A 24 Week, Open-Label Study to Evaluate the Efficacy and Safety of Upadacitinib in Patients With Moderate-to-Severe Prurigo Nodularis
Phase: PHASE4
Conditions: Prurigo Nodularis
Sponsor: Psoriasis Treatment Center of Central New Jersey

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Clinical Study Protocol 
A 24 Week, Open-Label Study to Evaluate the Efficacy and Safety of 
Upadacitinib in Patients with Moderate-to-Severe Prurigo Nodularis 
 
Testing Facility  
Eczema Treatment Center of New Jersey 
59 One Mile Road 
East Windsor, NJ 08520 
(609) 443-4500 
 
Study Sponsor and Principal Investigator  
Jerry Bagel, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
PROTOCOL TITLE PAGE 
1 
SYNOPSIS ...........................................................................................................................…4 
2 
ETHICS AND REGULATORY OBLIGATIONS ...................................................................6 
2.1 
Institutional Review Board (IRB) .....................................................................................6 
2.2 
Ethical Conduct of the Study ............................................................................................7 
2.3 
Subject Information and Consent ......................................................................................7 
3 
  INTRODUCTION ..................................................................................................................7 
3.1 
Overview of Prurigo Nodularis and Study Rationale .......................................................7 
4 
STUDY OBJECTIVE...............................................................................................................7 
5 
INVESTIGATIONAL PLAN...................................................................................................7 
5.1 
Overall Study Design and Plan .........................................................................................7 
5.2 
Study Population Criteria ..................................................................................................7 
5.2.1 
Inclusion Criteria ...........................................................................................................8 
5.2.2 
Exclusion Criteria ..........................................................................................................8 
5.3 
Source of Subjects and Recruitment Methods ................................................................10 
5.4 
Subject Enrollment and Treatment Assignment..............................................................10 
5.5 
Study Treatment ..............................................................................................................10 
5.5.1 
Upadacitinib Description .............................................................................................10 
5.5.1.1 
Upadacitinib Dosing Schedule .................................................................................10 
5.5.1.2 
Upadacitinib Dispensing ..........................................................................................11 
5.5.1.3 
Upadacitinib Dosage Adjustments ...........................................................................11 
5.5.3 
Permitted Concomitant Therapy ..............................................................................11 
5.6 
  Study Procedures ...........................................................................................................11 
5.6.1 
Inclusion and Exclusion Criteria .................................................................................12 
5.6.2 
Demographics and Medical History ............................................................................12 
5.6.3 
Pregnancy Test ............................................................................................................13 
5.6.4 
Laboratory Testing ......................................................................................................14 
5.6.5 
Physical Examination ...................................................................................................15 
5.6.6 
Investigator’s Global Assessment for Prurigo Nodularis (IGA-PN) ...........................15 
5.6.7 
Patient Reported Outcomes .........................................................................................15 

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5.6.7.1 Worst-Itch Numerical Rating Scale .............................................................................15 
5.6.7.2 Dermatology Life Quality Index .................................................................................15 
5.6.8 
Early Discontinuation Procedures ...............................................................................15 
6   COMPLAINTS/ADVERSE EVENTS/SERIOUS ADVERSE EVENTS............................16 
7    INVESTIGATIONAL PRODUCT HANDLING ................................................................20 
7.1          Investiational Product receipt .....................................................................................20 
7.2 
Investigational Product Storage ...................................................................................20 
8    RECORD RETENTION  .....................................................................................................21 
8.1 
Study Monitoring .........................................................................................................21 
8.2 
Statistics  ......................................................................................................................22 
8.2.1 
Additional Statistical Considerations ..........................................................................22 
8.3 
Schedule of Events ......................................................................................................23 
10    REFERENCES ...................................................................................................................24 
11    APPENDICES ...................................................................................................................25 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS 
Study Title 
A 24 Week, Open-Label Study to Evaluate the Efficacy and Safety of 
Upadacitinib in Patients with Moderate-to-Severe Prurigo Nodularis
Sponsors 
Jerry Bagel, MD 
Study Objectives 
Primary Objective: To explore the effectiveness of upadacitinib in patients with 
prurigo nodularis. 
 
Secondary Objectives:  To explore the safety of upadacitinib in patients with 
prurigo nodularis.
Study Design 
A single center, open-label study of 25 subjects to assess 24 weeks upadacitinib 
in patients with moderate-to-severe prurigo nodularis.
Study Centers 
Eczema Treatment Center of New Jersey 
59 One Mile Road, East Windsor, NJ 08520 
Study Population 
25 adult male and female subjects with moderate-to-severe prurigo 
nodularis  
Main Inclusion 
Criteria 
1. Male or female adult 18-64 years of age at time of screening. 
2. Diagnosis of prurigo nodularis for ≥ 3 months.  
3. Moderate-to-Severe prurigo nodularis as determined by at least 10 PN      
lesions on legs and/or arms and/or trunk at screening and baseline .  
4. Failure of at least a 2-week course of medium to super potent TCS or 
TCS is not medically advisable for subject. 
5. Females of childbearing potential must not have a positive serum 
pregnancy test at the Screening Visit and must have a negative urine 
pregnancy test at the Baseline Visit prior to study drug dosing. Note: 
subjects with borderline pregnancy test at Screening must have a serum 
pregnancy test ≥ 3 days later to determine eligibility. 
If female, subject must be postmenopausal OR permanently surgically sterile 
OR for females of childbearing potential practicing at least one protocol 
specified method of birth control, that is effective from the Baseline Visit 
through at least 30 days after the last dose of study drug. Female subject must 
not be pregnant, breastfeeding or considering becoming pregnant during the 
study or for approximately 30 days after the last dose of the study drug. 
6. Subject is a candidate for systemic therapy per investigator discretion. 
7. Able and willing to give written informed consent prior to performance 
of any study-related procedures. 
8. Subject must be in general good health as judged by the Investigator, 
based on medical history, physical examination. 

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Main Exclusion 
Criteria 
1. Presence of skin condition other than prurigo nodularis or atopic 
dermatitis that may interfere with study assessments.  
2. Diagnosis of active atopic dermatitis at screening and baseline.   
3. PN secondary to medications. 
4. PN secondary to medical conditions such as neuropathy or 
psychiatric disease. 
5. Severe concomitant illness(es) under poor control that, in the 
investigator's judgment, would adversely affect the patient's 
participation in the study. 
6. Severe renal conditions (eg, patients with uremia and/or on dialysis) 
7. Participants with uncontrolled thyroid disease. 
8. Active tuberculosis or non-tuberculous mycobacterial infection, or a 
history of incompletely treated tuberculosis unless documented 
adequately treated. Patients with latent TB at screening may be 
enrolled if tuberculosis treatment is initiated prior to first dose. 
9. 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. 
10. Active chronic or acute infection (except HIV infection) requiring 
treatment with systemic antibiotics, antivirals, antiprotozoals, or 
antifungals within 2 weeks before the screening visit or during the 
screening period. 
11. Known or suspected immunodeficiency. 
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.  
Background and 
Hypothesis 
Prurigo Nodularis (PN) is a chronic skin disorder that presents as multiple firm 
nodules commonly located on the extensor surfaces of the extremities.  The 
lesions are very pruritic and commonly associated with another disorder of 
cutaneous hypersensitivity such as atopic dermatitis.1 Treatment for PN varies 
from topical and intralesional corticosteroids for mild cases to phototherapy and 
systemic immunosuppressives for more severe cases.2 Upadacitinib is a novel 
selective orally available JAK1 inhibitor with the potential to decrease T helper 2 
cell-mediated skin inflammation and itch mediated by JAK1, while having 
minimal inhibitory effects on JAK2 and JAK3. This study will evaluate the 
safety and efficacy of upadacitinib in prurigo nodularis itch improvement as well 
as improvement of PN lesions.  A second Phase 3 trial evaluating Dupixent® 
(dupilumab) in adults with uncontrolled prurigo nodularis, a chronic type 2 
inflammatory skin disease, met its primary and key secondary endpoints, 
showing it significantly reduced itch and skin lesions compared to placebo at 24 
weeks in this investigational setting. The data confirm the positive results that 
were previously reported from the Phase 3 PRIME2 trial and will be submitted to 
regulatory authorities around the world starting in the first half of this year. The 
impact of prurigo nodularis on quality of life is one of the highest among 
inflammatory skin diseases due to the extreme itch. 3   Emerging research has 
shown that JAK inhibitors look promising for the treatment of PN.  A case report 
of tofacitinib for PN and the success of baricitinib for prurigo-type atopic 
dermatitis, both demonstrate the effectiveness of the JAK inhibitor for the 
treatment of PN. 4  This study aims to explore the efficacy of upadacitinib for PN.

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Study Visits 
 
Visit 1 (Screening) 
Visit 2 (Baseline) 
Visit 3 (Week 4) 
Visit 4 (Week 8) 
Visit 5 (Week 12) 
Visit 6 (Week 16) 
Visit 7 (Week 20) 
Visit 8 (Week 24)
Study Endpoints 
Primary Endpoint:Proportion of participants with improvement (reduction) in worst-
itch numeric rating scale (WI-NRS) by ≥4 from baseline to Week 12. 
[Time Frame: Baseline to Week  12 ]WI-NRS is a patient-reported outcome (PRO) 
comprised of a single item rated on a scale from 0 ("No itch") to 10 ("Worst imaginable 
itch. 
Secondary Endpoints:  
Proportion of patients with improvement in worst-itch numeric rating scale (WI-
NRS) by ≥4 from baseline to Week 24 
IGA PN-S 0 or 1 at weeks  12 & 24 
IGA PN-A 0 or 1 at week 12 & 24 
Percent improvement of PN-S & PN-A at week  12 & 24 
DLQI improvement at weeks  12 & 24 
Adverse Events 
References 
Tessa B. Mullins, Poonam Sharma, Christopher A. Riley, Sidharth Sonthalia. 
Prurigo Nodularis. StatPearls [Internet]. Treasure Island (FL): StatPearls 
Publishing; 2021 Jan. 
2020 Sep 15. 
 
Eric H Kowalski, Diana Kneiber, Manuel Valdebran, Umangi Patel, Kyle T 
Amber. Treatment-resistant prurigo nodularis: challenges and solutions. Clin 
Cosmet Investig Dermatol. 2019 Feb 28;12:163-172. doi: 
10.2147/CCID.S188070. eCollection 2019. 
 
 
2        ETHICS AND REGULATORY OBLIGATIONS 
2.1 Institutional Review Board (IRB) 
Written IRB approval of this protocol must be obtained before the study is initiated.  
Compliance with Title 21 of the US Code of Federal Regulations (CFR), Part 56, is 
required in order to protect the rights and welfare of human subjects involved in this study.   
2.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the ethical principles that have their 
origins in the Declaration of Helsinki and its amendments.  In addition, the study will be 
performed in compliance with Good Clinical Practices (GCP), including the archiving of 
essential documents. 

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2.3 Subject Information and Consent 
The Informed Consent Form will be reviewed and approved by the IRB.  The purpose, 
duration and possible risks and benefits will be explained to each potential subject.  
Consent in writing must be obtained from the subject before enrollment into the study.  
Consents will be signed and dated as required by Title 21 of CFR, Part 50.  The consent 
will also comply with the requirements of the Health Insurance Portability and 
Accountability Act (HIPAA).  The original, signed Informed Consent Form will be retained 
by the Investigator.  A signed copy of the Informed Consent Form will be given to the 
subject.  Each subject will be assigned a subject number that will be used in lieu of the 
subject’s name on further research documentation. 
 
3 
INTRODUCTION 
3.1 
Overview of Prurigo Nodularis and Study Rationale 
Prurigo Nodularis (PN) is a chronic skin disorder that presents as multiple firm nodules 
commonly located on the extensor surfaces of the extremities.  The lesions are very 
pruritic and commonly associated with another disorder of cutaneous hypersensitivity 
such as atopic dermatitis.1 Treatment for PN varies from topical and intralesional 
corticosteroids for mild cases to phototherapy and systemic immunosuppressives for 
more severe cases.2  Upadacitinib is a novel selective orally available JAK1 inhibitor 
with the potential to decrease T helper 2 cell-mediated skin inflammation and itch 
mediated by JAK1, while having minimal inhibitory effects on JAK2 and JAK3. This 
study will evaluate the safety and efficacy of upadacitinib in prurigo nodularis itch 
improvement as well as improvement of PN lesions.     
 
4. STUDY OBJECTIVE 
To explore the effectiveness and safety of upadacitinib in patients with moderate-to-
severe prurigo nodularis. 
 
5. INVESTIGATIONAL PLAN 
5.1 Overall Study Design and Plan 
25 subjects with prurigo nodularis with at least 10 PN lesions on arms, legs and/or trunk 
with moderate-to-severe itch will receive upadacitinib 15mg once daily.  
5.2  Study Population Criteria 
Males and females 18-64 years of age with moderate-to-severe prurigo nodularis 

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5.2.1 Inclusion Criteria 
Patients who meet all of the following criteria will be enrolled in the study: 
 
1. Male or female adult 18- 64 years of age at time of screening. 
 
2. Diagnosis of prurigo nodularis for ≥ 3 months  
 
3. Moderate-to-Severe prurigo nodularis as determined by at least 10 PN                               
lesions on legs and/or arms and/or trunk at screening and baseline.  
 
4. Failure of at least a 2 week course of medium to super potent TCS or TCS is not 
medically advisable for subject.  
 
5. Females of childbearing potential must not have a positive serum pregnancy test at 
the Screening Visit and must have a negative urine pregnancy test at the Baseline Visit 
prior to study drug dosing. Note: subjects with borderline pregnancy test at Screening 
must have a serum pregnancy test ≥ 3 days later to determine eligibility. 
If female, subject must be postmenopausal OR permanently surgically sterile OR for 
females of childbearing potential practicing at least one protocol specified method of 
birth control, that is effective from the Baseline Visit through at least 30 days after the 
last dose of study drug. Female subject must not be pregnant, breastfeeding or 
considering becoming pregnant during the study or for approximately 30 days after the 
last dose of the study drug. 
 
6. Subject is a candidate for systemic therapy 
 
7. Able and willing to give written informed consent prior to performance of any study-
related procedures. 
 
8. Subject must be in general good health as judged by the Investigator, based on 
medical history, physical examination. 
 
5.2.2 Exclusion Criteria 
Patients will NOT be enrolled in this study if they meet any of the following criteria: 
 
1. Presence of skin condition other than prurigo nodularis or atopic dermatitis that may 
interfere with study assessments. 
 
2. Diagnosis of active atopic dermatitis at screening and baseline. 
 
3. PN secondary to medications. 
 

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4. PN secondary to medical conditions such as neuropathy or psychiatric disease. 
 
5. Severe concomitant illness(es) under poor control that, in the investigator's judgment, 
would adversely affect the patient's participation in the study 
 
6. Severe renal conditions (eg, patients with uremia and/or on dialysis) 
 
7. Participants with uncontrolled thyroid disease. 
 
8.Active tuberculosis or non-tuberculous mycobacterial infection, or a history of 
incompletely treated tuberculosis unless documented adequately treated. Patients with 
latent TB at screening may be enrolled if tuberculosis treatment is initiated prior to first 
dose.  
 
9. 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. 
 
10. Active chronic or acute infection (except HIV infection) requiring treatment with systemic 
antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks before the screening visit 
or during the screening period. 
 
11. Known or suspected immunodeficiency. 
 
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. 
 
13. Use of oral systemic medications or phototherapy for the treatment of prurigo 
nodularis within 4 weeks. 
 
14. Patient received UVB phototherapy within 2 weeks of Baseline. 
 
15. Patient used topical therapies within 1 week of the Baseline Visit.  
 
16. Patient has used dupilumab within 12 weeks of Baseline Visit. 

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17.. Patient has a known hypersensitivity to the excipients of upadacitinib. 
 
18.Presence of significant lab abnormality or uncontrolled medical condition that in the 
opinion of the investigator would affect patient safety during the trial.  
 
19. . Prior use of upadacitinib. 
5.3 
Source of Subjects and Recruitment Methods 
The Investigator will manage the recruitment of subjects upon approval of the study by 
the Institutional Review Board.  Subjects may be recruited from internal patient lists  from 
the investigator’s clinic and external IRB approved advertisements.  The study site will 
manage recruitment campaigns with IRB approved documents. 
5.4 
Subject Enrollment and Treatment Assignment 
25 adult subjects of either gender with moderate-to-severe prurigo nodularis will receive 
upadacitinib 15mg once daily. Dosage will be increased to 30mg QD at week 8 based on 
subject response.  See dosage adjustments below.  IP will be managed by site personnel 
and stored in a temperature controlled limited access area at the study site.  
Accountability records will be maintained by site personnel for all IP receipt, dispensation 
and returns. 
5.5 STUDY TREATMENT 
5.5.1 Upadacitinib Description 
Upadacitinib is an oral selective and reversible inhibitor of Janus kinase (JAK) 1, which 
blocks signaling of many inflammatory cytokines including interleukin (IL)-6, IL-2, IL-7, 
and IL-15. A growing body of evidence suggests that JAK inhibition is an effective 
therapy for the treatment of signs and symptoms of multiple immune-mediated 
inflammatory diseases in humans.5 
5.5.1.1 
Upadacitinib Dosing Schedule 
Subjects will be instructed to take Upadacitinib 15mg once daily starting at the baseline 
visit. Study drug should be taken approximately the same time each day.  Study drug can 
be taken with or without food.  If a subject forgets to take their dose at the regularly 
scheduled time they should take it immediately, unless it is within 10 hours of the next 
scheduled dose. If the next dose is expected within 10 hours than the forgotten dose 

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should be considered missed and the next dose should be taken at the regularly 
scheduled time.  
5.5.1.2 
Upadacitinib Dispensing 
Subjects will return all unused upadacitinib tablets to the study site.  Site personnel will 
keep a record of upadacitinib dispensed to and returned by each subject and note any 
missed doses.   
 
5.5.1.3 
Upadacitinib Dosage Adjustments 
Upadacitinib will be dispensed and administered as 15mg QD at baseline.  For subjects 
who do not achieve ≤ 2-point reduction in itch at week 8, upadacitinib dosage will be 
increased to 30mg QD. The investigator may reduce the dose to 15mg QD after week 16 
per investigator discretion.  If an SAE or an adverse event that is thought to be related to 
study drug and is not alleviated by symptomatic intervention, study drug will be 
discontinued.  Subjects who permanently discontinue study drug under this protocol 
should receive standard care of prurigo nodularis treatment as prescribed by their 
physician. 
5.5.3  Permitted Concomitant Therapy and Rescue Therapy 
Starting from the screening visit, subjects will be instructed to use a daily non-medicated 
moisturizer through the end of study participation. Appropriate interventions (e.g., 
prescribed medications) may be performed as the investigator deems necessary to treat 
concomitant illnesses and/or safeguard the subjects’ wellbeing.  No investigational 
product or device may be used during the study 
5.6  Study Procedures  
This protocol will consist of a Screening Period (0-30 days), followed by open label 
treatment period of upadacitinib 15mg-30mg QD for 24 weeks. To date, Dupixent is the 
first and only medication to demonstrate positive results in prurigo nodularis at week 24 
and receive regulatory approval for PN. This study will explore efficacy over a 24-week 
period to evaluate clinical response.  
This Study will be conducted in compliance with CFR Title 21, Part 50 (Informed Consent 
of Human Subjects).  Informed consent will be obtained from each subject in writing 
before participation in the Study.  A signed copy of the Informed Consent Form will be 
provided to each subject.  A provision to obtain a signed authorization to provide protected 
health information to the study sponsor, internal quality assurance agencies, health 

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insurance agencies, and other parties as specified in the Federal Health Insurance 
Portability and Accountability Act (HIPAA) privacy regulation will be included in the 
Informed Consent Document.  HIPAA authorization is voluntary.  However, since the use 
and release of health information is critical to the conduct of the study, subjects who do 
not provide authorization to use and disclose their health information will not be enrolled 
into the study.  Subjects who withdraw their authorization to use and release health 
information during study participation will be formally discontinued from the study.  The 
investigator may use and release at any time all the information collected prior to a 
subject’s withdrawal of the authorization to all authorized parties to satisfy scientific, 
regulatory, and financial concerns. 
5.6.1 Inclusion and Exclusion Criteria 
Subjects’ eligibility to participate in the study will be determined according to the Inclusion 
and Exclusion Criteria during the screening period (0 – 30 days prior to the first dose of 
the study drug).  Subjects who ultimately do not satisfy the eligibility criteria except 
changing treatments and undergoing a washout period, will not be enrolled into the study.  
Subjects who need to meet eligibility requirements will be asked to make the necessary 
changes.  Subjects who agree and comply will be re-evaluated prior to Baseline.  
5.6.2 Demographics and Medical History 
The following information will be obtained for each subject during screening: date of birth, 
sex, race/ ethnic origin, relevant medical and surgical history, including year of diagnosis 
of prurigo nodularis, and current and previous prurigo nodularis treatments for the last 6 
months.  All current therapies for other medical conditions will be documented. Medical 
history will be reviewed and updated at the Baseline Visit to ensure that the patient 
remains eligible to participate in the study. 
5.6.3 Pregnancy Testing 
Serum Pregnancy testing (urine β-human chorionic gonadotrophin [β-HCG]) will be 
conducted in all female subjects, except those without childbearing potential at Screening 
(-30 to -1).  Urine pregnancy tests will be conducted at Baseline (prior to first dose of 
upadacitinib) and at each visit through week 24.  An interim urine pregnancy test may be 
performed if there is reason to believe the subject may have become pregnant during the 
study.  Subjects with a positive pregnancy test will not be eligible to participate or to 
continue to receive study treatment.  
 

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Contraception Requirements for Females 
A female who is permanently surgically sterile or postmenopausal is not considered to be 
a female of childbearing potential and is not required to follow contraception 
recommendations. 
Surgically sterile is defined as: 
•bilateral oophorectomy (surgical removal of both ovaries); or 
•bilateral salpingectomy (surgical removal of both fallopian tubes); or 
•hysterectomy ( surgical removal of uterus) 
Postmenopausal is defined as: 
•Age ≥ 55 years with no menses for 12 or more months without an alternative medical 
cause; or. 
•Age < 55 years with no menses for 12 or more months without an alternative medical 
cause AND a follicle-stimulating hormone (FSH) level > 40 IU/L. 
If the female subject is ≤ 55 years of age, postmenarchal, and has had no menses for ≥ 
12 months AND has no history of permanent surgical sterilization (defined above), FSH 
should be tested at Screening. 
•If FSH is not tested, it is assumed that the subject is of childbearing potential and protocol 
specified contraception is required. 
•If the FSH is tested and the result is consistent with postmenopausal status, 
contraception is not required. 
•If the FSH is tested and the result is consistent with premenopausal status, contraception 
is required, and pregnancy testing requirements for women of childbearing potential must 
be followed (see below). 
A female who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to practice at least one of 
the following highly effective methods of birth control that is effective from Baseline Visit 
(or earlier) through at least 30 days after the last dose of study drug. 
•Combined (estrogen and progestogen containing) hormonal contraception (oral, 
intravaginal, transdermal) associated with the inhibition of ovulation, initiated at least 30 
days prior to Baseline Visit. 
•Progestogen-only hormonal contraception (oral, injectable, implantable) associated with 
inhibition of ovulation, initiated at least 30 days prior to Baseline Visit. 
•Bilateral tubal occlusion/ligation. 
•Vasectomized partner(s) provided the vasectomized partner has received medical 
confirmation of the surgical success and is the sole sexual partner of the women of 
childbearing potential trial participant. 

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•Intrauterine device. 
•Intrauterine hormone-releasing system. 
•True abstinence (if acceptable per local requirements): Refraining from heterosexual 
intercourse when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (e.g., using calendar, ovulation, symptothermal, postovulation methods) and 
withdrawal are not acceptable. 
If required per local guidelines, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the birth 
control methods listed above (excluding true abstinence). 
If during the course of the study a female becomes surgically sterile or postmenopausal 
(defined above) and complete documentation is available, contraceptive measures as 
defined above are no longer required. It is important to note that contraception 
requirements described above are specifically intended to prevent pregnancy during 
exposure to the investigational therapy upadacitinib. 
 
Contraception recommendations related to use of concomitant therapies prescribed per 
standard of care should be based on the local label. 
Additional local requirements may apply.  
 
At each visit, the study staff should review the pregnancy avoidance recommendations 
with each female of childbearing potential and document this discussion in the subject's 
source records. 
5.6.4 Laboratory Testing 
Serum chemistry, hematology, Hepatitis B Surface Antibody and Antigen (HBV), Hepatitis 
C Antibody (HCV) and Quantiferon Gold testing will be performed at screening to ensure 
subject safety prior to baseline.  Serum chemistry and hematology will also be performed 
at weeks  12 and 24. 
5.6.5 Physical Examination 
A physical examination, including vital signs measurements (blood pressure, pulse and 
temperature), will be performed according to the schedule of events.  The physical 
examination should include a thorough evaluation of the subject's skin. Any clinically 
significant abnormalities discovered during physical examinations after the Screening / 
Baseline visit should be documented and evaluated as potential adverse events. 

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5.6.6 Investigator’s Global Assessment for Prurigo Nodularis (IGA-PN)  
IGA-PN will be determined for all subjects at all visits during the study. Investigator’s 
global assessment for prurigo nodularis (IGA PN) is a clinician-reported outcome 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). See Appendix A 
5.6.7 Patient Reported Outcomes 
Subjects will complete the PRO’s according to the schedule of assessments. 
Questionnaires should be prior to medical procedures and clinical evaluations.   
 
5.6.7.1 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.0.1 Worst Itch Numeric Rating Scale.4 See 
Appendix B 
 
5.6.7.2 Dermatology Life Quality Index 
Dermatology Life Quality Index (DLQI)5 to assess symptoms and impacts of 
dermatologic diseases on quality of life.   See Appendix C 
 
5.6.8  Early Discontinuation Procedures 
Subjects will be prematurely discontinued from the study under the following conditions: 
1. Subject requests to withdraw from the study. 
2. Subject experiences an adverse event that makes it difficult or intolerable for 
the subject to continue treatment, or increases risk to the subject, or interferes 
with the investigator’s ability to clinically evaluate the progress of the subject’s 
treatment. 
3. Subject begins an unapproved concomitant therapy for prurigo nodularis, 
atopic dermatitis or another medical condition that may increase risk to the 
subject if continuing study treatment. 
4. Subject cannot be reached / lost to follow-up. 
5. The study investigator suspends or terminates the study. 
6. Other unanticipated reason. 
 

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Any subject who prematurely discontinues the study should complete the week 24 (End 
of Study) assessments.   
6 COMPLAINTS/ADVERSE EVENTS/SERIOUS ADVERSE EVENTS 
Adverse events will be collected from the time of the first dose of product during the study 
until 30 days following the intake of the last dose taken during the study period.  An AE is 
defined as any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not the event 
is considered causally related to the use of the product.  
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal. Any 
worsening of a pre-existing condition or illness is considered an AE. Worsening in severity 
of a reported AE should be reported as a new AE. Laboratory abnormalities and changes 
in vital signs are considered to be AEs only if they result in discontinuation from the study, 
necessitate therapeutic medical intervention, meets protocol specific criteria  and/or if the 
investigator considers them to be AEs.  
The investigator will monitor each subject for clinical and laboratory evidence of AEs on 
a routine basis throughout the study. All AEs will be followed to a satisfactory conclusion. 
An elective surgery/procedure scheduled to occur during a study will not be considered 
an AE if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been preplanned prior to study entry. Elective surgery will not be 
allowed during the study until the primary endpoint has been assessed (Week 16). 
However, if the pre-existing condition deteriorates unexpectedly during the study (e.g., 
surgery performed earlier than planned), then the deterioration of the condition for which 
the elective surgery/procedure is being done will be considered an AE. If any of the 
following events are reported, then the following supplemental form must be completed.  
If an AE meets any of the following criteria, it is to be reported to AbbVie  as an SAE within 
24 hours of the site being made aware of the SAE: 
 
Death of Subject- An event that results in the death of a subject. 
 

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Life-Threatening- An event that, in the opinion of the investigator, would have resulted in 
immediate fatality if medical intervention had not been taken. This does not include an 
event that would have been fatal if it had occurred in a more severe form. 
 
Hospitalization or Prolongation of Hospitalization- An event that results in an admission 
to the hospital for any length of time or prolongs the subject's hospital stay. This does not 
include an emergency room visit or admission to an outpatient facility. 
 
Congenital Anomaly- An anomaly detected at or after birth, or any anomaly that results in 
fetal loss. 
 
Persistent or Significant Disability/Incapacity- An event that results in a condition that 
substantially interferes with the activities of daily living of a study subject. Disability is not 
intended to include experiences of relatively minor medical significance such as 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained 
ankle). 
 
Important Medical Event Requiring Medical or Surgical Intervention to Prevent Serious 
Outcome- An important medical event that may not be immediately life threatening or 
result in death or hospitalization, but based on medical judgment may jeopardize the 
subject and may require medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or significant disability/incapacity). 
Additionally, any elective or spontaneous abortion or stillbirth is considered an important 
medical event. Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse.  
 
Special Situations - accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, lack of efficacy, or drug 
withdrawal must be reported to AbbVie within 30 calendar days. 
 
All AEs reported from the time of study drug administration until 30 days after 
discontinuation of study drug administration will be collected, whether solicited or 
spontaneously reported by the subject. In addition, SAEs and protocol-specified 

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nonserious AEs will be collected from the time the subject signs the study-specific 
informed consentAdverse events will be monitored throughout the study to identify any of 
special interest that may indicate a trend or risk to subjects. 
 
Adverse Events of Special Interest 
The following AESIs will be monitored during the study: 
•Serious infections 
•Opportunistic infections 
•Herpes zoster 
•Tuberculosis 
•Malignancy (all types) 
•GI perforations 
•Adjudicated cardiovascular events (e.g., major adverse cardiovascular event [MACE]) 
•Anemia 
•Neutropenia 
•Lymphopenia 
•Increased serum creatinine and renal dysfunction 
•Hepatic events and increased hepatic transaminases 
•Elevated creatine phosphokinase 
• embolic and thrombotic events (non-cardiac, non-central nervous system) 
Adverse Event Severity and Relationship to Study Drug 
The investigators will rate the severity of each AE according to the National Cancer 
Institute Common 
Terminology Criteria for Adverse Events version 4.03. 
If no grading criteria are provided for the reported event, then the event should be graded 
follows:  
Mild (Grade 1) Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
 
Moderate (Grade 2) Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)  
 
Severe (Grade 3 to 5) Grade 3 Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL (selfcare ADL refer to bathing, dressing and undressing, feeding self, using 
the toilet, taking medications, and not bedridden)  

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Grade 4 Life-threatening consequences; urgent intervention indicated  
 
Grade 5 Death related to AE 
 
The investigator will use the following definitions to assess the relationship of the AE to 
the use of study drug:  
Reasonable Possibility – After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative causes, there is sufficient 
evidence (information) to suggest a causal relationship. 
 
No Reasonable Possibility – After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative causes, there is insufficient 
evidence (information) to suggest a causal relationship. For causality assessments, 
events assessed as having a reasonable possibility of being related to the study drug will 
be considered "associated." Events assessed as having no reasonable possibility of 
being related to study drug will be considered "not associated." In addition, when the 
investigator has not reported a causality or deemed it not assessable, AbbVie will 
consider the event associated.  
 
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the investigator for the SAE. 
 
Pregnancy 
While not an AE, pregnancy in a study subject must be reported to AbbVie within 1 
working day after the site becomes aware of the pregnancy. If a pregnancy occurs in a 
study subject or in the partner of a study subject, information regarding the pregnancy 
and the outcome will be collected. In the event of pregnancy occurring in a subject's 
partner during the study, written informed consent from the partner must be obtained prior 
to collection of any such information. AbbVie will provide a separate consent form for this 
purpose. Pregnancy in a subject's partners will be collected from the date of the first dose 
through 30 days following the last dose of study drug. Subjects should avoid pregnancy 
throughout the course of the study, starting with the Screening Visit through 30 days after 
the last study drug administration for female subjects. Results of a positive pregnancy 
test or confirmation of a pregnancy will be assessed starting with the Screening Visit 
through the final study visit. Subjects who become pregnant during the study must be 

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discontinued. The pregnancy outcome of an elective or spontaneous abortion, stillbirth or 
congenital anomaly is considered a SAE and must be reported to AbbVie within 24 hours 
after the site becomes aware of the event. 
 
7 INVESTIGATIONAL PRODUCT HANDLING 
 
7.1   Investigational Product Receipt 
At study initiation and as needed thereafter, upadacitinib 15mg will be shipped to a 
responsible person at the investigator's institution, who will check the amount and 
condition of the drug, and maintain a record of this information.  The master accountability 
log will be maintained by un-blinded pharmacy staff. 
 
7.2   Investigational Product Storage 
Investigational product will be stored per the storage conditions identified on drug label.  
At the study site, all IP will be stored in a locked, safe area to prevent unauthorized 
access. Records of the actual storage conditions during the period of the study will be 
maintained. 
 
8 RECORD RETENTION 
The investigator must retain these documents according to local laws or requirements. 
Essential documents include, but are not limited to, the following: 
  
 Signed informed consent documents for all subjects;  
 Subject identification code list, screening log (if applicable), and enrollment log;  
 Record of all communications between the Investigator and the IRB/EC;  
Composition of the IRB/EC; g 
 Record of all communications between the Investigator and Abbvie. 
 List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles 
in the study, curriculum vitae, and their signatures;  
 Copies of CRFs (if paper) and of documentation of corrections for all subjects;   
 IP accountability records;  
 All other source documents (subject records, hospital records, laboratory records, 
etc);  

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 All other documents as listed in Section 8 of the ICH consolidated guideline on 
GCP (Essential Documents for the Conduct of a Clinical Trial). 
 
The Investigator must notify Abbvie if he/she wishes to assign the essential 
documents to someone else, remove them to another location or is unable to retain 
them for a specified period.  If the Investigator is unable to meet this obligation, the 
Investigator must ask Abbvie for permission to make alternative arrangements.  
Details of these arrangements should be documented.  All study documents should 
be made available if required by relevant health authorities.  Investigator/Institution 
should take measures to prevent accidental or premature destruction of these 
documents. 
 
To protect subjects’ confidentiality, all subjects and their associated samples will be 
assigned numerical study identifiers or “codes.”  No identifiable information will be 
provided to Abbvie.  
8.1 Study Monitoring  
The investigator will self-monitor all study records for accuracy, completeness, and 
compliance with the protocol and GCPs and federal regulations.  All study records will be 
made available to Abbvie representatives upon request.  Study site facilities and study 
records will be made available to regulatory authorities’ inspectors if an inspection takes 
place.  The investigator will notify Abbvie if this occurs.   
 
8.2 Statistics 
It is desired to enroll 25 patients.  
Primary Endpoint: Proportion of participants with improvement (reduction) in worst-itch 
numeric rating scale (WI-NRS) by ≥4 from baseline to Week 16 [Time Frame: Baseline to 
Week  12] WI-NRS is a patient-reported outcome (PRO) comprised of a single item rated 
on a scale from 0 ("No itch") to 10 ("Worst imaginable itch. 
Secondary Endpoints: Percent improvement (reduction) in worst-itch numeric rating scale 
(WI-NRS) by ≥4 from baseline to Week 24 
IGA PN-S 0 or 1 at weeks  12 & 24 
IGA PN-A 0 or 1 at week 12 & 24 
Percent improvement of PN-S & PN-A at week 12 & 24 
DLQI improvement at weeks 12 & 24 
Adverse Events 

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8.2.1 Additional Statistical Considerations 
The objective of the statistical analyses is to assess the efficacy and safety of upadacitinib  
for the treatment of subjects with moderate to severe PN who are candidates for systemic 
therapy. The Primary Analysis for all efficacy endpoints will be conducted after all 
continuing subjects have completed the study activities up to Week 16. The Intent-to-
Treat (ITT) Population consists of all randomized subjects and will be used for the efficacy 
analyses. A Per-Protocol Population may be defined if deemed necessary to exclude 
subjects with major protocol violations. The criteria to define the Per-protocol Population 
will be detailed in the SAP. Subjects to be excluded from the Per-Protocol Population will 
be finalized before week 16. The Per-Protocol Population, if defined, will be used to 
analyze the primary efficacy endpoint. 
 
The Safety Population consists of all randomized subjects who received at least 1 dose 
of study drug.  An All Upadacitinib Treated Population consists of all subjects who 
received at least one dose of upadacitinib in the study. This population will be used to 
provide a comprehensive summary of safety. 
 
Statistical Analyses for Efficacy 
All efficacy endpoints will be analyzed on the ITT population. In addition, the primary 
efficacy endpoints will be analyzed in the Per-Protocol Population, if defined.  
No missing data imputation will be applied, and all assessments prior to premature 
discontinuation from study drug will be used. 
 
 
Statistical Analyses for Safety – how will data be summarized? % of patients with AEs? 
The safety analyses will be carried out using the Safety Population. % of patients with 
AE’s will be assessed inclusive of physical examination, laboratory assessments, and 
vital signabnormalities. 
Note that missing safety data will not be imputed. 
 
 
 
8.3 Schedule of Events 

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REFERENCES 
 
 
1.Tessa B. Mullins, Poonam Sharma, Christopher A. Riley, Sidharth Sonthalia. Prurigo Nodularis. StatPearls 
[Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. 
2020 Sep 15. 
 

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24 
 
2.Eric H Kowalski, Diana Kneiber, Manuel Valdebran, Umangi Patel, Kyle T Amber. Treatment-resistant 
prurigo nodularis: challenges and solutions. Clin Cosmet Investig Dermatol. 2019 Feb 28;12:163-172. doi: 
10.2147/CCID.S188070. eCollection 2019. 
 
3.https://www.sanofi.com/en/media-room/press-releases/2022/2022-01-19-06-00-00-2368986Press 
release Jan 2022. 
 
4. Peng C, Li C, Zhou Y et al. Tofacitinib for Prurigo Nodularis: A Case Report. Clin Cosmet Investig Dermatol 
2022 Mar 21;15:503-506. doi: 10.2147/CCID.S354025. eCollection 2022. 
 
5. Investigator Brochure for Upadacitinib. Edition 12 Aug2021. 
 
6.Phan NQ et al. Acta Derm Venereol. 2012;92:502-7 Verweyen E at al. Acta Derm Venereol. 2019;99:657-
66 
7. Finlay AY, Khan GK.  Dermatology Life Quality Index (DLQI).  April 1992.  Available from:  
www.dermatology.org.uk. 
 
 
 
 
 
 
 
 
 
 
 
7. APPENDICES 
 
Appendix A 
INVESTIGATOR’S GLOBAL ASSESSMENT OF PRURIGO NODULARIS: ACTIVITY 
AND STAGE  
 
Score 
Category 
Description: Activity (IGA PN-A) 
0 
 
 
Clear 
No nodules have excoriations or crusts 

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1 
 
Almost 
Clear 
Very small proportion of nodules have 
excoriations or crusts (up to approximately 10% of 
all nodules)
 
2 
 
 
Mild 
Minority of nodules have excoriations or crusts 
(approximately 11-25% of all nodules) 
 
3 
 
 
Moderate 
Many nodules have excoriations or crusts 
(approximately 26-75% of all nodules) 
 
4 
 
 
Severe 
Majority of nodules have excoriations or crusts 
(approximately 26-75% of all nodules) 
 
Score 
Category 
Description: Stage (IGA PN-S) 
0 
 
 
 
Clear 
No nodules (0 nodules) 
 
1 
 
Almost  
Clear 
Rare, flattened lesions, with no more than 5 dome-
shaped palpable nodules (approximately 1-5 
nodules)
 
2 
 
 
Mild 
Few, mostly flattened lesions, with small number 
of dome-shaped palpable nodules (approximately 
6-19 nodules) 
 
3 
 
 
Moderate 
Many lesions, partially flattened, and dome-
shaped palpable nodules (approximately 20-100 
nodules)
 
4 
 
 
Severe 
Abundant lesions, majority are dome-shaped 
palpable nodules (over 100 nodules) 
Appendix B 
WI-NRS 
 

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Appendix C 
Dermatology Life Quality Index 
 
DERMATOLOGY LIFE QUALITY INDEX 
 
 
 
 
 
 
 
 
 
 
 
 
 DLQI 
Hospital No:  
 
 
 
Date:  
 
 
 
 
 
Name:  
 
 
 
 
 
 
 
 
Score: 
Address: 
 
 
 
 
Diagnosis: 
 
 
 
 
 
 
The aim of this questionnaire is to measure how much your skin problem has 
affected your life OVER THE LAST WEEK.  Please tick one box for each question. 
 
1. 
Over the last week, how itchy, sore,  
 
 
Very much 
 
 
painful or stinging has your skin    
 
 
A lot 
 
 
 
been?   
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
2. 
Over the last week, how embarrassed 
 
 
Very much 
 
 
or self conscious have you been because  
A lot 
 
 
 
of your skin?  
  
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
3. 
Over the last week, how much has your   
 
Very much 
 
 
skin interfered with you going 
 
  
 
A lot 
 
 
 
shopping or looking after your home or   
 
A little  
 
 
garden?         
 
 
 
 
 
Not at all 
 
Not 
relevant  
 
4. 
Over the last week, how much has your   
 
Very much 
 
 
skin influenced the clothes  
 
 
 
A lot 
 
 
 
you wear? 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
Not 
relevant  
 
5. 
Over the last week, how much has your   
 
Very much 
 
 
skin affected any social or   
 
 
 
A lot 
 
 
 
leisure activities? 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
Not 
relevant  
 
6. 
Over the last week, how much has your   
 
Very much 
 
 
skin made it difficult for  
 
 
 
 
A lot 
 
 
 
you to do any sport? 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
Not 
relevant  
 
7. 
Over the last week, has your skin prevented 
 
Yes 
 
 
 
you from working or studying? 
 
 
 
No 
 
 
Not 
relevant  

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27 
 
 
 
 
If "No", over the last week how much has   
 
A lot 
 
 
 
your skin been a problem at  
 
 
 
A little  
 
 
work or studying?  
 
 
 
 
Not at all 
 
 
8. 
Over the last week, how much has your   
 
Very much 
 
 
skin created problems with your   
 
 
A lot 
 
 
 
partner or any of your close friends 
 
 
A little  
 
 
or relatives?   
 
 
 
 
 
Not at all 
 
Not 
relevant  
 
9. 
Over the last week, how much has your   
 
Very much 
 
 
skin caused any sexual  
 
 
 
 
A lot 
 
 
 
difficulties?  
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
Not 
relevant  
 
10. 
Over the last week, how much of a  
 
 
Very much 
 
 
problem has the treatment for your 
 
 
A lot 
 
 
 
skin been, for example by making  
 
 
A little  
 
 
your home messy, or by taking up time?   
 
Not at all 
 
Not 
relevant  
Please check you have answered EVERY question. Thank you.  
AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the 
authors.