Dupilumab for the Treatment of Moderate to Severe Chronic Hepatic Pruritus: an Open-Label, Single-Arm, Exploratory Study
Phase: PHASE2
Conditions: Pruritus
Sponsor: Mayo Clinic

 
 
Dupilumab for the Treatment of Moderate-to-
severe, Chronic Hepatic Pruritus: An Open-
label, Single-arm, Exploratory Study 
 
NCT04256759 
 
12October2020 

Oct 12, 2020   
Page 1 of 29 
Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
DUPILUMAB FOR THE TREATMENT OF MODERATE TO 
SEVERE CHRONIC HEPATIC PRURITUS: AN OPEN-LABEL, 
SINGLE-ARM, EXPLORATORY STUDY 
 
 
 
Regulatory Sponsor/ 
Principal Investigator: 
 
 
Sub-Investigators: 
Study Site Location: 
 
 
 
 
 
Funding Sponsor: Study 
Product: 
 
Protocol Number: (IRBe) 
IND Number: 
Jason C. Sluzevich MD 
 
 
 
Andrew P. Keaveny, MD 
 
Mayo Clinic Florida 
Department of Dermatology 
Department of Transplantation 
4500 San Pablo Road 
Jacksonville, FL 32224 
 
 
Regeneron Pharmaceuticals 
Dupilumab (Dupixent) 
19-002757 
 
 
TBD 
 
 
 
Initial version: [07JAN2019] Version (1.0) 
[03MAR2019] Version 1.11 
[18OCT2019] Version 1.12 
[12OCT2020] Version 1.13 
 
 
 

Oct 12, 2020   
Page 2 of 29 
Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
 
Table of Contents 
STUDY SUMMARY ..................................................................................................................... 6 
1 
INTRODUCTION. ................................................................................................................ 7 
1.1 
BACKGROUND ............................................................................................................................................... 7 
1.2 
INVESTIGATIONAL AGENT ........................................................................................................................ 7 
1.3 
PRECLINICAL DATA..................................................................................................................................... 7 
1.4 
CLINICAL DATA TO DATE ......................................................................................................................... 8 
1.5 
DOSE RATIONALE ........................................................................................................................................ 8 
1.6 
RISKS AND BENEFITS .................................................................................................................................. 8 
2 
STUDY OBJECTIVES ......................................................................................................... 9 
3 
STUDY DESIGN ................................................................................................................... 9 
3.1 
GENERAL DESCRIPTION ............................................................................................................................. 9 
3.2 
NUMBER OF SUBJECTS ............................................................................................................................ 10 
3.3 
DURATION OF PARTICIPATION .............................................................................................................. 10 
3.4 
PRIMARY STUDY ENDPOINTS ................................................................................................................ 10 
3.5 
SECONDARY STUDY ENDPOINTS ......................................................................................................... 10 
3.6 
PRIMARY SAFETY ENDPOINTS .............................................................................................................. 10 
3.7 
IDENTIFICATION OF SOURCE DATA ..................................................................................................... 11 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL .............................. 11 
4.1 
INCLUSION CRITERIA ............................................................................................................................... 11 
4.2 
EXCLUSION CRITERIA .............................................................................................................................. 11 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING .......................................................... 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS................................................................................................... 12 
4.4.1 When and How to Withdraw Subjects ....................................................................... 12 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects .......................................... 13 
5 
STUDY DRUG .................................................................................................................... 13 
5.1 
DESCRIPTION .............................................................................................................................................. 13 
5.1.1 Mechanism of Action. ................................................................................................ 13 
5.1.2 Pharmacodynamics ................................................................................................... 13 
5.1.3 Pharmacokinetics ...................................................................................................... 13 
5.2 
TREATMENT REGIMEN ............................................................................................................................ 14 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ................................................. 14 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ............................................................. 14 
5.5 
SUBJECT COMPLIANCE MONITORING ................................................................................................ 15 
5.6 
PRIOR AND CONCOMITANT THERAPY ................................................................................................ 15 
5.7 
PACKAGING ................................................................................................................................................. 16 
5.8 
MASKING/BLINDING OF STUDY ........................................................................................................... 16 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ........................................................................ 16 

Oct 12, 2020   
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Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
5.9.1 Receipt of Drug Supplies .......................................................................................... 16 
5.9.2 Storage ...................................................................................................................... 16 
5.9.3 Dispensing of Study Drug ......................................................................................... 16 
5.9.4 Return or Destruction of Study Drug ........................................................................ 17 
6 
STUDY PROCEDURES .................................................................................................... 17 
6.1 
VISIT 1 (WEEK -2/SCREENING & ENROLLMENT) ............................................................ 17 
6.2 
VISIT 2 (WEEK 0± 5 DAYS BASELINE) ............................................................................ 17 
6.3 
VISIT 3 (WEEK 6± 5 DAYS) ............................................................................................. 17 
6.4 
VISIT 4 (WEEK 12± 5 DAYS) ........................................................................................... 18 
6.5 
VISIT 5 (WEEK 18± 5 DAYS) ........................................................................................... 18 
6.6 
VISIT 6 (WEEK 20± 5 DAYS) ............................................................................................ 18 
7 
STATISTICAL PLAN ........................................................................................................ 19 
7.1 
SAMPLE SIZE DETERMINATION ............................................................................................................ 19 
7.2 
STATISTICAL METHODS .......................................................................................................................... 19 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ......................................................................................... 20 
8 
SAFETY AND ADVERSE EVENTS ................................................................................ 21 
8.1 
DEFINITIONS ............................................................................................................................................... 21 
8.2 
RECORDING OF ADVERSE EVENTS ...................................................................................................... 22 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................... 23 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB ......................................... 23 
8.3.2 Sponsor-Investigator reporting: Notifying the FDA ................................................. 24 
8.4 
UNMASKING/UNBLINDING PROCEDURES ......................................................................................... 24 
8.5 
STOPPING RULES ....................................................................................................................................... 24 
8.6 
MEDICAL MONITORING .......................................................................................................................... 24 
9 
DATA HANDLING AND RECORD KEEPING ............................................................. 24 
9.1 
CONFIDENTIALITY .................................................................................................................................... 24 
9.2 
SOURCE DOCUMENTS .............................................................................................................................. 24 
9.3 
CASE REPORT FORMS .............................................................................................................................. 25 
9.4 
RECORDS RETENTION .............................................................................................................................. 26 
10 STUDY MONITORING, AUDITING, AND INSPECTING .......................................... 26 
10.1 
STUDY MONITORING PLAN ................................................................................................................... 26 
10.2 
AUDITING AND INSPECTING .................................................................................................................. 26 
11 ETHICAL CONSIDERATIONS ....................................................................................... 27 
12 STUDY FINANCES. ........................................................................................................... 27 
12.1 
FUNDING SOURCE ..................................................................................................................................... 27 
12.2 
CONFLICT OF INTEREST .......................................................................................................................... 27 
12.3 
SUBJECT STIPENDS OR PAYMENTS ...................................................................................................... 27 
13 PUBLICATION PLAN ...................................................................................................... 28 

Oct 12, 2020   
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Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
14 REFERENCES .................................................................................................................... 28 
15 ATTACHMENTS ............................................................................................................... 29 

Oct 12, 2020   
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Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
 
List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CLDQ 
Chronic Liver Disease Questionnaire 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator's Brochure 
IL-4 
Interleukin-4 
IL-13 
Interleukin-13 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISR 
Injection Site Reaction 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SC 
Subcutaneous 
SOP 
Standard Operating Procedure 
VAS 
Visual Analogue Scale 
VRS 
Visual Rating Scale 
PNRS 
Pruritus Numerical Rating Score 

Oct 12, 2020   
Page 6 of 29 
Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
Study Summary 
Title 
Dupilumab for the treatment of moderate to severe chronic hepatic 
pruritus: An open-label, single-arm, exploratory study 
Running Title 
Dupilumab for chronic hepatic pruritus 
Protocol Number 
19-002757 
Phase 
Phase II 
Methodology 
Open-label, single-arm, exploratory study 
Overall Study 
Duration 
18 months 
Subject Participation 
Duration 
22 weeks 
Single or Multi-Site 
Single-Mayo Clinic Florida 
Objectives 
To investigate the potential efficacy of dupilumab in the treatment of 
moderate to severe chronic hepatic pruritus. 
Number of Subjects 
12 
Diagnosis and Main 
Inclusion Criteria 
Male and/or female subjects 18 years or older with chronic pruritus of 
moderate to severe severity in the setting of intrahepatic or extrahepatic 
cholestatic liver disease. Chronic is defined as greater than 6 weeks of 
symptom duration. Pruritus severity is based on the peak pruritus 
numerical rating score (PNRS) of  4 (moderate severity). 
Study Product, Dose, 
Route, Regimen 
Dupilumab 600 mg SC week 0; then every 2 weeks x 18 weeks 
Duration of 
Administration 
18 weeks 
Reference therapy 
None-open label use of study drug 
Statistical 
Methodology 
A paired t-test will be used to evaluate mean differences before and after 
treatment at a p=0.05 significance level. The primary endpoint of the 
study is the mean percent change from baseline peak pruritus numerical 
rating score (PNRS) after 18 weeks. Correlations between the percent 
mean changes in the PNRS and quality of life outcome measures will 
also be analyzed. 

Oct 12, 2020   
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Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
 
1 Introduction 
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures. 
 
1.1 
Background 
 
Chronic pruritus secondary to liver disease can negatively impact quality of life. These patients 
characteristically lack any skin inflammation, but are often severely symptomatic with chronic 
generalized involvement leading to significant quality life impairments in sleep, daily activities, 
and personal relationships. To date, no clear pathophysiologic mechanism has been elucidated in 
chronic hepatic pruritus. No correlation has been found between plasma bile salt levels and 
endogenous opioid levels; while serum autotaxin levels are elevated in cholestatic liver disease, 
they are also increased in other pathological conditions which are not associated with pruritus. 
Standard therapy with bile salt binders, rifampin, sedating anti-histamines, partial opioid 
antagonists, selective serotonin reuptake inhibitors, narrowband UVB phototherapy, and serum 
plasma exchange is frequently ineffective and associated with dose limiting side effects. There 
exists a significant unmet clinical need for new therapies in the management of chronic hepatic 
pruritus. 
 
1.2 
Investigational Agent 
 
Dupilumab, a licensed, FDA approved treatment for Atopic Dermatitis, is a human monoclonal 
IgG4 antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling by 
specifically binding to the IL-4Ra subunit shared by the IL-4 and IL-13 receptor complexes. 
Dupilumab is a clear to slightly opalescent, colorless to pale yellow solution available as an 
injection of 300 mg/2 mL in a single-dose pre-filled syringe with needle shield for subcutaneous 
administration. Published results consistently showed that, compared with placebo, subcutaneous 
dupilumab 300 mg once weekly (qw) or every 2 weeks (q2w) significantly improved objective 
signs and symptoms of AD including pruritus, symptoms of anxiety and depression, and quality 
of life using dermatology-specific measures. 
 
1.3 
Preclinical Data 
 
Recently, it has been established that IL-4 and IL-13 may directly activate sensory neurons in 
both mouse and human experimental models. Additionally, small diameter neurons mediating 
pruritus have been found to be enriched with IL-4 receptors and IL-13 receptors compared to 
other families of nociceptive and mechanoreceptive neurons. IL-4 has also been established to 
sensitize neurons to respond to previously subthreshold levels of histamine as well as other 
endogenous pruritogens. Therefore, inhibition of IL-4/IL-13 cytokine signaling on sensory 
neurons represents a potential therapeutic target in other conditions with chronic pruritus without 
overt skin inflammation. 

Oct 12, 2020   
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Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
1.4 
Clinical Data to Date 
 
Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has 
shown efficacy in the treatment of pruritus associated with moderate to severe atopic dermatitis. 
Notably, improvement of pruritus usually precedes clinically significant skin clearance 
suggesting other mechanisms beyond direct anti-inflammatory effects are of importance. 
Therefore we propose that dupilumab may have drug anti-pruritic effects independent of 
inflammatory effects. 
 
1.5 
Dose Rationale 
 
The dose regimen of subcutaneous (SC) dupilumab selected for this study is 300 mg every 2 
weeks for 18 weeks. All patients will get an initial loading dose of 600 mg (given as two 300 mg 
injections) at week 0. The administration of the loading dose of dupilumab will allow systemic 
concentrations to reach steady-state faster and reduce the time to onset of clinical effect. The 
dose of dupilumab for this study was based on the efficacy and safety results from multiple 
clinical trials that have led to the FDA approval of dupilumab at an initial dose of 600 mg then 
300 mg every 2 weeks, for 18 weeks, for the treatment of atopic dermatitis. 
 
1.6 
Risks and Benefits 
 
The postulated benefits of dupilumab include sustained immunomodulatory effects resulting in 
improvement of chronic hepatic pruritus. Mechanistically, as a biologic class medication, 
dupilumab has no hepatic metabolism; and since FDA approval for atopic dermatitis and asthma, 
no incidents of hepatic impairment have been reported 
 
The following risks of dupilumab therefore felt to be low and manageable with the study 
protocol and do not outweigh the aforementioned benefits: 
 
Hypersensitivity Reactions 
Hypersensitivity reactions, including generalized urticaria and serum sickness or serum sickness- 
like reactions were reported in less than 1% of subjects who received dupilumab in clinical trials. 
This risk is idiosyncratic and will be minimized by administrating dupilumab in a supervised 
medical setting for the first treatment dose. 
 
Conjunctivitis and Keratitis 
Conjunctivitis and keratitis occurred more frequently in atopic dermatitis subjects who received 
dupilumab. Conjunctivitis was the most frequently reported eye disorder. Most subjects with 
conjunctivitis recovered or were recovering during the treatment period. Among asthma subjects 
the frequency of conjunctivitis was similar between dupilumab and placebo. Therefore, the 
development of keratitis appears related to the pathophysiologic state of AD and may not be 
entirely a direct drug effect. Keratitis was reported in <1% of the dupilumab group (1 per 100 
subject-years) and in 0% of the placebo group (0 per 100 subject-years) in the 16-week atopic 
dermatitis monotherapy trials. In the 52 week dupilumab + topical corticosteroids (TCS) atopic 

Oct 12, 2020   
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Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
dermatitis trial, keratitis was reported in 4% of the dupilumab + TCS group (12 per 100 subject- 
years) and in 0% of the placebo + TCS group (0 per 100 subject-years). Most subjects with 
keratitis recovered or were recovering during the treatment period. Among asthma subjects the 
frequency of keratitis was similar between dupilumab and placebo. Subjects will be advised to 
report new onset or worsening eye symptoms and will be appropriately assessed and treated. 
 
Eosinophilic Conditions 
Patients being treated for asthma may present with serious systemic eosinophilia sometimes 
presenting with clinical features of eosinophilic pneumonia or vasculitis consistent with 
eosinophilic granulomatosis with polyangiitis, conditions which are often treated with systemic 
corticosteroid therapy. These events may be associated with the reduction of oral corticosteroid 
therapy. Physicians should be alert to vasculitic rash, worsening pulmonary symptoms, cardiac 
complications, and/or neuropathy presenting in their patients with eosinophilia. Cases of 
eosinophilic pneumonia and cases of vasculitis consistent with eosinophilic granulomatosis with 
polyangiitis have been reported with dupilumab in adult patients who participated in the asthma 
development program. A causal association between dupilumab and these conditions has not 
been established. 
 
Reduction of Corticosteroid Dosage 
Reductions in corticosteroid dose, if appropriate, will be gradual and performed under the direct 
supervision of a physician. 
 
Parasitic (Helminth) Infections 
Patients with known helminth infections were excluded from participation in clinical studies. It is 
unknown if dupilumab will influence the immune response against helminth infections. This risk 
will be minimized by excluding enrollment of study participants with known tapeworm or 
roundworm infections. 
 
2 Study Objectives 
 
Primary Objective: To investigate the potential efficacy of dupilumab in the treatment of adults 
with moderate to severe chronic hepatic pruritus. 
 
3 Study Design 
3.1 
General Description 
 
This is a 22-week (2 week screening, 18-week treatment period followed by a 2 week follow- 
up), phase II, open label, exploratory study to investigate the potential efficacy of FDA approved 
dupilumab in the treatment of adults with moderate to severe chronic hepatic pruritus. Subjects 
will be screened at outpatient clinic visit appointments and interested qualified subjects will be 
consented and offered participation in this trial. Once consent has been obtained, baseline values 
will be established and subjects will begin treatment and follow-up for the next 20 weeks. A final 
visit will be needed for evaluation and questionnaire completion. 

Oct 18, 2019 
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Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
3.2 
Number of Subjects 
 
A target of 12 subjects will be enrolled. 
 
3.3 
Duration of Participation 
 
Each subject's participation in the study will be up to 22 weeks including the screening period. 
 
3.4 
Primary Study Endpoints 
 
The primary endpoint of the study will be the mean percent change in the Peak Pruritus 
Numerical Rating Score (PNRS) before and after 20 weeks of treatment with dupilumab. Pruritus 
severity is measured using the peak NRS assessed as a single, self-completed item that assesses 
the intensity of peak (worst) pruritus during the past 24 hours using the query: "On a scale of 0 to 
10, with 0 being 'no itch 'and 10 being 'worst itch imaginable', how would you rate your itch at 
the worst moment during the previous 24 hours?". The baseline and treatment mean peak PNRS 
will be the average of the daily score for 7 days before treatment and then after the first treatment 
dose self-assessed by patients daily and then averaged for 7 days. 
 
3.5 
Secondary Study Endpoints 
 
The other secondary endpoints regarding pruritus will be assessed at baseline and as follows: 
 
1. Percentage of patients with an improvement in weekly average PNRS 3 from baseline. 
This will be assessed at week 6,12,18 
2. Percentage of patients with an improvement in weekly average PNRS 4 from baseline. 
This will be assessed at week 6,12,18 
3. Mean change in the verbal rating scale (VRS) of pruritus as measured 0=none; 1= mild; 
2=moderate; and 3=severe/intense. This will be assessed at week 6,12,18 
4. Mean change of 5D pruritus score. This is a multidimensional questionnaire designed to 
assess the degree, duration, direction, disability and distribution of pruritus longitudinally 
with scoring ranging from 5=no pruritus/well-controlled to 25=severe pruritus/poorly 
controlled. This will be assessed at baseline and at week 18. 
5. Chronic Liver Disease Questionnaire (CLDQ). This is a validated quality life instrument 
for patients with chronic liver disease evaluating systemic symptoms, fatigue, physical 
activity, emotional function, and worry using a 7 point scale with 1=all of the time; 
2=most of the time; 3=a good bit of the time; 4=some of the time; 5=a little of the time; 
6=hardly any of the time; and 7=none of the time. This will be assessed at baseline and 
week 18. 
 
3.6 
Primary Safety Endpoints 
 
This is an exploratory efficacy study with no specific primary safety endpoint. Adverse events 
will be tracked and reported using Good Clinical Practice standards and as described in Section 8 
of this protocol. 

Oct 18, 2019 
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Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
 
The safety of dupilumab in this population will be assessed by evaluating the detailed medical 
history through physical examination, vital signs, and clinical laboratory testing. Concomitant 
medications and procedures will be collected from time of informed consent to the end of the 
study. 
 
3.7 
Identification of Source Data 
 
The following source data will be directly recorded on the Case Report Form (CRF): 
x Screening and documentation of adverse events 
x Confirmation of patient counseling and education 
x PNRS score 
x VRS score 
x 5D Pruritus Score 
x CLDQ questionnaire 
 
The following source data will not be directly recorded in the CRF, but will be captured in 
supportive documentation to include study source documents and the EMR: 
x Laboratory results and clinical interpretation of the values 
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
 
Subjects who meet the following criteria will be considered eligible to participate in the clinical 
study: 
1. Male and/or female subjects 18 years or older with chronic pruritus of moderate to severe 
severity in the setting of intrahepatic or extrahepatic cholestatic liver disease. Chronic is 
defined as greater than 6 weeks of symptom duration. Pruritus severity is based on the 
peak pruritus numerical rating score of  4 (moderate severity). 
2. Documentation of a personally signed and dated informed consent indicating that the 
subject or their legally acceptable representative has been informed of all pertinent 
aspects of the trial. 
3. Willingness and ability to comply with scheduled clinic visits, physical exams, laboratory 
tests, questionnaires, effective contraception use, and other trial procedures. 
 
4.2 
Exclusion Criteria 
 
Subjects who meet one or more of the following criteria will not be considered eligible to 
participate in the clinical study: 
1. Male and/or female subjects under 18 years of age. 
2. Pruritus due to a primary inflammatory skin dermatosis or other forms of psychogenic 
pruritus utilizing skin biopsies as needed. 
3. Pregnant females 

Oct 18, 2019 
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Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
4. History of intrahepatic cholestasis of pregnancy 
5. Any form of chronic hepatic pruritus associated with underlying malignancy 
6. Liver transplant recipients 
7. Allergy to dupilumab or its ingredients 
8. Inability to provide informed consent 
9. Concomitant use of selective opioid antagonists 
10. Subjects with severe asthma (requiring high-dose inhaled or systemic corticosteroids) 
will be excluded from the study. 
11. Patients with known helminth infections 
 
4.3 
Subject Recruitment, Enrollment and Screening 
 
Subjects will be recruited from a single, tertiary-care facility from the principal investigator 
and/or co-investigator clinical practices located in the departments of dermatology, 
gastroenterology and hepatology, and transplantation at Mayo Clinic in Florida. Potential 
subjects will be screened to confirm a diagnosis of chronic hepatic pruritus based on clinical 
evaluation and documentation of inclusion/exclusion criteria. Patients will be provided with a 
Research Participant Consent and Privacy Authorization Form describing the study drug, 
protocol, inclusion and exclusion criteria, as well as risks and benefits of participation. 
 
4.4 
Early Withdrawal of Subjects 
 
4.4.1 When and How to Withdraw Subjects 
 
Patients are free to withdraw at any time and for whatever reason. No data will be collected for 
withdrawn subjects. Withdrawn subjects may be replaced within the accrual period. There will 
be no follow-up for withdrawn subjects. Pre-specified reasons for discontinuing include, but are 
not limited to, the following: 
• Patient Request: Patient decided that he/she did not want to continue (for any reason) 
• Sponsor/Principal Investigator Request: Patients may be withdrawn from the study for 
any reason, at the discretion of the Sponsor/PI. 
• Adverse Event: Patient experienced a related or unrelated event that would interfere with 
the study objectives/evaluation 
• Lost to Follow-up: Patient did not come in for a visit and could not be reached by phone 
• Treatment Failure: If in the Principal Investigator and/or Investigators' judgment, the 
patient's condition required another form of treatment 
• Inclusion/Exclusion Discrepancy/Violation: Patient should not have been enrolled 
• Noncompliance: Patient is not complying with the protocol requirements (i.e. visit 
schedule, dosing, regimen, etc.); a patient is to be withdrawn if he/she misses two 
consecutive visits 
• Other: Any other reason 

Oct 18, 2019 
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Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
If a participant withdraws from the study, no additional attempts will be made to contact the 
participant. 
 
5 Study Drug 
Dupilumab is FDA approved to treat adults with moderate-to-severe atopic dermatitis (eczema) 
that is not well controlled with prescription therapies used on the skin (topical), or who cannot 
use topical therapies. Dupilumab can be used with or without topical corticosteroids. It is not 
known if Dupilumab is safe and effective in children with atopic dermatitis under 18 years of 
age. 
 
Dupilumab is FDA approved to treat adults with other asthma medicines for the maintenance and 
treatment of moderate-to-severe asthma in people aged 12 years and older whose asthma is not 
controlled with their current asthma medicines. Dupilumab helps prevent severe asthma attacks 
and may also help reduce the amount of oral corticosteroids need while preventing severe asthma 
attacks. Dupilumab is not used to treat sudden breathing problems. It is not known if Dupilumab 
is safe and effective in children with asthma under 12 years of age. 
 
5.1.1 
Mechanism of Action 
 
Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and 
interleukin-13 (IL-13) signaling by specifically binding to the IL-4Ra 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-4Ra with dupilumab 
inhibits IL-4 and IL-13 cytokine-induced inflammatory responses, including the release of pro- 
inflammatory cytokines, chemokines, nitric oxide, and IgE. 
 
5.1.2 
Pharmacodynamics 
 
Consistent with receptor blockade, serum levels of IL-4 and IL-13 were increased following 
dupilumab treatment. The relationship between the pharmacodynamic activity and the 
mechanism(s) by which dupilumab exerts its clinical effects is unknown. 
 
5.1.3 
Pharmacokinetics 
 
Absorption: Following an initial subcutaneous (SC) dose of 600 mg, dupilumab reached peak 
mean ±SD concentrations (Cmax) of 70.1±24.1 mcg/mL by approximately 1 week post dose. 
Steady-state concentrations were achieved by Week 16 following the administration of 600 mg 
starting dose and 300 mg dose either weekly (twice the recommended dosing frequency) or every 
other week. Across clinical trials, the mean ±SD steady-state trough concentrations ranged from 
73.3±40.0 mcg/mL to 79.9±41.4 mcg/mL for 300 mg administered every 2 weeks and from 
173±75.9 mcg/mL to 193±77.0 mcg/mL for 300 mg administered weekly. The bioavailability of 
dupilumab following a SC dose is estimated to be 64%. 

Oct 18, 2019 
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Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
 
Distribution: The estimated total volume of distribution was approximately 4.8±1.3 L. 
 
Elimination: The metabolic pathway of dupilumab has not been characterized. As a human 
monoclonal IgG4 antibody, dupilumab is expected to be degraded into small peptides and amino 
acids via catabolic pathways in the same manner as endogenous IgG. After the last steady-state 
dose of 300 mg Q2W or 300 mg QW dupilumab, the median times to non-detectable 
concentration (<78 ng/mL) are 10 and 13 weeks, respectively. 
 
Dose Linearity: Dupilumab exhibited nonlinear target-mediated pharmacokinetics with 
exposures increasing in a greater than dose-proportional manner. The systemic exposure 
increased by 30-fold when the dose increased 8-fold following a single dose of dupilumab from 
75 mg to 600 mg (i.e., 0.25times to 2-times the recommended dose). 
 
Weight: Dupilumab trough concentrations were lower in subjects with higher body weight. 
 
Immunogenicity: Development of antibodies to dupilumab was associated with lower serum 
dupilumab concentrations. A few subjects who had high antibody titers also had no detectable 
serum dupilumab concentrations. 
 
Specific Populations: 
Geriatric Patients 
In subjects who are 65 years and older, the mean ±SD steady-state trough concentrations of 
dupilumab were 69.4±31.4 mcg/mL and 166±62.3 mcg/mL, respectively, for 300 mg 
administered every 2 weeks and weekly. No dose adjustment in this population is recommended. 
 
Renal or Hepatic Impairment 
No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of 
dupilumab was conducted. 
 
Drug Interaction Studies: Drug interaction studies have not been conducted with dupilumab. 
 
5.2 
Treatment Regimen 
 
All study participants will receive dupilumab 600 mg SC at week 0; then 300 mg SC every 2 
weeks for a total of 18 weeks. 
 
5.3 
Method for Assigning Subjects to Treatment Groups 
 
This is an open-label pilot investigation and all study participants are assigned to active 
treatment. There is no placebo arm in this study. 
 
5.4 
Preparation and Administration of Study Drug 

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The study drug will be stored and dispensed at the first study visit from the Mayo Clinic 
Research Pharmacy in Jacksonville, FL. Subsequent doses of the study drug will be self- 
administered by the subject until completion of the study. 
 
For subjects willing and able to self-administer or have a caregiver administer the study drug 
outside the clinic, the study staff will train the subject/caregiver on preparation and 
administration of study drug. Subjects who prefer to have clinic staff administer study drug may 
choose to have injections administered in the clinic. 
 
The procedure for preparing the dupilumab dose for SC injection will be provided in the 
pharmacy manual. Subcutaneous injection sites should be alternated among the different 
quadrants of the abdomen, upper tights, and upper arms, so that the same site is not injected for 2 
consecutive weeks. To allow for adequate assessment of possible injection site reactions (ISRs), 
study drug should be administered only into areas of normal-looking skin. Instructions for 
recording and reporting of ISRs will be provided in the study reference manual. 
 
Detailed instructions for transport, storage, preparation, and administration of study drug will be 
provided by the site to the patient (or caregiver). 
 
5.5 
Subject Compliance Monitoring 
 
All drug accountability records must be kept current. The investigator must be able to account 
for all opened and unopened study drug. These records should contain the dates, quantity, and 
study medication: dispensed to each patient, returned from each patient (if applicable), and 
disposed of at the site or returned to the sponsor or designee. All accountability records must be 
made available for inspection by the sponsor and regulatory agency inspectors; photocopies must 
be provided to the sponsor at the conclusion of the study. All drug compliance records must be 
kept current and must be made available for inspection by the sponsor and regulatory agency 
inspectors. Patients will complete a dosing diary to document compliance with self-injection of 
study drug. 
 
Any subject who is significantly non-compliant with the study drug regimen may be withdrawn 
from the study. 
 
5.6 
Prior and Concomitant Therapy 
 
Treatment with live (attenuated) vaccines, investigational drugs (other than dupilumab), or 
selective opioid antagonists are prohibited for patients actively enrolled onstudy. 
 
Treatment with concomitant medications for chronic hepatic pruritus except for selective opioid 
antagonists is permitted during the study. This includes basic skin care (cleansing and bathing), 
emollients, topical anesthetics, and antihistamines for any duration. Medications used to treat 
chronic disease such as diabetes, hypertension, and asthma are also permitted; if there is any 
question regarding whether a concomitant medication may be used during the study, the study 
site should contact the medical monitor. 

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5.7 
Packaging 
 
Dupilumab injection is a clear to slightly opalescent, colorless to pale yellow solution, supplied 
in single-dose pre-filled syringes with needle shield. Each pre-filled syringe with needle shield is 
designed to deliver 300 mg of dupilumab in 2 mL solution. Dupilumab is available in cartons 
containing 2 pre-filled syringes with needle shield. 
 
Pre-filled syringes will be shipped to the Mayo Clinic Research Pharmacy in Florida and then 
labeled upon receipt with statement "Caution: New Drug Limited by Federal law for 
investigational use." 
 
5.8 
Masking/Blinding of Study 
 
This is an open-label pilot investigation. Masking and blinding procedures are not applicable. 
Qualitative and quantitative evaluations of response to treatment will be recorded. 
 
5.9 
Receiving, Storage, Dispensing and Return 
 
5.9.1 Receipt of Drug Supplies 
 
The drug will be shipped by Regeneron Pharmaceuticals to the Mayo Clinic Research Pharmacy 
in Florida. Upon receipt, an inventory will be performed and a drug receipt log filled out by the 
person accepting the shipment. Designated study staff will count and verify that the shipment 
contains all the items noted in the shipping invoice. Any discrepancies, damaged or unusable 
study drug in a given shipment will be documented in the study files. The sponsor-investigator 
must be notified immediately of any discrepancies, damaged or unusable products that are 
received. 
 
5.9.2 Storage 
 
Dupilumab should be stored refrigerated at 36°F to 46°F (2°C to 8°C) in the original carton to 
protect from light. If necessary, pre-filled syringes may be kept at room temperature up to 77°F 
(25°C) for a maximum of 14 days. Dupilumab should not be stored above 77°F (25°C). After 
removal from the refrigerator, dupilumab must be used within 14 days or discarded. The syringe 
should not be exposed to heat or direct sunlight. 
 
5.9.3 Dispensing of Study Drug 
 
Regular study drug reconciliation will be performed to document drug assigned, drug dispensed, 
drug returns, and drug remaining. This reconciliation will be logged on tracked using  the 
Vestigo electronic ledger system. Drug dispensation will occur at the first treatment visit. 

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5.9.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
dispensed, drug returns, and drug remaining. This reconciliation will be logged on the drug 
reconciliation form, signed and dated. Any discrepancies noted will be documented and 
investigated, prior to return or destruction of unused study drug. Drug destroyed on site will be 
documented in the study files. 
 
6 Study Procedures 
6.1 
Visit 1 (Week -2/Screening & Enrollment) 
 
After the subject has provided written informed consent, the following information will be 
collected: 
1. Informed consent 
2. Inclusion and exclusion criteria 
3. Medical history 
 
The following procedures and assessments will be conducted: 
1. PRNS score 
2. Laboratory samples including; CBC with differential, AST, ALT, INR 
3. Dispense pruritus scoring journal; review instructions 
 
6.2 
Visit 2 (Week 0+7 days Baseline) 
 
The following information will be collected: 
1. Inventory of existing medications and procedures 
 
The following procedures and assessments will be conducted: 
1. Vital signs including; height, weight, body temperature, blood pressure, pulse rate 
2. Physical examination 
 
3. Dispense study drug, 12 week supply of dupilumab 
4. Instruct subject on self-injection of study drug 
5. Observe subject injection technique 
6. Review pruritus daily scoring journal; review instructions 
7. PRNS score 
8. VRS score 
9. CLDQ questionnaire 
 
6.3 
Visit 3 (Week 6± 5 days) 
 
The following information will be collected: 
1. Inventory of existing medications and procedures 

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2. Adverse events 
 
The following procedures and assessments will be conducted: 
1. PNRS score; collect pruritus scoring journal 
2. VRS score 
3. Vital signs including; height, weight, body temperature, blood pressure, pulse rate 
4. Physical examination 
5. Laboratory samples including; CBC with differential, AST, ALT, INR 
6. Dispense pruritus scoring journal; review instructions 
 
6.4 
Visit 4 (Week 12± 5 days) 
 
The following information will be collected: 
1. Inventory of existing medications and procedures 
2. Adverse events 
 
The following procedures and assessments will be conducted: 
1. PNRS score; collect pruritus scoring journal 
2. VRS score 
3. Vital signs including; height, weight, body temperature, blood pressure, pulse rate 
4. Physical examination 
5. Laboratory samples including; CBC with differential, AST, ALT, INR 
6. Dispense pruritus scoring journal; review instructions 
7. Dispense study drug 6 week supply of dupilumab 
 
6.5 
Visit 5 (Week 18+2 days) 
 
The following information will be collected: 
1. Inventory of existing medications and procedures 
2. Adverse events 
 
The following procedures and assessments will be conducted: 
1. PNRS score; review pruritus scoring journal 
2. VRS score 
3. CLDQ questionnaire 
4. 5D itch score questionnaire 
5. Vital signs including; height, weight, body temperature, blood pressure, pulse rate 
6. Physical examination 
7. Laboratory samples including; CBC with differential, AST, ALT, INR 

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6.6 
Visit 6-Follow-up (Week 20±5 days) 
 
The following information will be collected: 
1. Inventory of existing medications and procedures 
2. Adverse events 
 
The following procedures and assessments will be conducted: 
1. PNRS post-treatment score; collect pruritus scoring journal 
 
TABLE OF EVENTS SUMMARY 
Week 
Wk -2 
Screening 
Enrollment 
Wk 0 
Baseline 
Wk 6 
± 5 days 
Wk 12 
± 5 days 
Wk 18 
± 2 days 
Wk 20 
± 5 days 
Visit 
1 
2 
3 
4 
5 
6 
Consent/Enroll 
X 
Medical History 
X 
X 
X 
X 
X 
Dispense Drug 
X 
X 
Dispense Pruritus Log 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
PNRS 
X 
X 
X 
X 
X 
X 
VRS 
X 
X 
X 
5D Pruritus 
X 
X 
CLDQ 
X 
X 
CBC with diff 
X 
X 
X 
X 
AST/ALT 
X 
X 
X 
X 
PT/INR 
X 
X 
X 
X 
AE Event Screen 
X 
X 
X 
X 
X 
 
 
7 Statistical Plan 
7.1 
Sample Size Determination 
 
No formal power analysis was performed as this is a pilot study; however, the open-label study 
design aids in the detection of therapeutic efficacy given the well-established natural history of 
chronic hepatic pruritus that at baseline has been characterized as persistent, severe, and not 
association with a natural history of spontaneous improvement. 
 
7.2 
Statistical Methods 
Descriptive Statistics 

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Continuous variables will be summarized using the sample mean, median, standard deviation, 
interquartile range, and range. Categorical variables will be summarized using number and 
percentage of patients. 
 
Handling of Missing Data 
 
In the event of any unexpected missing data, this will be imputed using the last observation 
carried forward method. 
 
Multiplicity 
 
Since this is an exploratory pilot study, no adjustment for multiple testing will be undertaken. 
 
Primary Hypothesis: For subjects with chronic hepatic pruritus, treatment with dupilumab will 
improve the PRNS after 1 weeks of treatment. 
 
As previously described, the PRNS will be assessed on a daily basis for each patient. Separately 
for the 7 days prior to treatment (i.e. pre-treatment), the first 6 weeks of treatment (i.e. weeks 1  
to 6), the second six weeks of treatment (i.e. weeks 7 to 12), the third six weeks of treatment (i.e. 
weeks 13 to 18), and the final two weeks of treatment (i.e. weeks 19 and 20), the mean of these 
daily PRNS measures will be calculated for each patient, resulting in a pre-treatment, week 6, 
week 12, week 18, and week 20 mean PRNS measurement for each patient. We will summarize 
the percentage change in PRNS values from pre-treatment to week 6, week 12, week 18, and 
week 20 using the aforementioned descriptive statistics. Additionally, we will estimate the 
proportion of patients whose mean PRNS value improves by 3 or more point, and by 4 or more 
points, from pre-treatment to each of the week 6, week 12, week 18, and week 20 time periods. 
Comparisons of mean PRNS between the pre-treatment time period and each of the week 6, 
week 12, week 18, and week 20 time periods will be made using a paired Wilcoxon signed rank 
test. 
 
For secondary endpoints (VRS, 5D pruritus score, and CLDQ), these will be compared between 
the pre-treatment and follow-up time points using a paired Wilcoxon signed rank test. Although 
focus will be more on descriptive summaries rather than statistical significance due to the pilot 
nature of the study, p-values less than 0.05 will be considered as statistically significant. 
 
Interim Analysis 
 
There will not be any interim analysis given the low risk profile of the study formulation and the 
pilot nature of the study. 
 
7.3 
Subject Population(s) for Analysis 

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Each participant who received the study drug will be included in the primary analysis regardless 
of study withdrawal for any reason. In the event of any study withdrawals, for any secondary 
analysis, we will examine the sensitivity of our results to the exclusion of patients who withdrew. 
 
8 Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria: 
• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, DSMB reports, interim findings, product labeling change) that in the opinion 
of the local investigator may adversely affect the rights, safety, or welfare of the subjects 
or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator's Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
Adverse Event 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) in a patient or research subject. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. Serious problems/events can be well 
defined and include; 
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant disability or incapacity 
• birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-investigator 
may have adversely affected the rights, safety, or welfare of the subjects or others, or 
substantially compromised the research data. 

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Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non- 
serious adverse events. 
 
Adverse Event Reporting Period 
 
For this study, the study treatment follow-up period is defined as the last scheduled visit. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition. At the end of the study, any new clinically significant findings/abnormalities that  
meet the definition of an adverse event must also be recorded and documented as an adverse 
event. 
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the sponsor-investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained. At the last 
scheduled visit, the sponsor-investigator should instruct each subject to report, to the sponsor- 
investigator, any subsequent event(s) that the subject, or the subject's personal physician, 
believes might reasonably be related to participation in this study. 
 
Abnormal Laboratory Values 
 
Any clinical laboratory abnormality that can reasonably be related to the administration of 
dupilumab should be documented as an adverse event. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
 
Hospitalization, prolonged hospitalization, or surgery is to be reported as an adverse event if it 
can reasonably be related to use of dupilumab. 
 
8.2 
Recording of Adverse Events 
 
At each contact with the subject, the study team will seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event section of the case report form (CRF). All clearly related signs, symptoms, and abnormal 
diagnostic, laboratory or procedure results will be recorded in the source document. 

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All adverse events occurring during the study period will be recorded. The clinical course of 
each event should be followed until resolution, stabilization, or until it has been ultimately 
determined that the study treatment or participation is not the probable cause. Serious adverse 
events that are still ongoing at the end of the study period must be followed up, to determine the 
final outcome. Any serious adverse event that occurs during the Adverse Event  Reporting  
Period and is considered to be at least possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event Worksheet 
and log. The sponsor-investigator will evaluate the event and determine the necessary follow-up 
and reporting required. 
 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB 
 
The Principal Investigator and/or Investigators will report, as soon as possible, but no later than 5 
working days after first learning of the problem/event, to the Mayo Clinic IRB any UPIRTSOs 
and Non-UPIRTSOs according to the Mayo Clinic IRB Policy and Procedures. 
 
Documentation of adverse events will include the following information collected in the adverse 
event section of the case report form (and entered into the research database): 
• Subject's name: 
• Medical record number: 
• Disease: 
• The date the adverse event occurred: 
• Description of the adverse event: 
• Relationship of the adverse event to the research: 
• If the adverse event was expected: 
• The severity of the adverse event (defined by a severity scale): 
• If any intervention was necessary: 
• Resolution (was the incident resolved spontaneously, or after discontinuing treatment): 
• Date of Resolution: 
 
The Principal Investigator and/or Investigators will review all adverse event reports to determine 
if specific reports need to be made to the IRB and FDA. The Principal Investigator and/or 
Investigators will sign and date the adverse event report when it is reviewed. For this protocol, 
only directly related SAEs/UPIRTSOs will be reported to the IRB. 

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8.3.2 Sponsor-Investigator reporting: Notifying the FDA 
 
This protocol is not being conducted under an FDA investigational new drug application. 
 
8.4 
Unmasking/Unblinding Procedures 
 
This is an open-label pilot investigation. Unmasking and unblinding procedures are not 
applicable. 
 
8.5 
Stopping Rules 
 
This investigation is of low risk to study subjects. Stopping or interruption of the study may be 
necessary if a significant number of study participants develop unexpected clinical flaring or 
significant worsening that appears temporally linked with dupilumab administration. 
 
8.6 
Medical Monitoring 
 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site. This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety- 
monitoring plan (see section 10 "Study Monitoring, Auditing, and Inspecting"). Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Those regulations require a signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI 
 
9.2 
Source Documents 
 
Source data is all information, 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. Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects' 

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diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
 
9.3 
Case Report Forms 
 
All data requested on the Case Report Form (CRF) will be recorded for each participant. A 
standardized CRF will be generated by REDCap. All missing data will be explained. If a space 
on the CRF is left blank because the question was not asked, "N/D" will be recorded. If the item 
is not applicable to the individual case, "N/A" will be recorded. All entries will be printed  
legibly in black ink. If any entry error has been made, a single straight line through the incorrect 
entry will be drawn and the correct data will be written above it. All such changes will be 
initialed and dated. Errors will not be erased or whited-out. For clarification of illegible or 
uncertain entries, a clarification will be printed above the item, then initialed and dated. If the 
reason for the correction is not clear or needs additional explanation, details to justify the 
correction will be neatly included. 
 
Data Management 
 
Study data will be collected and managed using REDCap electronic data capture tools hosted at 
the Mayo Clinic. REDCap (Research Electronic Data Capture) is a secure, web-based  
application designed to support data capture for research studies, providing 1) an intuitive 
interface for validated data entry; 2) audit trails for tracking data manipulation and export 
procedures; 3) automated export procedures for seamless data downloads to common statistical 
packages; and 4) procedures for importing data from external sources. 
 
Data Processing 
 
All study data will be stored and analyzed at Mayo Clinic in Florida using the REDCap 
electronic data capture tool. 
 
Data Security and Confidentiality 
 
All source documents including clinical findings, observations or other activities will be stored in 
a REDCap database that will be designed by the Statistician. Access to the REDCap database 
will be limited to the Principal Investigator, Investigators, and Statistician. 
 
Data Quality Assurance 

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Once the study is completed the Principal Investigator will randomly select 3 participants and 
compare the data documented for each on the CRF with what is entered into the REDCap 
database. If there is any discrepancy, the Principal Investigator and/or Investigators will cross- 
reference all 12 patients to ensure accuracy. 
 
Data Clarification Process 
 
For any data query the Principal Investigator and Investigators will meet to clarify the data 
queried and make corrections based on consensus. 
 
9.4 
Records Retention 
 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study. These will include subject case histories and regulatory documents. 
 
The sponsor-investigator will retain the specified records and reports for; 
1. Up to 2 years after the marketing application is approved for the drug; or, if a marketing 
application is not submitted or approved for the drug, until 2 years after shipment and 
delivery of the drug for investigational use is discontinued and the FDA has been so 
notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual -"Retention of and Access to 
Research Data Policy"
 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
The investigator will allocate adequate time for such monitoring activities. The Investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access to 
all the study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
 
10.2 Auditing and Inspecting 
 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, and government regulatory agencies, of all study related documents (e.g. source 
documents, regulatory documents, data collection instruments, study data etc.). The investigator 
will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.). 

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Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
 
11 Ethical Considerations 
 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study. The decision of the IRB concerning the conduct of the study will be made in writing to  
the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study. The formal consent of a subject, using the Approved IRB consent form, must be 
obtained before that subject undergoes any study procedure. The consent form must be signed  
by the subject or the subject's legally authorized representative, and the individual obtaining the 
informed consent. This study will not include vulnerable study populations. 
 
12 Study Finances 
12.1 Funding Source 
 
This investigator initiated study is funded by a research grant from Regeneron Pharmaceuticals 
to Mayo Clinic. 
 
12.2 Conflict of Interest 
 
Any study team member who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) must 
have the conflict reviewed by a properly constituted Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 
study sponsor-investigator prior to participation in this study. 
 
No financial conflicts of interested are anticipated or have been identified for this study. 
 
12.3 Subject Stipends or Payments 

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Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
No payment is given to study participants. 
 
13 Publication Plan 
 
The primary responsibility for publication of the study results is with the Primary Investigator. 
After the complication of study and prior to publication, the study results will be shared with 
Regeneron Pharmaceuticals. The study will be registered at ClinicalTrials.gov prior to subject 
recruitment along with the posting of the results within 12 months of final data collection for the 
primary outcome measure. 
 
We anticipate the data collected in this study will result in a publishable manuscript and could 
also support a larger trial if the results are favorable to the proposed hypothesis. 
 
14 References 
 
1. Beck, L. A., et al. (2014). "Dupilumab treatment in adults with moderate-to-severe atopic 
dermatitis." N Engl J Med 371(2): 130-139. 
2. Oetjen, L. K., et al. (2017). "Sensory Neurons Co-opt Classical Immune Signaling 
Pathways to Mediate Chronic Itch." Cell 171(1): 217-228 e213. 
3. Wong, L. S., et al. (2017). "Inflammatory and Noninflammatory Itch: Implications in 
Pathophysiology-Directed Treatments." Int J Mol Sci 18(7). 
4. Ikoma, A., et al. (2003). "Neuronal sensitization for histamine-induced itch in lesional 
skin of patients with atopic dermatitis." Arch Dermatol 139(11): 1455-1458. 
5. Wang, H. and G. Yosipovitch (2010). "New insights into the pathophysiology and 
treatment of chronic itch in patients with end-stage renal disease, chronic liver disease, 
and lymphoma." Int J Dermatol 49(1): 1-11. 
6. Bhalerao, A. and G. S. Mannu (2015). "Management of pruritus in chronic liver disease." 
Dermatol Res Pract 2015: 295891. 
7. G. Yosipovitch (2017). "Validation of the peak pruritus numerical rating scale: Results 
from clinical studies of dupilumab in adult patients with moderate-to-severe atopic 
dermatitis." Journal of the American Academy of Dermatology 76(6): AB278. 
8. Kido-Nakahara, M., et al. (2015). "Comparative cut-off value setting of pruritus intensity 
in visual analogue scale and verbal rating scale." Acta Derm Venereol 95(3): 345-346. 
9. Phan, N. Q., et al. (2012). "Assessment of pruritus intensity: prospective study on validity 
and reliability of the visual analogue scale, numerical rating scale and verbal rating scale 
in 471 patients with chronic pruritus." Acta Derm Venereol 92(5): 502-507. 
10. Elman, S., et al. (2010). "The 5-D itch scale: a new measure of pruritus." Br J Dermatol 
162(3): 587-593. 
11. Orr, J. G., et al. (2014). "Health related quality of life in people with advanced chronic 
liver disease." J Hepatol 61(5): 1158-1165. 
12. Younossi, Z. M., et al. (1999). "Development of a disease specific questionnaire to 
measure health related quality of life in patients with chronic liver disease." Gut 45(2): 
295-300. 

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Jason C. Sluzevich, MD 
Andrew P. Keaveny, MD 
Ronald G. Racho, DO 
CONFIDENTIAL 
 
 
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