............................................................................................. 54 
8.1.9 
Missed school/work days ............................................................................................................... 54 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 55 
8.2.1 
Physical examinations ................................................................................................................... 55 
8.2.2 
Vital signs ....................................................................................................................................... 55 
8.2.3 
Electrocardiograms ........................................................................................................................ 55 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 55 
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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 56 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 57 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 58 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 58 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 58 
8.3.5 
Pregnancy ...................................................................................................................................... 58 
8.3.6 
Guidelines for reporting product complaints .................................................................................. 59 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 59 
8.5 
PHARMACOKINETICS .................................................................................................................. 59 
8.5.1 
Systemic drug concentration and antidrug antibodies ................................................................... 59 
8.5.1.1 
Sampling time ................................................................................................................................ 59 
8.5.1.2 
Handling procedures ...................................................................................................................... 60 
8.5.1.3 
Bioanalytic method ......................................................................................................................... 60 
8.6 
PHARMACODYNAMICS ............................................................................................................... 61 
8.7 
GENETICS ..................................................................................................................................... 61 
8.8 
BIOMARKERS ............................................................................................................................... 61 
8.9 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ........................................... 61 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 62 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 62 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 62 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 63 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 63 
9.4.1 
Efficacy analyses ........................................................................................................................... 63 
9.4.2 
Safety analyses .............................................................................................................................. 65 
9.4.3 
Other analyses ............................................................................................................................... 66 
9.5 
INTERIM ANALYSES  ................................................................................................................... 66 
9.5.1 
Data Monitoring Committee (DMC) ................................................................................................ 67 
9.5.2 
Unblinding plan .............................................................................................................................. 67 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 68 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 68 
10.1.1 
Regulatory and Ethical Considerations .......................................................................................... 68 
10.1.2 
Financial disclosure........................................................................................................................ 68 
10.1.3 
Informed consent process .............................................................................................................. 69 
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10.1.4 
Data protection ............................................................................................................................... 69 
10.1.5 
Committees structure ..................................................................................................................... 70 
10.1.6 
Dissemination of clinical study data ............................................................................................... 70 
10.1.7 
Data quality assurance .................................................................................................................. 71 
10.1.8 
Source documents ......................................................................................................................... 71 
10.1.9 
Study and site closure .................................................................................................................... 72 
10.1.10 Publication policy ........................................................................................................................... 72 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 73 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 75 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 79 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 81 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 83 
10.7 
APPENDIX 7: CLINICIANS-REPORTED OUTCOMES AND PATIENT-REPORTED 
OUTCOMES .................................................................................................................................. 86 
10.7.1 
Worst itch numeric rating scale (WI-NRS) ..................................................................................... 86 
10.7.2 
Investigator’s global assessment of prurigo nodularis (IGA PN) ................................................... 87 
10.7.3 
Prurigo activity score (PAS) ........................................................................................................... 88 
10.7.4 
Dermatology life quality index (DLQI) ............................................................................................ 90 
10.7.5 
Hospital anxiety and depression scale (HADS) ............................................................................. 91 
10.7.6 
EQ-5D-5L ....................................................................................................................................... 92 
10.7.7 
Pain numeric rating scale ............................................................................................................... 93 
10.7.8 
Sleep numeric rating scale ............................................................................................................. 94 
10.7.9 
Patient Global Impression of Change of disease (PGIC) .............................................................. 94 
10.7.10 Patient Global Impression of Severity (PGIS) ................................................................................ 95 
10.7.11 Missed school/work days ............................................................................................................... 96 
10.8 
APPENDIX 8: DEFINITION OF ANAPHYLAXIS ......................................................................... 100 
10.9 
APPENDIX 9: LIST OF OPPORTUNISTIC INFECTIONS........................................................... 100 
10.10 
APPENDIX 10: COUNTRY-SPECIFIC REQUIREMENTS .......................................................... 101 
10.11 
APPENDIX 11: ABBREVIATIONS ............................................................................................... 101 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY .............................................................. 103 
11 
REFERENCES ............................................................................................................................. 104 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 28 
Table 2 - Overview of study interventions administered ............................................................................... 40 
Table 3 - Summary of handling procedures .................................................................................................. 60 
Table 4 - Summary of bioanalytical methods for functional dupilumab and anti-dupilumab antibodies ....... 60 
Table 5 - Populations for analyses ................................................................................................................ 63 
Table 6 - Efficacy analyses ........................................................................................................................... 64 
Table 7 - Safety analyses .............................................................................................................................. 66 
Table 8 - Other analyses ............................................................................................................................... 66 
Table 9 - Protocol-required laboratory assessments .................................................................................... 73 
 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A randomized, double blind, placebo-controlled, multi-center, parallel 
group study to evaluate the efficacy and safety of dupilumab in patients with 
prurigo nodularis who are inadequately controlled on topical prescription 
therapies or when those therapies are not advisable  
Short title: 
Study of dupilumab for the treatment of patients with prurigo 
nodularis, inadequately controlled on topical prescription therapies or when those 
therapies are not advisable 
LIBERTY-PN PRIME2 (PRurigo Nodularis Itch Minimization Evaluation 2) 
Rationale: 
Prurigo nodularis (PN) is a skin disease characterized by multiple, intensely itchy skin eruptions 
in symmetrically distributed areas of the extremities (1). The main symptom is prolonged, 
repetitive and uncontrollable rubbing, scratching and uncontrollable itching which leads to 
hyperkeratotic eroding papules and nodules on the skin. It is difficult to treat and entails a high 
disease burden. Approximately 50% of patients have either past or current history of atopic 
dermatitis (AD) or other atopic disorders (2). While case reports suggest that dupilumab may 
successfully treat patients with PN regardless of a preexisting atopic background (3, 4, 5, 6, 7), it 
remains unclear to what extent Type 2 cytokines play a role in the pathogenesis in those PN 
lesions not associated with atopy (8). 
There are no United States (US) Food and Drug Administration (FDA) or European Medicines 
Agency (EMA) approved targeted therapies indicated for the treatment of PN, whether atopic or 
non-atopic forms. Topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI) are often 
used initially. While there is a mechanistic rationale for their use, no rigorous clinical studies 
confirming their efficacy were identified.  
Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin (IL)-4 and IL-13 
signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor 
complexes. Dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 
signaling through the Type II receptor.  
Dupilumab has shown clinical efficacy in multiple diseases with underlying Type 2 inflammation 
such as AD, asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), and eosinophilic 
esophagitis (EoE).  
Recently, case series were published that suggest dupilumab may also be effective in the 
treatment of PN (3, 4, 5, 6, 7).  
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Type 2 cytokine involvement is implicated to some extent in all forms of PN. It is postulated that 
dupilumab may play a fundamental role in pruritus based upon its ability to block IL4R activity at 
the level of the sensory dorsal root ganglion (9). The present protocol will evaluate the efficacy 
and safety of dupilumab in PN.  
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To demonstrate the efficacy of 
dupilumab on itch response in 
patients with PN, inadequately 
controlled on topical prescription 
therapies or when those therapies 
are not advisable.  
 
• 
Proportion of participants with improvement (reduction) in worst-itch 
numeric rating scale (WI-NRS) by ≥4 from baseline to Week 12. 
Secondary 
• 
To demonstrate the efficacy of 
dupilumab on additional itch 
endpoints in patients with PN, 
inadequately controlled on topical 
prescription therapies or when 
those therapies are not advisable.  
• 
Proportion of participants with improvement (reduction) in WI-NRS 
by ≥4 from baseline to Week 24 [Key secondary endpoint]. 
• 
Time to onset of effect on pruritus as measured by proportion of 
participants with an improvement (reduction) in WI-NRS by ≥4 from 
baseline during the 24-week treatment period.  
• 
Change from baseline in WI-NRS at Week 24. 
• 
Change from baseline in WI-NRS at Week 12. 
• 
Percent change from baseline in WI-NRS at Week 24. 
• 
Percent change from baseline in WI-NRS at Week 12. 
• 
Percent change from baseline in WI-NRS at Week 4. 
• 
Percent change from baseline in WI-NRS at Week 2. 
• 
Percent change from baseline in WI-NRS over time until Week 24. 
• 
Proportion of participants with WI-NRS reduction ≥4 at Week 4. 
• 
Proportion of participants with WI-NRS reduction ≥4 over time until 
Week 24. 
• 
Onset of action in change from baseline in WI-NRS (first p <0.05 
difference from placebo in the daily WI-NRS that remains significant 
at subsequent measurements) until Week 12. 
• 
To demonstrate efficacy of 
dupilumab on skin lesions of PN.  
• 
Proportion of participants with Investigator’s Global Assessment 0 or 
1 score for PN-Stage (IGA PN-S) at Week 24 [Key secondary 
endpoint].  
• 
Proportion of participants with IGA PN-S 0 or 1 score at Week 12. 
• 
Proportion of participants with IGA PN-S 0 or 1 score at Week 8.  
• 
Proportion of participants with IGA PN-S 0 or 1 score at Week 4. 
• 
Change from baseline in IGA PN-S score at Week 24. 
• 
Change from baseline in IGA PN-S score at Week 12. 
• 
Change from baseline in IGA PN-S score at Week 8. 
• 
Change from baseline in IGA PN-S score at Week 4. 
• 
Proportion of participants with Investigator’s Global Assessment 0 or 
1 score for PN-Activity (IGA PN-A) at Week 24. 
• 
Proportion of participants with IGA PN-A 0 or 1 score at Week 12. 
• 
Proportion of participants with IGA PN-A 0 or 1 score at Week 8. 
• 
Proportion of participants with IGA PN-A 0 or 1 score at Week 4. 
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Objectives 
Endpoints 
• 
To demonstrate the improvement in 
health-related quality of life 
(HRQoL).  
• 
Change from baseline in HRQoL, as measured by Dermatology Life 
Quality Index (DLQI) to Week 24. 
• 
Change from baseline in HRQoL, as measured by DLQI to 
Week 12. 
• 
To evaluate safety outcome 
measures.  
• 
Percentage of participants experiencing treatment-emergent 
adverse events (TEAEs) or serious adverse events (SAEs) from 
baseline through Week 24. 
 
• 
To evaluate immunogenicity of 
dupilumab.  
• 
Incidence of treatment-emergent antidrug antibodies (ADA) against 
dupilumab over time. 
 
Overall design: 
This study is a multi-center, 24-week treatment, parallel, double-blind, randomized, 
placebo-controlled study to evaluate the use of dupilumab in patients with PN inadequately 
controlled on topical prescription therapies or when those therapies are not advisable. The study 
will assess the effect of dupilumab on itch improvement as well as its effect on PN lesions, on 
patients’ HRQoL, anxiety and depression, sleep quality and skin pain, and overall health status. 
Disclosure Statement: This is a Parallel, Treatment study, with 2 arms, that is blinded/masked 
for participants and investigators. 
Number of participants: 
Approximately 150 participants will be randomized 1:1. This corresponds to approximately 
75 participants who will be randomly assigned to each intervention arm.  
Intervention groups and duration: 
Participants who satisfy the inclusion and exclusion criteria will be randomized (1:1) to one of the 
following investigational medicinal product (IMP) treatment groups:  
• Dupilumab 300 mg  
• Matched placebo  
Duration of study period (per participant) 
• Screening period (2-4 weeks) 
• Randomized IMP intervention period (24 weeks) 
• Follow-up period (12 weeks) 
Study interventions 
Investigational medicinal product:  
Dupilumab 300 mg and placebo matching dupilumab 300 mg supplied in prefilled syringes that 
are visually indistinguishable. 
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Dupilumab 
• Formulation: dupilumab 300 mg: a 150 mg/mL dupilumab solution in a pre-filled syringe 
to deliver 300 mg in a 2 mL injection. 
• Route of administration: subcutaneous (SC) injection. 
• Dose regimen: 300 mg every 2 weeks (Q2W) after an initial loading dose of 600 mg 
(2 injections of 300 mg) on Day 1. 
Placebo 
• Formulation: identical formulation to the active 300 mg formulation without dupilumab, in 
a pre-filled syringe to deliver placebo in a 2 mL injection. 
• Route of administration: SC injection. 
• Dose regimen: 1 injection Q2W after an initial loading dose (2 injections) on Day 1. 
Noninvestigational medicinal products 
Participants will be required to apply moisturizers (emollients) once or twice daily for at least 
5 out of the 7 consecutive days immediately before Day 1 and continue until Week 36. 
If participants are on a stable regimen of low to medium potency TCS or TCI at the screening 
visit, they can continue their topical steroid application once daily without tapering from 
Screening to Week 24. If specific lesions resolve, the participant can stop applying steroids to 
those sites but are permitted to continue applying to persistent lesions. If participants are on stable 
regimens of high potency or superpotent steroids, participants should decrease potency to medium 
potency TCS and continue to apply daily from screening to Week 24. Occlusion is not allowed 
from Screening to Week 24. 
Participants can be rescued with high potency or superpotent TCS/TCI as needed throughout the 
study. 
Post-trial access to study medication 
The sponsor does not plan to provide post-trial access to the study medication. 
Statistical considerations: 
• Randomization 
- 
The participants will be randomized to dupilumab or placebo in 1:1 ratio with 
stratification factors of documented history of atopy (atopic or non-atopic), stable use 
of TCS/TCI (yes or no), and country/territory code. Number of participants with active 
mild AD upon study entry will represent up to 10% of the atopic participants. Both the 
atopic and the non-atopic PN population will be capped at 60% of the total enrolled 
population. 
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• Sample size calculation 
- 
The primary endpoint is the proportion of participants with a WI-NRS reduction of 
≥4 from baseline to Week 12. Assuming a response rate of 
 in placebo 
and dupilumab respectively, 56 participants/arm will provide 90% power to detect the 
difference of 
 between dupilumab and placebo with Fisher exact test at 2-sided 
level of 0.05. Assuming 15% drop out during the 12 weeks of treatment, the target is to 
randomize 75 participants/arm to allow for up to 10% of atopic patients having active 
mild AD upon study entry. 
• Primary analysis 
- 
The analysis population for the efficacy endpoints will be the intent-to-treat (ITT) 
population defined as all randomized participants analyzed according to the treatment 
group allocated by randomization regardless if treatment kit is used or not. 
- 
The primary analysis on WI-NRS reduction ≥4 at Week 12 will be conducted by using 
Cochran-Mantel-Haenszel (CMH) test stratifying by stratification factors (documented 
history of atopy [atopic or non-atopic], stable use of TCS/TCI [yes or no], and region 
[countries combined]) and covariate of baseline anti-depressant use (yes or no). For 
participants discontinuing the study treatment before Week 12, their off-study 
treatment values measured up to Week 12 will be included in the analysis. Participants 
taking selected prohibited medications and/or rescue medications (details of selection 
will be specified in the statistical analysis plan [SAP]) prior to Week 12 or have 
missing data at Week 12 will be considered non-responders.  
- 
Sensitivity analyses using alternative methods will be performed to handle missing 
data and/or data collected after participants taking selected prohibited medications 
and/or rescue medications. A subgroup analysis will be performed excluding 
participants with a current diagnosis of AD. More details of the sensitivity and 
subgroup analyses will be specified in the SAP. 
• Analysis of secondary endpoints 
- 
Secondary efficacy endpoints that measure binary responses will be analyzed in the 
same fashion as the primary endpoint. 
- 
Time-to-event secondary efficacy endpoint will be analyzed using the Cox 
proportional hazards model, including treatment, stratification factors (countries 
combined to region), and covariate of baseline anti-depressant use (yes or no). The 
hazards ratio, its 95% confidence interval and p-value will be reported. Kaplan-Meier 
curves will be also provided. 
- 
Continuous secondary efficacy endpoints will be analyzed using a hybrid method of 
the worst observation carried forward (WOCF) and multiple imputations. Data of 
participants taking selected prohibited medications and/or rescue medications will be 
set to missing after the medication usage, and the worst postbaseline value on or before 
the time of the medication usage will be used to impute missing endpoint value (for 
participants whose postbaseline values are all missing, the baseline will be used to 
impute). Participants who discontinue the treatment prematurely are encouraged to 
follow the planned clinical visits and in those participants who did not take the selected 
prohibited medications and/or rescue medications, all data collected after treatment 
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discontinuation will be used in the analysis. For these participants, missing data may 
still happen despite all efforts have been tried to collect the data after treatment 
discontinuation. For participants who discontinue due to lack of efficacy, all data 
collected after discontinuation will be used in the analysis, and a WOCF approach will 
be used to impute missing data if needed. For participants who discontinued not due to 
lack of efficacy, a multiple imputation approach will be used to impute missing 
endpoint value, and this multiple imputation will use all participants excluding 
participants who have taken the selected prohibited medications and/or rescue 
medications prior to timepoint of endpoint of interest and excluding patients who 
discontinue due to lack of efficacy. Each of the imputed complete data will be 
analyzed by fitting an analysis of covariance (ANCOVA) model with treatment group, 
stratification factors (countries combined into region), baseline anti-depressant use 
(yes or no),  and relevant baseline measurement as covariates in the model. Statistical 
inference obtained from all imputed data will be combined using Rubin’s rule. 
- 
The safety variables will be summarized using descriptive statistics. 
- 
Antidrug antibodies variables including treatment-emergent ADA will be summarized 
using descriptive statistics by treatment group. 
• Multiplicity considerations 
- 
The multiplicity procedure is proposed to control the overall Type-I error rate for 
testing the primary endpoint and the key secondary endpoints. Detailed hierarchical 
testing procedure will be defined in the study SAP. The study is considered positive 
when the primary endpoint achieves statistical significance. 
• Planned database lock date 
- 
A primary database lock will be performed when all randomized participants have 
completed their 24-week treatment phase. 
- 
The database will be updated at the end of the study for all participants to include the 
post-treatment follow-up information and updates for the events previously ongoing at 
the time of the primary lock.  
• Unblinding plan 
- 
The unblinding plan will be detailed in the SAP or in a separate unblinding plan. 
Data Monitoring Committee: No
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1.2 
SCHEMA  
 
 
EOS: end of study; EOT: end of treatment; PN: prurigo nodularis; Q2W: every 2 weeks; R: randomization; SC: subcutaneous; TCI: topical calcineurin inhibitors; TCS: topical corticosteroids. 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
Procedure 
Screening  
(2 to 4 weeks 
before Day 1) 
Intervention period (Weeks) 
Follow-up 
(12 weeks) 
Notes 
0  
(Day 1) 
4 
8 
12 
24 
Visit 
1 
2a 
3 
4 
5 
6b 
(EOT) 
7  
(EOS) 
Visit window: ±3 days for Visits 3, 4, 5, 6, and 7. 
Screening and baseline 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Separate consent to be obtained for optional procedures 
(DNA and RNA sampling, and serum/plasma sampling for 
archival; HIV test if specific consent locally required). 
Medical history 
X 
 
 
 
 
 
 
 
Prior and concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication will be collected throughout the 
study. 
Demography 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
Hepatitisc, HIV serology, TB test 
X 
 
 
 
 
 
 
HBs Ag, HBs Ab, HBc Ab, HCV Ab, HIV screen (Anti-HIV-1 
and HIV-2 antibodies), TB test (performed locally if required 
and results noted in the eCRF).  
Randomization  
 
X 
 
 
 
 
 
 
Study interventiond 
 
 
 
 
 
Dispense or download e-diary 
X 
X 
X 
X 
X 
X 
X 
Device will be dispensed at Screening (including instructions 
for use). At EOS, the e-diary will be downloaded and 
returned to the site.  
Participant e-diary training 
X 
X 
 
 
 
 
 
 
Call IVRS/IWRS 
X 
X 
X 
X 
X 
X 
X 
At screening visit, IVRS/IWRS will be called after medical 
history check. 
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Procedure 
Screening  
(2 to 4 weeks 
before Day 1) 
Intervention period (Weeks) 
Follow-up 
(12 weeks) 
Notes 
0  
(Day 1) 
4 
8 
12 
24 
Visit 
1 
2a 
3 
4 
5 
6b 
(EOT) 
7  
(EOS) 
Visit window: ±3 days for Visits 3, 4, 5, 6, and 7. 
IMP administration 
 
X 
X 
X 
X 
 
 
IMP administration Q2W (±3 days) from Week 0 until 
Week 22. Between visits, the participants will self-inject IMP 
at home or may choose to have injections administered at 
home by a caregiver or at the study site. 
Safetyd 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
X 
X 
Including skin (full body skin exam), nasal cavities, eyes, 
ears, respiratory, cardiovascular, gastrointestinal, 
neurological, lymphatic, and musculoskeletal systems. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Including SBP and DBP (mmHg), pulse rate (beats per 
minute), body temperature (°C), and respiratory rate. Body 
weight will be recorded at Visits 1, 6, and 7 only. Height will 
be recorded at Visit 1 only. 
12-lead ECG 
X 
 
 
 
 
X 
 
Locally collected and read. 
Hematology, biochemistrye 
X 
X 
X 
X 
X 
X 
X 
Including hemoglobin, hematocrit, platelet count, total WBC 
count, differential count, total RBC count, creatinine, BUN, 
glucose, lactate dehydrogenase, uric acid, total cholesterol, 
total protein, albumin, total bilirubin, ALT, AST, alkaline 
phosphatase, electrolytes (sodium, potassium, chloride), 
bicarbonate, creatine phosphokinase, and hemoglobin A1c 
(only for diabetic patients without hemoglobin A1c laboratory 
results within 3 months before screening visit). 
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Procedure 
Screening  
(2 to 4 weeks 
before Day 1) 
Intervention period (Weeks) 
Follow-up 
(12 weeks) 
Notes 
0  
(Day 1) 
4 
8 
12 
24 
Visit 
1 
2a 
3 
4 
5 
6b 
(EOT) 
7  
(EOS) 
Visit window: ±3 days for Visits 3, 4, 5, 6, and 7. 
Urinalysis 
X 
X 
X 
X 
X 
X 
 
Dipstick analysis including specific gravity, pH, glucose, 
ketones, blood, protein, nitrite, leukocyte esterase, 
urobilinogen and bilirubin. If positive for protein and/or red 
blood cells, microscopic analysis will be performed by the 
central laboratory. Creatinine, leukotriene and tetranor 
PGDM will be tested by the central laboratory. Urine sample 
has to be collected at the same time (±1 hour) established at 
V2 in a given patient, if possible. 
CD4 T cell count and HIV viral 
load 
X 
 
 
 
 
X 
 
For participants with HIV history only. 
Pregnancy test (WOCBP only)g 
Serum 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
In between visit urine pregnancy tests will be performed at 
home (Weeks 16, 20, 28, 32). 
AE reporting, including SAEs  
X 
X 
X 
X 
X 
X 
X 
 
Rescue medication use 
 
--------------------------------------------------------------------------------------→ 
 
PK and ADAd, f 
 
 
 
 
 
Serum PK samples for 
dupilumab concentration 
 
X 
X 
X 
X 
X 
X 
 
Anti-dupilumab antibody 
 
X 
 
 
X 
X 
X 
 
Biomarkersd 
 
 
 
 
 
Total serum IgE 
 
X 
X 
X 
X 
X 
X 
 
Optional serum/plasma 
for archival samples 
 
X 
X 
X 
X 
X 
X 
Archive serum and plasma samples will be collected and 
stored for possible future analysis of potential biomarkers of 
drug response, disease activity, safety, and the Type 2 
inflammation pathway. 
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Procedure 
Screening  
(2 to 4 weeks 
before Day 1) 
Intervention period (Weeks) 
Follow-up 
(12 weeks) 
Notes 
0  
(Day 1) 
4 
8 
12 
24 
Visit 
1 
2a 
3 
4 
5 
6b 
(EOT) 
7  
(EOS) 
Visit window: ±3 days for Visits 3, 4, 5, 6, and 7. 
Optional DNA (whole blood) 
sampleh 
 
X 
 
 
 
 
 
 
Optional RNA (whole blood) 
sampleh 
 
X 
 
 
 
X 
 
 
Efficacyd 
 
 
 
 
 
WI-NRS 
 
 
 
 
 
 
 
 
Pain-NRS 
NRS: once a day from Screening to EOS 
To be recorded once a day in e-diary. 
Sleep-NRS 
 
 
 
 
 
 
 
 
DLQI 
 
X 
X 
X 
X 
X 
X 
 
HADS 
 
X 
 
 
X 
X 
X 
 
EQ-5D-5L 
 
X 
 
 
X 
X 
X 
 
PGIS 
X 
X 
X 
X 
X 
X 
 
 
PGIC 
 
 
X 
X 
X 
X 
 
Entered by participant during site visit on a tablet provided to 
the site. 
Missed school/work days 
(baseline version) 
 
X 
 
 
 
 
 
 
Missed school/work days 
(postbaseline version) 
 
 
 
 
X 
X 
X 
Modified PAS (screening-
baseline version) 
X 
X 
 
 
 
 
 
Investigator’s assessment to be entered on a tablet provided 
to the site. 
Modified PAS (follow-up version) 
 
 
X 
X 
X 
X 
X 
IGA PN-A and IGA PN-S 
 
X 
X 
X 
X 
X 
X 
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a All assessments at Visit 2 (Day 1) are to be conducted pre-IMP dose with the exception of the assessment of local tolerability of SC injections. 
b Participants who discontinue the study treatment prematurely (prior to completing the 24-week treatment period) will perform the EOT assessments at the time of discontinuation to assure a complete clinical 
assessment in close temporal proximity to the premature termination of study treatment. In addition, to allow assessment of participant outcomes over the stipulated study period, participants will be asked and 
encouraged to complete all remaining study visits and participate in all assessments according to the visit schedule. 
c In case of results showing HBs Ag (negative) and HBc Ab (positive), an HBV DNA testing will be performed and should be confirmed negative prior to randomization. In case of results showing HCV Ab (positive), 
HCV RNA testing will be performed and should be confirmed negative prior to randomization. 
d Assessments/procedures should be conducted in the following order: PRO, investigator assessments, safety and laboratory assessments (including sample collection for ADA, PK, biomarker, and optional DNA 
and RNA), and administration of IMP. 
e Refer to Section 10.2 and central lab manual for collection details. 
f 
PK and ADA samples to be collected prior to the administration of the drug. In the event of any SAE, any AE of severe injection site reaction lasting longer than 24 hours, or any AESI of anaphylactic reaction or 
systemic allergic reaction that is related to IMP and require treatment, PK and ADA samples will be collected at or near the onset of the event for any additional analysis if required or for archival purposes.  
g Pregnancy will lead to definitive treatment discontinuation in all cases. Female (WOCBP) participants will be supplied with urine dipsticks for use between visits and complete the Home pregnancy diary. 
h DNA sample should be collected at the Day 1 visit, but can be collected at any visit during the study. RNA samples must be collected before the administration of the first dose of study drug and at Week 24. 
ADA: antidrug antibodies; AE: adverse event; AESI: adverse event of special interest; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; DBP: diastolic blood pressure; 
DLQI: Dermatology Life Quality Index; DNA: deoxyribonucleic acid; ECG: electrocardiogram; eCRF: electronic case report form; EOS: end of study; EOT: end of treatment; EQ-5D-5L: Euroqol 5 dimensions 5 levels; 
HADS: Hospital Anxiety and Depression Scale; HBc Ab: hepatitis B core antibody; HBs Ab: hepatitis B surface antibody; HBs Ag: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; 
HCV Ab: hepatitis C virus antibody; HIV: human immunodeficiency virus; Ig: immunoglobulin; IGA PN: Investigator’s Global Assessment for prurigo nodularis; IGA PN-A: IGA PN-Activity; IGA PN-S: IGA PN-Stage; 
IMP: Investigational Medicinal Product; IVRS: interactive voice response system; IWRS: interactive web response system; NRS: numeric rating scale; PAS: prurigo activity score; PGIC: Patient Global Impression of 
Change; PGIS: Patient Global Impression of Severity; PK: pharmacokinetic; PRO: patient reported outcome; Q2W: every 2 weeks; RBC: red blood cells; RNA: ribonucleic acid; SAE: serious adverse event; 
SBP: systolic blood pressure; SC: subcutaneous; TB: tuberculosis; WBC: white blood cells; WI-NRS: worst itch numeric rating scale; WOCBP: woman of childbearing potential. 
 
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2 
INTRODUCTION  
Dupilumab is a human monoclonal IgG4 antibody that inhibits IL-4 and IL-13 signaling by 
specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. 
Dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling 
through the Type II receptor. Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13, key 
cytokines that drive Type 2 inflammatory responses, including the release of proinflammatory 
cytokines, chemokines, nitric oxide, and IgE.  
Dupilumab is approved by major regulatory agencies for use in AD and in asthma in adults and 
adolescents, and in the US for CRSwNP in adults. 
2.1 
STUDY RATIONALE  
Prurigo nodularis is a skin disease characterized by multiple, intensely itchy skin eruptions in 
symmetrically distributed areas of the extremities (1). It is difficult to treat and entails a high 
disease burden. 
Dupilumab has shown efficacy in multiple diseases with underlying Type 2 inflammation such as 
AD, asthma, CRSwNP and EoE. In light of the published research suggesting a principal role for 
Type 2 cytokines in the pathogenesis of PN (see Section 2.2), the Sponsor proposes that selective 
and simultaneous inhibition of IL-4 and IL-13 signaling such as that achieved with dupilumab 
treatment may provide clinical benefit in relieving the signs and symptoms of PN, especially in 
the high unmet need population of patients inadequately treated with, or ineligible for, TCS.  
Recently, case series were published that suggest that dupilumab may also be effective in the 
treatment of PN (3, 4, 5, 6). Type 2 cytokine involvement is implicated in all forms of PN. This is 
consistent with a recent case series of nine patients without an atopic history who benefitted from 
dupilumab treatment (7).   
The primary hypothesis of the study is that dupilumab will be effective in reducing itch and the 
secondary hypothesis is that it will reduce and promote the healing of lesions of PN, in patients 
who are inadequate responders to topical prescription therapies or when those therapies are not 
advisable. 
2.2 
BACKGROUND  
Prurigo nodularis is a skin disease characterized by multiple, intensely itchy skin eruptions in 
symmetrically distributed areas of the extremities (1). The main symptom is prolonged, repetitive 
and uncontrollable rubbing, scratching and uncontrollable itching which leads to hyperkeratotic 
eroding papules and nodules on the skin. A broadly accepted definition for chronic prurigo has 
been published by the European Academy of Dermatology and Venereology (EADV) (10). The 
convened experts agreed that chronic prurigo should be used as an umbrella term for the range of 
clinical manifestations (eg, papular, nodular, plaque or umbilicated types). Prurigo nodularis is 
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considered a distinct disease defined by the presence of chronic pruritus for ≥6 weeks, history 
and/or signs of repeated scratching and multiple localized/generalized pruriginous skin lesions 
(whitish, hyperpigmented, or pink papules, nodules and/or plaques).  
Pathophysiological studies in PN patients reveal increased dermal nerve fiber density and changes 
in many types of skin cells. These skin cells cause inflammation and pruritus (severe, constant 
itching) through the release of cytokine IL-31, tryptase, prostaglandins, eosinophil cationic 
protein, histamine, and neuropeptides, such as substance P, calcitonin gene-related peptide and 
nerve growth factor (11). The itch caused by primary dermatoses or systemic disorders is 
postulated to cause an itch scratch cycle which leads to neuronal hypersensitization. This neuronal 
hypersensitization is the final common pathway which drives the symptomatology of PN (1). 
Fukushi et al. studied 22 PN skin biopsies and found that 86% of them showed activation of 
STAT6, a marker for Type 2 inflammatory pathway activation downstream of the Type 2 
cytokines IL-4 and IL-13 (12). Consistent with this, IL-4 and IL-5 messenger RNA expression is 
upregulated in the skin of PN patients (13). Importantly, these two studies did not mention 
whether these skin biopsy specimens came from patients with or without atopy. The etiology of 
the profound pruritus in this disease is thought to be driven by high Type 2 inflammation driving 
activity at the level of the sensory neuron. Human sensory neurons in skin that transmit the 
sensation of itch are known to express IL- 4Rα, IL-13Ra1, and IL-31RA (14). On testing for 
functional stimulation, IL-4 was shown to enhance responsiveness to other pruritogens like 
histamine (14). These findings support that Type 2 cytokines may play a principal role in the 
pathogenesis of PN.  
Due to the central manifestation of itch, PN carries a significant burden of disease (10, 15). The 
effect on quality of life due to PN has been reported to be higher than other common skin 
disorders like AD and psoriasis (16). Patients report chronic sleep loss due to constant itching; 
constant burning, stinging, and pain at affected area; and chronic depression, anxiety, anger, 
disgust, and shame; and hence overall experience a great impact on their quality of life. According 
to a 5 year cross-sectional study on 909 adult PN patients in the John Hopkins hospital system 
(15), PN is a key contributing factor to mood disorders such as anxiety and depression. Of all 
patients with chronic pruritus, 70% have some type of psychiatric comorbidity, and the severity of 
depression in patients with chronic pruritus correlates with intensity of itch. The concomitant 
psychologic component of PN likely contributes to the challenging nature of treating this disease. 
Data on the epidemiology of PN are limited. Most studies show a predominance of older patients 
with a median age of more than 50 years (2, 10, 15). Prurigo nodularis is only occasionally 
observed in younger patients, in whom it is often associated with atopic conditions (17). 
There are no FDA or EMA approved targeted therapies indicated for the treatment of PN, whether 
atopic or non-atopic forms; the lesions of atopic and non-atopic PN are clinically 
indistinguishable and treatment options remain the same. Topical corticosteroids and TCI are 
often used initially. While there is a mechanistic rationale for their use, no rigorous clinical 
studies confirming their efficacy were identified. Anecdotal feedback obtained from 
dermatological experts indicate variable, modest efficacy. For thicker lesions, TCS is also 
administered intralesionally. Lesional cryotherapy is another available topical treatment; case 
reports indicate temporary relief. Antihistamines and antileukotrienes are occasionally used; their 
efficacy, however, is not supported by well conducted, randomized clinical trials and is rated low 
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by patients (18). Phototherapy, in particular narrowband ultraviolet B (UVB), is occasionally 
added in patients not responding to topical pharmacotherapy. While some improvements with 
phototherapy have been reported, they remain usually partial and complete remissions are 
uncommon.  
Oral immunosuppressants such as methotrexate and cyclosporine have been used off-label with 
some success as reported based on case reports and retrospective (18). Use of cyclosporine in 
PN is limited by commonly recognized toxicities including hypertension, impaired renal and 
hepatic function, and potential for increased susceptibility to infections and cancer, particularly 
skin cancer, due to decreased cancer immunosurveillance (19). Methotrexate has well established 
toxicities, in particular, myelosuppression and hepatotoxicity. In addition, the broad 
immunosuppression caused by all these drugs carries an increased risk of developing serious 
bacterial, fungal, viral, and mycobacterial infections. 
Neuromodulatory agents such as gabapentin and anti-inflammatory agents such as thalidomide 
have been used in PN with varying degrees of success (18), but have also considerable adverse 
effects. Adverse effects of thalidomide include peripheral neuropathies, sedation, dizziness and 
teratogenicity, while adverse effects of gabapentin include headache, sedation and dizziness. 
Overall, despite the use of multiple treatments, many patients with PN remain uncontrolled, and 
some of the available therapies are associated with serious potential adverse reactions. Given the 
lack of targeted treatments and the suboptimal efficacy associated with currently available 
therapies, there remains a significant unmet need in patients with PN.  
Dupilumab has shown efficacy in multiple diseases with underlying Type 2 inflammation such as 
AD, asthma, CRSwNP, and EoE. The most compelling data suggesting that PN is driven by 
Type 2 inflammation are the many case series of PN patients successfully treated with dupilumab. 
Recently, five case series were published that suggest that dupilumab may also be effective in the 
treatment of PN: Mollanazar et al. (4 patients, 3 of those without history of AD) (3), Beck et al. 
(3 patients) (4), Rambhia et al. (2 patients) (5), Calugareanu et al. (one patient) (6), and Zhai et al. 
(9 patients, all without history of AD) (7). These case series reported major improvements in 
treatment-refractory cases of PN after treatment with dupilumab 300 mg Q2W (after an initial 
loading dose of 600 mg). These published case reports show rapid and substantial effects of 
dupilumab on itch, and somewhat less well documented effects also on lesions in patients with PN 
refractory to standard treatment. 
2.3 
BENEFIT/RISK ASSESSMENT  
Dupilumab solution for injection is currently authorized: 
• In over 40 countries worldwide including the US, European Union (EU) (Centralised 
Procedure), and Japan for the treatment of adults with inadequately controlled 
moderate-to-severe AD. In the US and EU, it has also been authorized for use in 
adolescent patients (≥12 years) with inadequately controlled moderate-to-severe AD. 
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• In the US for use in moderate-to-severe eosinophilic or oral steroid dependent asthma, in 
the EU for severe Type 2 asthma in adults and adolescents, and in Japan for use in adults 
and adolescents (≥12 years) with severe or refractory bronchial asthma, 
• In the US for use in adults with inadequately controlled CRSwNP. 
Dupilumab has shown clinically relevant benefit in several Type 2 driven immunological 
disorders such as AD, bronchial asthma, CRSwNP, and EoE. In asthma and AD indications, 
studies were also conducted in adolescents and similar benefit to adults was observed. 
While the mechanism of PN is not well-known, there is some evidence of a Type 2 immunologic 
signature in prurigo nodule skin biopsy specimens and activation of Type 2 transcription factors 
STAT3 and STAT6 in the epidermis (12, 13). Therefore, it is hypothesized that dupilumab may 
show significant clinical benefit in the treatment of PN. This hypothesis is supported by a series of 
case reports that show dupilumab treatment resulting in a significant reduction in pruritus in 
19 PN patients (3, 4, 5, 6, 7). 
No tissue targets or specific hazards to humans were identified in nonclinical general and 
reproductive toxicology studies.  
Dupilumab has an extensive safety database. As of the 28 March 2019 (data lock point), 
8798 subjects were enrolled into the development program for dupilumab and are included in the 
safety population treated: 242 as healthy volunteers, 4227 from AD studies, 3377 from asthma 
studies, 782 from CRSwNP studies, 53 from EoE studies, 117 from grass allergy and peanut 
allergy studies. The number of subjects exposed to dupilumab in clinical studies was 7781 (218 in 
healthy volunteer studies, 3931 in AD studies, 3073 in asthma studies, 470 in CRSwNP studies, 
26 in EoE studies, and 63 in grass allergy and peanut allergy studies). Based on the sales figure 
retrieved from Intercontinental Marketing Services Health and using the World Health 
Organization’s defined average daily dose for dupilumab of 21.4 mg, the cumulative post 
marketing exposure to dupilumab is estimated to be 38 816 patient years (01 January 2017 
through 31 December 2018).  
Dupilumab was generally well tolerated in all populations tested in clinical development 
programs. The adverse drug reactions (ADRs) identified to date for dupilumab include injection 
site reactions, conjunctivitis, oral herpes, conjunctivitis allergic, conjunctivitis bacterial, herpes 
simplex, blepharitis, dry eye, eye pruritus, and eosinophilia. These ADRs occur with relatively 
low frequency with dupilumab treatment, and were generally mild or moderate, transient, and 
manageable. More significant serious allergic reactions were very rare. Importantly, no increased 
overall infection risk was observed in patients treated with dupilumab.  
Systemic hypersensitivity has been established as an important identified risk with dupilumab. 
As protein therapeutics, all monoclonal antibodies are potentially immunogenic. Rare serious and 
systemic hypersensitivity reactions have been observed in the dupilumab program including 
serum sickness/serum sickness-like reaction in the adult AD program and anaphylaxis related to 
dupilumab in the adult asthma clinical trials.  
It is hypothesized that dupilumab in patients with PN will have a favorable safety profile as 
observed across other Type 2-driven immunological disorders. 
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The safety data available to date, in conjunction with the risk monitoring and mitigation strategies 
in the study protocol, and the clinical benefit of dupilumab demonstrated in multiple Type 2 
indications (AD, asthma, CRSwNP) and case reports and series in PN so far, support a favorable 
benefit-risk profile for dupilumab. 
A risk-benefit statement with respect to the overall development program is provided in the 
investigator’s brochure (IB). 
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To demonstrate the efficacy of 
dupilumab on itch response in 
patients with PN, inadequately 
controlled on topical prescription 
therapies or when those therapies 
are not advisable.  
• 
Proportion of participants with improvement (reduction) in 
worst-itch numeric rating scale (WI-NRS) by ≥4 from baseline to 
Week 12. 
 
Secondary 
• 
To demonstrate the efficacy of 
dupilumab on additional itch 
endpoints in patients with PN, 
inadequately controlled on topical 
prescription therapies or when those 
therapies are not advisable.  
• 
Proportion of participants with improvement (reduction) in WI-NRS 
by ≥4 from baseline to Week 24 [Key secondary endpoint]. 
• 
Time to onset of effect on pruritus as measured by proportion of 
participants with an improvement (reduction) in WI-NRS by 
≥4 from baseline during the 24-week treatment period.  
• 
Change from baseline in WI-NRS at Week 24. 
• 
Change from baseline in WI-NRS at Week 12. 
• 
Percent change from baseline in WI-NRS at Week 24. 
• 
Percent change from baseline in WI-NRS at Week 12. 
• 
Percent change from baseline in WI-NRS at Week 4. 
• 
Percent change from baseline in WI-NRS at Week 2. 
• 
Percent change from baseline in WI-NRS over time until Week 24. 
• 
Proportion of participants with WI-NRS reduction ≥4 at Week 4. 
• 
Proportion of participants with WI-NRS reduction ≥4 over time 
until Week 24. 
• 
Onset of action in change from baseline in WI-NRS (first p <0.05 
difference from placebo in the daily WI-NRS that remains 
significant at subsequent measurements) until Week 12. 
• 
To demonstrate efficacy of 
dupilumab on skin lesions of PN.  
• 
Proportion of participants with Investigator’s Global 
Assessment 0 or 1 score for PN-Stage (IGA PN-S) at Week 24 
[Key secondary endpoint].  
• 
Proportion of participants with IGA PN-S 0 or 1 score at Week 12. 
• 
Proportion of participants with IGA PN-S 0 or 1 score at Week 8.  
• 
Proportion of participants with IGA PN-S 0 or 1 score at Week 4. 
• 
Change from baseline in IGA PN-S score at Week 24. 
• 
Change from baseline in IGA PN-S score at Week 12. 
• 
Change from baseline in IGA PN-S score at Week 8. 
• 
Change from baseline in IGA PN-S score at Week 4. 
• 
Proportion of participants with Investigator’s Global Assessment 
0 or 1 score for PN-Activity (IGA PN-A) at Week 24. 
• 
Proportion of participants with IGA PN-A 0 or 1 score at Week 12. 
• 
Proportion of participants with IGA PN-A 0 or 1 score at Week 8. 
• 
Proportion of participants with IGA PN-A 0 or 1 score at Week 4. 
• 
To demonstrate the improvement in 
health-related quality of life (HRQoL).  
• 
Change from baseline in HRQoL, as measured by Dermatology 
Life Quality Index (DLQI) to Week 24. 
• 
Change from baseline in HRQoL, as measured by DLQI to 
Week 12. 
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Objectives 
Endpoints 
• 
To evaluate safety outcome 
measures.  
• 
Percentage of participants experiencing treatment-emergent 
adverse events (TEAEs) or serious adverse events (SAEs) from 
baseline through Week 24. 
 
• 
To evaluate immunogenicity of 
dupilumab.  
• 
Incidence of treatment-emergent antidrug antibodies (ADA) 
against dupilumab over time. 
 
Tertiary/exploratory 
• 
To demonstrate a reduction in the 
use of rescue medication and 
systemic immunosuppressant 
• 
Use of high potency TCS or superpotent TCS rescue medication 
through Week 24 
• 
Use of systemic immunosuppressant through Week 24, 
constituting treatment failure 
 
• 
To evaluate exploratory outcome 
measures  
• 
Change from baseline in Hospital Anxiety and Depression Scale 
(HADS) total score to Week 24. 
• 
Change from baseline in EQ5D-5L to Week 24. 
• 
Change from baseline in Pain numeric rating scale (NRS) to 
Week 4, Week 8, Week 12, and Week 24, respectively. 
• 
Change from baseline in Sleep NRS to Week 4, Week 8, 
Week 12, and Week 24, respectively. 
• 
Missed school/work days through Week 24. 
• 
Incidence of skin-infection TEAEs (excluding herpetic infections) 
through Week 24. 
 
• 
To evaluate efficacy of dupilumab on 
skin lesions using a modified PAS 
5-item questionnaire 
• 
Proportion of patients who achieve ≥75% healed lesions from 
PAS at Week 4, Week 8, Week 12, and Week 24, respectively. 
• 
Change from baseline in exact number of lesions in representative 
area (as determined from PAS) at Week 4, Week 8, Week 12, and 
Week 24, respectively. 
• 
To evaluate efficacy of dupilumab on 
other PN endpoints 
• 
Change from baseline in Patient Global Impression of Severity 
(PGIS) of PN to Week 4, Week 8, Week 12, and Week 24, 
respectively. 
• 
Patient Global Impression of Change (PGIC) of PN at Week 4, 
Week 8, Week 12, and Week 24, respectively. 
 
PK 
• 
To evaluate pharmacokinetic (PK) 
and pharmacodynamic (PD) outcome 
measures 
 
• 
Serum functional dupilumab concentrations and PK profile. 
• 
Pharmacodynamic response for selected biomarkers (total IgE). 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
The study endpoints will include both assessments of itch and assessments of the PN lesions. As 
discussed in Section 2.2, the severe itch observed in this disease, the fact that lesions are typically 
observed in areas that are within reach for scratching, and the importance of itch-scratch cycles in 
the pathophysiology of the disease support itch as a reasonable primary endpoint. This choice is in 
line with the study design publicly available for other drug classes such as NK1-antagonists (20). 
Amongst standard measurement instruments for evaluation of chronic pruritus, NRS assessing 
worst itch in the past 24 hours features high reliability and concurrent validity and is a popular 
choice for all patients due to its simple format (21, 22, 23, 24). The proposed WI-NRS is currently 
being used in Phase 3 trial assessing serlopitant efficacy in PN (20). A similar pruritus NRS 
(peak pruritus) has been validated for AD. Additional validation work covering PN as additional 
indication will be conducted in the context of the current study. The primary assessment will be a 
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responder analysis based on an at least 4 points improvement of the WI-NRS at Week 12, similar 
to the assessment widely used in AD studies, and similar to the value proposed for assessment of 
clinical improvement in the WI-NRS as measures of response in the Phase 2 trial assessing 
serlopitant efficacy and safety in PN, and currently used in the Phase 3 trial (20). The itch 
response occurs typically faster than the lesion response but since improvement of both may occur 
prior to Week 12, responder analyses assessments will be performed at earlier time points as well, 
starting at Week 2 for itch, and Week 4 for lesions. A key secondary endpoint will be the 
responder analyses of itch improvement of at least 4 points at Week 24. 
As another key secondary endpoint, PN lesions will be assessed by an IGA PN-Stage, which is a 
scale that measures the approximate number of nodules. The estimated number of lesions 
correlates well with increasing DLQI scores (ie, worsened quality of life), and demonstrates very 
good inter-rater reliability and test-retest reliability (25). The IGA scale is widely used in several 
dermatological indications (eg, as Physician Global Assessment [PGA] in psoriasis). A modified 
PAS will be used as an exploratory measure. Both instruments are PN-specific and have been 
developed by experts in the field. These are the only two disease-specific instruments currently 
available for the lesion assessment. The validation of both instruments for use in PN will be 
conducted in the context of the Phase 3 trials.  
Secondary endpoints will also include HRQoL assessments using the skin-disease specific DLQI 
in recognition of the significant impacts on quality of life experienced by patients with PN. Even 
though not validated in PN specifically, the DLQI is well established and widely used to assess 
HRQoL in patients with skin conditions in clinical trials (26).  
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This study is a multi-center, 24-week treatment, parallel, double-blind, randomized, 
placebo-controlled study to evaluate the use of dupilumab in patients with PN inadequately 
controlled on topical prescription therapies or when those therapies are not advisable.  
The study will assess the effect of dupilumab on itch improvement as well as its effect on PN 
lesions, on patients’ health-related quality of life, anxiety and depression, sleep quality and skin 
pain, and overall health status. 
Participants who satisfy the inclusion and exclusion criteria will be randomized (1:1) to one of the 
following IMP treatment groups:  
• Dupilumab 300 mg 
• Matched placebo 
Duration of study period (per participant) 
• Screening period (2-4 weeks) 
• Randomized IMP intervention period (24 weeks) 
• Follow-up period (12 weeks) 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
This study is a multi-center, 24-week treatment, double-blind, randomized, placebo-controlled study 
to evaluate the use of dupilumab in patients with PN inadequately controlled on topical prescription 
therapies or when those therapies are not advisable. Based on mechanistic data (see Section 2), 
Type 2 inflammation may play a principal role in the pathogenesis of PN in all patients. 
The double-blind design intends to mitigate potential bias and placebo control is necessary to 
assess the net effect of active dupilumab treatment. 
The patient population to be studied in this trial is intended to include patients with underlying 
systemic medical conditions known to be associated with PN. Given that better control of severe 
manifestations of underlying systemic illnesses can confound the primary itch endpoint, we will 
enroll 40% to 60% of non-atopic PN patients that have medically well-controlled systemic 
conditions. Since the literature suggests that approximately 20%-60% of PN patients have a 
history of atopy (defined as having a medical history of AD, allergic rhinitis/rhinoconjunctivits, 
asthma, or food allergy), our study design will require that the remaining PN patients have a 
history or a current diagnosis of atopy. Because active AD can confound the primary endpoint, we 
will exclude moderate-to-severe AD patients and will institute a cap of up to 10% of the atopic 
patient subgroup having active mild AD. It is the goal of this design to mirror the overall PN 
patient population consistent with real-world estimates of overall prevalence while trying to 
minimize potential confounders on the primary endpoint. 
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The primary endpoint, WI-NRS, is a validated measurement of the highest PN burden, ie, extreme 
itching.  
Dupilumab treatment has shown clinical efficacy prior to Week 24 in all Phase 3 trials examined 
across all indications. In addition, available biomarker data of disease response, including TARC and 
eotaxin-3, plateau after Week 16 but before Week 24 in prior AD trials, including the 52-week AD 
study (R668-AD-1224; CHRONOS). The Sponsor considers that a 24-week treatment period is an 
appropriate duration to observe dupilumab’s effect in PN to ensure an adequate evaluation of PN 
lesions as the effect on pruritus is expected to plateau by Week 12 similar to that observed in the 
atopic dermatitis studies. Weeks 12 to Week 24 will then allow for evaluation of the maintenance of 
effect on pruritus. The duration of the 12-week follow-up period is based on the time expected for 
drug concentration to reach zero (below the lower limit of quantification) in most patients after the last 
dose of dupilumab. This follow-up period will allow assessment of the need for chronic treatment with 
dupilumab for this disease by an assessment of return of PN symptoms post-treatment. 
The study will not include adolescents because PN is rare in adolescent patients. 
4.3 
JUSTIFICATION FOR DOSE  
The selected dosing regimen is dupilumab 300 mg Q2W with a loading dose of 600 mg.  
This dose regimen is expected to achieve serum concentrations that saturate the target-mediated 
clearance pathway rapidly with the loading dose and maintain saturation thereafter. The PK of 
dupilumab is consistent across populations of patients with AD, asthma, CRSwNP, and EoE, as 
well as healthy volunteers. Furthermore, the sources of variability of dupilumab PK identified in 
each population and the magnitude of the covariate effects indicate that body weight is the most 
influential factor, whereas other covariates identified as being statistically significant have no 
meaningful impact on dupilumab PK. The immunogenicity of dupilumab is also comparable in 
these populations (see IB).  
Dosing regimens of 300 mg Q2W after a loading dose of 600 mg were used in the PN case 
studies, which resulted in marked improvement in itch within three months and subsequently 
a notable improvement of the skin lesions (see Section 2).  
The 300 mg Q2W dose, with loading dose, is the approved dose for AD and is an approved dose 
for asthma in the US and the EU. 
Therefore, based on the totality of the data, dupilumab 300 mg Q2W (with loading dose) regimen 
is adequate for patients with PN and a further dose ranging study is not necessary to select 
a Phase 3 dose regimen. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participants must be 18 to 80 years of age, at the time of signing the informed consent.  
Type of participant and disease characteristics 
Patients with a clinical diagnosis of PN, as defined by all of the following: 
I 02. Diagnosed by a dermatologist for at least 3 months before the Screening visit. 
I 03. On the WI-NRS ranging from 0 to 10, patients must have an average worst itch score of 
≥7 in the 7 days prior to Day 1. 
NOTE: Baseline pruritus NRS average score for maximum itch intensity will be 
determined based on the average of daily NRS scores for maximum intensity (the daily 
score ranges from 0 to 10) during the 7 days immediately preceding randomization. 
A minimum of 4 daily scores out of the 7 days is required to calculate the baseline average 
score. For patients who do not have at least 4 daily scores reported during the 7 days 
immediately preceding the planned randomization date, randomization should be 
postponed until this requirement is met, but without exceeding the 28-day maximum 
duration of the screening period. 
I 04. Patients must have a minimum of 20 PN lesions in total on both legs, and/or both arms 
and/or trunk, at Screening visit and on Day 1. 
NOTE: Patients need to have bilaterally symmetrical lesions on the extremities. The 
presence of lesions on at least 2 body surface areas is required.  
I 05. History of failing a 2-week course of medium-to-superpotent TCS or when TCS are not 
medically advisable. 
NOTE: Failure is defined as patients who are unable to achieve and/or maintain remission 
and low disease activity (similar to IGA PN-S score of ≤2 [≤19 nodules]) despite treatment 
with a daily regimen of medium-to-superpotent TCS (±TCI as appropriate), applied for at 
least 14 days, or for the maximum duration recommended by the product prescribing 
information, whichever is shorter.  
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I 06. Have applied a stable dose of topical emollient (moisturizer) once or twice daily for at least 
5 out of the 7 consecutive days immediately before Day 1 (NOTE: See exclusion 
criterion E 20 for limitations regarding emollients; see background treatment with topical 
emollient in Section 6.1.1). 
I 07. Participants must be willing and able to complete a daily symptom eDiary for the duration 
of the study. 
  
Sex 
I 08. Male or Female 
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
  
a) Female participants 
- 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
- 
Is not a WOCBP. 
OR 
- 
Is a WOCBP and agrees to use a contraceptive method as described in Appendix 4 
(Section 10.4) during the study (at a minimum until 12 weeks after the last dose of 
study intervention). 
- 
A WOCBP must have a negative highly sensitive (Section 10.2) pregnancy test 
(urine or serum as required by local regulations) on Day 1 before the first dose of 
study intervention. 
- 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. 
- 
Additional details can be found in Appendix 4 (Section 10.4). 
- 
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Informed Consent 
I 09. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) of 
the protocol which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol. In countries where legal age of majority 
is above 18 years, a specific ICF must also be signed by the participant’s legally authorized 
representative. 
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5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Presence of skin morbidities other than PN and mild AD that may interfere with the 
assessment of the study outcomes. Conditions such as, but not limited to, the following: 
scabies, insect bite, lichen simplex chronicus, psoriasis, acne, folliculitis, habitual picking, 
lymphomatoid papulosis, chronic actinic dermatitis, dermatitis herpetiformis, 
sporotrichosis, bullous disease. 
NOTE: patients with mild active AD will represent up to 10% of the atopic PN study 
population.  
E 02. PN secondary to medications (eg, opioids, angiotensin converting enzyme [ACE] 
inhibitors). 
E 03. PN secondary to medical conditions such as neuropathy or psychiatric disease (eg, notalgia 
paresthetica, brachioradial pruritus, neurotic excoriations, obsessive compulsive disorder, 
delusions of parasitosis, etc). 
E 04. Patients with a documented AD severity moderate to severe within 6 months before the 
screening visit, or documented diagnosis of moderate to severe AD from screening visit to 
randomization visit (eg, IGA AD of 3 or 4, eczema area and severity index [EASI] ≥16, 
scoring atopic dermatitis [SCORAD] ≥25). 
E 05. Severe concomitant illness(es) under poor control that, in the investigator’s judgment, 
would adversely affect the patient’s participation in the study. Examples include, but are 
not limited to patients with life expectancy shorter than 1 year, patients with uncontrolled 
diabetes (hemoglobin A1c ≥9% according to the laboratory results within 3 months before 
screening visit), patients with cardiovascular conditions (eg, Class III or IV heart failure 
according to the New York Heart Association classification), hepato-biliary conditions 
(eg, Child-Pugh Class B or C), neurological conditions (eg, demyelinating diseases), active 
major autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, 
etc), other severe endocrinological, gastrointestinal, metabolic, pulmonary, or lymphatic 
diseases. The specific justification for patients excluded under this criterion will be noted 
in study documents (chart notes, eCRF, etc). 
E 06. Severe renal conditions (eg, patients with uremia and/or on dialysis). 
E 07. Participants with uncontrolled thyroid disease. 
E 08. Active TB or non-tuberculous mycobacterial infection, or a history of incompletely treated 
TB will be excluded from the study unless it is well documented by a specialist that the 
participant has been adequately treated and can now start treatment with dupilumab in the 
medical judgment of the investigator and/or infectious disease specialist. Tuberculosis 
testing will be performed on a country-by-country basis, according to local guidelines if 
required by regulatory authorities or ethics boards. 
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E 09. Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic 
infection, unless clinical and (if necessary) laboratory assessment have ruled out active 
infection before randomization. 
E 10. Active chronic or acute infection (except HIV infection) requiring treatment with systemic 
antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks before screening visit 
or during the screening period. 
E 11. Known or suspected immunodeficiency, including history of invasive opportunistic 
infections (eg, TB, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, 
aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal 
frequency or prolonged duration suggesting an immune-compromised status, as judged by 
the investigator. 
E 12. Active malignancy or history of malignancy within 5 years before the baseline visit, except 
completely treated in situ carcinoma of the cervix, completely treated and resolved 
non-metastatic squamous or basal cell carcinoma of the skin. 
E 13. History of systemic hypersensitivity or anaphylaxis to any biologic therapy, including any 
excipients. 
E 14. Any other medical or psychological condition including relevant laboratory abnormalities 
at screening that, in the opinion of the investigator, suggest a new and/or insufficiently 
understood disease, may present an unreasonable risk to the study patient as a result of 
his/her participation in this clinical trial, may make patient’s participation unreliable, or 
may interfere with study assessments. The specific justification for patients excluded under 
this criterion will be noted in study documents (chart notes, eCRF, etc). 
E 15. History of substance and/or alcohol abuse. 
E 16. Planned major surgical procedure during the patient’s participation in this study. 
Prior/concomitant therapy 
E 17. Exposure to another systemic or topical investigative drug (monoclonal antibodies as well 
as small molecules) within a certain time period prior to Visit 1 (screening), as follows: 
an interval of less than 6 months or <5 PK half-lives for investigative monoclonal 
antibodies, whichever is longer, and an interval of less than 30 days or <5 PK half-lives, 
whichever is longer, for investigative small molecules.  
E 18. Having used any of the following treatments within 4 weeks before the screening visit 
- 
Systemic immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, 
cyclosporine, mycophenolate-mofetil, interferon gamma, Janus kinase inhibitors, 
azathioprine, methotrexate, hydroxychloroquine, dapsone, sulfasalazine, colchine, etc). 
- 
Intralesional corticosteroid injections and cryotherapy. 
- 
Phototherapy, including tanning beds. 
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- 
Naltrexone or other opioid antagonist. 
- 
Gabapentin, pregabalin, and thalidomide. 
Or starting to use the following treatments or changed the dose of the following treatments 
in 3 months before the screening visit or expected the dose of the following treatments will 
be changed throughout the study: 
- 
Paroxetine, fluvoxamine, or other selective serotonin reuptake inhibitors (SSRIs). 
- 
Serotonin and norepinephrine reuptake inhibitors (SNRIs) 
- 
Amitriptyline or other tricyclic or tetracyclic antidepressants. 
E 19. Previous treatment with biologic medicines within the following timeframe: 
- 
Any cell-depleting agents including but not limited to rituximab: within 6 months 
before the screening visit. 
- 
Omalizumab: within 5 months before screening visit. 
- 
Other immunomodulatory biologics: within 5 half-lives (if known) or 16 weeks before 
the screening visit, whichever is longer. 
E 20. Initiation of treatment with prescription moisturizers or moisturizers containing additives 
such as ceramide, hyaluronic acid, urea, menthol, polidocanol, or filaggrin degradation 
products during the screening period (patients may continue using stable doses of such 
moisturizers if initiated before the Screening visit). 
E 21. Initiation of treatment with TCS/TCI (any potency) during the screening period or 
treatment with high potency or superpotent TCS/TCI during the screening period. 
E 22. For participants who were on a stable regimen of TCS/TCI (maintain same medicine, same 
dose from 2 weeks prior to screening visit) at the screening visit: 
- 
Application of TCS/TCI on fewer than 6 days during the 7 days immediately 
preceding randomization. 
- 
Application of TCS/TCI of incorrect potency within 7 days before Day 1 according to 
the requirements of Section 6.1.1, ie, low potency if on low potency at screening visit 
and medium potency if on medium or higher potency at screening visit. 
E 23. Treatment with a live (attenuated) vaccine within 4 weeks before the screening visit. 
NOTE: For patients who have vaccination with live, attenuated vaccines planned during 
the course of the study (based on national vaccination schedule/local guidelines), it will be 
determined, after consultation with a physician, whether the administration of vaccine can 
be postponed until after the end of study, or preponed to before the start of the study, 
without compromising the health of the patient: 
- 
Patient for whom administration of live (attenuated) vaccine can be safely postponed 
would be eligible to enroll into the study. 
- 
Patients who have their vaccination preponed can enroll in the study only after a gap of 
4 weeks following administration of the vaccine. 
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E 24. Planned or anticipated use of any prohibited medications and procedures during screening 
and study treatment period. 
Prior/concurrent clinical study experience 
E 25. Participation in prior dupilumab clinical study; treated in the past with dupilumab; prior 
use of biologics for PN. 
Diagnostic assessments 
E 26. For participants without history of HIV infection before screening visit, positive HIV 
serology at screening. 
For participants with history of HIV infection with CD4+ counts ≤300 cells/µL and/or 
detectable HIV viral load at screening. 
E 27. Participants with any of the following result at screening: 
- 
Positive (or indeterminate) HBs Ag or,  
- 
Positive total HBc Ab confirmed by positive HBV DNA or, 
- 
Positive HCV Ab confirmed by positive HCV RNA. 
Other exclusions 
E 28. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or subjects who are legally institutionalized. 
E 29. Any country-related specific regulation that would prevent the subject from entering the 
study - see Section 10.10 (country-specific requirements). 
E 30. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 31. Participants are dependent on the Sponsor or Investigator (in conjunction with Section 1.61 
of the International Council for Harmonisation (ICH) good clinical practice (GCP) 
Ordinance E6). 
E 32. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals. 
E 33. Any specific situation during study implementation/course that may raise ethics 
considerations. 
E 34. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
  
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5.3 
LIFESTYLE CONSIDERATIONS  
Not applicable. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants 
to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure reasons, eligibility criteria, and any SAE. 
In the case of technical malfunction of equipment, the patient may be rescreened. Patients who 
fail the exclusion criteria may be rescreened once during the open screening period of the study. 
Rescreened participants will be assigned a new participant number versus the one received for the 
initial screening.  
There is no requirement for a waiting period between the screen-failure date and the rescreening 
date. The interactive response technology (IRT) report will flag rescreened patients. Patients that 
are rescreened must sign a new consent form and all Visit 1 procedures must be repeated. 
If certain dynamic laboratory tests do not meet the eligibility criteria at screening, these laboratory 
assessments may be repeated, at the discretion of the Investigator, if it is judged to be likely to 
return to acceptable range for study inclusion within the screening visit window prior to Day 1. 
There is no need to screen fail such participants if the test finally meets the eligibility criteria. 
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 2 - Overview of study interventions administered  
ARM name 
Dupilumab 
Placebo 
Intervention name 
Dupilumab 300 mg 
Placebo matching dupilumab 300 mg 
Type 
Biological/Vaccine 
Other 
Dose formulation 
A 150 mg/mL dupilumab solution in a pre-filled 
syringe to deliver 300 mg in 2 mL 
Identical formulation to the active 
300 mg formulation without 
dupilumab, in a pre-filled syringe to 
deliver placebo in 2 mL 
Unit dose strength(s) 
300 mg 
0 mg (placebo) 
Dosage level(s) 
300 mg every 14 ±3 days after an initial 
loading dose of 600 mg 
0 mg every 14 ±3 days with a loading 
dose of 0 mg  
Route of administration 
Subcutaneousa 
Subcutaneousa 
IMP and NIMP 
IMP 
IMP 
Packaging and labeling 
One glass pre-filled syringe packed in a 
patient kit box. Both the glass pre-filled 
syringe and the box will be labeled as required 
per country requirement. 
One glass pre-filled syringe packed in 
a patient kit box. Both glass pre-filled 
the syringe and the box will be labeled 
as required per country requirement 
a Subcutaneous injection sites should alternate between the upper thighs, 4 quadrants of the abdomen or the upper arms, so that the same 
site is not injected twice during consecutive administrations. Injection in the upper arms can only be done by a trained person (parent/legally 
authorized representative/caregiver trained by Investigator or Delegate) or health care professional but not the participant themselves.  
IMP: investigational medicinal product; NIMP: noninvestigational medicinal product. 
The Investigator or delegate will train the patient (or caregiver) how to prepare and inject IMP at 
Visit 2. He/she will inject the first of the two injections. The participant (or caregiver) will 
perform the second injection under the supervision of the Investigator or delegate. Patient should 
also be trained by the site staff to recognize potential signs and symptoms of hypersensitivity 
reaction in order to self-monitor at home for at least 30 minutes (or longer per country specific or 
local site-specific requirements) following injection. In case of hypersensitivity symptoms the 
patient should contact healthcare provider/emergency. The training must be documented in the 
participant’s study file.  
When the participant has a study visit, the IMP will be administered following clinical procedures 
and blood collection. Patients should be monitored for at least 30 minutes. The monitoring period 
may be extended as per country specific or local site-specific requirements. 
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Between the protocol-scheduled on-site visits, participants are allowed to self-inject IMP at home. 
Participants who prefer to have a healthcare professional administer the IMP may choose to have 
injections administered at home by a nurse or at the study site. 
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits, dupilumab 300 mg or matching placebo may be supplied from the 
site to the participant via a Sponsor-approved courier company where allowed by local regulations 
and approved by the participant. 
6.1.1 Noninvestigational medicinal products  
Starting from the screening visit, participants will be instructed to use their daily moisturizer, if it 
is not containing any compound with known anti-itch effect (such as menthol, polidocanol, 
pramoxine, lidocaine, prilocaine, capsaicin, naltrexone, N-palmitoylethanolamine, etc). It is not 
authorized changing emollients or moisturizers or applying products for itching relief during the 
course of the study. 
Participants will be required to apply moisturizers (emollients) once or twice daily for at least 
5 out of the 7 consecutive days immediately before Day 1 and continue until Week 36. All types 
of moisturizers are permitted, but patients may not initiate new treatment with prescription 
moisturizers or over-the-counter moisturizers containing additives during the screening period or 
during the intervention period. Patients may continue using stable doses of such moisturizers if 
initiated before the screening visit. 
If participants are on a stable regimen of low to medium potency TCS or TCI at the screening 
visit, they can continue their topical steroid application once daily without tapering from 
Screening to Week 24. If specific lesions resolve, the participant can stop applying steroids to 
those sites but are permitted to continue applying to persistent lesions. If participants are on stable 
regimens of high potency or superpotent steroids, participants should decrease potency to medium 
potency TCS and continue to apply daily from screening to Week 24. Stable regimen for TCS is 
maintaining the same medicine (low to medium potency TCS), and maintaining the same 
frequency of treatment (once or twice daily) used from 2 weeks prior to screening. Stable regimen 
for TCI is maintaining the same medicine of TCI and the treatment frequency (once or twice 
daily) used from 2 weeks prior to screening. If participant’s prior regimen was applying once 
daily, the participant will maintain daily application during study and for participants who had 
twice daily prior to screening, participation will maintain twice daily regimen during study. 
Ifspecific lesions resolve, the participant can stop applying steroids to those sites but are permitted 
to continue applying to persistent lesions. Occlusion is not allowed from Screening to Week 24. 
It is recommended that patients use triamcinolone acetonide 0.1% cream or fluocinolone 
acetonide 0.025% ointment for medium potency, and hydrocortisone 1% cream for low potency. 
If rescue with TCS is needed, it is recommended that patients use either betamethasone 
dipropionate 0.05% optimized ointment for high potency TCS or clobetasol propionate 
0.05% cream for super high potency TCS. If patients have tolerance issues with any of these 
steroids or if they are not commercially available in some countries, they may substitute with 
products of the same potency from the list provided by the Sponsor.  
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On areas treated with TCS, moisturizers must be applied once daily only at the time when TCS is 
not applied (ie, do not use moisturizers and TCS on the same areas at the same time during the 
day). For example, if TCS are applied in the evening, moisturizers will not be used in the evening 
on areas treated with TCS, but will be applied to those areas in the morning. On areas not treated 
with TCS, moisturizers will be applied twice daily - morning and evening.  
Rescue therapy is described in Section 6.5.1. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
6.2.1 Storage and handling  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
6.2.2 Responsibilities  
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.6). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for direct-to-
patient [DTP] shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP in any 
other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
All participants will be centrally assigned to randomized study intervention using an IRT. Before 
the study is initiated, the telephone number and call-in directions for the IVRS and/or the log in 
information & directions for the IWRS will be provided to each site. 
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At screening (Visit 1), the Investigator or designee will contact the IRT system to receive the 
participant number. If a patient who had previously failed screening is approached for re-screening, 
a new ICF must be signed. In such case, a new patient number will be assigned by IRT. 
Methods of assigning patients to treatment group  
The randomized intervention kit number list is generated centrally by Sanofi and IMPs are 
packaged in accordance with this list. The randomization and intervention allocation are 
performed centrally by an IRT. The IRT generates the participant randomization list and allocates 
the intervention number and the corresponding intervention kits to the participants according to it. 
Participants will be randomized in 1:1 ratio to treatment arms described in Table 2. 
Randomization will be stratified by the following factors:  
• documented history of atopy (atopic or non-atopic) 
- 
Atopic: Patients with a physician-documented history of atopic comorbidities defined 
as AD, allergic rhinitis/rhinoconjunctivits, asthma, or food allergy, or a current 
diagnosis of at least one of these atopic comorbidities, per investigator judgement. 
NOTE: enrollment of patients with a current diagnosis of active mild AD will be 
capped at up to 10% of the participants in this subgroup 
- 
Non-atopic: Patients without a physician-documented history of atopic comorbidities 
defined as AD, allergic rhinitis/rhinoconjunctivitis, asthma or food allergy, and 
without a current diagnosis of at least one of such atopic comorbidities, per 
investigator judgement 
• stable use of TCS/TCI (yes or no) 
• country/territory code 
A randomized participant is defined as a participant who has been allocated to a randomized 
intervention regardless whether the intervention kit was used or not (ie, participant registered by 
the IRT). 
A participant cannot be randomized more than once in the study. 
Study intervention will be dispensed at the study visits summarized in SoA (see Section 1.3). 
Returned study intervention should not be re-dispensed to the participants. 
Methods of blinding 
• Dupilumab 300 mg and placebo matching dupilumab 300 mg will be provided in 
identically matched 2 mL pre-filled syringes that are visually indistinguishable. Syringes 
and box will be labeled with a treatment kit number. 
• The unblinding plan is described in Section 9.5.2. 
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Randomization code breaking during the study 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a participant’s treatment 
assignment is warranted (eg, in case of available antidote). Participant safety must always be the 
first consideration in making such a determination. If the Investigator decides that unblinding is 
warranted, the Investigator should make every effort to contact the Sponsor prior to unblinding 
a participant’s treatment assignment unless this could delay emergency treatment of the 
participant. If a participant’s treatment assignment is unblinded, the Sponsor must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and case report form (CRF), as applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Investigator or his/her delegate must ensure that IMP will be administered to each participant 
according to the labeling instructions. 
IMP accountability: 
• Intervention units are returned by the participant at each visit. In case of DTP process, the 
intervention units can be returned by the carrier (if defined in the contract). 
• The Investigator counts the number of remaining kit/pre-filled syringe, and fills in the IMP 
accountability and inventory forms. 
• The Investigator or his/her delegate records the dosing information on the appropriate 
page(s) of the eCRF. 
• The monitor in charge of the study then checks the eCRF data by comparing them with the 
IMP which he/she has retrieved and source documents. 
Participant compliance with study intervention will be assessed at each visit. Compliance will be 
assessed by counting returned kit/pre-filled syringe. Deviation(s) from the prescribed dosage 
regimen should be recorded in the eCRF. 
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
The concomitant use of non-sedating antihistamine administration is allowed during the study 
except for treatment of AD or PN, but dose change of non-sedating antihistamine is not allowed 
both from Week 11 to Week 12 and from Week 23 to Week 24. 
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The concomitant use of the following therapies is prohibited during the entire study. Study 
treatment will need to be discontinued in participants receiving these treatments: 
• Systemic immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, 
cyclosporine, mycophenolate-mofetil, interferon gamma, Janus kinase inhibitors, 
azathioprine, methotrexate, hydroxychloroquine, dapsone, sulfasalazine, colchine, etc). 
• Other monoclonal antibodies (which are biological modifiers). 
• Phototherapy, including tanning beds. 
• Naltrexone or other opioid antagonist. 
• Gabapentin, pregabalin, and thalidomide. 
The concomitant use of the following therapies is prohibited except if the dose has been stable for 
at least 3 months prior to screening, but study treatment will not need to be discontinued in 
participants receiving the treatments listed below. The dose should also remain stable (can be 
reduced or discontinued if medically indicated), but should not be initiated or increased 
throughout the study. 
• Paroxetine, fluvoxamine, or other SSRIs. 
• SNRIs. 
• Amitriptyline or other tricyclic or tetracyclic antidepressants. 
The concomitant use of the following therapies is also prohibited during the entire study, but 
study treatment will not need to be discontinued in participants receiving the treatments listed 
below.  
• Intralesional corticosteroid injections and cryotherapy. 
• Sedating antihistamine. 
• Non-sedating antihistamine used specifically for the treatment of itch secondary to AD or 
PN. 
6.5.1 Rescue medicine  
The following rescue medications may be used: 
• Dermatological preparations of high potency or superpotent TCS and TCI. 
If medically necessary (ie, to control intolerable PN symptoms), rescue treatment for PN may be 
provided to study patients at the discretion of the Investigator. 
Although the use of rescue medications is allowed at any time during the study, the use of rescue 
medications should be delayed, if possible, for at least 14 days following the initiation of the 
investigational treatment. The date and time of rescue medication administration as well as the 
name and dosage regimen of the rescue medication must be recorded in the eCRF. 
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For the purpose of the efficacy responder analysis, a pre-specified algorithm will be used to 
classify rescue (details in the SAP). In addition, a blinded review of all post-baseline medications 
to adjudicate rescue treatment, based on medical judgment, will be performed to adjudicate 
rescue. Patients who receive rescue treatment as per this adjudication during the study will be 
considered treatment failures. 
6.6 
DOSE MODIFICATION  
No change in IMP dose is allowed. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
The Sponsor will not be responsible for intervention after the EOS Visit. Intervention after the 
EOS Visit will be at the discretion of investigator or treating physician. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
  
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Definitive discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in the 
study to be evaluated for safety. See the SoA (Section 1.3) for data to be collected at the time of 
discontinuation of study intervention. 
The participants may withdraw from treatment with the IMP if he or she decides to do so, at any 
time and irrespective of the reason, or this may be the investigator’s decision. All efforts should 
be made to document the reason(s) for treatment discontinuation and this should be documented 
in the eCRF. 
Participants must be permanently withdrawn from the study treatment for the following reasons:  
• At their own request or at the request of their legally authorized representative (legally 
authorized representative means an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective participant to the patient’s 
participation in the procedure(s) involved in the research).  
• If, in the investigator’s opinion, continuation in the study would be detrimental to the 
participant’s well-being.  
• At the specific request of the Sponsor.  
• If they are treated with the specific prohibited medications mentioned in Section 6.5. 
• If they miss more than 2 consecutive IMP doses. 
• In the event of a protocol deviation, at the discretion of the investigator or the Sponsor.  
• Any code broken at the requested of the investigator.  
• Pregnancy. 
• Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment (see Section 10.8).  
• Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin.  
• Any opportunistic infection or other infections whose nature or course may suggest 
an immunocompromised status (see Section 10.9).  
• Serum ALT >3 ULN and Total Bilirubin >2 ULN (see Section 10.6).  
• Serum ALT >5 ULN if baseline ALT ≤2 ULN or ALT >8 ULN if baseline ALT >2 ULN 
(see Section 10.6). 
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If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula [QTcF] after enrollment), the Investigator or 
qualified designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the ECG printed at the time of collection must 
be documented. Any new clinically relevant finding should be reported as an AE. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation within a reasonable timeframe as assessed by the Investigator before making a 
decision of definitive discontinuation of the IMP for the concerned participant. 
Handling of participants after definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
Participants who discontinue the study intervention prematurely (prior to completing the 24-week 
treatment period) will perform, as soon as possible, the early termination visit with all assessments 
normally planned for the EOT Visit (Visit 6), to assure a complete clinical assessment in close 
temporal proximity to the premature termination of study treatment is available. 
In addition, and to allow assessment of participant outcomes over the stipulated study period, 
patients will be asked and encouraged to complete all remaining study treatment visits, and 
participate in all assessments according to the visit schedule with a ±3 day window. Under 
exceptional circumstances when a participant cannot come to the site for a scheduled visit, 
a phone contact can be made. During the phone contact, at least information about AEs, 
concomitant medication and status of PN should be collected. 
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs.  
In addition, the following conditions will be causes for temporary discontinuation of study 
intervention: 
• Infections or infestations that do not respond to medical treatment 
• Any laboratory abnormality that meets temporary treatment discontinuation criteria as per 
Section 10.6 
Temporary intervention discontinuation decided by the Investigator corresponds to more than 
1 dose not administered to the participant. Following a temporary interruption or missed dose, the 
treatment should be reinitiated at the next scheduled administration, maintaining the planned dose. 
If more than 2 consecutive IMP doses have been missed, the study treatment will be permanently 
discontinued (see Section 7.1.1). 
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7.1.2.1 Rechallenge  
Reinitiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP(s) in the occurrence of the concerned event was 
unlikely and if the selection criteria for the study are still met (refer to Section 5). 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA (Section 1.3). See SoA for data to be collected 
at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be rerandomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused. 
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7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
• Discontinuation of specific sites or of the study as a whole are handled as part of 
Section 10.1. 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA (see Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA 
(see Section 1.3), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (see Section 1.3). 
• Patient-Reported Outcome questionnaires including NRS should be completed by the 
participants before the consultation and/or clinical tests, in a quiet place. The 
questionnaires should be completed by the participants themselves, independently from 
their physician, the study nurse or any other medical personnel and without any help from 
friends or relatives. 
• In light of the public health emergency related to Coronavirus disease 2019 (COVID-19) 
(or in case of any other pandemic requiring public health emergency), the continuity of 
clinical study conduct and oversight may require implementation of temporary or 
alternative mechanisms eg, phone contact, virtual visits, online meetings, use of local 
clinic or laboratory locations, and home visits by skilled staff. Implementation of such 
mechanisms may differ country by country, depending on country regulations and local 
business continuity plans. Additionally, no waivers to deviate from protocol enrollment 
criteria due to COVID-19 (or any other pandemic) will be granted. All temporary 
mechanisms utilized, and deviations from planned study procedures are to be documented 
as being related to COVID-19 (or any other pandemic) and will remain in effect only for 
the duration of the public health emergency. 
8.1 
EFFICACY ASSESSMENTS   
Efficacy data will be collected via electronic devices.  
The e-diary is used for daily recording of participant’s answers to the WI-NRS, pain-NRS, and 
sleep-NRS questionnaires. This device will be dispensed at screening visit (Visit 1), including 
instructions for use. Participants will be instructed on the use of the device.  
Recorded information will be downloaded from this device daily. At EOS Visit, the e-diary will 
be downloaded and returned to the site.  
On regular basis, the site staff should review on vendor’s website the information downloaded 
from participants’ e-diary. They should particularly check status of the disease reviewing 
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WI-NRS, as well as compliance to background therapy and overall e-diary compliance. The site 
should follow up with the participant as appropriate.  
Participants will fill in the DLQI, HADS, EQ-5D-5L, PGIC, PGIS, and missed school/work days 
questionnaires during their site visit on a tablet that will be provided to the site. This device is 
kept at the site during the study.  
8.1.1 Worst-itch numeric rating scale  
Worst-itch numerical rating scale (WI-NRS) is a PRO comprised of a single item rated on a scale 
from 0 (“No itch”) to 10 (“Worst imaginable itch”). Participants are asked to rate the intensity of 
their worst pruritus (itch) over the past 24 hours using this scale.  
Participants will complete the WI-NRS daily according to the SoA (see Section 1.3). The 
assessment tool is provided in Section 10.7.1. 
8.1.2 Investigator’s global assessment for prurigo nodularis  
Investigator’s global assessment for prurigo nodularis (IGA PN) is a clinician-reported outcome 
(ClinRO) that allows clinicians to assess the activity of PN (IGA PN-A) using a 5-point scale 
from 0 (clear) to 4 (severe); and the stage of the disease (IGA PN-S) using a 5-point scale from 
0 (clear) to 4 (severe). 
Clinicians will complete the IGA PN as described in the SoA (see Section 1.3). The assessment 
tool is provided in Section 10.7.2.  
8.1.3 Prurigo activity score  
The PAS is a ClinRO measurement. The original PAS questionnaire Version 0.9 consists of 
7 items, developed by expert clinicians in PN (25). The items of the PAS evaluate the pruriginous 
lesions in terms of:  
• Type (visible lesions: Item 1a; predominant lesions: Item 1b);  
• Estimated number (Item 2); 
• Distribution (Item 3, 4); 
• Size (biggest lesion: Item 6a; representative lesion: Item 6b). 
Other items evaluate the representative body area and exact number of lesions (Item 5), the 
activity in terms of percentage of pruriginous lesions with excoriations/crusts on top (reflecting 
active scratching; Item 7a) and the percentage of healed pruriginous lesions (reflecting healing of 
chronic prurigo; Item 7b). 
A 5-item simplified version of the PAS will be used in the current study. In particular, 
Item 3 (lesion distribution) and Item 6 (lesion monitoring) of the original PAS were removed, and 
the response options slightly modified and refined. 
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Clinicians will complete the screening/baseline version at screening and baseline visits, and will 
complete the follow-up version of the modified PAS at the other visits, as reported in the SoA 
(see Section 1.3). The assessment tool is provided in Section 10.7.3. 
8.1.4 Dermatology life quality index  
The DLQI is a PRO developed to measure dermatology-specific HRQoL in adult patients (27). 
The instrument comprises 10 items assessing the impact of skin disease on patients’ HRQoL over 
the previous week. The items cover symptoms, leisure activities, work/school or holiday time, 
personal relationships including intimate, the side effects of treatment, and emotional reactions to 
having a skin disease. It is a validated questionnaire used in clinical practice and clinical trials 
(26). Response scale is a 4-point Likert scale (0 = “not at all” and 3 = “very much”) for 
nine items. The remaining one item about work/studying asks whether work/study has been 
prevented and then (if “No”) to what degree the skin condition has been a problem at work/study; 
the item is rated on a 3-point Likert scale (“Not at all” to “A lot”). Overall scoring ranges from 
0 to 30, with a high score indicative of a poor HRQoL.  
Participants will complete the questionnaire at time points according to SoA (see Section 1.3). 
The assessment tool is provided in Section 10.7.4.  
8.1.5 Pain and sleep numeric rating scales  
Participants will be asked to rate their worst skin pain in the past 24 hours using a 0 to 10 NRS, 
with 0 = No pain to 10 = Worst pain possible.  
In addition, participants will be asked to rate their sleep quality on their past night upon 
awakening, using a 0 to 10 NRS, with 0 = Worst possible sleep and 10 = Best possible sleep. 
Participants will complete the skin pain NRS and sleep quality NRS once a day. 
The assessment tools are provided in Section 10.7.7 and Section 10.7.8.  
8.1.6 Hospital anxiety and depression scale  
The HADS is a PRO instrument for screening anxiety and depression in non-psychiatric 
populations; repeated administration also provides information about changes to a patient’s 
emotional state (28, 29). The HADS consists of 14 items, 7 each for anxiety and depression 
symptoms; possible scores range from 0 to 21 for each subscale. The following cut-off scores are 
recommended for both subscales:  
• 0 to 7: normal 
• 8 to 10: borderline abnormal (borderline case)  
• 11 to 21: abnormal 
Participants will complete the questionnaire as described in the SoA (see Section 1.3). The 
assessment tool is provided in Section 10.7.5. 
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8.1.7 Patient Global Impression of Change of disease and Patient Global Impression of 
Severity  
The PGIC is a one-item questionnaire that asks patients to provide the overall self-assessment of 
change in their PN overall on a 7-point scale, compared to just before patient started taking the 
study injection. Response choices are: 0 = “Very much better”, 1 = “Moderately better”, 
2 = “A little better”, 3 = “No change”, 4 = “A little worse”, 5 = “Moderately worse”, 6 = “Very 
much worse”.  
The PGIS is a one-item questionnaire that asks patients to provide the overall self-assessment of 
their disease severity on a 4-point scale for the past week. Response choices are: 1 = “none”, 
2 = “Mild”, 3 = “Moderate”, 4 = “Severe”. 
Participants will complete the 2 items as described in the SoA (see Section 1.3). The items are 
provided in Section 10.7.9 and Section 10.7.10.  
8.1.8 Euroqol 5 dimensions questionnaire  
The Euroqol-5 dimensions (EQ-5D) is a standardized PRO measure of health status developed by 
the EuroQOL Group in order to provide a simple, generic measure of health for clinical and 
economic appraisal (30). The EQ-5D consists of 2 parts: the descriptive system and the EQ visual 
analog scale (VAS). The EQ-5D descriptive system comprises the following 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 
5 levels of perceived problems: “no problem”, “slight problems”, “moderate problems”, “severe 
problems” and “inability to do the activity”. The respondent is asked to indicate his/her health 
state by ticking (or placing a cross) in the box against the most appropriate statement in each of 
the 5 dimensions; this results in a 1-digit number expressing the level for that dimension. The 
digits for 5 dimensions can be combined in a 5-digit number describing the respondent’s health 
state. The EQ VAS records the respondent’s self-rated health on a vertical VAS where the 
endpoints are labeled “best imaginable health state (100)” and “worst imaginable health state (0)”. 
This information can be used as a quantitative measure of health outcome as judged by the 
individual respondents. 
Participants will complete the questionnaire as described in the SoA (see Section 1.3). The 
assessment tool is provided in Section 10.7.6. 
8.1.9 Missed school/work days  
Participants who are employed or enrolled in school will be asked to report the number of sick 
leave/missed school days since the last study assessment. 
Participants will complete the questionnaire as described in the SoA (see Section 1.3). The 
assessment tool is provided in Section 10.7.11.  
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8.2 
SAFETY ASSESSMENTS   
Planned time points for all safety assessments are provided in the SoA (see Section 1.3). 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the skin (full 
body skin exam), nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, 
neurological, lymphatic, and musculoskeletal systems. 
• Participants must be disrobed and provided with a hospital gown before the skin examination. 
• Investigators should pay special attention to clinical signs related to previous serious illnesses. 
• Any new finding or worsening of previous finding should be reported as a new AE. 
8.2.2 Vital signs  
• Vital signs will be measured in a semi-supine or sitting position after 5 minutes rest and 
will include body temperature, SBP and DBP, and pulse and respiratory rate. Blood 
pressure and pulse measurements should be assessed using the same arm with a 
completely automated device. Manual techniques will be used only if an automated device 
is not available.  
• Body weight (kg) will be measured at screening (Visit 1), EOT, and EOS visits. Height 
will be measured at screening visit (Visit 1). Height and weight should be measured with 
indoor clothing but without shoes. 
8.2.3 Electrocardiograms  
• Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTcF intervals. Refer to Section 7 for QTcF withdrawal criteria and any additional QTcF 
readings that may be necessary. The ECG should be recorded after 10 minutes of rest in 
the supine position. 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (see Section 1.3) for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 12 weeks after the last dose of study intervention 
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should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or medical monitor. 
- 
If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified and the Sponsor notified. 
- 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA 
(see Section 1.3). 
- 
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the CRF.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. 
For these AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described in Section 10.3, even if not fulfilling a seriousness criterion, using the 
corresponding pages in the CRF (to be sent) or screens in the eCRF. If an SAE or any AESI of 
anaphylactic reactions or systemic allergic reactions that are related to IMP and require treatment, 
or severe injection site reactions lasting longer than 24 hours, occurs in a participant, blood 
samples should be collected for determination of functional dupilumab concentration, and ADA 
assessment at or near the onset and completion of the occurrence of the event, if possible. 
• Anaphylactic reactions 
• Systemic hypersensitivity reactions 
• Helminthic infections  
• Any severe type of conjunctivitis or blepharitis  
• Keratitis 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms) 
• Pregnancy of a female subject entered in a study as well as pregnancy occurring in 
a female partner of a male subject entered in a study with IMP/NIMP;  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria. 
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- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined.  
- 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
• Significant ALT elevation  
- 
ALT >5 x ULN in participants with baseline ALT ≤2 x ULN;  
OR 
- 
ALT >8 x ULN if baseline ALT >2 x ULN 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP  
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least 
twice the intended dose during an interval of less than 11 days. The circumstances 
(ie, accidental or intentional) should be clearly specified in the verbatim and 
symptoms, if any, entered on separate AE forms. 
- 
An overdose (accidental or intentional) with any NIMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least 
twice the maximum prescribed daily dose, within the intended therapeutic interval. 
The circumstances (ie, accidental or intentional) should be clearly specified in the 
overdose form. 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs, serious or nonserious, will be collected from the signing of the ICF until the EOS visit at 
the time points specified in the SoA (Section 1.3). 
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study participation. 
However, if the Investigator learns of any SAE, including a death, at any time after a participant has 
been discharged from the study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the Investigator must promptly notify the Sponsor. 
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8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs and 
nonserious AESI (as defined in Section 8.3) will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is given in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• Adverse events that are considered expected will be specified in the reference safety 
information. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until the outcome has been 
determined.  
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• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 Guidelines for reporting product complaints  
Any defect in the IMP/NIMP/device must be reported as soon as possible by the Investigator to 
the monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
TREATMENT OF OVERDOSE  
Overdose is an AESI (defined in Section 8.3). No antidote is available for dupilumab. Sponsor 
does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator/treating physician should: 
1. Provide symptomatic care. 
2. Contact the Medical Monitor immediately. 
3. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
dupilumab can no longer be detected systemically. 
4. Obtain a plasma sample for PK analysis as soon as possible if requested by the Medical 
Monitor (determined on a case-by-case basis). 
5. Document appropriately in the CRF. 
Decisions regarding dose interruptions will be made by the Investigator in consultation with the 
Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
8.5.1 Systemic drug concentration and antidrug antibodies  
8.5.1.1 Sampling time  
Blood samples will be collected for determination of functional dupilumab and anti-dupilumab 
antibodies in serum as specified in the SoA (Section 1.3). Special procedures for collection, 
storage, and shipping of serum are described in separate operational manuals. The date of 
collection should be recorded in the eCRF. 
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8.5.1.2 Handling procedures  
Special procedures for collection, storage, and shipping of serum are described in separate 
operational manuals. An overview of handling procedure for samples used in the determination of 
systemic drug concentration and ADA is provided in Table 3. 
Table 3 - Summary of handling procedures  
Sample type 
Functional dupilumab 
Anti-dupilumab antibody 
Matrix 
Serum 
Serum 
Blood sample volume 
5 mL 
5 mL 
Anticoagulant 
None 
None 
Blood handling procedures 
See Operational Manual 
See Operational Manual 
Serum aliquot split 
2 aliquots 
2 aliquots 
Storage conditions 
<6 months: below -20°C 
<24 months: below -80°C (preferred) 
<6 months: below -20°C 
<24 months: below -80°C (preferred) 
Serum shipment condition 
In dry ice 
In dry ice 
 
8.5.1.3 Bioanalytic method  
Serum PK and ADA samples will be assayed using validated methods as described in Table 4. 
Note: In the event of any SAE, any AE of severe injection site reaction lasting longer than 
24 hours, or any AESI of anaphylactic reaction or systemic allergic reaction that is related to IMP 
and require treatment, PK and ADA samples will be collected at or near the onset of the event for 
any additional analysis if required or for archival purposes. The exact date and time of sample 
collection must be recorded and entered into the database by the central laboratory. An 
unscheduled systemic drug concentration page in the eCRF must be completed as well. If 
necessary for safety monitoring, additional PK and ADA samples may be collected after the EOS 
Visit until resolution of AE. 
Specifically for PK, any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team member and then 
archived in the Sponsor and site study files, but will not constitute a protocol amendment. The 
IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the ICF.  
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8.6 
PHARMACODYNAMICS  
See Section 8.8 for IgE measurement. No other PD parameters will be evaluated in this study. 
8.7 
GENETICS  
For those participants who consent to the optional pharmacogenetic/pharmacogenomic sample 
collection section of the ICF, blood samples for exploratory genetic analysis of DNA or RNA will 
be collected and stored for possible future use (see Section 10.5). Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in the 
study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant.  
Details on processes for collection and shipment and destruction of these samples can be found in 
the laboratory manual.  
8.8 
BIOMARKERS  
• Venous blood samples will be collected for measurement of total serum IgE. Total IgE 
will be measured using validated quantitative methods. 
• Optional samples for biomarker research that should be collected from participants in the 
study with their consent include: 
- 
Serum and plasma: samples will be collected and stored for possible future analysis of 
potential biomarkers of drug response, disease activity, safety, and Type 2 inflammation. 
Plasma and serum samples may be stored for a maximum of 5 years, and DNA or RNA samples 
for 15 years (or according to local regulations) following the last participant’s last visit for the 
study at a facility selected by the Sponsor. 
8.9 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS  
Number of missed school/work days collection is described in Section 8.1.9. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
The statistical hypotheses for comparing dupilumab to placebo on the primary endpoint of the 
proportion of participants with WI-NRS reduction of ≥4 (minimally important difference) at 
Week 12 are as follows: 
• Null hypothesis H0: No treatment difference between dupilumab and placebo 
• Alternative hypothesis H1: There is a treatment difference between dupilumab and 
placebo 
The statistical hypotheses to be tested on secondary endpoints can be specified similarly to those 
on the primary endpoint. 
9.2 
SAMPLE SIZE DETERMINATION  
The primary endpoint is the proportion of participants with WI-NRS reduction of ≥4 from 
baseline to Week 12. By assuming the response rate is 
 in placebo and dupilumab 
respectively, 56 participants/arm will provide 90% power to detect the difference of 
 between 
dupilumab and placebo with Fisher exact test at 2-sided level of 0.05. Assuming 15% drop out 
during the 12 weeks of treatment, the target is to randomize 75 participants/arm with a cap of up 
to 10% of participants in the atopic population having active mild AD. 
Approximately 150 participants will be randomized 1:1. This corresponds to approximately 
75 participants that will be randomly assigned to each intervention arm. 
The sample size calculation was performed using SAS 9.4 power procedure. The assumptions 
were based on the effect of dupilumab versus placebo in WI-NRS reduction ≥4 at Week 16 
observed in patients with moderate to severe AD as seen in studies of R668-AD-1334 (Solo1) and 
R668-AD-1416 (Solo2).  
Participants will be randomized to dupilumab or placebo in 1:1 ratio with stratification factors of 
documented history of atopy (atopic or non-atopic, see definition in Section 6.3), stable use of 
TCS/TCI (yes or no), and country/territory code. Both the atopic and the non-atopic PN 
population will be capped at 60% of the total enrolled population. 
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9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 5): 
Table 5 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the ICF. 
Randomized 
The randomized population includes all participants with a treatment kit number allocated 
and recorded in the IRT database, and regardless of whether the treatment kit was used or 
not. 
Participants treated without being randomized will not be considered randomized and will 
not be included in any efficacy population. 
Intent-to-treat (ITT) 
All randomized participants analyzed according to the treatment group allocated by 
randomization regardless if treatment kit is used or not 
Efficacy 
The ITT population 
Safety 
All participants randomly assigned to study intervention and who take at least 1 dose of 
study intervention. Participants will be analyzed according to the intervention they actually 
received.  
Randomized participants for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized.  
For participants who accidentally receive different treatment from the planned, the actual 
intervention allocation for as-treated analysis will be the dupilumab group. 
The PD analyses will be performed on the safety population. 
Pharmacokinetic (PK) 
The PK population includes all participants in the safety population with at least 
one non-missing result for functional dupilumab concentration in serum after first dose of 
the study treatment. Participants will be analyzed according to the intervention actually 
received. 
Antidrug antibody (ADA) 
ADA population includes all participants in the safety population who have at least 
one non-missing ADA result after first dose of the study treatment. Participants will be 
analyzed according to the intervention actually received. 
ADA: antidrug antibody; ICF: informed consent form; ITT: intent to treat; PD: pharmacodynamics: PK: pharmacokinetic 
9.4 
STATISTICAL ANALYSES  
The SAP will be developed and finalized before primary database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data. This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints. 
9.4.1 Efficacy analyses  
The multiplicity procedure is proposed to control the overall Type-I error rate for testing the 
primary endpoint and the key secondary endpoints. Detailed hierarchical testing procedure will be 
defined in the study SAP. The study is considered positive when the primary endpoint achieves 
statistical significance with two-sided significance level 0.05. 
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Table 6 - Efficacy analyses  
Endpoint 
Statistical analysis methods 
Primary: 
Proportion of participants with 
improvement (reduction) in WI-NRS by 
≥4 from baseline to Week 12 
 
The primary analysis will be conducted by using CMH test stratifying by 
stratification factors (documented history of atopy [atopic or non-atopic], stable use 
of TCS/TCI [yes or no], and region [countries combined]) and covariate of baseline 
anti-depressant use (yes or no).  
For participants discontinuing the study treatment before Week 12, their off-study 
treatment values measured up to Week 12 will be included in the analysis. 
Participants taking selected prohibited medications and/or rescue medications 
(details of selection will be provided in the SAP) prior to Week 12 or have missing 
data at Week 12 will be considered non-responders.  
Sensitivity analyses:  
The data collected after taking selected prohibited medications and/or rescue 
medications will not be censored and included in the sensitivity analysis to 
evaluate the robustness of the primary analysis results with respect to the method 
of handling data while taking selected prohibited medications. Details of the 
sensitivity analyses will be provided in the SAP.  
Subgroup analyses: 
To assess the consistency in treatment effects across different subgroup levels, 
subgroup analyses will be performed for the primary efficacy endpoint with respect 
to documented history of atopy (atopic or non-atopic), age group, gender, region, 
and other factors that will be specified in the SAP. A subgroup analysis will be 
performed excluding participants with a current diagnosis of AD. 
Key secondary: 
Proportion of participants with 
improvement (reduction) in WI-NRS by 
≥4 from baseline to Week 24. 
Proportion of participants with IGA PN-S 
0 or 1 score at Week 24. 
Key secondary efficacy endpoints that measure binary responses will be analyzed 
in the same fashion as the primary endpoint. 
Secondary: 
Proportion of participants with WI-NRS 
reduction ≥4 over time until Week 24. 
Proportion of participants with IGA PN-S 
0 or 1 score at Week 12. 
Proportion of participants with IGA PN-S 
0 or 1 score at Week 8. 
Proportion of participants with IGA PN-S 
0 or 1 score at Week 4. 
Proportion of participants with IGA PN-A 
0 or 1 score at Week 24. 
Proportion of participants with IGA PN-A 
0 or 1 score at Week 12. 
Proportion of participants with IGA PN-A 
0 or 1 score at Week 8. 
Proportion of participants with IGA PN-A 
0 or 1 score at Week 4. 
Proportion of participants with WI-NRS 
reduction ≥4 at Week 4. 
 
Secondary efficacy endpoints that measure binary responses will be analyzed in 
the same fashion as the primary endpoint. 
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Endpoint 
Statistical analysis methods 
Time to onset of effect on pruritus as 
measured by proportion of participants 
with improvement (reduction) in WI-NRS 
by ≥4 from baseline during the 
24-week treatment period. 
This time-to-event endpoint will be analyzed using the Cox proportional hazards 
model, including treatment, stratification factors (countries combined to region), 
and covariate of baseline anti-depressant use (yes or no). The hazards ratio, its 
95% confidence interval and p-value will be reported. Kaplan-Meier curves will be 
also provided. 
Change from baseline in WI-NRS at 
Week 24. 
Change from baseline in WI-NRS at 
Week 12. 
Percent change from baseline in WI-NRS 
at Week 24. 
Percent change from baseline in WI-NRS 
at Week 12. 
Percent change from baseline in WI-NRS 
at Week 4. 
Percent change from baseline in WI-NRS 
at Week 2. 
Percent change from baseline in WI-NRS 
over time until Week 24. 
Change from baseline in IGA PN-S score 
at Week 24.  
Change from baseline in IGA PN-S score 
at Week 12.  
Change from baseline in IGA PN-S score 
at Week 8.  
Change from baseline in IGA PN-S score 
at Week 4.  
Change from baseline in HRQoL, as 
measured by DLQI to Week 24. 
Change from baseline in HRQoL, as 
measured by DLQI to Week 12. 
Onset of action in change from baseline 
in WI-NRS (first p <0.05 difference from 
placebo in the daily WI-NRS that remains 
significant at subsequent measurements) 
until Week 12. 
Continuous secondary efficacy endpoints will be analyzed using a hybrid method 
of the WOCF and multiple imputations.  
Data of participants taking selected prohibited medications and/or rescue 
medications will be set to missing after the medication usage, and the worst 
postbaseline value on or before the time of the medication usage will be used to 
impute missing endpoint value (for participants whose postbaseline values are all 
missing, the baseline will be used to impute).  
Participants who discontinue the treatment prematurely are encouraged to follow 
the planned clinical visits and in those participants who did not take the selected 
prohibited medications and/or rescue medications, all data collected after 
treatment discontinuation will be used in the analysis. For these participants, 
missing data may still happen despite all efforts have been tried to collect the data 
after treatment discontinuation. For participants who discontinue due to lack of 
efficacy, all data collected after discontinuation will be used in the analysis, and a 
WOCF approach will be used to impute missing data if needed. For participants 
who discontinued not due to lack of efficacy, a multiple imputation approach will be 
used to impute missing endpoint value, and this multiple imputation will use all 
participants excluding patients who have taken the selected prohibited 
medications and/or rescue medications prior to timepoint of endpoint of interest 
and excluding participants who discontinue due to lack of efficacy.  
Each of the imputed complete data will be analyzed by fitting an ANCOVA model 
with treatment group, stratification factors (documented history of atopy [atopic or 
non-atopic], stable use of TCS/TCI [yes or no], and region [countries combined]), 
baseline antidepressant use (yes or no), and relevant baseline measurement as 
covariates included in the model. Statistical inference obtained from all imputed 
data will be combined using Rubin’s rule. Descriptive statistics including number of 
subjects, mean, standard error, and least squares (LS) mean change and 
standard error will be provided. In addition, difference of the dupilumab group 
against placebo in LS means and the corresponding 95% confidence interval will 
be provided along with the p-values. 
Detailed analyses will be described in the SAP finalized before database lock. The 
sensitivity analyses will be also detailed in the SAP to evaluate the robustness of 
the hybrid method of the WOCF and multiple imputations handling intercurrent 
events such as taking prohibited medication, rescue medication, or missing data 
due to study treatment withdrawal. 
Tertiary/exploratory 
Will be described in the SAP finalized before database lock. 
ANCOVA: analysis of covariance; CMH: Cochran-Mantel-Haenszel; DLQI: Dermatology Life Quality Index; IGA: Investigator’s global 
assessment; LS: Least squares; NRS: numeric rating scale; PAS: prurigo activity score; WI-NRS: worst itch numeric rating scale. 
9.4.2 Safety analyses  
All safety analyses will be performed on the Safety Population. The summary of safety results 
will be presented by treatment group. The baseline value is defined generally as the last available 
value before randomization. 
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Table 7 - Safety analyses  
Endpoint 
Statistical analysis methods 
Percentage of participants 
experiencing TEAEs or SAEs 
from baseline through Week 24 
Adverse event incidence tables will present by SOC (sorted by internationally agreed 
order), and PT sorted in alphabetical order for each treatment group, the number (n) and 
percentage (%) of participants experiencing an AE. Multiple occurrences of the same event 
in the same participant will be counted only once in the tables within a treatment phase. 
The denominator for computation of percentages is the safety population within each 
treatment group. 
Proportion of participants with at least one TEAE, treatment emergent SAE, TEAE leading 
to death, and TEAE leading to permanent treatment discontinuation will be tabulated by 
treatment group. In addition TEAEs will be described according to maximum intensity and 
relation to the study intervention. Serious AEs and AEs leading to study discontinuation that 
occur outside the treatment-emergent period will be summarized separately. 
AE: adverse event; PT: preferred term; SOC: system organ class; SAE: serious adverse event; TEAE: treatment-emergent adverse event 
9.4.3 Other analyses  
Table 8 - Other analyses  
Endpoint 
Statistical analysis methods 
Incidence of treatment-emergent 
ADA against dupilumab over time 
The ADA analysis will be conducted on ADA population. ADA variables including 
treatment-emergent ADA will be summarized using descriptive statistics by treatment 
group. Drug concentration data will be examined and the influence of ADAs on 
individual concentration-time profiles will be evaluated. Assessment of the potential 
impact of ADA on safety and efficacy may be provided. 
ADA: antidrug antibodies 
Other PK, PD, biomarker, and outcome measures exploratory analyses will be described in the 
SAP finalized before database lock. The population PK analysis and PD analyses will be 
presented separately from the main clinical study report (CSR). 
Data collected regarding the impact of the COVID-19 or other pandemics, on the patients will be 
summarized (eg, discontinuation due to COVID-19). Any additional analyses and methods 
required to investigate the impact of COVID-19 or other pandemics requiring public health 
emergency on the efficacy (eg; missing data due to COVID-19) and safety will be detailed in the 
SAP. 
9.5 
INTERIM ANALYSES   
No interim analysis is planned. 
A primary database lock will be performed when all randomized participants in this study have 
completed their 24-week treatment phase. Final analyses in the CSR will be based on this 
database. 
The database will be updated at the end of the study for all participants to include the 
post-treatment follow-up information and updates for the events previously ongoing at the time of 
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the primary lock. Additional data between this database lock and last participant completing last 
visit will be summarized in a CSR addendum. 
More details will be described in the SAP. 
9.5.1 Data Monitoring Committee (DMC)  
Due to extensive safety record of the post marketed IMP (dupilumab), it is not planned to have 
a DMC for this study. 
9.5.2 Unblinding plan  
Unblinding plan is not applicable for this study. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and Ethical Considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. 
- 
Applicable ICH GCP Guidelines. 
- 
Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples as 
well as additional serum/plasma samples for optional exploratory research. The Investigator or 
authorized designee will explain to each participant the objectives of the exploratory research. 
Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. An optional consent will be required to 
document a participant's agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate in this optional research will not provide this 
optional consent. 
The ICF will also contains a separate section concerning the other optional procedure (genetic 
testing [DNA/RNA sampling]). An optional consent will be required to document a participant’s 
agreement to each of this procedure. Participants who decline to participate will not provide this 
optional consent. A specific consent will be provided for HIV testing if specific consent is locally 
required. 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the Global Data Protection Regulation. 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
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Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, for reporting effectiveness data by racial subgroup in marketing 
authorization applications for FDA, or to report on the Japanese population for the 
Pharmaceuticals and Medical Devices Agency in Japan). In addition, race has been identified to 
influence PN incidence (15). 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
10.1.5 Committees structure  
There will be no study committees. 
10.1.6 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publically accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
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10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
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• Source data is all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents. 
Source documents are original documents, data and records such as hospital records, clinic 
and office charts, laboratory notes, memoranda, pharmacy dispensing records, recorded 
data from automated instruments, etc. 
10.1.9 Study and site closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio. 
- 
Discontinuation of further study intervention development. 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator. 
- 
Total number of participants included earlier than expected. 
10.1.10 
Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
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10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
The tests detailed in Table 9 will be performed by the central laboratory. 
• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central analysis 
is obtained at the same time. Additionally, if the local laboratory results are used to make 
either a study intervention decision or response evaluation, the results must be entered into 
the CRF. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the subject's participation in the study. 
Table 9 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
 
 
Platelet count 
 
RBC count 
 
Hemoglobin 
 
Hematocrit 
 
WBC count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
CD4 T cell count (for participants with HIV history only) 
Clinical chemistrya 
 
 
BUN 
 
Creatinine 
 
Glucose 
 
Lactate dehydrogenase 
Uric acid 
Total cholesterol 
Potassium 
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Laboratory assessments 
Parameters 
 
Sodium 
 
Chloride 
Bicarbonate 
 
AST/SGOT 
 
ALT/SGPT 
 
Alkaline phosphatase 
Creatine phosphokinase 
 
Total bilirubin 
 
Total protein 
Albumin 
 
Hemoglobin A1c (only for diabetic patients without hemoglobin A1c laboratory results within 
3 months before screening visit) 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick 
• 
Creatinine and leukotriene (central laboratory) 
• 
Microscopic examination (if blood or protein is abnormal) 
• 
Tetranor PGDM (central laboratory) 
Other screening tests 
• 
Highly sensitive serum (at screening) or urine (at other timepoints) hCG 
pregnancy test (as needed for WOCBP)b  
• 
Serologyc: HBs Ag, HBs Ab, HBc Ab, HCV Ab, HIV screen (Anti-HIV-1 and HIV-2 
antibodies); HIV viral load test (for participants with HIV history only) 
• 
Tuberculosis test 
• 
All study-required laboratory assessments will be performed by a central 
laboratory, with the exception of TB test, urine pregnancy test, and routine 
urinalysis. 
NOTES: 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are 
given in Section 7.1 and Section 10.6. All events which may indicate severe liver injury (meeting Hy’s Law laboratory criteria; ALT or AST 
>3 x ULN and total bilirubin >2 x ULN) must be reported as an SAE.  
b After screening, local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
c In case of results showing HBs Ag (negative) and HBc Ab (positive), an HBV DNA testing will be performed and should be confirmed 
negative prior to randomization. In case of results showing HCV Ab (positive), HCV RNA testing will be performed and should be 
confirmed negative prior to randomization. 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; DNA: deoxyribonucleic acidHBc Ab: hepatitis B 
core antibody; HBs Ab: hepatitis B surface antibody; HBs Ag: hepatitis B surface antigen; HBV: hepatitis B virus; hCG: human chorionic 
gonadotropin; HCV: hepatitis C virus; HCV Ab: hepatitis C virus antibody; HIV: human immunodeficiency virus; IEC: Independent Ethics 
Committee; IRB: Institutional Review Board; RBC: red blood cells; RNA: ribonucleic acid; SAE: serious adverse event; SGOT: serum 
glutamic-oxaloacetic transaminase; SGPT: serum glutamic-pyruvic transaminase; TB: tuberculosis; ULN: upper limit of normal; WBC: white 
blood cells; WOCBP: woman of childbearing potential 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
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10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
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• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
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- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In such case, care should be taken to ensure that the patient's 
identity is protected and the patient's identifiers in the study are properly mentioned on any 
copy of a source document provided to the Sponsor. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
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• The Investigator will use clinical judgment to determine whether or not the relationship is 
causal. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representative. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor’s representative with a copy of any 
post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
REPORTING OF SAES 
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
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• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the protocol. 
SAE reporting to the Sponsor’s representative via paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
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Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 consecutive months without an 
alternative medical cause.  
- 
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the non-estrogen hormonal highly effective 
contraception methods if they wish to continue their HRT during the study. 
CONTRACEPTION GUIDANCE 
Female participants of childbearing potential are eligible to participate if they agree to use 
a highly effective method of contraception consistently and correctly as described below. 
 
Contraceptivesa allowed during the study include: 
Highly effective methodsb that have low user dependency  
Failure rate of <1% per year when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
- 
Intrauterine device (IUD) 
- 
Intrauterine hormone-releasing system (IUS)b 
• 
Bilateral tubal occlusion 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used. Spermatogenesis cycle is approximately 90 days.) 
Highly effective methodsb that are user dependent  
Failure rate of <1% per year when used consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
- 
oral 
- 
intravaginal 
- 
transdermal 
- 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
- 
oral 
- 
injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.) 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to 
those which inhibit ovulation as the primary mode of action. 
WOCBP: woman of childbearing potential 
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COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive dupilumab. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of 
a participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy will be reported as 
an AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4 of the protocol. While the Investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention.  
10.5 
APPENDIX 5: GENETICS  
Use/Analysis of DNA and RNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; safety, disease etiology; and/or molecular 
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subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants. 
• DNA and RNA samples will be used for research related to dupilumab or PN and related 
diseases. They may also be used to develop tests/assays including diagnostic tests related 
to dupilumab or related drugs and atopic/allergic diseases. Genetic research may consist of 
the analysis of one or more candidate genes or the analysis of genetic markers throughout 
the genome including whole-exome sequencing, whole-genome sequencing, and DNA 
copy number variation. Transcriptome sequencing (or other methods for quantitating RNA 
expression) may also be performed. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to dupilumab or study interventions of this class to understand 
study disease or related conditions. 
• The results of genetic analyses will not be reported in the CSR.  
• The Sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 
• The samples will be retained no longer than 15 years or other period as per local 
requirements. 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS  
 
*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation. 
Note: 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline visit. The 
algorithm does not apply to the instances of increase in ALT during screening. 
See Section 10.3 for guidance on safety reporting. 
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 
INCREASE IN ALT
ALT > 3 ULN
Confirm ALT > 3 ULN
Retest within 72 hours of initial 
sample*
No
Yes
COMPLETE the specific CRF forms for 
„ALT Increase” and inform the 
Monitoring Team within 24 hours
Total Bilirubin > 2 ULN 
No
Yes
ALT > 5 ULN (if baseline ALT ≤ 2 ULN), or 
ALT >8 ULN (if baseline ALT > 2 ULN)
Continue IMP administration
No
Monitor LFTs every 72 hours
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
Yes
Permanent Discontinuation of IMP
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or hypotension and/or episode of 
arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV  IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances suggesting hepatic 
encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to normal/baseline or clinical 
resolution.
8.
FREEZE serum sample (5ml x 2)
9.   In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
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Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting AEs in Section 10.3 is met. 
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Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting AEs in Section 10.3 is met. 
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10.7 
APPENDIX 7: CLINICIANS-REPORTED OUTCOMES AND PATIENT-REPORTED 
OUTCOMES  
10.7.1 Worst itch numeric rating scale (WI-NRS)  
 
 
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10.7.2 Investigator’s global assessment of prurigo nodularis (IGA PN)  
 
Copyright @ Center for Chronic Pruritus, University Hospital Münster Under license. For 
permission to use refer to: KCPadministration@ukmuenster.de 
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10.7.3 Prurigo activity score (PAS)  
 
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Copyright @ Center for Chronic Pruritus, University Hospital Münster Under license. For 
permission to use refer to: KCPadministration@ukmuenster.de 
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10.7.4 Dermatology life quality index (DLQI)  
 
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10.7.5 Hospital anxiety and depression scale (HADS)  
 
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10.7.6 EQ-5D-5L  
 
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10.7.7 Pain numeric rating scale  
 
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10.7.8 Sleep numeric rating scale  
 
10.7.9 Patient Global Impression of Change of disease (PGIC)  
 
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10.7.10 
Patient Global Impression of Severity (PGIS)  
 
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10.7.11 
Missed school/work days  
 
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10.8 
APPENDIX 8: DEFINITION OF ANAPHYLAXIS  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death (31).” 
Clinical criteria for diagnosing anaphylaxis 
 
10.9 
APPENDIX 9: LIST OF OPPORTUNISTIC INFECTIONS  
• Aspergillosis 
• Blastomyces dermatitidis (endemic in the south-eastern and south-central states US, along 
Mississippi and Ohio Rivers) 
• Candidiasis - only systemic or extensive mucosal or cutaneous candidiasis  
• Coccidioides immitis (endemic south-western US and Central and South America) 
• Cryptococcus 
• Cytomegalovirus 
• Herpes Simplex (disseminated) 
• Herpes Zoster (disseminated; ophthalmic; involvement of 2 or more dermatomes) 
• Histoplasmosis (pulmonary or disseminated; most common tropical areas 
Tennessee-Ohio-Mississippi river basins) 
• Listeriosis 
• Mycobacterium avium 
• Nontuberculosis mycobacteria 
• Pneumocystis pneumonia 
This list is indicative and not exhaustive. 
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10.10 APPENDIX 10: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 
10.11 APPENDIX 11: ABBREVIATIONS  
 
ACE: 
angiotensin converting enzyme 
AD: 
atopic dermatitis 
ADA: 
antidrug antibody 
ADR: 
adverse drug reaction 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
BUN: 
blood urea nitrogen 
CFR: 
Code of Federal Regulations 
CIOMS: 
Council for International Organizations of Medical Sciences 
ClinRO: 
clinician-reported outcome 
CMH: 
Cochran-Mantel-Haenszel 
CONSORT: 
Consolidated Standards of Reporting Trials 
COVID-19: 
coronavirus disease 2019 
CRF: 
case report form 
CRSwNP: 
chronic rhinosinusitis with nasal polyposis 
CSR: 
clinical study report 
DBP: 
diastolic blood pressure 
DLQI: 
dermatology life quality index 
DMC: 
data monitoring committee 
DNA: 
deoxyribonucleic acid 
DTP: 
direct-to-patient 
EADV: 
European Academy of Dermatology and Venereology 
EASI: 
eczema area and severity index 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
ELISA: 
enzyme-linked immunosorbent assay 
EMA: 
European Medicines Agency 
EoE: 
eosinophilic esophagitis 
EOS: 
end of study 
EOT: 
end of treatment 
EQ-5D: 
Euroqol 5 dimensions 
EQ-5D-5L: 
Euroqol 5 dimensions 5 levels 
EU: 
European Union 
FDA: 
Food and Drug Administration 
GCP: 
Good Clinical Practice 
HADS: 
hospital anxiety and depression scale 
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HBc Ab: 
hepatitis B core antibody 
HBs Ab: 
hepatitis B surface antibody 
HBs Ag: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
hCG: 
human chorionic gonadotropin 
HCV: 
hepatitis C virus 
HCV Ab: 
hepatitis C virus antibody 
HIV: 
human immunodeficiency virus 
HRQoL: 
health-related quality of life 
HRT: 
hormone replacement therapy 
IB: 
investigator's brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation  
IEC: 
Independent Ethics Committee 
Ig: 
immunoglobulin 
IGA: 
investigator's global assessment 
IGA PN: 
investigator's global assessment for prurigo nodularis 
IGA PN-A: 
IGA PN-Activity 
IGA PN-S: 
IGA PN-Stage 
IL: 
interleukin 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ITT: 
intent to treat 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
LS: 
least squares 
NIMP: 
noninvestigational medicinal product 
NRS: 
numeric rating scale 
PAS: 
prurigo activity score 
PD: 
pharmacodynamic 
PGA: 
physician global assessment 
PGIC: 
Patient Global Impression of Change 
PGIS: 
Patient Global Impression of Severity 
PK: 
pharmacokinetic 
PN: 
prurigo nodularis 
PRO: 
patient reported outcome 
PT: 
preferred term 
Q2W: 
every 2 weeks 
QTcF: 
QT interval corrected using Fridericia's formula 
RBC: 
red blood cells 
RNA: 
ribonucleic acid 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SC: 
subcutaneous 
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SCORAD: 
scoring atopic dermatitis 
SGOT: 
serum glutamic-oxaloacetic transaminase 
SGPT: 
serum glutamic-pyruvic transaminase 
SNRI: 
serotonin and norepinephrin reuptake inhibitor 
SoA: 
schedule of activities 
SOC: 
system organ class 
SSRI: 
selective serotonin reuptake inhibitor 
SUSAR: 
suspected unexpected serious adverse reaction 
TB: 
tuberculosis 
TCI: 
topical calcineurin inhibitors 
TCS: 
topical corticosteroids 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal 
US: 
United States 
UVB: 
ultraviolet B 
VAS: 
visual analog scale 
WBC: 
white blood cells 
WI-NRS: 
worst-itch numeric rating scale 
WOCBP: 
woman of childbearing potential 
WOCF: 
worst observation carried forward 
 
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
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11 
REFERENCES  
1. Zeidler C, Athanasios T, Pereira M, Stander H, Yosipovitch G, Stander S. Chronic prurigo of 
nodular type: A Review. Acta Derm Venereol 2018;98(2):173-9.  
2. 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(5):550-7. 
3. Mollanazar NK, Elgash M, Weaver L, Valdes-Rodriguez R, Hsu S. Reduced itch associated 
with dupilumab treatment in 4 patients with prurigo nodularis. JAMA Dermatol. 
2019;155(1):121-2. 
4. Beck KM, Yang EJ, Sekhon S, Bhutani T, Liao W. Dupilumab treatment for generalized 
prurigo nodularis. JAMA Dermatol. 2019;155(1):118-20. 
5. Rambhia PH, Levitt JO. Recalcitrant prurigo nodularis treated successfully with dupilumab. 
JAAD Case Rep. 2019;5(5):471-3. 
6. Calugareanu A, Jachiet M, Lepelletier C, De Masson A, Rybojad M, Bagot M, et al. Dramatic 
improvement of generalized prurigo nodularis with dupilumab. J Eur Acad Dermatol 
Venereol. 2019; 33(8):e303-4. 
7. Zhai LL, Savage KT, Qiu CC, Jin A, Valdes-Rodriguez R, Mollanazar NK. Chronic Pruritus 
Responding to Dupilumab-A Case Series. Medicines (Basel). 2019;6(3):E72. 
8. Weigelt N, Metze D, Stander S. Prurigo nodularis: systematic analysis of 58 histological 
criteria in 136 patients. J Cutan Pathol. 2010;37(5):578-86 
9. Yang TB, Kim BS. Pruritus in allergy and immunology. J Allergy Clin Immunol. 
2019;144(2):353-60. 
10. Pereira MP, Steinke S, Zeidler C, Forner C, Riepe C, Augustin M, et al. European academy of 
dermatology and venereology European prurigo project: expert consensus on the definition, 
classification and terminology of chronic prurigo. J Eur Acad Dermatol Venereol. 
2018;32(7):1059-65. 
11. Zeidler C, Ständer S. The pathogenesis of Prurigo nodularis--'Super-Itch' in exploration. Eur J 
Pain. 2016;20(1):37-40. 
12. Fukushi S, Yamasaki K, Aiba S. Nuclear localization of activated STAT6 and STAT3 in 
epidermis of prurigo nodularis. Br J Dermatol. 2011;165(5):990-6. 
13. Tokura Y, Yagi H, Hanaoka K, Ito T, Towyama K, Sachi Y, et al. Subacute and chronic 
prurigo effectively treated with recombination interferon-gamma: implications for 
participation of Th2 cells in the pathogenesis of prurigo. Acta Derm Venereol. 
1997;77(3):231-4. 
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14. Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, Guo CJ, et al. Sensory neurons co-opt 
classical immune signaling pathways to mediate chronic itch. Cell. 2017;171(1):217-28. 
15. Boozalis E, Tang O, Patel S, Semenov YR, Pereira MP, Stander S, et al. Ethnic differences 
and comorbidities of 909 prurigo nodularis patients. J Am Acad Dermatol. 2018;79(4):714-9. 
16. Steinke S, Zeidler C, Riepe C, Bruland P, Soto-Rey I, Storck M, et al. Humanistic burden of 
chronic pruritus in patients with inflammatory dermatoses: Results of the European Academy 
of Dermatology and Venereology Network on Assessment of Severity and Burden of Pruritus 
(PruNet) cross-sectional trial. J Am Acad Dermatol. 2018;79(3):457-63. 
17. Tanaka M, Aiba S, Matsumura N, Aoyama H, Tagami H. Prurigo nodularis consists of two 
distinct forms: early-onset atopic and late-onset non-atopic. Dermatology. 1995;190(4):269-
76. 
18. Kowalski EH, Kneiber D, Valdebran M, Patel U, Amber KT. Treatment-resistant prurigo 
nodularis: challenges and solutions. Clin Cosmet Investig Dermatol. 2019;12:163-72. 
19. Novartis Laboratories. NEORAL Soft Gelatin Capsules (cyclosporine capsules, USP) 
MODIFIED NEORAL Oral Solution (cyclosporine oral solution, USP) MODIFIED. 
Prescribing information. 2009. 
20. Ständer S, Kwon P, Hirman J, Perlman AJ, Weisshaar E, Metz M, et al. Serlopitant reduced 
pruritus in patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial. J 
Am Acad Dermatol. 2019;80(5):1395-402. 
21. Verweyen E, Ständer S, Kreitz K, Höben I, Osada N, Gernart M, et al. Validation of a 
Comprehensive Set of Pruritus Assessment Instruments: The Chronic Pruritus Tools 
Questionnaire PRURITOOLS. Acta Derm Venereol. 2019;99(7):657-63. 
22. Reich A, Bożek A, Janiszewska K, Szepietowski JC. 12-Item Pruritus Severity Scale: 
Development and Validation of New Itch Severity Questionnaire. Biomed Res Int. 
2017;2017:3896423. 
23. Reich A, Riepe C, Anastasiadou Z, Mędrek K, Augustin M, Szepietowski JC, et al. Itch 
Assessment with Visual Analogue Scale and Numerical Rating Scale: Determination of 
Minimal Clinically Important Difference in Chronic Itch. Acta Derm Venereol. 
2016;96(7):978-80. 
24. Phan NQ, Blome C, Fritz F, Gerss J, Reich A, Ebata T, et al. 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;92(5):502-7. 
25. Pölking J, Zeidler C, Schedel F, Osada N, Augustin M, Metze D, et al. Prurigo Activity Score 
(PAS): validity and reliability of a new instrument to monitor chronic prurigo. J Eur Acad 
Dermatol Venereol. 2018;32(10):1754-60. 
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26. Chernyshov PV. The evolution of quality of life assessment and use in dermatology. 
Dermatology. 2019;235(3):167-74. 
27. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure 
for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-6. 
28. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 
1983;67(6):361-70. 
29. Herrmann C. International experiences with the Hospital Anxiety and Depression Scale--a 
review of validation data and clinical results. J Psychosom Res. 1997;42(1):17-41. 
30. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20(10):1727-36. 
31. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report - 
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
 
 
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According to template: QSD-002643 VERSION 8.0 (17-JUN-2020) 
Page 1 
 
STATISTICAL ANALYSIS PLAN         
Protocol title: 
A randomized, double blind, placebo-controlled, 
multi-center, parallel group study to evaluate the 
efficacy and safety of dupilumab in patients with 
prurigo nodularis who are inadequately controlled on 
topical prescription therapies or when those 
therapies are not advisable 
Protocol number: 
EFC16460 
Compound number 
(INN/Trademark): 
SAR231893/REGN668 
dupilumab/Dupixent 
Study phase: 
Phase 3  
Short title: 
Study of dupilumab for the treatment of patients with 
prurigo nodularis, inadequately controlled on topical 
prescription therapies or when those therapies are 
not advisable 
LIBERTY-PN PRIME 2 
Statistician: 
 
Statistical project leader: 
 
Date of issue: 
08-Aug-2021 
Regulatory agency identifier number(s): 
IND: 
IND107969 
EudraCT: 
2019-003801-90 
NCT: 
NCT04202679 
WHO: 
U1111-1241-8174 
Other: 
Not applicable 
 
 
 
Total number of pages: 64 
 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 7 
1.1 
STUDY DESIGN .............................................................................................................................. 7 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 7 
1.2.1 
Estimands ...................................................................................................................................... 10 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 14 
3 
ANALYSIS POPULATIONS .......................................................................................................... 15 
4 
STATISTICAL ANALYSES ........................................................................................................... 17 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 17 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 17 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 18 
4.3.1 
Definition of endpoint(s) ................................................................................................................. 18 
4.3.2 
Main analytical approach ............................................................................................................... 20 
4.3.3 
Sensitivity analysis ......................................................................................................................... 21 
4.3.4 
Supplementary analyses ................................................................................................................ 21 
4.3.5 
Subgroup analyses ........................................................................................................................ 22 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 23 
4.4.1 
Key/Confirmatory secondary endpoint(s) ...................................................................................... 23 
4.4.1.1 
Definition of endpoint(s) ................................................................................................................. 23 
4.4.1.2 
Main analytical approach ............................................................................................................... 23 
4.4.2 
Supportive secondary endpoint(s) ................................................................................................. 24 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 26 
4.5.1 
Definition of endpoint(s) ................................................................................................................. 26 
4.5.2 
Main analytical approach ............................................................................................................... 29 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 29 
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4.7 
SAFETY ANALYSES ..................................................................................................................... 30 
4.7.1 
Extent of exposure ......................................................................................................................... 30 
4.7.2 
Adverse events .............................................................................................................................. 31 
4.7.3 
Additional safety assessments ....................................................................................................... 36 
4.7.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 36 
4.8 
OTHER ANALYSES....................................................................................................................... 38 
4.8.1 
Pharmacokinetic analyses ............................................................................................................. 38 
4.8.2 
Immunogenicity analyses ............................................................................................................... 39 
4.8.3 
Pharmacodynamic/genomics endpoints ........................................................................................ 41 
4.9 
INTERIM ANALYSES .................................................................................................................... 42 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 43 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 43 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 45 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS/PROCEDURES ........................................................................ 46 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 50 
5.5 
APPENDIX 5 SAMPLE SAS CODE............................................................................................... 57 
5.6 
APPENDIX 6 SELECTION CRITERIA FOR AE/MEDICATION GROUPINGS ............................. 59 
5.7 
APPENDIX 7 MEDICATION/PROCEDURE ADJUDICATION ALGORITHM ................................ 61 
6 
REFERENCES ............................................................................................................................... 64 
 
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LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 5 
Table 2 - Objectives and endpoints ................................................................................................................. 7 
Table 3 - Summary of primary estimand for main endpoints ........................................................................ 11 
Table 4 - Populations for analyses ................................................................................................................ 15 
Table 5 - Prohibited medications/procedures and rescue medications that impact efficacy ........................ 19 
Table 6 - Sorting of AE tables ....................................................................................................................... 32 
Table 7 - Analyses of adverse events ........................................................................................................... 33 
Table 8 - Selections for AESIs and other AEs of interest .............................................................................. 34 
Table 9 - Major statistical changes in protocol amendment(s) ...................................................................... 45 
Table 10 - Time window for eDiary efficacy variables ................................................................................... 51 
Table 11 - Time window for efficacy variables .............................................................................................. 53 
Table 12 - Time window for safety endpoints ................................................................................................ 55 
Table 13 - Time window for pharmacokinetics/pharmacodynamics variables .............................................. 56 
Table 14 - List of PTs or Medications for CMQs/CDGs ................................................................................ 59 
 
 
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VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study EFC16460 is based on the Protocol Amendment 1 
dated 20-May-2020 and a health authority’s feedback on EFC16459 Protocol Amendment 2 dated 
14-Apr-2021 (See EFC16459 SAP for details). This section summarizes major changes to the
statistical analysis features in the SAP.  All changes to the statistical analysis features from the
original protocol to Amendment 1 are described in Appendix 2.
Table 1 - Major changes in statistical analysis plan 
SAP 
Version 
Approval 
Date 
Changes 
Rationale 
1.0 
04-Feb-2021
Not Applicable 
Original version 
2.0 
Current version 
Add objective “To demonstrate efficacy of dupilumab 
on both itch as well as skin lesions within the same 
participant” and multicomponent endpoint 
(Proportion of participants with both an improvement 
(reduction) in WI-NRS by ≥4 from baseline to 
Week 24 and an IGA PN-S 0 or 1 score at Week 24) 
as a key secondary endpoint for the US and US 
reference countries hierarchy. 
To add this multicomponent endpoint as 
another measure of treatment success 
based on feedback from a health 
authority.  
Add supplementary analysis (tipping point analyses) 
for primary and key secondary endpoints 
This additional supplementary analysis 
was recommended by a health authority 
to assess whether the estimate, and the 
inference thereof, was robust to 
departure from the strategies used in 
primary analysis for handling intercurrent 
events and missing data.    
Add subgroup analyses for key secondary 
endpoints. 
To evaluate whether the treatment effect 
is consistent across pre-specified sub-
groups on the key secondary endpoints 
in addition to the primary endpoint. 
Add subgroup analyses for participants who have 
been impacted (or not) by COVID-19 
To address a health authority’s request 
to assess the impact of the treatment 
effect by COVID-19. 
Modify hierarchical order for multiplicity procedure 
for US and US reference countries 
To include the multicomponent endpoint 
in the hierarchy to address the health 
authority’s feedback requesting 
assessment of this endpoint as another 
measure of treatment success. 
Add as-observed plus multiple imputation 
supplementary analysis for the secondary endpoint 
(percent change from baseline in WI-NRS at 
Week 24) 
To explore the robustness of the 
estimate, and the inference thereof, with 
a different strategy for handling 
intercurrent events and missing data 
Remove “selected” in the text including “selected 
prohibited and/or rescue medication” 
Since a participant who takes any 
protocol specified prohibited 
medications/procedures and/or rescue 
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SAP 
Version 
Approval 
Date 
Changes 
Rationale 
medications is considered as a non-
responder after medical 
adjudication/confirmation conducted in a 
blinded fashion, use of the word 
"selected" is confusing. 
 
 
Add additional exposure-adjusted adverse event 
incidence rate tables that will provide the number of 
patients with at least 1 event per 100 patient-years. 
As requested by a health authority to 
include exposure-adjusted incidence rate 
and patient years in the summaries for 
TEAEs and AESIs. 
 
 
Added “Keratitis FDA” to other AE groupings 
For consistency with other dupilumab 
studies 
 
The first participant was randomized on 2020-02-03.  
 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This study is a multi-center, 24-week treatment, parallel group, double-blind, randomized, 
placebo-controlled study to evaluate the use of dupilumab in participants with prurigo nodularis 
(PN) inadequately controlled on topical prescription therapies or when those therapies are not 
advisable. The study will assess the effect of dupilumab on itch improvement as well as its effect 
on PN lesions, on participants’ health-related quality of life (HRQoL), anxiety and depression, 
sleep quality, skin pain, and overall health status. 
After 2-4 weeks of screening, participants will be centrally randomized using a permuted block 
randomization schedule via Interactive Voice Response System/Interactive Web Response System 
(IVRS/IWRS) in a 1:1 randomization ratio to dupilumab 300 mg q2w or matching placebo. 
Randomization will be stratified by documented history of atopy (atopic or non-atopic), stable use of 
topical corticosteroids (TCS)/ topical calcineurin inhibitors (TCI) (yes or no), and country/territory 
code. 
A total of approximately 150 participants will be randomized to two treatment arms 
(75 participants/arm). The number of participants with active mild AD upon study entry will 
represent up to 10% of the atopic participants. Both the atopic and the non-atopic PN populations 
will each be capped at 60% of the total enrolled population.  
The study duration consists of the following periods: 
• Screening period (2-4 weeks) 
• Randomized IMP intervention period (24 weeks) 
• Follow-up period (12 weeks) 
1.2 
OBJECTIVE AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To demonstrate the efficacy of dupilumab on itch 
response in participants with PN, inadequately 
controlled on topical prescription therapies or 
when those therapies are not advisable.  
• 
Proportion of participants with improvement 
(reduction) in worst-itch numeric rating scale (WI-NRS) 
by ≥4 from baseline to Week 12. 
Secondary 
• 
To demonstrate the efficacy of dupilumab on 
additional itch endpoints in participants with PN, 
inadequately controlled on topical prescription 
therapies or when those therapies are not 
advisable.  
• 
Proportion of participants with improvement 
(reduction) in WI-NRS by ≥4 from baseline to Week 24 
[Key secondary endpoint]. 
• 
Time to onset of effect on pruritus as measured by 
proportion of participants with an improvement 
(reduction) in WI-NRS by ≥4 from baseline during the 
24-week treatment period.  
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Objectives 
Endpoints 
• 
Change from baseline in WI-NRS at Week 24. 
• 
Change from baseline in WI-NRS at Week 12. 
• 
Percent change from baseline in WI-NRS at Week 24. 
• 
Percent change from baseline in WI-NRS at Week 12. 
• 
Percent change from baseline in WI-NRS at Week 4. 
• 
Percent change from baseline in WI-NRS at Week 2.  
• 
Percent change from baseline in WI-NRS over time 
until Week 24.  
• 
Proportion of participants with WI-NRS reduction ≥4 at 
Week 4. 
• 
Proportion of participants with WI-NRS reduction 
≥4 over time until Week 24a. 
• 
Onset of action in change from baseline in WI-NRS 
(first p <0.05 difference from placebo in the daily 
WI-NRS that remains significant at subsequent 
measurements) until Week 12b. 
• 
To demonstrate efficacy of dupilumab on skin 
lesions of PN.  
• 
Proportion of participants with Investigator’s Global 
Assessment 0 or 1 score for PN-Stage (IGA PN-S) at 
Week 24 [Key secondary endpoint].  
• 
Proportion of participants with IGA PN-S 0 or 1 score 
at Week 12. 
• 
Proportion of participants with IGA PN-S 0 or 1 score 
at Week 8c. 
• 
Proportion of participants with IGA PN-S 0 or 1 score 
at Week 4c.  
• 
Change from baseline in IGA PN-S score at Week 24. 
• 
Change from baseline in IGA PN-S score at Week 12. 
• 
Change from baseline in IGA PN-S score at Week 8. 
• 
Change from baseline in IGA PN-S score at Week 4. 
• 
Proportion of participants with Investigator’s Global 
Assessment 0 or 1 score for PN-Activity (IGA PN-A) at 
Week 24. 
• 
Proportion of participants with IGA PN-A 0 or 1 score 
at Week 12. 
• 
Proportion of participants with IGA PN-A 0 or 1 score 
at Week 8. 
• 
Proportion of participants with IGA PN-A 0 or 1 score 
at Week 4. 
• 
To demonstrate efficacy of dupilumab on both 
itch as well as skin lesions within the same 
participant 
• 
Proportion of participants with both an improvement 
(reduction) in WI-NRS by ≥4 from baseline to Week 24 
and an IGA PN-S 0 or 1 score at Week 24 (key 
secondary endpoint for US and US reference 
countries only) 
• 
To demonstrate the improvement in health-
related quality of life (HRQoL).  
• 
Change from baseline in HRQoL, as measured by 
Dermatology Life Quality Index (DLQI) to Week 24.  
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Objectives 
Endpoints 
• 
Change from baseline in HRQoL, as measured by 
DLQI to Week 12. 
• 
To evaluate safety outcome measures.  
• 
Percentage of participants experiencing treatment-
emergent adverse events (TEAEs) or serious adverse 
events (SAEs) from baseline through Week 24.  
• 
To evaluate immunogenicity of dupilumab.  
• 
Incidence of treatment-emergent antidrug antibodies 
(ADA) against dupilumab over time. 
Tertiary/exploratory 
• 
To demonstrate a reduction in the use of rescue 
medication and systemic immunosuppressant 
• 
Use of high potency or superpotent TCS rescue 
medication through Week 24 
• 
Use of systemic immunosuppressants through 
Week 24, constituting treatment failure 
• 
To evaluate exploratory outcome measures  
• 
Change from baseline in Hospital Anxiety and 
Depression Scale (HADS) total score to Week 24. 
• 
Change from baseline in EQ5D-5L to Week 24. 
• 
Change from baseline in skin Pain numeric rating 
scale (NRS) to Week 4, Week 8, Week 12, and 
Week 24, respectively. 
• 
Change from baseline in Sleep NRS to Week 4, 
Week 8, Week 12, and Week 24, respectively. 
• 
Missed school/work days through Week 24. 
• 
Incidence of skin-infection TEAEs (excluding herpetic 
infections) through Week 24. 
• 
To evaluate the efficacy of dupilumab on skin 
lesions using a modified PAS 5-item 
questionnaire 
• 
Proportion of participants who achieve ≥75% healed 
lesions from Prurigo Activity Score (PAS) at Week 4, 
Week 8, Week 12, and Week 24, respectively. 
• 
Change from baseline in exact number of lesions in 
representative area (as determined from PAS) at 
Week 4, Week 8, Week 12, and Week 24, 
respectively. 
• 
To evaluate the efficacy of dupilumab on other 
PN endpoints 
• 
Change from baseline in Participant Global Impression 
of Severity (PGIS) of PN to Week 4, Week 8, 
Week 12, and Week 24, respectively. 
• 
Participant Global Impression of Change (PGIC) of PN 
at Week 4, Week 8, Week 12, and Week 24, 
respectively. 
PK 
• 
To evaluate pharmacokinetic (PK) and 
pharmacodynamic (PD) outcome measures 
 
• 
Serum functional dupilumab concentrations and PK 
profile. 
• 
Pharmacodynamic response for selected biomarkers 
(total IgE). 
a The early onset for significant change in the proportion of responders with WI-NRS reduction ≥4 between dupilumab and placebo will be 
claimed at Week xx if the p-value for Week xx is <0.05 and the remaining timepoints also have nominal p-value ≤0.05 until Week 12. 
b The early onset for significant change in WI-NRS from baseline between dupilumab and placebo will be claimed at Week xx if the p-value for 
Week xx is <0.05 and the remaining timepoints also have nominal p-value ≤0.05 until Week 12. 
c The early onset for reaching IGA PN-S(0,1) between dupilumab and placebo will be claimed at Week xx if the p-value for Week xx is <0.05 
and the remaining timepoints also have nominal p-value ≤0.05 until Week 12. 
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1.2.1 Estimands  
The primary estimands defined for main endpoints are summarized in below Table 3. More details 
are provided in Section 4. 
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Table 3 - Summary of primary estimand for main endpoints  
Endpoint Category 
 
Estimands 
Endpoint(s)a 
Population 
Intercurrent event(s) strategy and missing data handling 
Population-level 
summary 
 
Primary objective: To demonstrate the efficacy of dupilumab on itch response in participants with PN, inadequately controlled on topical prescription therapies or when those 
therapies are not advisable. 
Primary endpoint  
 
Proportion of participants 
with improvement 
(reduction) in worst-itch 
numeric rating scale 
(WI-NRS) by ≥4 from 
baseline to Week 12 
ITT 
The intercurrent events will be handled as follows: 
• 
Discontinuation of study treatment before Week 12: Off-study treatment data up 
to Week 12 will be included in the analysis (treatment policy strategy). 
• 
Taking the prohibited medications/procedures and/or rescue medicationsb prior 
to Week 12: Participants will be considered as non-responders (composite 
strategy). 
In addition, the missing data imputation rules are as follows: 
• 
Having missing data at Week 12:  Participants will be considered as non-
responders. 
CMH test adjusted by 
documented history of 
atopy (atopic or non-
atopic), stable use of 
TCS/TCI (yes or no), 
region (countries 
combined), and 
baseline antidepressant 
use (yes or no). 
 
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Endpoint Category 
 
Estimands 
Endpoint(s)a 
Population 
Intercurrent event(s) strategy and missing data handling 
Population-level 
summary 
 
Secondary objective: To demonstrate the efficacy of dupilumab on additional itch endpoints in participants with PN, inadequately controlled on topical prescription therapies or 
when those therapies are not advisable. 
Secondary endpoint  
Time to onset of effect on 
pruritus as measured by 
proportion of participants 
with an improvement 
(reduction) in WI-NRS by 
≥4 from baseline during 
the 24-week treatment 
period 
ITT 
The intercurrent events will be handled as follows: 
• 
Discontinuation of study treatment before Week 24: Off-study treatment data up 
to Week 24 will be included in the analysis (treatment policy strategy). 
• 
Taking the prohibited medications/procedures and/or rescue medicationsb prior 
to Week 24: Analyses will be censored at Week 24 (composite strategy). 
In addition, the missing data imputation rules are as follows: 
• 
Discontinuing the study follow-up before Week 24: Analyses will be censored at 
the time of last WI-NRS assessment. 
 
 
This time-to-event 
endpoint will be 
analyzed using the Cox 
proportional hazards 
model, including 
intervention group, 
documented history of 
atopy (atopic or non-
atopic), stable use of 
TCS/TCI (yes or no), 
region (countries 
combined), and 
baseline antidepressant 
use (yes or no). The 
hazards ratio, its 95% 
confidence interval and 
p-value will be reported. 
Kaplan-Meier curves 
will be also provided.  
 
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Endpoint Category 
 
Estimands 
Endpoint(s)a 
Population 
Intercurrent event(s) strategy and missing data handling 
Population-level 
summary 
 
Secondary endpoint  
Change from baseline in 
WI-NRS at Week 24 
ITT 
The intercurrent events will be handled as follows: 
• 
Discontinuing the study treatment: all data collected following schedule after 
treatment discontinuation will be used in the analysis (treatment policy strategy).  
• 
Taking the prohibited medications/procedures and/or rescue medicationsb prior 
to Week 24: data will be set to missing values after the medication usage, and 
the participant’s worst postbaseline value on or before the time of the medication 
usage will be used to impute missing endpoint value (for participants whose 
postbaseline values are all missing, the participant’s baseline will be used to 
impute the missing endpoint value) (hypothetical strategy) 
 
In addition, the missing data imputation rules are as follows: 
• 
After discontinuation of the study treatment due to lack of efficacy prior to Week 
24: WOCF approach will be used to impute missing data if needed2.  
• 
After discontinuation of the study treatment due to reasons other than lack of 
efficacy prior to Week 24:  multiple imputation (MI) approach will be used to 
impute missing endpoint value, and this multiple imputation will use all 
participants excluding participants who have taken the prohibited medications 
and/or rescue medications prior to Week 24 and excluding participants who 
discontinue due to lack of efficacy prior to Week 24.  
ANCOVA model with 
intervention group, 
documented history of 
atopy (atopic or non-
atopic), stable use of 
TCS/TCI (yes or no), 
region (countries 
combined), baseline 
antidepressant use (yes 
or no), and relevant 
baseline measurement 
as covariates is used. 
Statistical inference 
obtained from all 
imputed data by 
ANCOVA model will be 
combined using Rubin’s 
rule. 
 
a Additional secondary objectives/endpoints are not included in this table but would be handled with a similar strategy as the endpoint type (ie continuous, proportion, time-to-event) at other weeks 
b Prohibited medications and/or rescue medications are listed in Table 5. 
 
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2 
SAMPLE SIZE DETERMINATION  
The primary endpoint is the proportion of participants with WI-NRS reduction of ≥4 from 
baseline to Week 12. By assuming the response rate is 
 in the placebo and 
dupilumab arms, respectively, 56 participants/arm will provide 90% power to detect the difference 
of 
 between dupilumab and placebo with Fisher exact test at 2-sided level of 0.05. Assuming 
15% drop out during the 12 weeks of treatment, the target is to randomize 75 participants/arm 
with a cap of up to 10% of participants in the atopic population having active mild AD. 
The assumptions were based on the effect of dupilumab versus placebo in WI-NRS reduction 
≥4 at Week 16 observed in participants with moderate to severe AD as seen in studies of AD-1334 
(Solo1) and AD-1416 (Solo2).  
Approximately 150 participants will be randomized to dupilumab or placebo in a 1:1 ratio with 
stratification factors of documented history of atopy (atopic or non-atopic), stable use of TCS/TCI 
(yes or no), and country/territory code. Both the atopic and the non-atopic PN population will be 
capped at 60% of the total enrolled population. 
The sample size calculation was performed using SAS 9.4 power procedure. 
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3 
ANALYSIS POPULATIONS  
The following populations for analyses are defined:  
Table 4 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the ICF. 
Randomized 
The randomized population includes all participants with a treatment kit number allocated 
and recorded in the interactive response technology (IRT) database, and regardless of 
whether the treatment kit was used or not. 
Participants treated without being randomized will not be considered randomized and will 
not be included in any efficacy population. 
Intent-to-treat (ITT) 
All randomized participants analyzed according to the intervention group allocated by 
randomization regardless if treatment kit is used or not 
Efficacy 
The ITT population 
Safety 
All participants randomly assigned to study intervention and who take at least 1 dose of 
study intervention. Participants will be analyzed according to the intervention they actually 
received.  
Randomized participants for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized.  
For participants who accidentally receive different treatment from the planned, the actual 
intervention allocation for as-treated analysis will be the dupilumab group. 
The PD analyses will be performed on the safety population. 
Pharmacokinetic (PK) 
The PK population includes all participants in the safety population with at least one non-
missing result for functional dupilumab concentration in serum after first dose of the study 
treatment. Participants will be analyzed according to the intervention actually received. 
Antidrug antibody (ADA) 
ADA population includes all participants in the safety population who have at least one non-
missing ADA result after first dose of the study treatment. Participants will be analyzed 
according to the intervention actually received. 
ADA: antidrug antibody; ICF: informed consent form; ITT: intent to treat; PD: pharmacodynamics: PK: pharmacokinetic. 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population.  The safety experience 
of these participants will be reported separately. 
Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant randomized more than once, only the data associated with the first 
randomization will be used in any analysis population.  The safety experience associated with any 
later randomization will be reported separately. 
For participants receiving more than one study intervention (placebo and dupilumab) during the 
study, the intervention group for as-treated analysis will be the dupilumab group.  
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Regarding the COVID-19 pandemic, additional summaries by COVID-19 subgroups (i.e., 
impacted by the COVID-19 pandemic and NOT impacted by the COVID-19 pandemic) will be 
provided to assess the impact of COVID-19 on treatment effect. Participants impacted by the 
COVID-19 pandemic are defined as randomized participants with any critical or major deviation 
related to COVID-19 or who permanently discontinued study intervention or study due to 
COVID-19. 
 
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4 
STATISTICAL ANALYSES  
4.1 
GENERAL CONSIDERATIONS  
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SD), median, minimum, and maximum. Categorical and ordinal data will be 
summarized using the count and percentage of participants. 
The baseline value of efficacy parameters is defined as the last available value before 
randomization and prior to the first dose of study medication unless below eDiary data (WI-NRS, 
skin Pain-NRS and Sleep-NRS) score or otherwise specified.  
The baseline for weekly average WI-NRS (skin Pain-NRS and Sleep-NRS) score is defined as the 
average of daily non-missing scores obtained during the 7 days prior to randomization.  
The baseline value of the other parameters is defined as the last available value prior to the first 
dose of investigational medicinal product (IMP) if the participant is treated, or the last available 
value up to randomization if the participant is not exposed to IMP. 
Observation period 
The observation period will be divided into 4 segments:  
• The pre-treatment period is defined as the period up to first IMP administration. 
• The treatment-emergent (TE) period is defined as the period from the first IMP 
administration to the last IMP administration + 98 days. The treatment-emergent period 
includes the following 2 periods:  
- 
The on-treatment period is defined as the period from the first IMP administration to 
the last administration of the IMP + 14 days 
- 
The residual treatment period is defined as the period from the end of the on-
treatment period to the end of the treatment-emergent period.  
• The post-treatment period is defined as the period from the end of the treatment-
emergent period. 
The on-study observation period is defined as the time from start of intervention until the end of 
the study defined as the status date collected on e-CRF page “Completion of End of Study”. 
4.2 
PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 4 will 
be summarized. 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently randomized. The number (%) of screen failures and reasons for screen failures will 
be provided in the screened population. 
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The number (%) of participants in the following categories will be provided:  
• Randomized participants 
• Randomized but not exposed participants  
• Randomized and exposed participants 
• Participants who completed the study treatment period as per protocol  
• Participants who did not complete the study treatment period as per protocol and 
discontinued study treatment prior to Week 12 by main reason for permanent intervention 
discontinuation including due to COVID-19 
• Participants who did not complete the study treatment period as per protocol and 
discontinued study treatment prior to Week 24 by main reason for permanent intervention 
discontinuation including due to COVID-19 
• Participants who completed the study period as per protocol 
• Participants who did not complete the study period as per protocol and discontinued study 
by main reason for study discontinuation including due to COVID-19.  
• Vital status at last study contact 
The number (%) of exposed and not randomized participants will also be summarized.  
In addition, the number (%) of participants screened, screened-failed, randomized, with permanent 
intervention discontinuation and with early study discontinuation will be provided by country and 
site.  
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the 
randomized population and according to COVID-19 impact (i.e. deviations related to the COVID-
19 pandemic and deviations not related to the COVID-19 pandemic). In addition, deviations 
potentially impacting the primary endpoint analysis will be summarized. 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS  
4.3.1 Definition of endpoint(s)  
The primary endpoint for this study is the proportion of participants with improvement (reduction) 
in worst-itch numeric rating scale (WI-NRS) by ≥4 from baseline to Week 12. 
WI-NRS is a patient-reported outcome (PRO) comprised of a single item rated on a scale from 0 
(“No itch”) to 10 (“Worst imaginable itch”). Participants are asked to rate the intensity of their 
worst pruritus (itch) over the past 24 hours using this scale. 
The weekly average WI-NRS score at each week, which is defined as the average of daily non-
missing scores within the week window of each week (see Section 5.4), will be used for analyses. 
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For efficacy analysis, Table 5 presents the prohibited and rescue medications/procedures which 
will be considered as intercurrent events if the last column indicates as “Yes” and therefore be 
handled in the estimands for endpoints defined in Table 3. 
Table 5 - Prohibited medications/procedures and rescue medications that impact efficacy  
Medication/procedure 
Comment 
Data to be set as non-
responder after taking 
medication in the main 
statistical analysis 
(Yes/No) a/ Selection 
criteria 
Prohibited medications/procedures 
Systemic immunosuppressive/immunomodulating drugs 
(eg, systemic corticosteroids, cyclosporine, 
mycophenolate-mofetil, interferon gamma, Janus kinase 
inhibitors, azathioprine, methotrexate, 
hydroxychloroquine, dapsone, sulfasalazine, colchine, etc) 
IMP to be discontinued 
Yes (CDGb Immunosuppressant 
drugs Narrow and 
SDGbCorticosteroids Narrow ) 
Other monoclonal antibodies (that are biological response 
modifiers). 
IMP to be discontinued 
Yes (SDGb Monoclonal antibodies 
Narrow) 
Phototherapy, including tanning beds. 
IMP to be discontinued 
Yes (CMQb HLT Phototherapies, 
CMQb Tanning_single PT) 
Naltrexone or other opioid antagonist 
IMP to be discontinued 
  Yes (SDGb Analgesia producing 
opioids NARROW) 
Gabapentin, pregabalin, and thalidomide 
IMP to be discontinued 
Yes (CDGb Gabapentin mono and 
multi ingredients, Pregabalin mono and 
multi ingredients, or Thalidomide mono 
and multi ingredients) 
Paroxetine, fluvoxamine or other SSRIs.  
No IMP discontinuation, 
see requirement in the 
footnote 
Yesc,d (CDGb N06AB selective 
serotonin reuptake inhibitors) 
SNRIs.  
No IMP discontinuation, 
see requirement in the 
footnote 
Yesc,d (CDGb serotonin and 
norepinephrine reuptake inhibitors) 
Amitriptyline or other tricyclic or tetracyclic 
antidepressants 
No IMP discontinuation, 
see requirement in the 
footnote 
Yesc,d (CDGb N06AA non-selective 
monoamine reuptake inhibitors) 
Intralesional corticosteroid injections and cryotherapy.  
No IMP discontinuation 
Yesd (CMQb Injection_single pt, 
cryotherapy or skin cryotherapy 
PT) 
Sedating antihistamine 
No IMP discontinuation 
Yesd,e (CDGb sedating 
antihistamines) 
Non-sedating antihistamine if used specifically for the 
treatment of itch secondary to AD or PN 
No IMP discontinuation 
Yesd,e (CDGb non-sedating 
antihistamines) 
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Medication/procedure 
Comment 
Data to be set as non-
responder after taking 
medication in the main 
statistical analysis 
(Yes/No) a/ Selection 
criteria 
Rescue medications 
Dermatological preparations of high potency or 
superpotent TCS and TCI 
No IMP discontinuation 
Yesd (CDGb calcineurin inhibitors 
and corticosteroids narrow, Ticked 
'RESCUE THERAPY' in CRF page) 
a. 
When yes, the estimand for the intercurrent event handling strategy will be as follows: hypothetical for continuous endpoints, and 
composite for responder and time-to-event endpoints.  When no, a treatment policy strategy will be applied. 
b. 
CDG=company drug groupings, CMQ=company MedDRA query, SDG= Standardized drug groupings. 
c. 
Only if the antidepressant is initiated during the study or its dose is increased from baseline provided that medication was taken at least 
3 months prior to screening. 
d. 
As per medical adjudication, see Appendix 7 for details. 
e. 
Only if the medication is initiated at Week 12 or Week 24, or the dose is increased from Week 11 to Week 12 or from Week 23 to 
Week 24. 
Blinded review of prohibited/rescue treatment (medication or procedure) based on Table 5 and a 
pre-specified algorithm (Appendix 7) will be implemented before database locks by considering 
the type of medication or procedure, indication, timing, frequency and the potential impact of the 
use of the prohibited medications/procedures and rescue medications.  
4.3.2 Main analytical approach  
The primary estimand for the primary endpoint is the treatment policy/composite approach as 
defined in Table 3. 
The primary analysis population for the efficacy endpoints will be the ITT population. 
The following null hypothesis H0 and alternative hypothesis H1 will be tested for dupilumab 
against placebo:  
• H0: No treatment difference between dupilumab and placebo. 
• H1: There is a treatment difference between dupilumab and placebo 
The primary analysis will be conducted by using Cochran–Mantel–Haenszel test (CMH)  test 
adjusted by documented history of atopy (atopic or non-atopic), stable use of TCS/TCI (yes or 
no), region, and baseline anti-depressant use (yes or no). Comparisons of the response rates 
between dupilumab and placebo will be derived.  In addition, odds ratio and response rate 
difference as well as the corresponding 95% confidence intervals (CI) will be provided along with 
the p-values.  
As defined in Table 3 for participants discontinuing the study treatment before Week 12, their off-
study treatment values measured up to Week 12 will be included in the analysis. Participants 
taking the prohibited medications/procedures and/or rescue medications (see Table 5) prior to 
Week 12 or having missing data at Week 12 will be considered non-responders. 
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4.3.3 Sensitivity analysis  
For the primary estimand for the primary endpoint, no sensitivity analysis will be performed. 
However, three supplementary analyses will be performed as described in the section below.  
4.3.4 Supplementary analyses  
The following supplementary analyses will be performed: 
As-observed analysis (including all data after taking the prohibited and/or rescue medications)  
The data collected after taking all prohibited medications and/or rescue medications will be 
included in the supplementary analysis to evaluate the robustness of the primary analysis results 
with respect to the method of handling data while taking the prohibited medications (e.g. 
treatment policy strategy). In addition, for participants discontinuing the study treatment before 
Week 12, their off-study treatment values measured up to Week 12 will be included in the 
analysis. The participants having missing data at Week 12 regardless of reason(s) will be 
considered non-responders at that timepoint. 
Hybrid method analysis (the worst-observation carried forward (WOCF) and multiple imputation 
(MI)) 
In the primary analysis of change from baseline in WI-NRS (continuous variable) at Week 12, the 
hybrid method of the WOCF and MI will be used (see Section 4.4.2). Similar to the continuous 
variable, the same imputation method will be used in the analysis of the proportion of participants 
with improvement (reduction) in WI-NRS by ≥4 from baseline to Week 12, which is consistent 
for the intercurrent event strategy and missing data handling in the binary variables and 
continuous variable. That is, after the imputation of continuous WI-NRS data at Week 12 using 
the hybrid method of the WOCF and MI (see Section 4.4.2), responders will be defined as 
participants with improvement in WI-NRS by ≥4 from baseline to Week 12 in each of the imputed 
datasets with about 40 imputations, and then the CMH test adjusted by documented history of 
atopy (atopic or non-atopic), stable use of TCS/TCI (yes or no), region, and baseline anti-
depressant use (yes or no) will be used. Statistical inference obtained from all imputed data will 
be combined using Rubin’s rule.  
Tipping point analysis 
The intercurrent events will be handled as follows: 
• Discontinuation of study treatment before Week 12: Off-study treatment data up to 
Week 12 will be included in the analysis (treatment policy strategy). 
• Taking the prohibited medications/procedures and/or rescue medications prior to Week 
12: Data after the intercurrent events will be censored and then imputed with the below 
tipping point method 
In addition, the missing data imputation rules are as follows: 
• Having missing data at Week 12:  Data will be imputed with the following tipping point 
method. 
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Tipping point method:  
• A sequence of analyses will be performed with the adjustment to artificially decrease the 
response rate in the dupilumab group and increase the response rate in the placebo group 
with a fixed and definite set of values for data imputation.  
• For each combination of increasing response rate in placebo and decreasing response 
rate in dupilumab, multiple imputed datasets will be generated and analyzed using CMH 
test. The results obtained from multiple imputed datasets will be combined to generate  
statistical inference, i.e. p-value and treatment difference between 2 treatment groups.  
• A “tipping point” will be identified while the result is no longer statistically significant 
(i.e. p-value >0.05). 
4.3.5 Subgroup analyses  
To assess the homogeneity of the treatment effect across various subgroups, analyses will be 
performed on the primary endpoint across the following subgroups (categories with fewer than 5 
participants may be combined with other categories): 
• Age group (<65, ≥65 years) 
• Gender (Male, Female) 
• Region  
• Territory 
• Race (Caucasian/White, Black/of African descent, Asian/Oriental, Others) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Baseline weight (<60, ≥60- < 90, ≥ 90 kg) 
• Baseline BMI (<25, ≥25- <30, ≥30 kg/m2)  
• Participants without a current diagnosis of AD 
• History of atopy (atopic or non-atopic) 
• Stable use of TCS/TCI (yes or no) 
• Antidepressant use (yes or no) at baseline 
• Baseline IGA PN-S moderate versus severe (3 vs. 4) 
• Participants who have not been impacted by COVID-19 vs impacted by COVID-19 (for 
participants who have been impacted by the COVID-19, the efficacy data will be 
descriptive only if the number of participants is not enough to perform statistical tests. 
Participants impacted by the COVID-19 pandemic are defined as randomized participants 
with any critical or major deviation related to COVID-19 or who permanently 
discontinued study intervention or study due to COVID-19.) 
 
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To test the interaction between intervention and subgroup factor, a logistic regression model 
incorporating subgroup-by-treatment interaction will be built for each subgroup factor except the 
subgroup of participants without a current diagnosis of AD (very few AD participants will be 
excluded). The model will include all the covariates in the main statistical model plus the 
subgroup variable and the subgroup-by-treatment interaction. A p-value for the test of interaction 
will be provided.  
In each subgroup, the treatment effects for the primary endpoint will be provided, as well as the 
corresponding 95% CI, using the same method as applied to the primary analysis.  Forest plots 
will be provided. 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS  
The weekly average skin Pain-NRS or Sleep-NRS score at each week, which is defined as the 
average of non-missing daily scores within the week window of each week (see Section 5.4), will 
be used for analyses. 
4.4.1 Key/Confirmatory secondary endpoint(s)  
4.4.1.1 Definition of endpoint(s)  
The key secondary endpoints are: 
• Proportion of participants with improvement (reduction) in WI-NRS by ≥4 from baseline 
to Week 24, and 
• Proportion of participants with IGA PN-S 0 or 1 score at Week 24. 
In addition, for US and US reference countries only, there is another key secondary endpoint: 
• Proportion of participants with both an improvement (reduction) in WI-NRS by ≥4 from 
baseline to Week 24 and an IGA PN-S 0 or 1 score at Week 24. 
 
Investigator’s global assessment for prurigo nodularis (IGA PN)  
The IGA PN is a clinician-reported outcome (ClinRO) that allows clinicians to assess the activity 
of PN (IGA PN-A) using a 5-point scale from 0 (clear) to 4 (severe); and the stage of the disease 
(IGA PN-S) using a 5-point scale from 0 (clear) to 4 (severe). 
4.4.1.2 Main analytical approach  
For the key secondary efficacy endpoints, the analysis will be conducted by using CMH test 
adjusted by documented history of atopy (atopic or non-atopic), stable use of TCS/TCI (yes or 
no), region, and baseline anti-depressant use (yes or no). The same estimand, i.e., intercurrent 
event strategy and missing data handling method, as the primary endpoint, by replacing Week 12 
with Week 24, is used. 
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The same supplementary and subgroup analyses used for the primary endpoint will also be 
performed for the key secondary efficacy endpoints.  
4.4.2 Supportive secondary endpoint(s)  
The other secondary endpoints are as follows: 
• Proportion of participants with WI-NRS reduction ≥4 over time until Week 24. 
• Proportion of participants with WI-NRS reduction ≥4 at Week 4 
• Proportion of participants with IGA PN-S 0 or 1 score at Week 12 
• Proportion of participants with IGA PN-S 0 or 1 score at Week 8 
• Proportion of participants with IGA PN-S 0 or 1 score at Week 4 
• Proportion of participants with IGA PN-A 0 or 1 score at Week 24 
• Proportion of participants with IGA PN-A 0 or 1 score at Week 12 
• Proportion of participants with IGA PN-A 0 or 1 score at Week 8 
• Proportion of participants with IGA PN-A 0 or 1 score at Week 4 
• Time to onset of effect on pruritus as measured by proportion of participants with an 
improvement (reduction) in WI-NRS by ≥4 from baseline during the 24-week treatment 
period 
• Change from baseline in WI-NRS at Week 24 
• Change from baseline in WI-NRS at Week 12 
• Percent change from baseline in WI-NRS at Week 24 
• Percent change from baseline in WI-NRS at Week 12 
• Percent change from baseline in WI-NRS at Week 4 
• Percent change from baseline in WI-NRS at Week 2 
• Percent change from baseline in WI-NRS over time until Week 24. 
• Onset of action in change from baseline in WI-NRS (first p <0.05 difference from placebo 
in the daily WI-NRS that remains significant at subsequent measurements) until Week 12 
• Change from baseline in IGA PN-S score at Week 24 
• Change from baseline in IGA PN-S score at Week 12 
• Change from baseline in IGA PN-S score at Week 8 
• Change from baseline in IGA PN-S score at Week 4 
• Change from baseline in HRQoL, as measured by Dermatology Life Quality Index 
(DLQI) to Week 24 
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• Change from baseline in HRQoL, as measured by Dermatology Life Quality Index 
(DLQI) to Week 12 
Dermatology life quality index (DLQI) 
The DLQI is a PRO developed to measure dermatology-specific HRQoL in adult participants. The 
instrument comprises 10 items assessing the impact of skin disease on participants’ HRQoL over 
the previous week. The items cover symptoms, leisure activities, work/school or holiday time, 
personal relationships including intimate, the side effects of treatment, and emotional reactions to 
having a skin disease. It is a validated questionnaire used in clinical practice and clinical trials. 
Response scale is a 4-point Likert scale (0 = “not at all” and 3 = “very much”) for nine items. The 
remaining one item about work/studying asks whether work/study has been prevented and then (if 
“No”) to what degree the skin condition has been a problem at work/study; the item is rated on a 
3-point Likert scale (“Not at all” to “A lot”). Overall scoring ranges from 0 to 30, with a high 
score indicative of a poor HRQoL. 
Time-to-event secondary efficacy endpoint  
Time to first onset of effect on pruritus defined as an improvement (reduction) in WI-NRS by ≥4 
from baseline during the 24-week treatment period will be analyzed using the Cox proportional 
hazards model, including treatment, documented history of atopy (atopic or non-atopic), stable 
use of TCS/TCI (yes or no), region, and baseline anti-depressant use (yes or no). The hazards 
ratio, its 95% confidence interval and p-value will be reported. Kaplan-Meier curves will be also 
provided.  
For time to first WI-NRS response (WI-NRS by ≥4 from baseline), participants who receive the 
prohibited medications and/or rescue medications (see Table 5), data prior to start of the 
medications will be used, but after medication start, the participants’ data will not be used and 
they will be censored at Week 24 (i.e. Day 172). For other participants, all available data up to 
Week 24 (i.e. Day 172) including those collected during the off-treatment period will be used. 
Participants without events will be censored at Day 172 or their last WI-NRS assessment date if 
discontinued from the study, whichever is earlier. 
Secondary efficacy endpoints that measure binary responses  
Secondary efficacy endpoints that measure binary responses will be analyzed in the same fashion 
as the primary endpoint using primary statistical model.  
Continuous secondary efficacy endpoints  
The primary estimand for continuous secondary efficacy endpoints is defined in Table 3 and will 
be analyzed using an analysis of covariance (ANCOVA) model with intervention group, 
documented history of atopy (atopic or non-atopic), stable use of TCS/TCI (yes or no), region 
(countries combined), baseline antidepressant use (yes or no), and relevant baseline measurement 
as covariate, with intercurrent event strategy and missing data handling as defined as in Table 3. 
Specifically, data of participants taking the prohibited medications/procedures and/or rescue 
medications will be set to missing after the medication usage, and the worst postbaseline value on 
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or before the time of the medication usage will be used to impute missing endpoint value (for 
participants whose postbaseline values are all missing, the baseline will be used to impute). 
Participants who discontinue the treatment prematurely are encouraged to follow the planned 
clinical visits and in those participants who did not take the prohibited medications/procedures 
and/or rescue medications, all data collected after treatment discontinuation will be used in the 
analysis. For these participants, missing data may still happen despite all efforts have been tried to 
collect the data after treatment discontinuation. For participants who discontinue due to lack of 
efficacy, all data collected after discontinuation will be used in the analysis, and a WOCF 
approach will be used to impute missing data if needed. For participants who discontinued not due 
to lack of efficacy, a multiple imputation (MI) approach will be used to impute missing endpoint 
value, and this MI method will use all participants excluding participants who have taken the 
prohibited medications/procedures and/or rescue medications prior to timepoint of endpoint of 
interest and excluding participants who discontinue due to lack of efficacy.  
Each of the imputed complete data will be analyzed by fitting an ANCOVA model as described 
above. The imputation number will be about 40. Statistical inference obtained from all imputed 
data will be combined using Rubin’s rule. Descriptive statistics including number of participants, 
mean, standard error, and least squares (LS) mean changes (and standard error) will be provided. 
In addition, difference of the dupilumab group against placebo in LS means and the corresponding 
95% confidence intervals (CI) will be provided along with the p-values.  
See Section 5.5 for the sample SAS code for the imputation and the analysis. 
For the endpoint of percent change from baseline in WI-NRS at week 24, we will also perform an 
as-observed plus multiple imputation supplementary analysis as described below. 
The data collected after taking all prohibited medications and/or rescue medications will be 
included in the supplementary analysis to evaluate the robustness of the primary analysis results 
with respect to the method of handling data while taking the prohibited medications (e.g. 
treatment policy strategy). In addition, for participants discontinuing the study treatment before 
Week 24, their off-study treatment values measured up to Week 24 will be included in the 
analysis. For participants having missing data at Week 24 regardless of reason(s), a multiple 
imputation (MI) approach will be used to impute the missing endpoint value. 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
4.5.1 Definition of endpoint(s)  
The exploratory endpoints are as follows: 
• Use of high potency or superpotent TCS rescue medication through Week 24 
• Use of systemic immunosuppressant through Week 24, constituting treatment failure 
• Change from baseline in Hospital Anxiety and Depression Scale (HADS) total score to 
Week 24 
• Change from baseline in EQ-5D-5L Single Index score to Week 24 
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• Change from baseline in EQ-5D visual analog scale (VAS) to Week 24 
• Change from baseline in skin Pain-NRS to Week 4, Week 8, Week 12, and Week 24, 
respectively 
• Change from baseline in Sleep-NRS to Week 4, Week 8, Week 12, and Week 24, 
respectively 
• Missed school/work days through Week 24 
• Incidence of skin-infection TEAEs (excluding herpetic infections) through Week 24 
• Proportion of participants who achieve ≥75% healed lesions from PAS at Week 4, 
Week 8, Week 12, and Week 24, respectively 
• Change from baseline in exact number of lesions in representative area (as determined 
from PAS) at Week 4, Week 8, Week 12, and Week 24, respectively 
• Change from baseline in Participant Global Impression of Severity (PGIS) of PN to Week 
4, Week 8, Week 12, and Week 24 respectively 
• Proportion of participants with PGIS  score of “none” at Week 4, Week 8, Week 12, and 
Week 24 respectively 
•  Proportion of participants with PGIS score of “none” or “mild” at Week 4, Week 8, Week 
12, and Week 24 respectively 
• Participant Global Impression of Change (PGIC) of PN at Week 4, Week 8, Week 12, and 
Week 24, respectively 
• Proportion of participants with PGIC score of “very much better” at Week 4, Week 8, 
Week 12, and Week 24 respectively 
• Proportion of participants with PGIC score of “very much better” or “moderately better” at 
Week 4, Week 8, Week 12, and Week 24 respectively 
Hospital anxiety and depression scale (HADS) 
The HADS is a PRO instrument for screening anxiety and depression in non-psychiatric 
populations; repeated administration also provides information about changes to a participant’s 
emotional state. The HADS consists of 14 items, 7 each for anxiety and depression symptoms; 
possible scores range from 0 to 21 for each subscale. The following cut-off scores are 
recommended for both subscales:  
• 0 to 7: normal 
• 8 to 10: borderline abnormal (borderline case)  
• 11 to 21: abnormal 
Euroqol 5 dimensions questionnaire (EQ-5D) 
The Euroqol-5 dimensions (EQ-5D) is a standardized PRO measure of health status developed by 
the EuroQOL Group in order to provide a simple, generic measure of health for clinical and 
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economic appraisal. The EQ-5D consists of 2 parts: the descriptive system and the EQ visual 
analog scale (VAS). The EQ-5D descriptive system comprises the following 5 dimensions: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 
5 levels of perceived problems: “no problem”, “slight problems”, “moderate problems”, “severe 
problems” and “inability to do the activity”. The respondent is asked to indicate his/her health 
state by ticking (or placing a cross) in the box against the most appropriate statement in each of 
the 5 dimensions; this results in a 1-digit number expressing the level for that dimension. The 
digits for 5 dimensions can be combined in a 5-digit number describing the respondent’s health 
state. The EQ VAS records the respondent’s self-rated health on a vertical VAS where the 
endpoints are labeled “best imaginable health state (100)” and “worst imaginable health state (0)”. 
This information can be used as a quantitative measure of health outcome as judged by the 
individual respondents. 
Skin Pain and sleep numeric rating scales (skin Pain-NRS, Sleep-NRS) 
Participants will be asked to rate their worst skin pain in the past 24 hours using a 0 to 10 NRS, 
with 0 = No pain to 10 = Worst pain possible.  
In addition, participants will be asked to rate their sleep quality on their past night upon 
awakening, using a 0 to 10 NRS, with 0 = Worst possible sleep and 10 = Best possible sleep. 
Participants will complete the skin pain NRS and sleep quality NRS once a day. 
Prurigo activity score (PAS) 
The PAS is a clinician-reported outcome (ClinRO) measurement. The original PAS questionnaire 
Version 0.9 consists of 7 items, developed by expert clinicians in PN.  
A 5-item simplified version of the PAS will be used in the current study. Item 4 (exact number of 
pruriginous lesions in representative area) and Item 5b (percentage of healed prurigo lesions in all 
pruriginous lesions) will be used for analyses. In addition, Item 2 (number of prurigo lesions) may 
be used for analysis too. 
Participant Global Impression of Change of disease (PGIC) and Participant Global Impression of 
Severity (PGIS) 
The PGIC is a one-item questionnaire that asks participants to provide the overall self-assessment 
of change in their PN overall on a 7-point scale, compared to just before participant started taking 
the study injection. Response choices are: 0 = “Very much better”, 1 = “Moderately better”, 2 = 
“A little better”, 3 = “No change”, 4 = “A little worse”, 5 = “Moderately worse”, 6 = “Very much 
worse”.  
The PGIS is a one-item questionnaire that asks participants to provide the overall self-assessment 
of their disease severity on a 4-point scale for the past week. Response choices are: 1 = “none”, 
2 = “Mild”, 3 = “Moderate”, 4 = “Severe”. 
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Missed school/work days 
Participants who are employed or enrolled in school will be asked to report the number of sick 
leave/missed school days since the last study assessment. 
4.5.2 Main analytical approach  
Exploratory efficacy endpoints will be analyzed using the same methodology as secondary 
efficacy for similar data (continuous or proportion) except the endpoints below. 
• Use of high potency or superpotent TCS rescue medication through Week 24 
• Use of systemic immunosuppressant through Week 24, constituting treatment failure 
• Missed school/work days through Week 24 
• Incidence of skin-infection TEAEs (excluding herpetic infections) through Week 24 
The number of participants and percentage with the events for these endpoints will be provided in 
observed cases. In addition, the time (week) to first event for those participants will also be 
analyzed using Kaplan-Meier method and the duration of the rescue medication use may be 
summarized if applicable.  
An additional exploratory endpoint of time to first select prohibited/rescue medication that impact 
efficacy will be provided.  This includes medications where WOCF will be applied (see Table 5).  
4.6 
MULTIPLICITY ISSUES  
The multiplicity procedure is proposed to control the overall type-I error rate for testing the 
primary and selected secondary endpoints. The overall alpha is 0.05. The comparisons with 
placebo will be tested based on the hierarchical order below at 2-sided α = 0.05: 
In US and US reference countries: 
• Proportion of participants with improvement (reduction) in WI-NRS by ≥4 from baseline 
to Week 12. 
• Proportion of participants with improvement (reduction) in WI-NRS by ≥4 from baseline 
to Week 24 
• Proportion of participants with IGA PN-S 0 or 1 score at Week 24 
• Proportion of participants with both an improvement (reduction) in WI-NRS by ≥4 from 
baseline to Week 24 and an IGA PN-S 0 or 1 score at Week 24 
• Proportion of participants with IGA PN-S 0 or 1 score at Week 12 
• Percent change from baseline in WI-NRS at Week 24 
• Change from baseline in HRQoL, as measured by Dermatology Life Quality Index 
(DLQI) to Week 24 
• Change from baseline in skin Pain-NRS to Week 24 
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• Change from baseline in Sleep-NRS to Week 24 
• Change from baseline in Hospital Anxiety and Depression Scale (HADS) total score to 
Week 24 
In all other countries (including EU and EU reference countries, as well as China and 
Japan): 
• Proportion of participants with improvement (reduction) in WI-NRS by ≥4 from baseline 
to Week 12. 
• Proportion of participants with improvement (reduction) in WI-NRS by ≥4 from baseline 
to Week 24 
• Proportion of participants with IGA PN-S 0 or 1 score at Week 24 
• Percent change from baseline in WI-NRS at Week 24 
• Proportion of participants with IGA PN-S 0 or 1 score at Week 12 
• Change from baseline in HRQoL, as measured by Dermatology Life Quality Index 
(DLQI) to Week 24 
• Change from baseline in skin Pain-NRS to Week 24 
• Change from baseline in Sleep-NRS to Week 24 
• Change from baseline in Hospital Anxiety and Depression Scale (HADS) total score to 
Week 24 
The study is considered positive when the primary endpoint achieves statistical significance. 
4.7 
SAFETY ANALYSES  
All safety analyses will be performed on the safety population as defined in Section 3, unless 
otherwise specified, using the following common rules: 
• The analysis of the safety variables will be descriptive, and no testing is planned.  
• Safety data in participants who do not belong to the safety population (e.g., exposed but 
not randomized) will be provided separately. 
4.7.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and compliance and 
summarized within the safety population. 
Duration of IMP exposure 
Duration of IMP exposure is defined as last dose date – first dose date + 14 days, regardless of 
unplanned intermittent discontinuations. Duration of IMP exposure will be summarized 
descriptively as a quantitative variable (number, mean, SD, median, minimum, and maximum).  
In addition, duration of treatment exposure will also be summarized categorically by numbers and 
percentages for each of the following categories and cumulatively according to these categories:  
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• >0 and ≤2 weeks 
• >2 and ≤4 weeks 
• >4 and ≤8 weeks 
• >8 and ≤12 weeks 
• >12 and ≤16 weeks 
• >16 and ≤20 weeks 
• >20 and ≤24 weeks 
• >24 weeks and ≤ 24 weeks + 3 days 
• > 24 weeks + 3 days 
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all participants, and will be expressed in participant 
years. 
Treatment compliance 
A given administration will be considered noncompliant if the participant did not take the planned 
dose as required by the protocol.  No imputation will be made for participants with missing or 
incomplete data. 
Percentage of treatment compliance for a participant will be defined as the number of 
administrations that the participant was compliant divided by the total number of administrations 
that the participant was planned to take from the first administration of IMP up to the actual last 
administration of IMP. 
Treatment compliance will be summarized quantitatively and categorically: <80%, ≥80%. 
Cases of overdose (defined as at least twice the intended dose during an interval of less than 
11 days) will be considered an AESI per dupilumab clinical programs and will be listed as such. 
4.7.2 Adverse events  
General common rules for adverse events 
All adverse events (AEs) will be coded to a lower-level term (LLT), preferred term (PT), high-
level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version currently in 
effect at Sanofi at the time of database lock.  
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the pre-
treatment period. 
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• Treatment-emergent adverse events (TEAE)s: AEs that developed, worsened or became 
serious during the treatment-emergent period 
• Post-treatment AEs: AEs that developed, worsened or became serious during the post-
treatment period  
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
The primary focus of AE reporting will be on TEAEs.  Pre-treatment and post-treatment AEs will 
be described separately.  
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a pre-
treatment or a post-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. If the severity is missing for 1 of the treatment-emergent occurrences of an AE, 
the severity will be imputed with the maximal severity of the other occurrences. If the severity is 
missing for all the occurrences, the severity will be left as missing. 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment phase.  
The AE tables will be sorted as indicated in Table 6.  
Table 6 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC, HLGT, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLGTs, HLTs and PTs.  
SOC, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLTs and PTs. 
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa, b 
SMQ/CMQ and PT 
By decreasing frequency of SMQs/CMQs and PTsa 
PT 
By decreasing frequency of PTsa 
a Sorting will be based on the SAR231893 dupilumab group 
b The table of all TEAEs presented by SOC and PT will define the presentation order for all other tables (eg, treatment-emergent SAE) 
presented by SOC and PT, unless otherwise specified.   
Analysis of all adverse events 
The overview of TEAE with the details below will be generated: 
• Any TEAE  
• Any severe TEAE 
• Any treatment emergent SAE 
• TEAE leading to death  
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• Any TEAE leading to permanent intervention discontinuation  
• Any treatment emergent AESI 
• Any treatment emergent other AE of interest grouping 
• Any TEAE related to IMP  
 
The AE summaries of Table 7 will be generated with number (%) of participants experiencing at 
least one event.  
Table 7 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, HLGT, HLT and PT 
 
Primary SOC and PT 
 
PT 
 
Primary and secondary SOC, HLGT, HLT and PT 
Common TEAE (≥2% and 5% in any group) 
Primary SOC and PT 
TEAE related to IMP as per Investigator’s judgment 
Primary SOC, HLGT, HLT and PT 
 
Primary SOC and PT 
TEAE by maximal intensity 
Primary SOC and PT  
Treatment emergent SAE 
Primary SOC, HLGT, HLT and PT 
 
Primary SOC and PT 
Treatment emergent SAE related to IMP as per Investigator’s 
judgment 
Primary SOC, HLGT, HLT and PT 
TEAE leading to permanent intervention discontinuation 
Primary SOC, HLGT, HLT and PT 
 
Primary SOC and PT 
TEAE leading to death (death as an outcome of the AE as reported 
by the Investigator in the AE page) 
Primary SOC, HLGT, HLT and PT 
Pretreatment AE 
Overviewa 
 
Primary SOC and PT 
a Will include the following AE categories: any AEs, any serious AEs, any AEs leading to death, any AEs leading to permanent intervention 
discontinuation 
Analysis of deaths 
In addition to the analyses of deaths included in Table 6 the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods 
• Deaths in non-randomized or randomized but not treated participants 
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Analysis of adverse events of special interest (AESIs) and other AEs of interest 
Adverse events of special interest (AESIs) and other AEs of interest will be selected for analyses 
as indicated in Table 8. Number (%) of participants experiencing at least one event will be 
provided for each event of interest. Tables will be sorted as indicated in Table 6.  
Table 8 - Selections for AESIs and other AEs of interest  
AE Grouping 
Criteria 
AESI 
 
Anaphylactic reaction 
Anaphylactic reaction algorithmic approach (Introductory 
Guide for Standardised MedDRA Queries (SMQs) Version 
18.1): includes anaphylactic reaction narrow SMQ (20000021) 
terms and programmatic identification of cases based on 
occurrence of at least two preferred terms meeting the 
algorithm criteria occurring within 24 hours of each other. The 
latter cases identified using the algorithm will undergo blinded 
medical review taking into account the timing of events 
relative to each other and to IMP administration for final 
determination of an anaphylactic reaction or not. 
Systemic hypersensitivity reactions 
SMQ [20000214] hypersensitivity narrow search and [AE 
corrective treatment/therapy=’Y’ or Action taken with 
IMP=’Drug withdrawn’ or Action taken with IMP=’Drug 
interrupted’] followed by blinded medical review (documented 
process) for selection of relevant systemic hypersensitivity 
events  
Helminthic infections 
CMQ10544 based on HLGT as “Helminthic disorder” 
Any severe type of conjunctivitis  
CMQ10498 based on PTs (See Section 5.6)a and “Severe” 
ticked in Adverse Events eCRF page  
Any severe type of blepharitis  
CMQ10497 based on HLT as “Lid, lash and lacrimal 
infections, irritations and inflammations” and “Severe” ticked 
in Adverse Events eCRF page 
Keratitis 
CMQ10642 based on the following PTs [keratitis, allergic 
keratitis, ulcerative keratitis, atopic keratoconjunctivitis, 
herpes ophthalmic, ophthalmic herpes simplex, corneal 
infection]a 
Clinically symptomatic eosinophilia (or eosinophilia associated 
with clinical symptoms)b  
CMQ10641 based on HLT = Eosinophilic disorders or 
PT=Eosinophil count increased  
Pregnancy of a female participants entered in a study as well 
as pregnancy occurring in a female partner of a male 
participant entered in a study with IMP/NIMP 
“Pregnancy” or “Partner Pregnancy” checked on the 
Pregnancy eCRF page as reported by the investigator 
Significant ALT elevation 
“ALT increase” and AESI answer “Yes” checked on AE eCRF 
as reported by the investigator (ALT >5 x ULN in participants 
with baseline ALT ≤2 x ULN; OR ALT >8 x ULN if baseline 
ALT >2 x ULN) 
Symptomatic overdose with IMP 
Symptomatic Overdose is answered Yes, with Overdose of 
IMP answered Yes on AE eCRF.  
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AE Grouping 
Criteria 
Symptomatic overdose with NIMP 
Symptomatic Overdose is answered Yes, with Overdose of 
NIMP answered Yes on AE eCRF.  
Other selected AE Grouping 
 
 
Serious injection site reactions or severe injection site 
reactions that last longer than 24 hours  
HLT = ‘Injection site reaction’ and either with serious status, or 
with severe status and (AE end date/time - AE start date/time) 
≥ 24 hours or ongoing 
Severe or serious infection 
Primary SOC = ‘Infections and infestations’ and with severe or 
serious status 
Drug-related hepatic disorder 
SMQ [20000006] Drug-related hepatic disorders- narrow  
Injection site reaction  
HLT = ‘Injection site reaction’  
Malignancy 
SMQ [20000091]– Malignant or unspecified tumors narrow 
Suicidal behavior 
CMQ10639 based on the following PTs [Completed suicide, 
Suicidal ideation, Depression suicidal, Suicidal behavior, 
Suicide attempt]a 
Conjunctivitis (narrow) 
CMQ10644 based on the following PTs [Conjunctivitis, 
Conjunctivitis allergic, Conjunctivitis bacterial, Conjunctivitis 
viral, Atopic keratoconjunctivitis]a 
Conjunctivitis (broad) 
CMQ10645 based on the following PTs [Conjunctivitis, 
Conjunctivitis allergic, Conjunctivitis bacterial, Conjunctivitis 
viral, Atopic keratoconjunctivitis, Blepharitis, Dry eye, Eye 
irritation, Eye pruritus, Lacrimation increased, Eye discharge, 
Foreign body sensation in eyes, Photophobia, Xerophthalmia, 
Ocular hyperaemia, Conjunctival hyperaemia]a 
Conjunctivitis (FDA)c 
CMQ10643 based on the following PTs [Conjunctivitis, 
Conjunctivitis allergic, Conjunctivitis bacterial, Conjunctivitis 
viral, Eye irritation, Eye inflammation, Giant papillary 
conjunctivitis]a 
Keratitis (FDA)c 
 
CMQ30102 based on the following PTs in (keratitis, ulcerative 
keratitis, allergic keratitis, atopic keratoconjunctivitis, and 
ophthalmic herpes simplex) 
a The list of terms may be adjusted according to MedDRA version changes 
b All cases of Eosinophilia will be included in the analysis, where cases associated with clinical symptoms will be further described in the 
CSR 
c  FDA requested for US labeling 
The following summaries will be provided: 
•  All TEAEs, by selected standardized MedDRA query (SMQ)/Customized MedDRA 
query (CMQ) and PT or by laboratory values (as in alanine aminotransferase (ALT) 
elevation), showing the number (%) of participants with at least 1 PT, 
• For each AESI and other selected AE groupings,  
- 
Number (%) of participants with any specific TEAE  
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- 
Number (%) of participants with any specific serious AE (regardless of treatment 
emergent status) 
- 
Number (%) of participants with any specific treatment emergent serious AE 
- 
Number (%) of participants with any specific AE leading to death 
- 
Number (%) of participants with any specific TEAE leading to permanent study drug 
discontinuation 
- 
Number (%) of participants with any specific TEAE related to IMP reported by 
investigator 
- 
Number (%) of participants with any specific TEAE by maximum intensity, corrective 
treatment, and final outcome 
- 
Number of any specific TEAE adjusted by the exposure duration 
- 
Number of participants with any specific TEAE adjusted by the exposure duration at 
risk. For each specific TEAE, Kaplan-Meier estimates of cumulative incidence at 
Week 12, and 24 and K-M plot may be provided to depict the course of onset over 
time if the number of events is large enough. 
- 
Number (%) of participants with injection site reactions by IMP injection. 
- 
Number (%) of participants with different number of injection site reactions. 
• In addition, AESIs reported by the investigator in eCRF will be summarized separately. 
In addition, the exposure-adjusted adverse event incidence rate tables will provide the number of 
patients with at least 1 event per 100 patient-years for the summaries of TEAEs, treatment 
emergent SAE, TEAE leading to permanent intervention discontinuation, and AESIs and other 
selected AE groups in Table 8 
4.7.3 Additional safety assessments  
4.7.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following laboratory variables, vital signs and electrocardiogram (ECG) variables will be 
analyzed. They will be converted into standard international units. 
• Hematology:  
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, red blood cell 
count, platelet count 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils  
• Clinical chemistry: 
- 
Metabolism:  glucose, total cholesterol, total protein, creatine phosphokinase 
- 
Electrolytes:  sodium, potassium, chloride, bicarbonate  
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- 
Renal function:  creatinine, blood urea nitrogen, uric acid 
- 
Liver function:  alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, total bilirubin, albumin 
- 
Pregnancy test:  Serum β-human chorionic gonadotropin (all female participants) will 
be performed at screening (V1) in women of childbearing potential, and a urine 
pregnancy test will be performed at V2 and every 4 weeks thereafter.   
- 
Hepatitis screen:  hepatitis B surface antigen (HBs Ag), hepatitis B surface antibody 
(HBs Ab), hepatitis B core antibody (HBc Ab), hepatitis C virus antibodies (HCV Ab) 
will be tested at screening (V1). In case of results showing HBs Ag (negative) and 
HBc Ab (positive), an hepatitis B virus (HBV) deoxyribonucleic acid (DNA) testing 
will be performed and should be confirmed negative prior to randomization. In case of 
results showing HCV Ab (positive), an HCV ribonucleic acid (RNA) testing will be 
performed and should be confirmed negative prior to randomization. 
- 
HIV screen: Anti-HIV-1 and HIV-2 antibodies will be tested at Visit 1. 
- 
TB test (performed locally if required and results noted in the eCRF). 
• Urinalysis: 
- 
Urinalysis will include specific gravity, pH, glucose, ketones, blood, protein, nitrate, 
leukocyte esterase, urobilinogen and bilirubin. If positive for protein and/or red blood 
cells, microscopic analysis will be performed by the central laboratory. Creatinine, 
leukotriene and tetranor PGDM will be tested by the central laboratory.  
• Vital signs: pulse rate (beats per minute), systolic and diastolic blood pressure (mmHg) in 
a semi-supine or sitting position after 5 minutes, weight, respiratory rate (breaths per 
minute), temperature (degrees Celsius) and height (screening only). 
• ECG variables: heart rate, PR, QRS, QT, and QTcF intervals after 10 minutes of rest in the 
supine position. Data are locally collected and read at screening (V1) and Week 24 (V6). 
Data below the lower limit of quantitation/detection limit (LLOQ) will be replaced by half of the 
LLOQ, data above the upper limit of quantification will be replaced by ULOQ value. 
Quantitative analyses 
For all laboratory variables, vital signs and ECG variables above, descriptive statistics for results 
and changes from baseline will be provided for each analysis window, the last value and the worst 
value during the on-treatment period. These analyses will be performed using central 
measurements only (when available) for laboratory variables.  
For all parameters, mean changes from baseline with the corresponding standard error will be 
plotted over time.  
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Analyses according to PCSA  
Analysis of potentially clinically significant abnormality (PCSA) will be performed based on the 
PCSA list in effect at Sanofi at the time of the database lock. For parameters for which no PCSA 
criteria are defined, similar analyses will be done using the normal range, if applicable. 
Analyses according to PCSA will be performed based on the worst value during the treatment-
emergent period, using all measurements (either local or central, either scheduled, nonscheduled 
or repeated). 
For laboratory variables, vital signs and ECG variables above, the incidence of participants with at 
least one PCSA during the treatment-emergent period will be summarized regardless of the 
baseline level and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
Additional analyses for suspect drug-induced liver injury 
The following additional analyses will be performed for drug-induced liver injury:  
• Time to onset of the initial ALT or aspartate aminotransferase (AST) elevation (>3 x 
ULN) and total bilirubin elevation (>2 x ULN) during the treatment-emergent period will 
be analyzed using Kaplan-Meier method.  
• A graph of the distribution of peak values of ALT versus peak values of total bilirubin 
during the treatment-emergent period will be provided.   
• For each liver function test (eg, ALT), participants having a PCSA (eg, ALT >5 ULN) will 
be summarized using the following categories: Returned to baseline PCSA status (or 
returned to value ≤ ULN in case of missing baseline) before last IMP dose, Returned to 
baseline PCSA status after last IMP dose, Never returned to baseline PCSA status, No 
assessment after elevation. This summary will be performed by categories of elevation 
(ALT >3, >5, >10, >20 ULN). 
4.8 
OTHER ANALYSES  
4.8.1 Pharmacokinetic analyses   
Predose dupilumab concentrations in serum at Visit 2 (Day 1), dupilumab trough concentrations at 
Week 4, Week 8, Week 12, Week 24/EOT Visit and post-treatment dupilumab concentrations at 
Week 36/EOS Visit will be provided. 
Concentrations of dupilumab in serum will be summarized in the PK population using arithmetic 
and geometric means, SD, standard error of the mean (SEM), coefficient of variation (CV), 
minimum, median and maximum per sampling time. If date and/or time of the drug injection 
and/or sampling is missing then the concentration will not be taken into account. For drug-treated 
participants, where concentration values are below the lower limit of quantification (LLOQ), 
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one-half of the LLOQ will be used. Values will be expressed in the tables with no more than three 
significant figures. For participants in the placebo group, concentration values that are below the 
LLOQ will be taken into account with a plasma concentration considered equal to 0. 
4.8.2  Immunogenicity analyses   
Anti-drug antibody (ADA) status to dupilumab (negative or titer value, if positive in the ADA 
assay) at Visit 2 (Day 1), Week 12, Week 24/EOT and follow up at Week 36 will be provided. 
The neutralizing antibody status for ADA positive samples will be provided.  
Incidence will be provided for the following ADA response categories: 
Pre-existing immunoreactivity is defined as:  
An ADA positive response in the assay at baseline with all post first dose ADA results negative, 
OR an ADA positive response at baseline with all post first dose ADA responses less than 4-fold 
over baseline titer levels. 
Treatment-emergent ADA response is defined as:  
A positive response in the ADA assay post first dose, when baseline results are negative or 
missing. 
Treatment-emergent ADA responses are further classified as Persistent, Indeterminate or 
Transient 
a) Persistent Response- defined as a treatment-emergent ADA response with two or more 
consecutive ADA positive sampling time points, separated by greater than (>) 12-week 
period (84 days), with no ADA negative samples in between. 
b) Indeterminate Response- defined as a treatment-emergent response with only the last 
collected sample positive in the ADA assay  
c) Transient Response - defined as a treatment-emergent response that is not considered 
persistent OR indeterminate 
Treatment-boosted response is defined as:   
An ADA positive response in the assay post first dose that is greater-than or equal to 4-fold over 
baseline titer levels, when baseline results are positive. 
Titer values (Titer value category) 
• Low (Titer <1000) 
• Moderate (1,000 ≤ Titer ≤10,000) 
• High (Titer >10,000) 
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The following summary will be provided based on ADA population: 
• Number (%) of participants with pre-existing immunoreactivity 
• Number (%) of participants with treatment-emergent ADA  
• The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for participants with treatment-emergent ADA, and 
participants with persistent, indeterminate and transient ADA response 
• Number (%) of participant with transient treatment-emergent ADA  
• Number (%) of participants with persistent treatment-emergent ADA  
• Number (%) of participants with indeterminate treatment-emergent ADA  
• Number (%) of participants with treatment-boosted ADA  
• The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for participants with treatment-boosted ADA  
• The summary statistics (including number, mean, SD, median, Q1, Q3, minimum and 
maximum) of the ratio of peak post-baseline titer to baseline titer for participants with 
treatment-boosted ADA  
• Listing of ADA peak titer levels and neutralizing antibody status  
• Number (%) of participants with neutralizing antibody status  
Kinetics of treatment-emergent ADA response 
Number (%) of participants with treatment-emergent ADA positive response at each visit will be 
summarized, including titer categories (lower, moderate, and high titer), by each intervention 
group. 
A plot of percentage of participants with treatment-emergent ADA positive response at each visit 
will be provided by each intervention group. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
The safety and efficacy analyses mentioned below will be conducted using the following 
categories: 
• ADA positive participants: Participants with treatment-emergent or treatment-boosted 
response. 
• ADA negative participants: Participants with pre-existing immunoreactivity or negative in 
the ADA assay at all time points. 
Association of ADA with PK 
Associations between ADA variables (eg, ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent, indeterminate and transient response, treatment-boosted) and 
concentration of dupilumab in serum may be explored for each dupilumab dose group. A plot of 
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concentration of functional dupilumab versus visit will be provided by ADA classifications for the 
dupilumab dose group. Individual participant plots of dupilumab concentration according to ADA 
status will be provided to assess the impact of ADA on PK. 
Association of ADA with clinical efficacy endpoints 
Associations between the ADA variables (eg, ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent and treatment-boosted) and the primary efficacy endpoint may be 
explored for the dupilumab dosed group. 
Association of ADA with clinical safety endpoints 
Association of safety versus ADA status may be analyzed in the ADA population. The safety 
assessment may focus on the following events: 
• Severe injection site reactions last longer than 24 hours or serious injection site reactions 
• Hypersensitivity reactions (SMQ (20000214) hypersensitivity narrow search confirmed by 
medical review) 
• Anaphylactic reactions (SMQ (20000021) anaphylactic reaction narrow search) 
Associations between ADA variables (eg, ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent and treatment-boosted) and safety may be explored. 
4.8.3  Pharmacodynamic/genomics endpoints   
Venous blood samples will be collected at Visit 2 (Week 0), Visit 3 (Week 4), Visit 4 (Week 8), 
Visit 5 (Week 12), Visit 6 (Week 24), and Visit 7 (Week 36), for measurement of total serum IgE. 
Total IgE will be measured using validated quantitative methods. 
For those participants who consent to the optional pharmacogenetic/pharmacogenomic sample 
collection section of the ICF, blood (serum/plasma) for possible future analysis of potential 
biomarkers of drug response, disease activity, safety, and the type 2 inflammation pathway, and 
blood samples for exploratory genetic analysis of DNA or RNA will be collected and stored for 
possible future use. Participation is optional. Participants who do not wish to participate in the 
genetic research may still participate in the study. 
Total IgE will be summarized in the safety population defined as participants who actually 
received at least 1 dose or part of a dose of the IMP.  Baseline values will be the last value 
collected prior to the first IMP. Descriptive statistics (including number, mean, SD, median, Q1, 
Q3, min, max) of biomarkers at baseline will be summarized. In addition, for participants who 
take the prohibited medications/procedures or rescue medications defined in Table 5, the data 
after the medications will be censored and then last observation carried forward (LOCF) method 
will be implemented for missing data imputation in the analysis..  
Summary plots (median with interquartile range) on values at each visit, absolute changes from 
baseline and percent changes from baseline will be provided for the total IgE by intervention 
group and visit. 
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Exploratory analysis of DNA, RNA and urine biomarkers will be addressed in a separate 
document. 
4.9 
INTERIM ANALYSES  
No interim analysis is planned. 
A primary database lock will be performed when all randomized participants in this study have 
completed their 24-week treatment phase. Final analyses in the CSR will be based on this 
database. 
The database will be updated at the end of the study for all participants to include the 
post-treatment follow-up information and updates for the events previously ongoing at the time of 
the primary lock. Additional data between this database lock and last participant completing last 
visit will be summarized in a CSR addendum. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
ATC: 
anatomic category 
CI: 
confidence interval 
CLcr: 
creatinine clearance 
CMH: 
Cochran-Mantel-Haenszel 
CMQ: 
customized MedDRA query 
CSR: 
clinical study report 
DLQI: 
Dermatology Life Quality Index 
DNA: 
deoxyribonucleic acid 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EMA: 
European Medicines Agency 
EOT: 
end of treatment 
EQ-5D-5L: 
5-level EuroQol 5-dimensional questionnaire 
FDA: 
Food and Drug Administration 
HADS: 
hospital anxiety and depression scale 
HBc Ab: 
hepatitis B core antibody 
HBs Ab: 
hepatitis B surface antibody 
HBs Ag: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
HCV Ab: 
hepatitis C virus antibodies 
HLGT: 
high level group term 
HLT: 
high level term 
HRQoL: 
health-related quality-of-life 
IGA PN: 
Investigator's global assessment for prurigo nodularis 
IMP: 
investigational medicinal product 
ITT: 
intent-to-treat 
LLT: 
lower-level term 
LS: 
least squares 
MedDRA: 
Medical Dictionary for Regulatory Activities 
PCSA: 
potentially clinically significant abnormality 
PGIC: 
Participant Global Impression of Change 
PGIS: 
Global Impression of Severity 
PK: 
pharmacokinetic 
PN: 
prurigo nodularis 
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PT: 
preferred term 
RNA: 
ribonucleic acid 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
standard deviation 
SDG: 
standardized drug grouping 
SMQ: 
standardized MedDRA query 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal 
WHO-DD: 
World Health Organization-Drug Dictionary 
WI-NRS: 
worst-itch numeric rating scale 
WOCF: 
worst-observation carried forward 
 
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5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
This section summarizes major statistical changes in the protocol amendment. 
Table 9 - Major statistical changes in protocol amendment(s)  
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
1 
20-May-2020 
To add “proportion of participants with 
Investigator’s Global Assessment 0 or 1 
score for PN-Stage (IGA PN-S) at 
Week 24” as another key secondary 
endpoint 
To include a lesion-related key 
secondary endpoint according to the 
health authority’s recommendations 
 
 
To remove the endpoint “Change from 
baseline in PAS total score at Week 4, 
Week 8, Week 12, and Week 24” in the 
exploratory endpoint and modify the 
exploratory endpoint regarding the healed 
lesions from PAS questionnaire analysis 
To clarify the analysis on efficacy 
evaluation of dupilumab on skin 
lesions using a modified prurigo 
activity score (PAS) 5-item 
questionnaire 
 
 
To break out the secondary endpoints with 
multiple measuring timepoints into 
individual endpoints.  
To clearly define the timepoints of 
each endpoint according to health 
authority’s recommendation 
 
 
To add the sensitivity analysis for 
secondary endpoints information, and to 
separate key secondary endpoints in a 
different row 
To evaluate the robustness of the 
missing data imputation assumption 
by sensitivity analyses, and to clarify 
the endpoints analyses 
 
 
To add the covariate “baseline anti-
depressant use (yes or no)” to primary and 
secondary endpoint analyses 
To adjust for potential impact of anti-
depressant use on the treatment effect 
in primary and secondary efficacy 
analyses 
 
 
The following wording was added: “Data 
collected regarding the impact of the 
COVID-19 or other pandemics, on the 
participants will be summarized 
(eg, discontinuation due to COVID-19). 
Any additional analyses and methods 
required to investigate the impact of 
COVID-19 or other pandemics requiring 
public health emergency on the efficacy 
(eg, missing data due to COVID-19) and 
safety will be detailed in the SAP”. 
To describe alternative temporary 
mechanism that can be implemented 
in the study conduct in case of 
pandemic requiring public health 
emergency eg, COVID-19 
 
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5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS/PROCEDURES  
Demographics, baseline characteristics, medical surgical history 
The following demographics and baseline characteristics, medical and surgical history and disease 
characteristics at baseline will be summarized using descriptive statistics in the randomized 
population. 
Demographic variables are  
• Age in years (quantitative and qualitative variable: 18-<40, 40–<65, 65-<75, and ≥75 
years), 
• Gender (Male, Female),  
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Island, unknown),  
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown) 
• Region (Asia: Taiwan, South Korea; East Europe: Hungary; Latin America: Chile; 
Western Countries: USA, Canada, France, Italy, Portugal, Spain, and UK) 
• Territory (North America: USA, Canada; European Union: France, Italy, Portugal, Spain, 
Hungary, and UK; Rest of World: Taiwan, South Korea, Chile) 
• Weight in kg (quantitative and qualitative variable: (<60, ≥60- <90, ≥90 kg) 
• BMI in kg/m2 (quantitative and qualitative variable: <25, ≥25- <30, ≥30 kg/m2)  
Baseline safety and efficacy parameters (apart from those listed above) will be presented along 
with the safety and efficacy summaries.  
Medical (or surgical) history includes all the relevant medical (or surgical) history during the 
lifetime of the participant. 
This information will be coded using the version of MedDRA currently in effect at Sanofi at the 
time of database lock.  
Comorbidity will be summarized separately.  The following comorbid diseases will be 
summarized from electronic case report form (eCRF) pages which were filled in by investigators 
based on participant reporting.  
• Prurigo nodularis (Yes, Ongoing condition) 
• Atopic dermatitis (Yes, Ongoing condition) 
• Allergic rhinitis history (Yes, Ongoing condition) 
• Allergic rhinoconjunctitvitis (Yes, Ongoing condition) 
• Asthma history (Yes, Ongoing condition) 
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• Food allergy history (Yes, Ongoing condition) 
• Eosinophilic esophagitis history (Yes, Ongoing condition) 
Disease characteristics at baseline   
The following baseline disease characteristics will be summarized by intervention group: 
• Duration of PN and grouping (years; <3 and ≥3) to be derived as 
- 
(Year of randomization – Year of first diagnosis of PN) + (month of randomization – 
month of first diagnosis of PN)/12 
• Age of onset of PN (years) 
• History of atopy (atopic or non-atopic) 
- 
Number of mild AD participants under atopic 
• Stable use of TCS/TCI (yes or no) 
• Baseline WI-NRS score  
• Baseline IGA PN-S score (summary and frequency by each score level)  
• Baseline IGA PN-A score (summary and frequency by each score level) 
• Baseline skin Pain-NRS score 
• Baseline Sleep-NRS score 
• Baseline PGIS score 
• PAS (number of prurigo lesions in a total and in representative area, and healed prurigo 
lesions) at baseline  
• Baseline Hospital Anxiety and Depression Scale (HADS) total score 
- 
 Baseline Hospital Anxiety score 
- 
Baseline Depression Scale score 
• Baseline Dermatology Life Quality Index (DLQI) score 
• Baseline EuroQol five dimensions questionnaire (ED-5D-5L) (single index score and 
VAS) 
• Frequency of alcohol drinking in the past 12 months (never, occasional, at least monthly, 
at least weekly, at least daily) and number of drinks on  a typical day (1 or 2, >2) 
• Antidepressant use (yes or no) at baseline 
• HIV (positive versus negative) 
Prior or concomitant medications and procedure  
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock.  
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All procedures will be coded to a PT and associated primary SOC using the version of MedDRA 
currently in effect at Sanofi at the time of database lock. 
• Prior medications/procedures are those the participant used prior to first investigational 
medicinal product (IMP) injection.  Prior medications/procedures can be discontinued 
before first administration or can be ongoing during treatment phase.   
• Concomitant medications/procedures are any interventions received by the participant 
concomitantly to the IMP, from first administration of IMP to last IMP intake + 98 days.   
• Post-treatment medications/procedures are those the participant took in the period running 
from the end of the concomitant medications period up to the end of the study.  
• A given medication/procedure can be classified as a prior medication/procedure and/or as 
a concomitant medication/procedure and/or as post-treatment medication/procedure. If it 
cannot be determined whether a given medication/procedure was taken prior or 
concomitantly or post, it will be considered as prior, concomitant, and post-treatment 
medication/procedure. 
The prior and concomitant medications/procedure will be summarized for the randomized 
population.  
Medications will be summarized by intervention group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the first 
3 digits of the ATC class (therapeutic category).  All ATC codes corresponding to a medication 
will be summarized, and participants will be counted once in each ATC category (anatomic or 
therapeutic) linked to the medication. Therefore participants may be counted several time for the 
same medication.  
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across intervention groups.  In case of 
equal frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be 
used. 
Concomitant medication received during first IMP to last IMP +14 days and concomitant 
medication received during first IMP to last IMP +98 days will be summarized separately. The 
tables for concomitant medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the incidence in the dupilumab group. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used.  
Medications will also be summarized by generic name sorted by decreasing frequency based on 
the incidence in the dupilumab group. 
Procedures will be summarized by intervention group by primary SOC (sorted by internationally 
agreed order) and PT (sorted in alphabetical order), sorting is based on the overall incidence 
across intervention groups. 
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Background intervention 
Participants will be required to apply moisturizers (emollients) once or twice daily for at least the 
7 consecutive days immediately before baseline (Day 1) and continue until Week 36. 
The compliance of moisturizers (emollients) used from 7 days before the baseline visit to Week 
36 (or end of study), which is defined as the (number of days moisturizers used during the period) 
/ (number of days within the period) x 100%, will be summarized by intervention group.  
Similarly, the compliance of moisturizers (emollients) used from the baseline visit to Week 12 
and Week 24 will be summarized by intervention group respectively. 
 
In addition, the compliance of use of TCS/TCI from the baseline visit to Week 12 and Week 24 
for participants with the stratification of stable use of TCS/TCI (yes) will be summarized by 
intervention group respectively.  
. 
Prohibited medications/procedures 
The concomitant use of the following therapies is prohibited during the entire study. Study 
treatment will need to be discontinued in participants receiving these treatments: 
• Systemic immunosuppressive/immunomodulating drugs (eg, systemic corticosteroids, 
cyclosporine, mycophenolate-mofetil, interferon gamma, Janus kinase inhibitors, 
azathioprine, methotrexate, hydroxychloroquine, dapsone, sulfasalazine, colchine, etc) 
• Other monoclonal antibodies (which are biological modifiers) 
• Phototherapy, including tanning beds 
• Naltrexone or other opioid antagonist 
• Gabapentin, pregabalin, and thalidomide 
The concomitant use of the following therapies is prohibited except if the dose has been stable for 
at least 3 months prior to screening, but study treatment will not need to be discontinued in 
participants receiving the treatments listed below. The dose should also remain stable (can be 
reduced or discontinued if medically indicated) and should not be increased during the study. 
• Paroxetine, fluvoxamine, or other SSRIs 
• SNRIs 
• Amitriptyline or other tricyclic or tetracyclic antidepressants 
The concomitant use of the following therapies is also prohibited during the entire study, but 
study treatment will not need to be discontinued in participants receiving the treatments listed 
below:  
• Intralesional corticosteroid injections and cryotherapy 
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• Sedating antihistamine 
• Non-sedating antihistamine if used specifically for the treatment of itch secondary to AD 
or PN 
The number and percentage of participants who take the prohibited medications/procedures will 
be provided. In addition, the time (week) of first prohibited medication/procedure taken will also 
be analyzed using Kaplan-Meier method. 
Rescue medications  
The following rescue medications may be used: 
• Dermatological preparations of high potency or superpotent TCS and TCI. 
If medically necessary (i.e., to control intolerable PN symptoms), rescue treatment for PN may be 
provided to study participants at the discretion of the Investigator. 
Although the use of rescue medications is allowed at any time during the study, the use of rescue 
medications should be delayed, if possible, for at least 14 days following the initiation of the 
investigational treatment. The date and time of rescue medication administration as well as the 
name and dosage regimen of the rescue medication must be recorded in the eCRF. 
• For the purpose of the efficacy responder analysis, a pre-specified algorithm will be used 
to classify rescue. In addition, a blinded review of all post-baseline medications to 
adjudicate rescue treatment, based on medical judgment, will be performed to adjudicate 
rescue. Participants who receive rescue treatment as per this adjudication during the study 
will be considered treatment failures. 
The rescue medications will be analyzed by the same method as that used for prohibited 
medications/procedures. 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
Demographic formulas 
 
Age of onset of PN is calculated as: 
Year of PN diagnosis – Year of birth 
 
BMI is calculated as: 
Weight in kg / (height2 in meters) 
 
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Renal function formulas  
For adults, creatinine clearance (CLcr) value will be derived using the equation of Cockroft and 
Gault: 
CLcr (ml/min) = (140 - age)  weight (kg)   (1 - 0.15  sex (0-M, 1-F))/ (0.814  
creatinine 
(μmol/l)) 
CLcr will be calculated using the last weight measurement on or before the visit of the creatinine 
measurement and age at the lab sampling day. Here age is calculated as following: 
Age = age collected at screening + integer part of (lab sampling analysis day/365.25) 
Analysis windows for time points 
Efficacy assessment 
For the efficacy assessment, the reference date for the derivation of relative days of events or 
findings will be the randomization day. If a participant receives IMP prior to the randomization by 
mistake, the reference date of efficacy assessment will be the date of the first IMP administration 
for that participant.  
For daily eDiary data (WI-NRS, skin Pain-NRS, Sleep-NRS), all available values of daily 
measurements will be assigned to each week window according to Table 10, and then weekly 
average score will be calculated. Randomization day is used as the reference day (Day 1). 
Table 10 - Time window for eDiary efficacy variables  
Time 
Target day 
Day range for calculating 
weekly score 
Baseline (Week 0) 
1 
-7- <1 
Week 1 
8 
1-11 
Week 2 
15 
12-18 
Week 3 
22 
19-25 
Week 4 
29 
26-32 
Week 5 
36 
33-39 
Week 6 
43 
40-46 
Week 7 
50 
47-53 
Week 8 
57 
54-60 
Week 9 
64 
61-67 
Week 10 
71 
68-74 
Week 11 
78 
75-81 
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Time 
Target day 
Day range for calculating 
weekly score 
Week 12 
85 
82-88 
Week 13 
92 
89-95 
Week 14 
99 
96-102 
Week 15 
106 
103-109 
Week 16 
113 
110-116 
Week 17 
120 
117-123 
Week 18 
127 
124-130 
Week 19 
134 
131-137 
Week 20 
141 
138-144 
Week 21 
148 
145-151 
Week 22 
155 
152-158 
Week 23 
162 
159-165 
Week 24 
169 
166-172 
Week 25 
176 
173-179 
Week 26 
183 
180-186 
Week 27 
190 
187-193 
Week 28 
197 
194-200 
Week 29 
204 
201-207 
Week 30 
211 
208-214 
Week 31 
218 
215-221 
Week 32 
225 
222-228 
Week 33 
232 
229-235 
Week 34 
239 
236-242 
Week 35 
246 
243-249 
Week 36 
253 
250-256 
 
For other efficacy variables, all available values of scheduled measurements will be assigned to 
the appropriate visit window according to Table 11. In the event of multiple measurements of the 
same test in the same window, the one closest to the targeted visit date will be used for the 
by-visit summary. If they are at the same number of days away from the target day, the latest one 
will be used.  
 
 
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Table 11 - Time window for efficacy variables  
Visit 
Target 
Day 
Time windows for  
DLQI,  
IGA PN-A/PN-S  
HADS, 
EQ-5D-5L, Missed school/work 
days 
PGIS 
PGIC 
PAS 
Visit 1 (Week -4 to -2) 
<1 
 
 
<-14 
 
<-14 
Visit 2 (Week 0) 
1 
1- 
1- 
-14-1- 
 
-14-1- 
Visit 3 (Week 4) 
29 
1+-42 
 
1+-42 
1+-42 
1+-42 
Visit 4 (Week 8) 
57 
43-70 
 
43-70 
43-70 
43-70 
Visit 5 (Week 12) 
85 
71-126 
1+-126 
71-126 
71-126 
71-126 
Visit 6 (Week 24) 
169 
127-210 
127-210 
>126 
>126 
127-210 
Visit 7 (Week 36) 
253 
>210 
>210 
 
 
>210 
1-: up to randomization and before 1st dose date/time; 1+: after randomization or 1st dose date/time   
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Safety assessment 
For the safety assessment, the reference date for the derivation of relative days of events or 
findings will be the date of first IMP administration. Selected safety variables will be summarized 
by the analysis window define in Table 12 for the by visit descriptive analysis. All available 
values from central lab will be assigned to the appropriate visit window. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same number of days away from the target 
day, the latest one will be used. For procedures planned on Visit 2, if it is done on the same date 
as the first IMP injection but the performance time is missing, it will belong to Visit 2 time 
window. 
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Table 12 - Time window for safety endpoints  
 
Target Day 
 
 
 
Time windows for 
Visit 
Vital signs 
Hematology, 
biochemistry  
Urinalysis 
CD4 T cell 
count and 
HIV test 
Serum 
Pregnancy 
test 
Urine Pregnancy 
test 
Physical 
examination 
ECG 
Visit 1 (Week -4 
to -2) 
<1 
<-14 
<-14 
<-14 
1- 
<-14 
 
<-14 
1- 
Visit 2 (Week 0) 
1 
-14-1- 
-14-1- 
-14-1- 
 
 
-14-1- 
-14-1- 
 
Visit 3 (Week 4) 
29 
1+-42 
1+-42 
1+-42 
 
 
1+-42 
 
 
Visit 4 (Week 8) 
57 
43-70 
43-70 
43-70 
 
 
43-70 
 
 
Visit 5 (Week 12) 
85 
71-126 
71-126 
71-126 
 
 
71-126 
 
 
Visit 6 (Week 24) 
169 
127-210 
127-210 
>126 
1+ 
 
127-210 
1+-210 
1+ 
Visit  7 (Week 36) 
253 
>210 
>210 
 
 
 
>210 
>210 
 
1-: up to 1st dose date/time; 1+: after 1st dose date/time; 
 
 
 
 
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Pharmacokinetics/pharmacodynamics assessment 
For the pharmacokinetics/pharmacodynamics variables summary, the reference date for the 
derivation of relative days of measurements will be the date of first IMP administration if the 
participant is treated with study treatment, or the randomization date if the participant is not 
treated. Pharmacokinetics /pharmacodynamics variables will be summarized by the analysis 
window defined in Table 13 for the by visit descriptive analyses. All available values of 
measurements will be assigned to the appropriate visit window. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same distance to the target day, the latest one 
will be used. For procedures planned on Visit 2, if it is done on the same date as the first IMP 
injection but the performance time is missing, it will belong to Visit 2 time window. 
Table 13 - Time window for pharmacokinetics/pharmacodynamics variables  
 
 
Time windows for 
Visit 
Target 
day 
Serum dupilumab 
concentration 
Anti-drug antibodies 
Total IgE 
Visit 1 (Week -4) 
<1 
 
 
 
Visit 2 (Week 0) 
1 
1- 
1- 
1- 
Visit 3 (Week 4) 
29 
1+-42 
 
1+-42 
Visit 4 (Week 8) 
57 
43-70 
 
43-70 
Visit 5 (Week 12) 
85 
71-126 
1+-126 
71-126 
Visit 6 (Week 24) 
169 
127-210 
127-210 
127-210 
Visit  7(Week 36) 
253 
>210 
>210 
>210 
1-: up to 1st dose date/time or randomization if participant is not treated; 1+: after 1st dose date/time or randomization date if participant is not 
treated; 
Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline, the last on-treatment value, analysis according to PCSAs, and the shift 
summaries for safety. They will also be included in the by-visit summaries if they are re-allocated 
to scheduled visits. 
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5.5 
APPENDIX 5 SAMPLE SAS CODE  
The multiple imputation and analysis model for the primary analysis of change from baseline in 
WI-NRS at Week 12 will be built with the following sample SAS code. 
 
1.  40 datasets with a monotone missing pattern will be obtained, induced by Markov Chain 
Monte Carlo (MCMC) method on participants who have not taken the prohibited 
medications and/or rescue medications or have discontinued study treatment due to lack of 
efficacy prior to Week 12. 
proc mi data=dat_etd seed=16460 nimpute=40 out=dat_mc; 
    mcmc impute=monotone; 
    var atopicyn stableyn region antidblyn trt01p winrsbl chg1winrs …  
chg24winrs; 
run; 
2. For each of the imputed dataset with monotone missing pattern in step 1, the remaining 
missing data will be imputed using the regression method for the monotone pattern with 
adjustment for covariates including intervention groups, documented history of atopy 
(atopic or non-atopic), stable use of TCS/TCI (yes or no), region, baseline anti-depressant 
use (yes or no),  and baseline value of the response variable. 
 
proc mi data=dat_mc nimpute=1 seed=16461 out=dat_mi;   
    by _imputation_; 
class atopicyn stableyn region antidblyn trt01p; 
monotone method=reg; 
var atopicyn stableyn region antidblyn trt01p winrsbl chg1winrs … 
chg24winrs; 
run; 
 
3. Each of the 40 imputed datasets will be merged with the one dataset imputed by WOCF 
approach, and then be analyzed using the main statistical model. These 40 imputed 
datasets will be saved. 
 
%macro w1; 
%do i=1%to 40; 
data wocf&i.; 
set wocf; 
_imputation_=&i.; 
run; 
%end; 
data wocf_all; 
set %do j=1 %to 40; wocf&j. %end;; 
run; 
    
%mend w1; 
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%w1 
 
data dat_imp; 
    
 
set dat_mi  wocf_all; 
Run;  
 
proc sort data=dat_imp; 
       
by _imputation_; 
run; 
 
proc glm data= dat_imp; 
       
by _imputation_; 
       
class atopicyn stableyn region antidblyn trt01p;  
       
model  chg24winrs = atopicyn stableyn region antidblyn          
                      trt01p winrsbl; 
 
 
lsmeans trt01p / stderr; 
       
estimate 'Diff Dupilumab vs Placebo' trt01p -1 1; 
       
ods output LSMeans=implsmeans Estimates=implsmeandiff; 
  
run; 
 
4. Applying Rubin’s rule to combine analysis results (point estimates and standard errors) 
from 40 imputations using PROC MIANALYZE for the LS means and difference in LS 
means between dupilumab and placebo. Sample code: 
 
   
proc sort data=implsMeans; by trt01pn _imputation_;run; 
 
   
proc mianalyze data= implsmeans; 
       
by trt01pn; 
       
modeleffects lsmean; 
       
stderr stderr; 
       
ods output ParameterEstimates=lsmeans; 
     run; 
 
    
proc mianalyze data=implsmeandiff; 
       
modeleffects estimate; 
       
stderr stderr; 
       
ods output ParameterEstimates=lsmeandiff; 
     run;   
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5.6 
APPENDIX 6 SELECTION CRITERIA FOR AE/MEDICATION GROUPINGS  
Table 14 - List of PTs or Medications for CMQs/CDGs  
Grouping 
Preferred Term/Medication 
Code 
Preferred Term/Medication 
Conjunctivitis 
10001257 
Adenoviral conjunctivitis 
Conjunctivitis 
10010725 
Conjunctival irritation 
Conjunctivitis 
10010726 
Conjunctival oedema 
Conjunctivitis 
10010736 
Conjunctival ulcer 
Conjunctivitis 
10010741 
Conjunctivitis 
Conjunctivitis 
10010744 
Conjunctivitis allergic 
Conjunctivitis 
10010745 
Conjunctivitis chlamydial 
Conjunctivitis 
10010749 
Conjunctivitis gonococcal neonatal 
Conjunctivitis 
10010754 
Conjunctivitis tuberculous 
Conjunctivitis 
10010755 
Conjunctivitis viral 
Conjunctivitis 
10018258 
Giant papillary conjunctivitis 
Conjunctivitis 
10021629 
Inclusion conjunctivitis 
Conjunctivitis 
10030861 
Ophthalmia neonatorum 
Conjunctivitis 
10048908 
Seasonal allergy 
Conjunctivitis 
10049458 
Herpes simplex virus conjunctivitis 
neonatal 
Conjunctivitis 
10051625 
Conjunctival hyperaemia 
Conjunctivitis 
10053991 
Inclusion conjunctivitis neonatal 
Conjunctivitis 
10061784 
Conjunctivitis bacterial 
Conjunctivitis 
10062889 
Pingueculitis 
Conjunctivitis 
10063669 
Photoelectric conjunctivitis 
Conjunctivitis 
10067317 
Oculorespiratory syndrome 
Conjunctivitis 
10067817 
Acute haemorrhagic conjunctivitis 
Conjunctivitis 
10069166 
Blebitis 
Conjunctivitis 
10071570 
Ligneous conjunctivitis 
Conjunctivitis 
10074701 
Noninfective conjunctivitis 
Conjunctivitis 
10075264 
Oculoglandular syndrome 
Conjunctivitis 
10080825 
Conjunctivitis fungal 
Conjunctivitis 
10084034 
Conjunctival suffusion 
Intravenous immunoglobulin therapy 
CAS 8000012671 
IMMUNOGLOBULIN HUMAN NORMAL 
Intravenous immunoglobulin therapy 
CAS 8000050682 
IMMUNOGLOBULIN, PORCINE 
Intravenous immunoglobulin therapy 
CAS 8000056919 
IMMUNOGLOBULIN G HUMAN 
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Grouping 
Preferred Term/Medication 
Code 
Preferred Term/Medication 
Intravenous immunoglobulin therapy 
CAS 8600000563 
IMMUNOGLOBULINS NOS 
Intravenous immunoglobulin therapy 
CAS 8600001670 
IMMUNOGLOBULIN HUMAN NORMAL 
SLRA 
Intravenous immunoglobulin therapy 
CAS 8600001671 
IMMUNOGLOBULIN HUMAN NORMAL 
IFAS 
Intravenous immunoglobulin therapy 
RECNO 900708 
OTHER IMMUNOGLOBULINS 
Intravenous immunoglobulin therapy 
RECNO 900722 
IMMUNE SERA AND 
IMMUNOGLOBULINS 
Intravenous immunoglobulin therapy 
RECNO 900728 
IMMUNOGLOBULINS 
Intravenous immunoglobulin therapy 
RECNO 900914 
SPECIFIC IMMUNOGLOBULINS 
Intravenous immunoglobulin therapy 
RECNO 901112 
IMMUNOGLOBULINS, NORMAL 
HUMAN 
Abbreviations: CAS : Chemical Abstract Service Registry Number RECNO : Drug Record Number 
 
 
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5.7 
APPENDIX 7 MEDICATION/PROCEDURE ADJUDICATION ALGORITHM  
Algorithm for determining whether treatment with following medications or procedures 
constitutes treatment failure resulting in setting data as non-responder after taking 
medication or undergoing procedure in the main statistical analysis 
1. Not required to adjudicate post-baseline medications (WHODD-coded) or procedures 
(CMQ-coded) as these will be considered treatment failures if used at any time1. 
a) Always considered treatment failure 
• ATC2 = CORTICOSTEROIDS FOR SYSTEMIC USE 
• ATC2 = IMMUNOSUPPRESSANTS (systemic, e.g. oral or parenteral route) 
• Preferred Drug Name = Ciclosporin 
• Preferred Drug Name = Methotrexate 
• Preferred Drug Name = Mycophenolate sodium 
• Preferred Drug Name = Mycophenolic acid 
• Preferred Drug Name = Azathioprine 
• Preferred Drug Name = Gabapentin 
• Preferred Drug Name = Pregabalin 
• Preferred Drug Name = Thalidomide 
• Preferred Drug Name = Lenalidomide 
• Preferred Drug Name = Baricitinib 
• Preferred Drug Name = Ruxolitinib 
• Preferred Drug Name = Tofacitinib 
• Preferred Drug Name = AbrocitinibPreferred Drug Name = Delgocitinib 
• Preferred Drug Name = Nalbuphine 
• Preferred Drug Name = Naltrexone 
• Preferred Drug Name = Naloxone 
• Preferred Drug Name = Vixarelimab 
• Preferred Drug Name = Nemolizumab 
• Preferred Drug Name = Serlopitant 
• Preferred Drug Name = Aprepitant 
• CMQb HLT Phototherapies 
• CMQ Tanning_single PT 
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b) Never considered treatment failure: 
• ATC2 = EMOLLIENTS AND PROTECTIVES 
• ATC2 = GENERAL NUTRIENTS  
• ATC2 = VITAMINS 
• ATC2 = ANTIVIRALS FOR SYSTEMIC USE  
• ATC2 = ANTIFUNGALS FOR DERMATOLOGICAL USE  
• ATC2 = ANTISEPTICS AND DISINFECTANTS 
• ATC2 = ANTIBIOTICS AND CHEMOTHERAPEUTICS FOR 
DERMATOLOGICAL USE 
• ATC2 = ANTI-ACNE PREPARATIONS, excluding D10AA Corticosteroids, 
combinations for treatment of acne 
• ATC2 = OPHTHALMOLOGICALS 
• ATC1 = ANTIINFECTIVES FOR SYSTEMIC USE, excluding D07C 
Corticosteroids, combinations with antibiotics 
• ATC1 = BLOOD AND BLOOD FORMING ORGANS  
• ATC1 = ALIMENTARY TRACT AND METABOLISM  
• ATC1 = MUSCULO-SKELETAL SYSTEM, excluding M01BA 
Antiinflammatory/antirheumatic agents in combination with corticosteroids 
• ATC2 = COUGH AND COLD PREPARATIONS 
• ATC2= PSYCHOLEPTICS, excluding N05BB Diphenylmethane derivatives and 
N05C HYPNOTICS AND SEDATIVES 
1 A blinded review of all post-baseline medications or procedures to adjudicate whether treatment constitutes treatment failure, 
based on medical judgment, may be performed in addition. A listing of treatments or procedures classified as treatment failure in 
a manner inconsistent with the classification under #1 will be provided, along with supporting rationale. 
 
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2. Require to adjudicate medications or procedures that may constitute treatment 
failure 
• All other medications and procedures listed in the protocol and Table 5 of the SAP (not 
noted in 1. above) given for indications consistent with PN2 
• Considerations in determining treatment failure include the criteria already set forth in 
Table 5 of the SAP in addition to the type of medication or procedure, indication, dose, 
route of administration, timing, frequency and the potential impact of the use of the 
prohibited medications/procedures and rescue medications on the primary and key 
secondary efficacy endpoints.  
2 Below is a list of indications consistent with PN based on PT level from concomitant medication/procedure data using MedDRA 
dictionary 
 
System Organ Class  
High Level Term 
Preferred Term 
Preferred Term Code 
Skin and subcutaneous tissue 
disorders 
Dermatitis and eczema 
Neurodermatitis 
10029263 
Infections and infestations 
Bacterial infections NEC 
Eczema impetiginous 
10051890 
Infections and infestations 
Skin structures and soft tissue 
infections 
Dermatitis infected 
10012470 
Infections and infestations 
Skin structures and soft tissue 
infections 
Eczema infected 
10014199 
Skin and subcutaneous tissue 
disorders 
Dermatitis and eczema 
Dermatitis 
10012431 
Skin and subcutaneous tissue 
disorders 
Dermatitis and eczema 
Dermatitis atopic 
10012438 
Skin and subcutaneous tissue 
disorders 
Dermatitis and eczema 
Eczema 
10014184 
 
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6 
REFERENCES  
1. Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol deviation: 
a framework for relevant, accessible assumptions, and inference via multiple imputation. J 
Biopharm Stat. 2013;23(6):1352-71. 
 
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