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
Phase: PHASE3
Conditions: Neurodermatitis
Sponsor: Sanofi

 
 
 
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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 
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According to template: RDSD-002540 VERSION N° 3.0 (19-FEB-2019) based on TransCelerate CPT version 5 
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AMENDED CLINICAL TRIAL PROTOCOL 03  
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: 
EFC16459 
Amendment number: 
03 
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  
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address: 
1 avenue Pierre Brossolette 
Chilly-Mazarin 
France 
Monitoring Team’s 
Representative Name 
and Contact Information 
  
Regulatory agency identifier number(s): 
IND: 
IND107969 
EudraCT: 
2019-003774-41 
NCT: 
NCT04183335 
WHO: 
U1111-1241-8153 
Other: 
Not applicable 
Approval Date: 
21-Oct-2021 
Total number of pages: 115 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 03 
All 
21 Oct 2021, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 02 
All 
14 Apr 2021, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01  
All 
20 May 2020, version 1 (electronic 1.0) 
Original Protocol 
 
25 October 2019, version 1 (electronic 3.0) 
Amended protocol 03 (21 October 2021) 
This Amended Protocol 03 (Amendment 03) 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  
EFC16460, a second Phase 3 study in prurigo nodularis (PN) with a similar design and 
population, provided evidence of the positive treatment effect of dupilumab in PN participants, 
based on the recently completed primary analysis. Results of the primary analysis evidenced that 
the effect of dupilumab over time showed continuous improvement after Week 12 across all 
endpoints, with a similar time course of improvement in both itch and lesion endpoints through at 
least Week 24. Based on these data, the Amendment is changing the primary endpoint to be the 
proportion of participants with improvement (reduction) in worst-itch numeric rating scale 
(WI-NRS) by ≥4 from baseline to Week 24, which represents the overall treatment effect more 
accurately and synchronizes the primary itch assessment with the primary lesion assessment. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis: 
Objectives and 
endpoints 
3 Objectives and 
Endpoints 
 
To promote the “proportion of participants with 
improvement (reduction) in worst-itch numeric 
rating scale (WI-NRS) by ≥4 from baseline to 
Week 24 as primary endpoint and to move the 
“proportion of participants with improvement 
(reduction) in WI-NRS by ≥4 from baseline to 
Week 12” to a secondary endpoint  
Based on the data from EFC16460, the treatment 
effect of dupilumab continued to improve over 
time through Week 24. Therefore, the Sponsor 
proposes to assess the proportion of participants 
with improvement (reduction) in WI-NRS by ≥4 at 
Week 24, which represents the effect more 
accurately and synchronizes the primary itch 
assessment with the primary lesion assessment.  
1.1 Synopsis 
Statistical 
considerations – 
Sample size 
calculation 
To update the sample size calculation based on the 
observed effect sizes from EFC16460.  
To assess a timepoint that reflects the optimal 
dupilumab treatment effect as a primary endpoint 
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Section # and 
Name 
Description of Change 
Brief Rationale 
 
1.1 Synopsis 
Statistical 
considerations – 
Analysis of primary 
endpoint 
To update the primary analysis considerations to 
the Week 24 timepoint. 
To be consistent with primary endpoint change 
1.2 Schema 
To update Week 24 timepoint as the primary 
endpoint.  
To be consistent with primary endpoint change 
3.1 Appropriateness 
of measurement 
To remove the sentence “A key secondary 
endpoint will be the responder analyses of itch 
improvement of at least 4 points at Week 24.” as it 
is now the primary endpoint, and to provide 
rationale for choosing the primary endpoint 
timepoint at Week 24 with the following language: 
“The timing of the primary assessment, ie, at 
Week 24, was based on the results of the primary 
analysis of EFC16460, showing that the effect of 
dupilumab over time showed continuous 
improvement after Week 12 across all endpoints, 
with a similar time course of improvement in both 
itch and lesion endpoints through at least Week 24. 
Since improvement of itch and lesions may occur 
prior to Week 24, responder analyses assessments 
will be performed at earlier time points as well, 
starting at Week 2 for itch, and Week 4 for lesions.” 
To provide rationale and maintain consistency in 
language with the change in the primary endpoint. 
4.2 Scientific 
Rationale for Study 
Design 
To specify that the rationale for a 24-week duration 
of the trial is an appropriate duration based on data 
observed from EFC16460 and to remove 
references to atopic dermatitis trials.  
To reflect that data from EFC16460 has informed 
our understanding of the dupilumab treatment 
effect continuing to improve itch through 
Week 24. The Week 24 timepoint most accurately 
represents the overall treatment effect and 
synchronizes the primary itch assessment with 
the primary lesion assessment. 
9.1 Statistical 
hypotheses 
9.2 Sample size 
determination 
To reflect that the primary endpoint timepoint is 
Week 24. 
To maintain consistency in language with the 
change in the primary endpoint. 
9.4.1 Efficacy 
Analyses 
To update Table 6 to reflect that the primary 
endpoint is assessed at Week 24. 
To maintain consistency in language with the 
change in the primary endpoint. 
1.1 Synopsis – 
Primary analysis, 
Planned database 
lock, and Unblinding 
plan 
9.3 Populations for 
analyses 
9.4.1 Efficacy 
analyses 
To remove the possibility of re-evaluating the timing 
of the primary database lock of EFC16459 based 
on the observed treatment effect size in EFC16460, 
that was added per Amendment 02. 
And to consequently remove the 2 populations 
(ITT-Week 12 and ITT-Week 24) that were added 
per Amendment 02. 
Amended protocol 02 was submitted in few 
countries but was withdrawn following a Health 
Authority feedback and was not implemented in 
any country. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
9.4.2 Safety 
analyses 
9.6 Timing of 
primary database 
lock 
9.8 Unblinding plan 
10.12 Appendix 12 
Protocol 
amendment history 
Subsection 10.12.2 was added and the overall 
rationale and table with summary of changes for 
Amended protocol 02 were moved from the cover 
page to this section. 
This is aligned with Sanofi procedures. 
Global 
Minor editorial/formatting changes were done 
throughout the document. 
To correct minor editorial/formatting issues. 
 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 03 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 5 
LIST OF TABLES ........................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
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 
8.1.10 
Photography ................................................................................................................................... 55 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 55 
8.2.1 
Physical examinations ................................................................................................................... 55 
8.2.2 
Vital signs ....................................................................................................................................... 55 
8.2.3 
Electrocardiograms ........................................................................................................................ 55 
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8.2.4 
Clinical safety laboratory assessments .......................................................................................... 55 
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 ...................................................................................................................................... 59 
8.3.6 
Guidelines for reporting product complaints .................................................................................. 59 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 59 
8.5 
PHARMACOKINETICS .................................................................................................................. 60 
8.5.1 
Systemic drug concentration and antidrug antibodies ................................................................... 60 
8.5.1.1 
Sampling time ................................................................................................................................ 60 
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 ........................................... 62 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 63 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 63 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 63 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 64 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 64 
9.4.1 
Efficacy analyses ........................................................................................................................... 64 
9.4.2 
Safety analyses .............................................................................................................................. 67 
9.4.3 
Other analyses ............................................................................................................................... 68 
9.5 
INTERIM ANALYSES  ................................................................................................................... 68 
9.6 
TIMING OF PRIMARY DATABASE LOCK .................................................................................... 68 
9.7 
DATA MONITORING COMMITTEE (DMC) ................................................................................... 68 
9.8 
UNBLINDING PLAN....................................................................................................................... 68 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 69 
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10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 69 
10.1.1 
Regulatory and Ethical Considerations .......................................................................................... 69 
10.1.2 
Financial disclosure........................................................................................................................ 69 
10.1.3 
Informed consent process .............................................................................................................. 70 
10.1.4 
Data protection ............................................................................................................................... 70 
10.1.5 
Committees structure ..................................................................................................................... 71 
10.1.6 
Dissemination of clinical study data ............................................................................................... 71 
10.1.7 
Data quality assurance .................................................................................................................. 72 
10.1.8 
Source documents ......................................................................................................................... 72 
10.1.9 
Study and site closure .................................................................................................................... 73 
10.1.10 Publication policy ........................................................................................................................... 73 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 74 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 76 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 80 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 82 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 84 
10.7 
APPENDIX 7: CLINICIANS-REPORTED OUTCOMES AND PATIENT-REPORTED 
OUTCOMES .................................................................................................................................. 87 
10.7.1 
Worst itch numeric rating scale (WI-NRS) ..................................................................................... 87 
10.7.2 
Investigator’s global assessment of prurigo nodularis (IGA PN) ................................................... 88 
10.7.3 
Prurigo activity score (PAS) ........................................................................................................... 89 
10.7.4 
Dermatology life quality index (DLQI) ............................................................................................ 91 
10.7.5 
Hospital anxiety and depression scale (HADS) ............................................................................. 92 
10.7.6 
EQ-5D-5L ....................................................................................................................................... 93 
10.7.7 
Pain numeric rating scale ............................................................................................................... 94 
10.7.8 
Sleep numeric rating scale ............................................................................................................. 95 
10.7.9 
Patient Global Impression of Change of disease (PGIC) .............................................................. 95 
10.7.10 Patient Global Impression of Severity (PGIS) ................................................................................ 96 
10.7.11 Missed school/work days ............................................................................................................... 97 
10.8 
APPENDIX 8: DEFINITION OF ANAPHYLAXIS ......................................................................... 101 
10.9 
APPENDIX 9: LIST OF OPPORTUNISTIC INFECTIONS........................................................... 101 
10.10 
APPENDIX 10: COUNTRY-SPECIFIC REQUIREMENTS .......................................................... 102 
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10.11 
APPENDIX 11: ABBREVIATIONS ............................................................................................... 102 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY .............................................................. 104 
10.12.1 Amended protocol 01 (20 May 2020)........................................................................................... 104 
10.12.2 Amended protocol 02 (14 April 2021) .......................................................................................... 108 
11 
REFERENCES ............................................................................................................................. 113 
 
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 ................................................................................................................ 64 
Table 6 - Efficacy analyses ........................................................................................................................... 65 
Table 7 - Safety analyses .............................................................................................................................. 67 
Table 8 - Other analyses ............................................................................................................................... 68 
Table 9 - Protocol-required laboratory assessments .................................................................................... 74 
 
 
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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 PRIME (PRurigo Nodularis Itch Minimization Evaluation) 
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).  
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Recently, case series were published that suggest dupilumab may also be effective in the 
treatment of PN (3, 4, 5, 6, 7).  
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 24. 
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.  
• 
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 improvement (reduction) in 
WI-NRS ≥4 from baseline to Week 12. 
• 
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. 
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Objectives 
Endpoints 
• 
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. 
• 
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) 
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Study interventions 
Investigational medicinal product:  
Dupilumab 300 mg and placebo matching dupilumab 300 mg supplied in prefilled syringes that 
are visually indistinguishable. 
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. 
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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. 
• Sample size calculation 
- 
The primary endpoint is the proportion of participants with a WI-NRS reduction of 
≥4 from baseline to Week 24. Assuming a response rate of 
 and 
 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 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.  
• 
Analysis of primary endpoint 
- 
The primary analysis on WI-NRS reduction ≥4 at Week 24 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 24, their off-study 
treatment values measured up to Week 24 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 24 or have 
missing data at Week 24 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 
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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 
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 is currently planned to be performed when all randomized 
participants have completed their 24-week treatment period.  
- 
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 collected between the primary database 
lock and last participant completing last visit will be summarized in a separate clinical 
study report (CSR) addendum, as needed. Details will be included in the SAP. 
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• Unblinding plan 
- 
Unblinding plan is not applicable for this study. 
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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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. 
Samples for ADA will only be collected for analysis in the event of any SAE for participants from China sites. 
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.  
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It is hypothesized that dupilumab in patients with PN will have a favorable safety profile as 
observed across other type 2-driven immunological disorders. 
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 24. 
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.  
• 
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 improvement (reduction) in 
WI-NRS ≥4 from baseline to Week 12. 
• 
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. 
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Objectives 
Endpoints 
• 
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. 
• 
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 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). 
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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 
responder analysis based on an at least 4 points improvement of the WI-NRS at Week 24. The 
4-point improvement was 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 used in the Phase 3 trial (20). 
The timing of the primary assessment, ie, at Week 24, was based on the results of the primary 
analysis of EFC16460, showing that the effect of dupilumab over time showed continuous 
improvement after Week 12 across all endpoints, with a similar time course of improvement in 
both itch and lesion endpoints through at least Week 24. Since improvement of itch and lesions 
may occur prior to Week 24, responder analyses assessments will be performed at earlier time 
points as well, starting at Week 2 for itch, and Week 4 for lesions.  
As a 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.  
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 and itch as the effect is 
expected to continue to increase over time and treatment effects will be most apparent by 
Week 24 similar to that observed in the completed primary analysis of the EFC16460 study of 
dupilumab in PN. 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, 
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- 
Patients who have their vaccination preponed can enroll in the study only after a gap of 
4 weeks following administration of the vaccine. 
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. 
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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. 
  
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. If 
specific 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 9.8. 
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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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8.1.10 Photography  
Participants in selected sites who decide to participate in this substudy need to provide separate 
consent as described in the SoA (see Section 1.3). One or several lesions will be photographed at 
baseline. The same lesions will be photographed at subsequent visits to evaluate their progression. 
The detailed information will be provided in the photography user guide. 
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. 
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• 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 
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. 
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• 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, 
- 
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). 
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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. 
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. 
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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.  
• 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. 
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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. 
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. 
Table 4 - Summary of bioanalytical methods for functional dupilumab and anti-dupilumab 
antibodies  
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 
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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.  
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 are the following: 
- 
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, 
- 
Skin biopsy (sub-study): samples will be taken from lesion and non-lesion skin using 
punch biopsy; gene expression and immunohistological analyses may be used to 
investigate drug response, disease activity, and type 2 inflammation. 
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Plasma, serum and skin biopsy 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 24 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 24. By assuming the response rate is 
 and 
 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 treatment, the target is to randomize 75 participants/arm with a cap of up to 10% of 
participants in the atopic population having mild active 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 analysis population for the efficacy endpoints will be 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; IRT: interactive response technology; 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 of 0.05. 
The analysis population for the efficacy endpoints will be the ITT population. 
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Modification in accordance with the above proposal will be documented in the SAP prior to the 
database lock. 
Table 6 - Efficacy analyses  
Endpoint 
Statistical analysis methods 
Primary: 
Proportion of participants with 
improvement (reduction) in WI-NRS 
by ≥4 from baseline to Week 24 
 
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 24, their off-study 
treatment values measured up to Week 24 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 24 or have missing data at Week 24 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 IGA 
PN-S 0 or 1 score at Week 24. 
The key secondary efficacy endpoint that measures binary responses will be analyzed 
in the same fashion as the primary endpoint. 
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Endpoint 
Statistical analysis methods 
Secondary: 
Proportion of participants with 
improvement (reduction) in WI NRS 
by ≥4 from baseline to Week 12 
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. 
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.  
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-
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Endpoint 
Statistical analysis methods 
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. 
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. 
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. In addition, exposure-adjusted AE 
incidence rate tables will provide the number of patients with at least 1 event per 
100 patient-years, presented by SOC and PT. 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. 
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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 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. 
9.6 
TIMING OF PRIMARY DATABASE LOCK  
A primary database lock is currently planned to 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 data 
collected after the primary data cut-off and updates for the events previously ongoing at the time 
of the primary database lock. Additional data collected between the primary database lock and last 
participant completing last visit will be summarized in a separate CSR addendum, as needed. 
Details will be included in the SAP. 
9.7 
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. 
9.8 
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 procedures (genetic 
testing [DNA/RNA sampling] and, for selected sites, skin biopsy and photography). An optional 
consent will be required to document a participant’s agreement to each of these procedures. 
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. 
• 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. 
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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. 
- 
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. 
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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. 
• The Investigator will use clinical judgment to determine whether or not the relationship is 
causal. 
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• 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. 
• 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. 
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• 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. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
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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 
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. 
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• 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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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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10.7.7 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  
China: 
1. Urine pregnancy test can be done at local lab according to the local requirement at 
Week 16, Week 20, Week 28, and Week 32. 
2. Scheduled PK and ADA samples will not be collected. 
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 
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EU: 
European Union 
FDA: 
Food and Drug Administration 
GCP: 
Good Clinical Practice 
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 
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 
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SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SC: 
subcutaneous 
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). 
10.12.1 
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. 
 
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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 
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  
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Section # and 
Name 
Description of Change 
Brief Rationale 
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 
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 
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Section # and 
Name 
Description of Change 
Brief Rationale 
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 
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. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
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 
10.10 Appendix 10: 
Country-specific 
Requirements 
1.3 Schedule of 
activities (Footnote 
f) 
To add country-specific requirements for China, 
urine pregnancy test can be done at local lab, and 
scheduled PK and ADA samples will not be 
collected (samples for ADA will be collected for 
analysis in the event of any SAE for patients from 
China site).  
Based on China health authority, local Ethics 
Committee and site requirement 
 
Minor editorial and formatting changes were done 
throughout the document. 
To correct minor errors or formatting issues.  
10.12.2 
Amended protocol 02 (14 April 2021)  
Amended protocol 02 was submitted in few countries but was withdrawn following FDA’s 
feedback and was not implemented in any country. 
This Amended Protocol 02 (Amendment 02) 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. 
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Overall rationale for the Amendment 
EFC16459 and EFC16460 are 2 pivotal phase 3 studies of identical design. The purpose of this 
protocol amendment is to allow for the timing for the primary database lock of EFC16459 to be 
re-evaluated based on the observed treatment effect size in EFC16460. 
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis:  
Statistical 
considerations -
Primary 
analysis 
 
 
 
 
 
 
 
 
 
 
Added text: 
In the case of an early primary database lock, the 
analysis population will be the ITT-Week-12 population 
for endpoints which occur earlier than or equal to 
Week 12. The ITT-Week-12 population consists of all 
participants who had been randomized by 
14 June 2021. The analysis population for Week 24 
endpoints will be the ITT-Week-24 population. The ITT-
Week-24 population consists of all participants who 
had been randomized by 22 March 2021. 
Modification in accordance with the above proposal will 
be documented in the statistical analysis plan (SAP) 
prior to the database lock. 
 
 
 
 
 
EFC16459 and EFC16460 are 2 pivotal phase 3 
studies of identical design with EFC16460 data that 
will be available prior to EFC16459 data. Using 
data from EFC16460, the sample size calculation 
will be revisited aiming for a statistical power of at 
least 90% at an alpha level of 0.05 for the primary 
and key secondary endpoints in the respective 
analysis populations and the database lock will be 
performed when the number of participants based 
on this revised sample size are expected to have 
reached their Week 24 visit. This revised estimation 
may result in database lock occurring earlier than 
last participant reaching the end of treatment 
(EOT). At a minimum, this will include at least 
135 participants having Week 24 pertinent data 
included at the time of database lock. Based on the 
timing of the availability of the EFC16460 results, 
and to ensure a minimum of 135 participants have 
the opportunity to reach the Week 24 endpoint, the 
randomization cut-off dates have been assessed as 
22 March 2021 for Week 24 and 14 June 2021 for 
Week 12. 
1.1 Synopsis: 
Statistical 
considerations -
Planned 
database lock 
date 
 
 
 
 
 
 
 
 
 
 
 
 
Adapted text:  
A primary database lock is currently planned to be 
performed when all randomized participants have 
completed their 24-week treatment period. However, 
the timing for the primary analysis will be re-evaluated 
based on the observed treatment effect size in 
EFC16460. If the revised sample size calculation using 
EFC16460 treatment effect size maintains a statistical 
power of at least 90% at an alpha level of 0.05 for the 
primary and key secondary endpoints in the respective 
analysis populations, a database lock will be performed 
when the number of participants based on this revised 
sample size are expected to have reached their Week 
24 visit. This database lock will be based on this 
revised estimation and may occur earlier than last 
participant reaching EOT. At a minimum, this will 
include 135 participants having Week 24 pertinent data 
included at the time of database lock. In the case of an 
earlier database lock prior to the last participant 
reaching the EOT visit, the primary endpoint at 
Week 12 and all secondary endpoints at Week 12, 
 
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Section # 
and Name 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
 
 
 
1.1 Synopsis: 
Statistical 
considerations - 
Unblinding plan 
Week 24, and other study weeks would be analyzed as 
the final analysis for these endpoints, and enrollment of 
any additional participants will stop. 
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 
collected between the primary database lock and last 
participant completing last visit will be summarized in a 
separate clinical study report (CSR) addendum, as 
needed. Details will be included in the SAP. 
Added text: 
If database lock occurs prior to when the last enrolled 
participant has reached the EOT visit, specific steps 
will be taken to maintain the blind of the study to all 
individuals involved in the conduct of the study and/or 
analysis, and to protect the overall blinding and 
integrity of the study data, after the primary database 
lock has been performed. 
9.3 Populations 
for Analyses – 
Table 5 
Added 2 more populations for analyses in Table 5 in 
the case an earlier primary database lock occurs. 
The ITT-Week-12 population consists of all participants 
who had been randomized by 14 June 2021. 
The ITT-Week-24 population consists of all participants 
who had been randomized by 22 March 2021. 
Efficacy: the analysis population for the efficacy 
endpoints was adapted as described below. 
To detail how the endpoints will be analyzed in the 
case of an early primary database lock. Based on 
the timing of the availability of the EFC16460 
results, and to ensure a minimum of 
135 participants have the opportunity to reach the 
Week 24 endpoint, the randomization cut-off dates 
have been assessed as 22 March 2021 for 
Week 24 and 14 June 2021 for Week 12. 
9.4.1 Efficacy 
analyses 
Added text:  
The analysis population for the efficacy endpoints will 
be the ITT population. In the case of an early primary 
database lock prior to the last enrolled participant 
reaching EOT, the analysis population will be the ITT-
Week-12 population for endpoints which occur earlier 
than or equal to Week 12. The ITT-Week-12 population 
consists of all participants who had been randomized 
by 14 June 2021. The analysis population for Week 24 
endpoints will be the ITT-Week-24 population. The ITT-
Week-24 population consists of all participants who 
had been randomized by 22 March 2021. 
Modification in accordance with the above proposal will 
be documented in the SAP prior to the database lock. 
To provide detail of how data from timepoint 
evaluations will be handled in the case of an early 
primary database lock. 
9.4.2 Safety 
analyses 
Added text: 
In the case of an early primary database lock prior to 
the last enrolled participant reaching EOT, the analysis 
of safety will be performed on all available and safety 
data collected up to the time of the primary database 
lock. 
 
With an early primary analysis, participants may 
have different treatment exposure because of study 
design. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
Added text in Table 7: 
In addition, exposure-adjusted AE incidence rate tables 
will provide the number of patients with at least 1 event 
per 100 patient-years, presented by SOC and PT. 
9.5 Interim 
Analyses 
Removed text: 
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. More details will be 
described in the SAP. 
This text was adapted and moved to Section 9.6 
(new section dedicated to timing of primary 
database lock) and added in Section 1.1 Planned 
Database lock date.  
9.5.1 Data 
Monitoring 
Committee 
This section has been moved to Section 9.7. 
This text does not belong to the interim analysis 
section. 
9.5.2 Unblinding 
plan 
This section has been moved to Section 9.8. 
This text does not belong to the interim analysis 
section. 
9.6 Timing of 
primary 
database lock 
New section created 
A primary database lock is currently planned to be 
performed when all randomized participants have 
completed their 24-week treatment phase. However, 
the timing for the primary analysis will be re-evaluated 
based on the observed treatment effect size in 
EFC16460. If the revised sample size calculation using 
EFC16460 treatment effect size maintains a statistical 
power of at least 90% at an alpha level of 0.05 for the 
primary and key secondary endpoints in the respective 
analysis populations, a database lock will be performed 
when the number of participants based on this revised 
sample size are expected to have reached their Week 
24 visit. This database lock will be based on this 
revised estimation and may occur earlier than last 
participant reaching EOT. At a minimum, this will 
include 135 participants having Week 24 pertinent data 
included at the time of database lock. In the case of an 
earlier database lock prior to the last participant 
reaching the EOT visit, the primary endpoint at 
Week 12 and all secondary endpoints at Week 12, 
Week 24, and other study weeks would be analyzed as 
the final analysis for these endpoints, and enrollment of 
any additional participants will stop. 
The database will be updated at the end of the study 
for all participants to include the data collected after the 
primary data cut-off and updates for the events 
previously ongoing at the time of the primary database 
lock. Additional data collected between the primary 
The timing for the primary analysis of EFC16459 
will be re-evaluated based on the observed 
treatment effect size in the identical study 
EFC16460. If the revised sample size calculation 
using EFC16460 treatment effect size maintains a 
statistical power of at least 90% at an alpha level of 
0.05 for the primary and key secondary endpoints 
in the respective analysis populations, a database 
lock will be performed when the number of 
participants based on this revised sample size are 
expected to have reached their Week 24 visit. This 
database lock will be based on this revised 
estimation and may occur earlier than last 
participant reaching EOT. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
database lock and last participant completing last visit 
will be summarized in a separate CSR addendum, as 
needed. Details will be included in the SAP. 
9.7 Data 
Monitoring 
Committee 
(DMC) 
New section created, replacing former Section 9.5.1. 
 
9.8 Unblinding 
plan 
New section created, replacing former Section 9.5.2. 
Added text: 
If database lock occurs prior to when the last enrolled 
participant has reached the EOT visit, specific steps 
will be taken to maintain the blind of the study to all 
individuals involved in the conduct of the study and/or 
analysis, and to protect the overall blinding and 
integrity of the study data, after the primary database 
lock has been performed. 
 
To ensure the study data integrity for the data after 
the potential early primary database lock. 
10.12 
Appendix 12: 
Protocol 
amendment 
history 
The overall rationale and table with summary of 
changes for Amended protocol 01 were moved from 
the cover page to Section 10.12.1. 
This is aligned with Sanofi procedures. 
Global 
Minor editorial and formatting changes were done 
throughout the document. 
To correct minor errors or formatting issues.  
 
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11 
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