A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Dupilumab in Patients With Allergic Bronchopulmonary Aspergillosis
Phase: PHASE2
Conditions: Allergic Bronchopulmonary Aspergillosis
Sponsor: Regeneron Pharmaceuticals

Clinical Study Protocol 
R668-ABPA-1923 Amendment 4 
EudraCT: 2019-002619-24 
IND Number: 105,379 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-
GROUP STUDY TO EVALUATE THE EFFICACY AND SAFETY OF DUPILUMAB 
IN PATIENTS WITH ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS  
Compound: 
Dupilumab (REGN668) 
Study Name: 
Investigating Treatment with Dupilumab in 
Patients with ABPA (LIBERTY-ABPA 
AIRED) 
Clinical Phase: 
2 
Protocol Number: 
R668-ABPA-1923 
Protocol Version: 
R668-ABPA-1923 Amendment 4  
Amendment 4 Date of Issue 
See appended electronic signature page 
Amendment 3 Date of Issue: 
02 February 2023 
Amendment 2 Date of Issue: 
11 February 2021 
Amendment 1 Date of Issue: 
29 January 2020 
Original Date of Issue: 
03 December 2019 
Medical /Study Director: 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
Confidential: This submission contains confidential and proprietary commercial information 
and/or trade secrets which are subject to protection under laws and regulations worldwide 
including, but not limited to TRIPS Article 39 and regional, national, or state laws whether by 
legislation or in equity.  For the purposes of compliance with all applicable freedom of 
information laws, and regulations, and their equivalents anywhere in the world including but not 
limited to the US Freedom of Information Act 5 U.S.C. §552, Regeneron expects that, prior to 
disclosure to third parties of any information and/or data related to, or contained within, this 
VV-RIM-00295189-1.0 Approved - 24 Mar 2023 GMT-5:00
NCT04442269

Clinical Study Protocol  
R668-ABPA-1923 Amendment 4 
 
REGENERON CONFIDENTIAL 
Page 2 of 99 
submission, it will be given every opportunity under applicable laws to protect its commercial 
interests and/or its trade secrets including the opportunity to object to such disclosure and/or 
provide redaction proposals. 
AMENDMENT HISTORY 
Amendment 4 
The purpose of this amendment is to modify the study phase designation. 
Description of Change 
Rationale 
Section Changed 
The study phase has been 
changed from phase 4 to phase 2. 
 
 
Clinical Study Protocol Synopsis: 
Study Design 
Section 6.1 Study Description and 
Duration 
A minor editorial correction was 
made concerning matching visit 
number and study week. 
The correction was made to align with 
the schedule of events table.  
Section 9.1.1 Footnotes for the 
Schedule of Events Table 
Section 9.1.4 End of Treatment 
Visit 
 
Amendment 3 
The purpose of this protocol amendment is to modify the study phase, number of participants to 
be enrolled, study schedule, treatment period, and endpoints. These changes are due to difficulty 
reaching the study enrollment goal during the COVID-19 pandemic and the low prevalence of 
ABPA. The study has changed from phase 3 to phase 4, the primary and secondary endpoints 
have been changed, and the sample size has been reduced. The following table outlines the 
changes made to the protocol and the affected sections: 
Description of Change 
Rationale 
Section Changed 
The sample size has been reduced 
from 170 participants to 60 
participants, and the primary 
endpoint has been changed. 
New primary endpoint: “Change 
from baseline in pre-
bronchodilator FEV1 compared 
to placebo at week 24” 
Previous primary endpoint, which 
is now a secondary endpoint and 
no longer compared to placebo: 
“Annualized rate of severe 
The decision to stop enrollment was 
made because of difficulties enrolling 
participants due to the COVID-19 
pandemic and the low prevalence of 
ABPA. Nearly 60 patients had been 
enrolled when the decision to stop 
enrollment was made. 
A sample size of 60 participants has 
insufficient power to detect a 
difference in severe exacerbation rates 
between treatment and control groups 
but does have enough power to detect 
Clinical Study Protocol Synopsis: 
Population – Sample Size; 
Objectives; Endpoints – Primary; 
Statistical Plan 
Section 2.1 Primary Objective 
Section 2.2 Secondary Objectives 
Section 3.1 Hypothesis 
Section 4.1.1 Primary Endpoint 
Section 4.1.2 Secondary Endpoints 
Section 6.1 Study Description and 
Duration 
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Description of Change 
Rationale 
Section Changed 
respiratory exacerbations defined 
as new onset of symptoms or 
clinical worsening requiring 
systemic corticosteroid treatment 
for ≥3 days; for patients who are 
on maintenance daily systemic 
corticosteroids, at least doubling 
of the dose of systemic 
corticosteroids for ≥3 days (with 
or without antibiotic therapy if 
indicated) over the 52-week 
treatment period compared to 
placebo” 
a change from baseline in pre-
bronchodilator FEV1 after 24 weeks 
of treatment. 
Section 7.1 Number of Patients 
Planned 
Section 8.6 Method of Treatment 
Assignment 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of 
Sample Size 
Section 11.4.3 Primary Efficacy 
Analysis 
The secondary endpoint “change 
from baseline in pre-
bronchodilator FEV1 compared 
to placebo at week 52” has been 
removed, along with the 
corresponding secondary 
objective “to evaluate the effects 
of dupilumab on lung function in 
patients with ABPA.” 
The endpoint has been removed to 
avoid redundancy, as the exploratory 
endpoint “change from baseline in 
lung function parameters (pre-
bronchodilator FEV1, 
 
 
 from 
baseline to weeks 4, 8, 12, 24, 36, 44, 
and 52" will include the same data. 
Clinical Study Protocol Synopsis: 
Objectives; Endpoints – Secondary  
Section 2.2 Secondary Objectives 
Section 4.1.2 Secondary Endpoints 
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Description of Change 
Rationale 
Section Changed 
The study treatment period has 
been changed from 52 weeks to at 
least 24 and no more than 52 
weeks. 
Changes in lung function between 
treatment groups can be adequately 
assessed after 24 weeks of treatment; 
however, some study patients will 
have already received 52 weeks of 
treatment at the time this amendment 
is approved. 
Modification of the treatment period 
will result in all patients who complete 
the treatment period being treated for 
a minimum of 24 weeks and a 
maximum of 52 weeks. This change 
will shorten the time to study 
completion while allowing for 
collection of endpoint data to evaluate 
efficacy in patients with ABPA. 
Clinical Study Protocol Synopsis: 
Study Duration; Statistical Plan 
Section 3.2.1 Rationale for Study 
Design 
Section 4.1.3 Exploratory 
Endpoints 
Section 6.1 Study Description and 
Duration 
Figure 1 
Section 8.2 Background 
Treatments 
Table 1 
Section 9.1.1 Footnotes for Table 1 
Schedule of Events 
Section 9.1.2 Early Termination 
Visit 
Section 9.1.4 End of Treatment 
Visit 
Section 11.4.3 Primary Efficacy 
Analysis 
The caps for percentage of 
patients receiving chronic 
systemic corticosteroids and oral 
antifungals at baseline have been 
removed. 
By decreasing the sample size, the 
proportion of patients already enrolled 
who are on chronic systemic 
corticosteroids or oral antifungals has 
changed and the caps are no longer 
meaningful. 
Clinical Study Protocol Synopsis: 
Target Population – Inclusion 
Criteria 
Section 6.1 Study Description and 
Duration 
Section 7.2 Study Population 
Section 7.2.1 Inclusion Criteria: #4 
Section 8.2 Background Treatment 
Section 9.2.2.4 Patient-Reported 
Outcome Questionnaires 
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Description of Change 
Rationale 
Section Changed 
The study phase has been 
changed from phase 3 to phase 4. 
Dupixent has market authorization for 
the treatment of asthma, and all 
patients must have asthma in addition 
to ABPA to be eligible for study 
participation. ABPA is diagnosed by 
the ISHAM criteria, which for this 
study requires asthma in addition to 
evidence of immediate 
hypersensitivity to Aspergillus as well 
as other serologic and radiologic 
confirmation. 
Clinical Study Protocol Synopsis: 
Study Design 
Section 6.1 Study Description and 
Duration 
Secondary and exploratory 
endpoints will no longer be 
analyzed compared to placebo. 
The secondary and exploratory 
endpoints are underpowered for 
comparison to placebo as a result of 
the reduced sample size. 
Clinical Study Protocol Synopsis: 
Endpoints – Secondary; Statistical 
Plan 
Section 4.1.2 Secondary Endpoints 
Section 4.1.3 Exploratory 
Endpoints 
Section 11.4.3.2 Secondary 
Efficacy Analysis (this section has 
been removed in amendment 3) 
Section 11.4.4 Control of 
Multiplicity 
Language regarding the safety 
profile of dupilumab has been 
updated. 
New language was provided by 
Global Patient Safety to ensure the 
most up-to-date information is 
contained in the protocol. 
Section 3.3.1 Risk/Benefit for 
Dupilumab 
Minor clarifications and editorial 
corrections have been made. 
For clarification and completeness 
 
Throughout the document, 
including: 
Section 5.2 Efficacy Variables 
Section 7.2.2 Exclusion Criteria 
Section 9.2.2.4 Patient-Reported 
Outcome Questionnaires 
Section 11.4.5.1 Adverse Events 
Section 11.4.5.3 Treatment 
Exposure 
 
 
 
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Amendment 2 
The purpose of this protocol amendment is to update the inclusion and exclusion criteria to address 
 for patients on antifungal therapy and to allow a broader population to 
enroll that are still within the recognized International Society for Human and Animal Mycology 
(ISHAM) diagnostic criteria. Provisions were also added to protect patient safety and data integrity 
during the COVID-19 pandemic by allowing for certain study procedures to occur at delayed time 
points and/or outside of the clinic environment. Other changes were made for clarification and 
consistency. The following table outlines the changes made to the protocol and the rationale. 
Description of Change 
Rationale 
Section Changed 
Antifungal therapy related changes 
The inclusion and exclusion 
criteria were modified such that 
patients on antifungal therapy at 
screening may enroll in the study.  
Patients on oral antifungal 
therapy at baseline will be capped 
at 45% of the study population. 
Furthermore, randomization will 
now be stratified by oral 
antifungal use at screening 
(yes/no), in addition to the prior 
stratification criteria. The 
statistical analysis models for this 
study were updated accordingly. 
 
Clinical Study Protocol Synopsis: Target 
Population, Statistical Plan 
Section 4.1.3 Exploratory Endpoints 
Section 6.1 Study Description and Duration 
Section 7.2 Study Population 
Section 7.2.1 Inclusion Criteria: #7, #10 
Section 7.2.2 Exclusion Criteria: #4 
Section 8.2 Background Treatments 
Section 8.3 Rescue treatments 
Section 8.6 Method of Treatment 
Assignment 
Section 8.10.2 Permitted Medications 
Section 9.1.1.1 Footnotes for Table 1 
Schedule of Events: footnote a 
Section 11.2 Justification of Sample Size 
Section 11.4.3.1 Primary Efficacy Analyses 
Section 11.4.3.2 Secondary Efficacy 
Analyses 
Additional changes to inclusion and exclusion criteria 
The allergic bronchopulmonary 
aspergillosis (ABPA) diagnostic 
criteria were updated to include a 
broader range of eosinophil 
counts at screening. 
Additionally, the inclusion 
criteria were modified to permit a 
documented historical positive 
test result for the presence of 
serum precipitating or IgG 
antibodies to A fumigatus within 
12 months prior to screening. 
 
To provide flexibility to sites 
and reduce the screen failure 
rate by broadening the entry 
criteria related to ABPA 
while still adhering to the 
ISHAM 2013 diagnostic 
criteria for ABPA. 
 
Clinical Study Protocol Synopsis: Target 
Population 
Section 1 Introduction 
Section 6.1 Study Description and Duration 
Section 7.2.1 Inclusion Criteria: #2, #4, #5 
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Description of Change 
Rationale 
Section Changed 
Exclusion criteria were modified 
to allow patients to repeat an 
assessment during screening and 
to allow for re-screening if 
patients screen fail for a condition 
which may be transient in nature 
(eg, abnormal lab values).  
To provide flexibility to sites.  Section 7.2.2 Exclusion Criteria 
Section 9.1.1.1 Footnotes for Table 1 
Schedule of Events: footnote e 
The exclusion criterion for a 
positive respiratory culture for 
Pseudomonas or other multi-drug 
resistant bacteria was removed.  
 
To broaden the population of 
patients able to enroll in this 
study. Note that this change 
is not anticipated to impact 
efficacy or safety.  
Section 7.2.2 Exclusion Criteria: #8  
An exclusion criterion was added 
to exclude participants for 
country-specific exclusions. 
To ensure compliance with 
local country-specific 
regulations. 
Clinical Study Protocol Synopsis: Target 
Population 
Section 7.2.2 Exclusion Criteria: #42  
The exclusion criterion for 
treatment with a live vaccine was 
updated to be “4 weeks” prior to 
the baseline visit (rather than “12 
weeks”). 
To align with the dupilumab 
development program 
standard. 
Section 7.2.2 Exclusion Criteria: #27 
COVID-19 pandemic related changes 
The following changes were 
made for the COVID-19 
pandemic:  
• 
Added text to clarify general 
changes to study conduct in 
the context of the COVID-19 
pandemic. 
• 
Revised Schedule of Events 
(SOE) to reduce in-clinic 
visits and allow for study 
drug to be shipped to 
patients’ home. Removed 
sputum component of the 
optional immunophenotyping 
substudy. The exploratory 
endpoint examining sputum 
in this substudy was also 
removed. 
To reduce the burden on 
patients and to protect patient 
safety and data integrity in 
the context of the COVID-19 
pandemic.  
 
 
Clinical Study Protocol Synopsis: Site 
Location(s) 
Section 2.3 Exploratory Objectives 
Section 3.3 Risk/Benefit 
Section 4.1.3 Exploratory Endpoints 
Section 6.1 Study Description and Duration 
Section 7.2.1 Inclusion Criteria: #7 
Section 9.1 Schedule of Events 
Section 9.2.6.6 Blood Immunophenotyping 
Substudy (Optional) 
Table 1 Schedule of Events  
Section 9.1.1.1 Footnotes for Table 1 
Schedule of Events: footnote l, m, p, and y 
Section 11 Statistical Plan 
 
Other updates  
Primary estimands were added for 
key endpoints. 
To implement concept 
estimands in the primary and 
secondary analysis 
approaches for the key 
endpoints based on ICH E9 
(R1). 
Section 11.4.3.1 Primary Efficacy Analysis 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
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Description of Change 
Rationale 
Section Changed 
Conditions for not performing 
 
 were 
clarified (eg, recent chest CT scan 
consistent with the criteria 
described in the imaging manual 
of adequate quality as assessed by 
the central reader).  
 
 
 
 
To reduce the burden on 
patients as well as radiation 
exposure. 
Clinical Study Protocol Synopsis: 
Objective(s), Population, Endpoint(s) 
Section 2.2 Secondary Objectives 
Section 2.3 Exploratory Objectives 
Section 4.1.2 Secondary Endpoints 
Section 4.1.3 Exploratory Endpoints 
Section 7.2.1 Inclusion Criteria: #2 
Section 9.1.1.1 Footnotes for Table 1 
Schedule of Events: footnote j 
Section 9.2.2.4 Patient Reported Outcome 
Questionnaires  
An Asthma Control 
Questionnaire (ACQ-5) 
assessment was added to the SOE 
for visit 24 (week 44). 
To assess asthma control 
during the period of the study 
in which in-clinic visits were 
reduced for the COVID-19 
pandemic. 
Table 1 Schedule of Events  
Antineutrophil cytoplasmic 
antibodies (ANCA) testing was 
added to the SOE. 
To clarify that this testing 
should occur at screening. 
(ANCA was previously listed 
in the safety procedure 
section for laboratory testing 
at screening, but not in the 
SOE.) 
Table 1 Schedule of Events 
Minor clarifications and editorial 
corrections. 
For clarification.  
 
Throughout the document. 
 
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Amendment 1 
The following table outlines the changes made to the protocol and the affected sections: 
Change and Rationale for Change 
Section Changed 
Language was updated to remove specific mentions 
of the 2019 American Thoracic Society 
(ATS)/European Respiratory Society (ERS) 
spirometry guideline. Software that is compliant 
with the 2019 guideline has not been developed yet 
and is not expected to be available in the near future. 
Section 9.1.1.1 Table 1 Schedule of Events, 
footnote d 
Section 9.2.2.2 Lung Function 
Section 19 References 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibody 
ABPA 
Allergic bronchopulmonary aspergillosis 
ACQ 
Asthma Control Questionnaire 
AD 
Atopic dermatitis 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCA 
Antineutrophil cytoplasmic antibodies 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society  
BD 
Bronchodilator 
BUN 
Blood urea nitrogen 
CCL 
Chemokine (C-C motif) ligand  
COPD 
Chronic obstructive pulmonary disease 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CRSwNP 
Chronic rhinosinusitis with nasal polyps 
CSR 
Clinical study report 
CT 
Computed tomography 
DMC 
Data monitoring committee 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ED 
Emergency department 
EDC 
Electronic data capture 
EGPA 
Eosinophilic granulomatous with polyangiitis 
EMA 
European Medicines Agency 
EOE 
Eosinophilic esophagitis 
EOS 
End of study 
EOT 
End of treatment 
ERS 
European Respiratory Society 
EU 
European Union 
FAS 
Full analysis set 
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FDA 
Food and Drug Administration 
 
 
FeNO 
Fractional exhaled nitric oxide 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
 
 
GCP 
Good Clinical Practice 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLA 
Human leucocyte antigen 
HU 
Hounsfield units  
HRQoL 
Health-related quality of life 
 
 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICS 
Inhaled corticosteroids 
IDMC 
Independent data monitoring committee 
Ig 
Immunoglobulin  
IgE 
Immunoglobulin E 
IgG4 
Immunoglobulin G4 
IL 
Interleukin 
IL4Rα 
Interleukin-4 receptor alpha 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
ISHAM 
International Society for Human and Animal Mycology 
IVRS 
Interactive voice response system  
IWRS 
Interactive web response system  
LABA 
Long-acting beta agonist 
LAMA 
Long-acting muscarinic receptor antagonist 
LDH 
Lactate dehydrogenase 
LTRA 
Leukotriene receptor antagonist 
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MMRM 
Mixed-effects model with repeated measures 
MRI 
Magnetic resonance imaging 
NAb 
Neutralizing antibody 
OCS 
Oral corticosteroids 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
Q2W 
Every two weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SABA 
Short-acting bronchodilators 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SCIT 
Subcutaneous immunotherapy 
SGRQ 
St. George’s Respiratory Questionnaire 
SLIT 
Sublingual immunotherapy 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
 
 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................10 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................19 
1. 
INTRODUCTION ......................................................................................................25 
2. 
STUDY OBJECTIVES ..............................................................................................28 
2.1. 
Primary Objective .......................................................................................................28 
2.2. 
Secondary Objectives .................................................................................................28 
2.3. 
Exploratory Objectives ...............................................................................................28 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................30 
3.1. 
Hypotheses ..................................................................................................................30 
3.2. 
Rationale .....................................................................................................................30 
3.2.1. 
Rationale for Study Design .........................................................................................30 
3.2.2. 
Rationale for Dose Selection ......................................................................................31 
3.3. 
Risk/Benefit ................................................................................................................31 
3.3.1. 
Risk/Benefit for Dupilumab .......................................................................................31 
4. 
ENDPOINTS ..............................................................................................................33 
4.1. 
Primary and Secondary Endpoints..............................................................................33 
4.1.1. 
Primary Endpoint ........................................................................................................33 
4.1.2. 
Secondary Endpoints ..................................................................................................33 
4.1.3. 
Exploratory Endpoints ................................................................................................33 
5. 
STUDY VARIABLES................................................................................................35 
5.1. 
Demographic and Baseline Characteristics ................................................................35 
5.2. 
Efficacy Variables ......................................................................................................35 
5.3. 
Safety Variables ..........................................................................................................35 
5.4. 
Pharmacokinetic Variables .........................................................................................35 
5.5. 
Immunogenicity Variables ..........................................................................................35 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................35 
6. 
STUDY DESIGN .......................................................................................................36 
6.1. 
Study Description and Duration .................................................................................36 
6.1.1. 
End of Study Definition ..............................................................................................38 
6.2. 
Planned Interim Analysis ............................................................................................39 
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6.3. 
Study Committees .......................................................................................................39 
6.3.1. 
Independent Data Monitoring Committee ..................................................................39 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............40 
7.1. 
Number of Patients Planned .......................................................................................40 
7.2. 
Study Population .........................................................................................................40 
7.2.1. 
Inclusion Criteria ........................................................................................................40 
7.2.2. 
Exclusion Criteria .......................................................................................................42 
7.3. 
Premature Withdrawal from the Study .......................................................................46 
7.4. 
Replacement of Patients .............................................................................................47 
8. 
STUDY TREATMENTS............................................................................................48 
8.1. 
Investigational and Reference Treatments ..................................................................48 
8.2. 
Background Treatments ..............................................................................................48 
8.3. 
Rescue Treatments ......................................................................................................49 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................49 
8.4.1. 
Dose Modification ......................................................................................................49 
8.4.2. 
Study Drug Discontinuation .......................................................................................49 
8.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................49 
8.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................50 
8.5. 
Management of Acute Reactions ................................................................................51 
8.5.1. 
Systemic Injection Reactions ......................................................................................51 
8.6. 
Method of Treatment Assignment ..............................................................................51 
8.7. 
Blinding ......................................................................................................................51 
8.8. 
Emergency Unblinding ...............................................................................................52 
8.9. 
Treatment Logistics and Accountability .....................................................................52 
8.9.1. 
Packaging, Labeling, and Storage ..............................................................................52 
8.9.2. 
Supply and Disposition of Treatments .......................................................................52 
8.9.3. 
Treatment Accountability ...........................................................................................53 
8.9.4. 
Treatment Compliance ................................................................................................53 
8.10. 
Concomitant Medications and Procedures .................................................................53 
8.10.1. 
Prohibited Medications and Procedures .....................................................................53 
8.10.2. 
Permitted Medications ................................................................................................54 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................55 
9.1. 
Schedule of Events .....................................................................................................55 
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9.1.1. 
Footnotes for the Schedule of Events Table ...............................................................60 
9.1.2. 
Early Termination Visit ..............................................................................................62 
9.1.3. 
Unscheduled Visits .....................................................................................................63 
9.1.4. 
End of Treatment Visit ...............................................................................................63 
9.2. 
Study Procedures ........................................................................................................63 
9.2.1. 
Procedures Performed at the Screening/Baseline Visit ..............................................63 
9.2.2. 
Efficacy Procedures ....................................................................................................63 
9.2.2.1. 
Severity of Respiratory Exacerbations .......................................................................63 
9.2.2.2. 
Lung Function .............................................................................................................63 
9.2.2.3. 
Allergic Bronchopulmonary Aspergillosis-Related Exacerbations ............................64 
9.2.2.4. 
Patient-Reported Outcome Questionnaires .................................................................65 
9.2.3. 
Safety Procedures .......................................................................................................67 
9.2.3.1. 
Vital Signs ..................................................................................................................67 
9.2.3.2. 
Physical Examination .................................................................................................67 
9.2.3.3. 
Electrocardiogram .......................................................................................................67 
9.2.3.4. 
Laboratory Testing ......................................................................................................67 
9.2.4. 
Drug Concentration and Measurements .....................................................................68 
9.2.5. 
Immunogenicity Measurements and Samples ............................................................68 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................69 
9.2.6.1. 
Fractional Exhaled Nitric Oxide .................................................................................69 
9.2.6.2. 
Serum Total IgE ..........................................................................................................69 
9.2.6.3. 
Serum A Fumigatus-Specific IgE ...............................................................................69 
9.2.6.4. 
 ........................................................................................................70 
9.2.6.5. 
 ...............................70 
9.2.6.6. 
Blood Immunophenotypying Substudy (Optional) ....................................................70 
9.2.7. 
Future Biomedical Research (Optional) .....................................................................70 
9.2.7.1. 
Pharmacogenomic Analysis (Optional) ......................................................................71 
10. 
SAFETY EVALUATION AND REPORTING .........................................................72 
10.1. 
Recording and Reporting Adverse Events ..................................................................72 
10.1.1. 
General Guidelines .....................................................................................................72 
10.1.2. 
Reporting Procedure ...................................................................................................73 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................73 
10.2. 
Definitions ..................................................................................................................74 
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10.2.1. 
Adverse Event .............................................................................................................74 
10.2.2. 
Serious Adverse Event ................................................................................................74 
10.2.3. 
Adverse Events of Special Interest .............................................................................74 
10.2.4. 
Severity .......................................................................................................................75 
10.2.5. 
Causality .....................................................................................................................75 
10.3. 
Safety Monitoring .......................................................................................................76 
10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics Committee, 
and Investigators .........................................................................................................77 
11. 
STATISTICAL PLAN................................................................................................78 
11.1. 
Statistical Hypothesis ..................................................................................................78 
11.2. 
Justification of Sample Size........................................................................................78 
11.3. 
Analysis Sets ...............................................................................................................78 
11.3.1. 
Efficacy Analysis Sets ................................................................................................78 
11.3.2. 
Safety Analysis Set .....................................................................................................79 
11.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................79 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................79 
11.4. 
Statistical Methods ......................................................................................................79 
11.4.1. 
Patient Disposition ......................................................................................................79 
11.4.2. 
Demography and Baseline Characteristics .................................................................79 
11.4.3. 
Primary Efficacy Analysis ..........................................................................................80 
11.4.4. 
Control of Multiplicity ................................................................................................81 
11.4.5. 
Safety Analysis ...........................................................................................................81 
11.4.5.1. 
Adverse Events ...........................................................................................................81 
11.4.5.2. 
Other Safety ................................................................................................................82 
11.4.5.3. 
Treatment Exposure ....................................................................................................82 
11.4.5.4. 
Treatment Compliance ................................................................................................82 
11.4.5.5. 
Analysis of Drug Concentration Data .........................................................................83 
11.4.6. 
Analysis of Immunogenicity Data ..............................................................................83 
11.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................83 
11.5. 
Statistical Considerations Surrounding the Premature Termination of a Study .........84 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................85 
12.1. 
Data Management and Electronic Systems ................................................................85 
12.1.1. 
Data Management .......................................................................................................85 
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12.1.2. 
Electronic Systems ......................................................................................................85 
12.2. 
Study Monitoring ........................................................................................................85 
12.2.1. 
Monitoring of Study Sites ...........................................................................................85 
12.2.2. 
Source Document Requirements ................................................................................86 
12.2.3. 
Case Report Form Requirements ................................................................................86 
12.3. 
Audits and Inspections ................................................................................................86 
12.4. 
Study Documentation .................................................................................................87 
12.4.1. 
Certification of Accuracy of Data ...............................................................................87 
12.4.2. 
Retention of Records ..................................................................................................87 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................88 
13.1. 
Good Clinical Practice Statement ...............................................................................88 
13.2. 
Informed Consent .......................................................................................................88 
13.3. 
Patients Confidentiality and Data Protection ..............................................................89 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................89 
13.5. 
Clinical Study Data Transparency ..............................................................................90 
14. 
PROTOCOL AMENDMENTS ..................................................................................91 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................92 
15.1. 
Premature Termination of the Study ...........................................................................92 
15.2. 
Close-out of a Site ......................................................................................................92 
16. 
CONFIDENTIALITY ................................................................................................92 
17. 
FINANCING AND INSURANCE .............................................................................92 
18. 
PUBLICATION POLICY ..........................................................................................92 
19. 
REFERENCES ...........................................................................................................93 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................96 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................99 
 
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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................56 
Table 2: 
 
 
 ............................................................................................................97 
Table 3: 
 
 
 .........................................................................................................98 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................38 
 
LIST OF APPENDICES 
APPENDIX A. ORAL CORTICOSTEROIDS (OCS) DOSE REDUCTION 
SCHEDULE DURING THE RANDOMIZED TREATMENT 
PERIOD FOR PATIENTS WHO ENTER THE STUDY ON OCS AT 
BASELINE ........................................................................................................97 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Efficacy and Safety of Dupilumab in Patients with Allergic 
Bronchopulmonary Aspergillosis  
Site Location(s) 
 
Principal Investigator 
Approximately 80 to 100 sites are planned, in the United States (US), European 
Union (EU), and other world regions. 
(PI TBD) 
Objective(s) 
The primary objective of the study is to evaluate the efficacy of dupilumab on  
lung function in patients with allergic bronchopulmonary aspergillosis 
(ABPA).  
The secondary objectives of the study are: 
• 
To evaluate the effects of dupilumab on exacerbations in patients with 
ABPA  
• 
To evaluate the effects of dupilumab on ABPA-related exacerbations 
• 
To evaluate the effects of dupilumab on hospitalization/emergency 
department (ED)/urgent care visits in patients with ABPA 
• 
To evaluate the effects of dupilumab on asthma control in patients 
with ABPA   
• 
To evaluate the effects of dupilumab on health-related quality of life 
(HRQoL) in patients with ABPA  
• 
To evaluate the effects of dupilumab on serum total IgE and 
Aspergillus-specific IgE concentrations 
• 
To evaluate the effects of dupilumab on fractional exhaled nitric oxide 
(FeNO) levels  
• 
To evaluate safety and tolerability of dupilumab in patients with 
ABPA 
• 
To evaluate dupilumab concentrations in serum and the incidence of 
anti-dupilumab antibodies in patients with ABPA 
Study Design 
Phase 2, global, multicenter, randomized, double-blind, placebo-controlled, 
parallel group study to evaluate efficacy and safety of dupilumab in patients 
with ABPA. The 3 study periods include a screening period, a randomized 
treatment period, and a post-treatment follow-up period. Patients will be 
randomized 1:1 to receive either dupilumab 300 mg given subcutaneously (SC) 
after a loading dose of 600 mg, or matching placebo given SC every 2 weeks 
(Q2W). 
Study Duration 
The study duration is 36–64 weeks, excluding the 4-week screening period. 
The randomized treatment period is 24–52 weeks, with all patients being 
treated for a minimum of 24 weeks and a maximum of 52 weeks. The post-
treatment follow-up period is 12 weeks. 
End of Study Definition 
The end of study is defined as the date the last patient completes the last study 
visit, withdraws from the study, or is lost to follow-up (ie, the study patient can 
no longer be contacted by the investigator).  
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Population 
 
 
Sample Size: 
Approximately 60 patients will be enrolled. 
 
Target Population: 
Adults and adolescents (≥12 years of age) with ABPA who meet modified 
International Society for Human and Animal Mycology (ISHAM) working 
group 2013 criteria for ABPA. 
Main inclusion criteria 
• 
Males and females ≥12 years of age at screening  
• 
Diagnosis of ABPA defined by the following criteria at screening: 
Obligatory criteria at screening (must meet all 3 criteria): 
o 
Physician diagnosis of asthma for at least 12 months based 
on the Global Initiative for Asthma (GINA) 2019 guidelines 
o 
Evidence of sensitization to Aspergillus fumigatus by skin 
testing (at screening or documented historical positive skin 
test in the previous 12 months), or elevated A 
fumigatus-specific IgE in serum (≥0.35 kU/L) at screening 
o 
Elevated serum total IgE > 1000 IU/mL. If all 3 supportive 
criteria for ABPA (below) are met, IgE ≤1000 IU/mL is 
acceptable. If the patient is receiving oral corticosteroids 
(OCS) at screening, a documented historical IgE >1000 
IU/mL within the previous 12 months is acceptable 
And 2 or more of the following supportive criteria 
o 
For patients on OCS, blood eosinophil count >500 cells/µL 
at screening or a documented historical blood eosinophil 
count >500 cells/µL within 12 months of screening. For 
patients not on OCS, blood eosinophil count >500 cells/µL 
at screening or blood eosinophil ≥300 to ≤500 cells/µL at 
screening with a documented historical blood eosinophil 
count >500 cells/µL within 12 months of screening. 
o 
The presence of serum precipitating or IgG antibodies to 
A fumigatus at screening or a documented historical positive 
test result within 12 months prior to screening. 
o 
Documented radiological findings consistent with ABPA 
(such as fleeting pulmonary parenchymal opacities, mucoid 
impaction, high-attenuation mucus, centrilobular nodular 
opacities, atelectasis, bronchiectasis, etc) by historical chest 
x-ray or chest computed tomography (CT) or magnetic 
resonance imaging (MRI) within the previous 18 months or 
at screening 
• 
On a maintenance therapy for their asthma with controller medication 
which must include inhaled corticosteroids (ICS) and may include 1 
or more additional controller medications including a long-acting beta 
agonist (LABA), leukotriene receptor antagonist (LTRA), and/or 
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long-acting muscarinic receptor antagonist (LAMA), etc for at least 
12 weeks, with a stable dose and regimen with no change in the dose 
or frequency of administration for at least 4 weeks prior to the 
screening 
visit, 
and 
between 
the 
screening 
and 
baseline/randomization visits 
• 
For patients on OCS:  must be on a chronic stable dose (no change in 
the dose) of OCS of up to 10 mg/day (for patients taking daily 
corticosteroids) or up to 30 mg every alternate day (for patients taking 
alternate day corticosteroids) of OCS (prednisone/prednisolone or the 
equivalent) for at least 4 weeks prior to the screening visit and 
between the screening and the baseline/randomization visit. In 
addition, patients must agree to switch to study-required 
prednisone/prednisolone as their OCS at visit 1 and use it per protocol 
for the duration of the study. 
• 
Must have experienced ≥1 severe respiratory exacerbation requiring 
treatment with systemic corticosteroids or hospitalization or treatment 
in ED/urgent care within 12 months prior to the screening visit, or 
must be receiving chronic stable low-dose OCS  
• 
ACQ-5 score of ≥1.5 at screening and at baseline visit 
• 
For patients receiving oral antifungals at baseline: must be on a stable 
dose and regimen of a single antifungal medication for at least 4 
weeks prior to screening and between the screening and baseline visit.  
Main exclusion criteria 
• 
Weight less than 30.0 kilograms 
• 
Current smoker or e-cigarette user, or cessation of smoking or e-
cigarette use within 6 months prior to randomization, or > 10 pack-
years smoking history 
• 
Post-bronchodilator forced expiratory volume in 1 second (FEV1) < 
30% predicted normal at screening  
• 
For those receiving OCS at baseline: Considered to be at high risk for 
adverse events due to tapering of OCS, in the opinion of the 
investigator 
• 
Respiratory exacerbation requiring systemic corticosteroids within 
4 weeks prior to screening and between screening and baseline visit 
(for patients on daily or alternate day OCS, exacerbation requiring at 
least double the maintenance dose of corticosteroids) 
• 
Upper or lower respiratory tract infection within the 4 weeks prior to 
screening (visit 1) or between the screening and randomization visits 
• 
Significant chronic pulmonary disease other than asthma with ABPA 
(eg, physician-diagnosed bronchiectasis due to a condition other than 
ABPA ; cystic fibrosis; sarcoidosis; interstitial lung disease not due to 
ABPA; chronic obstructive pulmonary disease [COPD] not due to 
ABPA; hypereosinophilic syndrome; etc) or a diagnosed pulmonary 
or systemic disease associated with elevated peripheral eosinophil 
counts 
• 
Diagnosis or suspected diagnosis of eosinophilic granulomatous with 
polyangiitis (EGPA) also called Churg-Strauss Syndrome 
• 
Diagnosis of aspergilloma, invasive or disseminated aspergillosis, or 
chronic pulmonary aspergillosis 
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• 
Any country-specific regulation that would prevent the participant 
from entering the study 
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Dupilumab, as 150 mg/mL solution for SC injection. 
Loading dose of 600 mg on day 1, followed by 300 mg SC, Q2W. 
 
Placebo 
 
Route/Schedule: 
Placebo, matching dupilumab formulation without addition of protein. 
Administered SC, Q2W 
Endpoint(s) 
 
 
Primary: 
The primary endpoint is the change from baseline in pre-bronchodilator forced 
expiratory volume in one second (FEV1) compared to placebo at week 24. 
 
Secondary: 
1. Annualized rate of severe respiratory exacerbations, defined as new onset 
of symptoms or clinical worsening of respiratory symptoms requiring 
systemic corticosteroid treatment for ≥3 consecutive days; for patients who 
are on maintenance systemic corticosteroids, at least double the dose of 
maintenance systemic corticosteroids for ≥3 consecutive days (with or 
without antibiotic therapy if indicated) over the 24–52-week treatment 
period 
2. Annualized rate of ABPA-related exacerbations, defined as severe 
respiratory exacerbations (as defined above) that are associated with a 
doubling of serum total IgE from the prior pre-exacerbation value, over the 
24–52-week treatment period 
3. Annualized rate of severe respiratory exacerbations requiring either 
hospitalization or observation for >24 hours in an ED/urgent care facility 
during the 24–52-week treatment period 
4. Change from baseline in Asthma Control Questionnaire (ACQ-5) over the 
24–52-week treatment period  
5. Change from baseline in St. George’s Respiratory Questionnaire (SGRQ) 
total score over the 24–52-week treatment period  
6. Percentage of participants achieving a reduction in the SGRQ score of 
4 points or greater from baseline to weeks 12, 24, 36, and 52 
7. Percent change from baseline in total IgE in serum over the 24–52-week 
treatment period  
8. Percent change from baseline in A fumigatus-specific IgE in serum over the 
24–52-week treatment period  
9. Percent and absolute change from baseline in fractional exhaled nitric 
oxide (FeNO) over the 24–52-week treatment period 
10. Incidence of treatment-emergent adverse events (TEAEs) from baseline 
through the end of treatment (week 24–52)  
11. Immunogenicity of dupilumab, as determined by the incidence, titer, and 
clinical impact of treatment-emergent ADA to dupilumab over time 
12. Concentrations of functional dupilumab in serum by treatment regimen at 
each assessment time point from baseline to the end of study  
Procedures and Assessments 
Efficacy procedures and assessments include:  the number of severe respiratory 
exacerbations over the treatment period and clinical signs and symptoms of 
respiratory exacerbation; assessment of lung function parameters, using 
spirometry, such as FEV1, 
 
 number of ABPA-related exacerbations (ie, those 
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associated with a doubling of serum IgE compared to the pre-exacerbation 
level) over the treatment period; number of severe respiratory exacerbations 
that are associated with hospitalization, ED, or urgent care visits; 
 
; patient-reported outcome questionnaires 
(SGRQ, ACQ-5); systemic corticosteroid use; oral antifungal use and 
 
 
Safety 
procedures 
include: 
vital 
signs; 
physical 
examination; 
electrocardiogram; laboratory testing.  
Samples will be collected for trough dupilumab concentrations, anti-drug 
antibody (ADA) and neutralizing antibody (NAb) assessment, and 
pharmacodynamic/biomarker assessments. Fractional exhaled nitric oxide, 
serum IgE, A fumigatus-specific IgE, 
 
 will be measured. 
A subset of study sites may be selected to perform evaluations of circulating 
immune cells before and after dupilumab treatment. 
Participation in future biomedical research and pharmacogenomic analysis will 
be optional.  
Statistical Plan 
The power calculation for this study is based on a comparison between 
dupilumab 300 mg Q2W and placebo with regard to the primary endpoint of 
the absolute change from baseline in pre-bronchodilator FEV1 at week 24. 
Assuming a randomization ratio of 1:1, a standard deviation (SD) for the 
change from baseline in pre-bronchodilator FEV1 at week 24 of 
 in 
both groups, a 2-sided Type 1 error of 0.05, and a dropout rate of 
by week 
24, with approximately 60 randomized patients (~30 patients per group), the 
study will have approximately 96% power to detect a difference of 
 in 
the change from baseline in pre-bronchodilator FEV1 at week 24 between the 
dupilumab and placebo groups, based on the 2-sample t-test. 
 
 
 
 
For the primary analysis, the absolute change from baseline in pre-
bronchodilator FEV1 at week 24 will be analyzed using a mixed-effects model 
with repeated measures (MMRM) approach. The vector of responses will 
consist of the absolute change from baseline in pre-bronchodilator FEV1 at 
weeks 2, 4, 8, 12, and 24. For patients who discontinue study treatment prior 
to week 24, any off-study treatment pre-bronchodilator FEV1 values collected 
after the discontinuation of study treatment through week 24 will be included 
in the analysis. The MMRM model will include OCS use at screening, OAF 
use at screening, region, age, sex, height, baseline eosinophil count, treatment, 
visit, treatment-by-visit interaction, baseline pre-bronchodilator FEV1 value, 
and baseline pre-bronchodilator FEV1 value-by-visit interaction as covariates. 
An unstructured covariance matrix will be used to model the correlations 
between repeated measurements. Parameters will be estimated using the 
restricted maximum likelihood (REML) method and the Newton-Raphson 
algorithm. Statistical inference for the treatment comparison of the absolute 
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change from baseline in pre-bronchodilator FEV1 at week 24 will be derived 
from the MMRM model using the Kenward Roger method for calculation of 
the denominator degrees of freedom for the tests of the fixed effects. If the 
model does not converge, alternative model specifications (eg, a different 
covariance structure or reduction in the number of covariates) will be applied; 
details will be provided in the SAP. 
For safety analysis, the summary of safety results will be presented by 
treatment group. All safety analyses will be performed on the safety analysis 
set (SAF). 
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1. 
INTRODUCTION 
Allergic bronchopulmonary aspergillosis (ABPA) is a progressive, immunologic lung disease 
caused by hypersensitivity to the fungus Aspergillus fumigatus (A fumigatus) that occurs in patients 
with asthma or cystic fibrosis (Agarwal, 2014). The prevalence of ABPA is estimated to be 1% to 
3% in patients with severe asthma referred for specialty care (Eaton, 2000) (Kurup, 2009). 
Clinically, asthma patients with ABPA have a more severe clinical course with poorly controlled 
asthma, poor response to treatment, and frequent episodes of exacerbations compared to patients 
with asthma who do not have ABPA. In addition, ABPA is often associated with thick mucoid 
secretions that can lead to obstruction of large and small airways, bronchiectasis (which does not 
otherwise occur in asthma), and lung function impairment beyond that seen in a typical asthma 
patient. A staging system is described for patients with asthma and ABPA to monitor disease 
progression clinically. Depending on the stage of the disease, clinical features in ABPA vary from 
mild asthma with occasional episodes of wheezing and cough, to patients with fibrosis, honeycomb 
lung, and respiratory failure (Patterson, 1982). Stage I is the initial acute stage of ABPA 
manifesting clinically with productive cough, wheeze, shortness of breath, fever, malaise, pleuritic 
chest pain, elevated serum immunoglobulin E (IgE), peripheral and tissue eosinophilia, and 
fleeting pulmonary infiltrates on imaging studies. In stage II, the disease goes into remission for a 
variable period; symptoms are reduced, the lung infiltrates clear, and the serum IgE value declines. 
Stage III is characterized by respiratory exacerbations with the recurrence of symptoms, 
production of thick sputum plugs, and an increase in serum total IgE levels that occur in up to 
24% to 50% of patients each year (Agarwal, 2016) (Muthu, 2019). During episodes of 
exacerbations, thick brown mucoid sputum may contain A fumigatus hyphae. Stage IV is reached 
when, despite treatment, the disease progresses to extensive mucoid impaction of airways visible 
on chest x-ray or computed tomography (CT) imaging, lung function decline, and corticosteroid 
dependence. Stage V is the fibrotic stage. Unlike asthma, which does not progress to fibrotic lung 
disease, if the diagnosis is delayed or the disease is undertreated, ABPA progresses to a fibrotic 
end-stage lung disease that can lead to pulmonary hypertension, cor pulmonale, and respiratory 
failure.  
The diagnosis of ABPA is based on clinical, serological, and radiological criteria. Diagnostic 
criteria for ABPA have evolved over the past several decades with an increased understanding of 
the disease, recognition of “severe asthma with fungal sensitization” as a distinct clinical entity, 
and improvement in serological testing. Diagnostic criteria for ABPA, modified in 2013 by the 
International Society for Human and Animal Mycology (ISHAM) Working Group, are widely 
used clinically, wherein the items are broadly divided into ‘obligatory’ and other supportive 
criteria (Agarwal, 2013). The obligatory diagnostic criteria include the presence of a predisposing 
condition (asthma or cystic fibrosis), elevated serum total IgE >1000 IU/mL, and evidence of 
sensitization to A fumigatus (either a positive immediate hypersensitivity skin test or elevated 
serum-specific IgE to A fumigatus). Supportive criteria for the diagnosis include 2 of the 
following 3 criteria: 1) eosinophilia >500 cells/µL in steroid naïve patients (may be historical); 2) 
serum precipitating or IgG antibodies to A fumigatus; and 3) radiographic findings consistent with 
ABPA.  
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Approximately 20% to 30% of asthma patients are sensitized to A fumigatus (Eaton, 2000) 
(Schwartz, 1978); however, only a small minority of these patients develop ABPA. In individuals 
who develop ABPA, exposure to fungal antigens results in immune deviation toward a robust 
type 2 inflammatory response with release of type 2 cytokines (eg, interleukin 4 or IL-4, IL-5, 
IL-9, IL-13); activation of mast cells, eosinophils, and basophils; and isotype switching of 
lymphocytes to IgE-producing B lymphocytes and plasma cells (Knutsen, 2011) (Chauhan, 2000). 
Ultimately, this florid type 2 inflammatory response is deleterious, resulting in mucoid impaction 
of bronchi, bronchiectasis, eosinophilic inflammation, bronchocentric granulomatosis, and 
exudative or obliterative bronchiolitis. This type 2-skewed immune response is thought to be 
related to genetically determined risk factors. Human leucocyte antigen (HLA) haplotypes 
(HLA‑DRB1*1501 and HLA‑DRB1*1503) are associated with a high risk of developing ABPA 
and promote exaggerated type 2 immune responses with continued synthesis of IgE upon exposure 
to A fumigatus antigens (Chauhan, 2000). Conversely, HLA‑DQ2 (HLA‑DQB1*0201 in 
particular) is associated with a lower risk of ABPA (Chauhan, 2000). There are increasing numbers 
of reports of single nucleotide polymorphisms in host response genes (eg, polymorphisms in IL4R, 
IL13, IL10, TLR3, EEA1) found in ABPA patients, suggesting a panoply of underlying 
abnormalities in both adaptive and innate immunity (Knutsen, 2006a) (Overton, 2018) 
(Overton, 2016). Gain-of-function variants in IL4R are prevalent in atopic disease and lead to 
exaggerated synthesis of IgE antibodies and increases in the number of tissue mast cells 
(Hershey, 1997). Of note, a gain-of-function mutation in the extracellular coding region of IL4R 
(ile75val) was present in 80% of the ABPA patients in 1 study (Knutsen, 2006b). Studies have 
shown that B cells from patients with ABPA have higher sensitivity to IL‑4 and spontaneously 
produce larger amounts of IgE, IgG, and IgA antibodies against A fumigatus antigens 
(Hershey, 1997) (Knutsen, 1990).  
The current mainstay of treatment for ABPA is administration of systemic corticosteroids, with 
many patients becoming corticosteroid-dependent to control the disease. However, not all patients 
respond to systemic corticosteroids. Long-term use of systemic corticosteroids is not 
recommended due to the lack of evidence supporting prevention of progressive bronchial 
destruction and the potential for serious side effects associated with chronic use. 
ABPA-complicating asthma does not respond clinically to conventional asthma therapy including 
high doses of inhaled corticosteroids (ICS). Various antifungal agents (eg, itraconazole, 
voriconazole, ketoconazole, amphotericin B) are used as adjunctive treatments for ABPA in 
patients who respond poorly to corticosteroids in an effort to reduce the fungal antigenic stimulus 
(Agbetile, 2014) (Stevens, 2000) (Agarwal, 2018). However, clinical response to antifungals is 
variable, antifungal therapy is not curative, and the side effects of antifungals - which include 
nausea, vomiting, diarrhea, fever, rash, headache, and hepatotoxicity  ̶ limit their use. Long-term 
studies to evaluate the effect of treatment with these agents to modify the progressive decline in 
lung function in ABPA are lacking.  
One prior clinical trial of omalizumab (an anti-IgE monoclonal antibody) has been published 
(Voskamp, 2015). In this randomized crossover trial of 13 patients with ABPA and asthma, 
4 months of omalizumab was associated with a reduced rate of exacerbation. The efficacy and 
safety of biologics that target eosinophilic or type 2 inflammation have not been established in 
ABPA. No biologic has been approved for the treatment of ABPA by either the Food and Drug 
Administration (FDA) or European Medicines Agency (EMA). 
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Thus, there is an unmet need for more effective and safe treatments that target the immunological 
underpinnings of ABPA to prevent irreversible airway and parenchymal disease, improve clinical 
symptoms, and obviate the need for systemic corticosteroids with their accompanying safety 
concerns. 
Dupilumab is a human monoclonal IgG4 antibody that inhibits IL-4 and IL-13 signaling by 
specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. 
Dupilumab inhibits IL-4 signaling via the type I receptor and both IL-4 and IL-13 signaling 
through the type II receptor. Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13, key 
cytokines that drive the type 2 inflammatory response, including the release of proinflammatory 
cytokines, chemokines, nitric oxide, and IgE. Dupilumab, therefore, may have the potential to treat 
ABPA, a disease driven by type 2 inflammation. 
Dupilumab (brand name DUPIXENT®) has been approved as an add-on maintenance treatment in 
patients with moderate to severe asthma aged 6 years and older with an eosinophilic phenotype or 
with oral corticosteroid (OCS)-dependent asthma in the United States (US), and in the European 
Union (EU) for severe asthma with type 2 inflammation characterized by raised blood eosinophils, 
and/or raised fractional exhaled nitric oxide (FeNO) in patients who are inadequately controlled 
with high-dose ICS plus another medicinal product for maintenance treatment. In Japan, 
dupilumab has been approved for patients aged ≥12 years with severe or refractory asthma whose 
symptoms are inadequately controlled with existing therapy. Additionally, dupilumab has been 
approved in over 50 countries for the treatment of patients aged ≥6 years with inadequately 
controlled moderate-to-severe atopic dermatitis (AD) or with severe AD who are candidates for 
systemic therapy. In the US, dupilumab is approved for use in pediatric patients aged ≥6 months. 
Dupilumab is also approved in the US and EU in adult patients with chronic rhinosinusitis with 
nasal polyposis (CRSwNP), and in the US in adult patients with prurigo nodularis and patients ≥12 
years (and ≥40 kg) with eosinophilic esophagitis.  
This study is designed to provide evidence of the efficacy and safety of dupilumab in patients with 
ABPA who remain uncontrolled despite ICS.  
Additional background information on the study drug and dupilumab development program can 
be found in the Investigator’s Brochure (IB). 
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2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of dupilumab on lung function in 
patients with ABPA. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the effects of dupilumab on exacerbations in patients with ABPA  
• To evaluate the effects of dupilumab on ABPA-related exacerbations 
• To evaluate the effects of dupilumab on hospitalization/emergency department 
(ED)/urgent care visits in patients with ABPA 
• To evaluate the effects of dupilumab on asthma control in patients with ABPA 
• To evaluate the effects of dupilumab on health-related quality of life (HRQoL) in 
patients with ABPA  
• To evaluate the effects of dupilumab on serum total IgE and Aspergillus-specific IgE 
concentrations  
• To evaluate the effects of dupilumab on FeNO levels  
• To evaluate safety and tolerability of dupilumab in patients with ABPA 
• To evaluate dupilumab concentrations in serum and the incidence of anti-dupilumab 
antibodies in patients with ABPA  
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
Treatment with dupilumab will be efficacious in improving lung function and will be well tolerated 
in adult and adolescent patients ≥12 years of age with ABPA compared to treatment with placebo. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This study is designed to investigate the efficacy and safety of dupilumab in patients with ABPA.  
A double-blinded, randomized trial design is chosen to minimize bias in data collection and result 
interpretation. The presence of a placebo arm is appropriate for the objectives of this study as this 
will allow for the most robust assessment of the efficacy and safety of dupilumab. Although 
dupilumab has been shown to be efficacious and safe to treat patients with moderate-to-severe 
asthma, neither the safety nor the efficacy of dupilumab for ABPA in patients who have asthma 
has been established. In contrast to asthma, ABPA is characterized by irreversible airway damage 
and parenchymal involvement, thus the known efficacy of dupilumab on key asthma outcomes 
cannot be easily extrapolated to ABPA. In addition, all patients will be allowed to receive rescue 
treatment with systemic corticosteroids (standard of care) and antifungal therapy (widely though 
not universally used) as necessary and will be closely monitored throughout the study. The 
proposed treatment duration of at least 24 and no more than 52 weeks provides an opportunity to 
assess the impact of dupilumab on multiple clinical outcome measures of ABPA including long-
term changes in lung function; symptom control; rate of severe respiratory exacerbations; 
; and pharmacodynamic (PD) effects on biomarkers of type 2 inflammation 
in ABPA, including serum total and A fumigatus-specific IgE levels. Patients will be treated for a 
minimum of 24 weeks and a maximum of 52 weeks. Details on the variable treatment period can 
be found in Section 9.1.1. 
A 12-week post-treatment safety follow-up period is chosen based on the time expected for 
dupilumab drug levels to reach below the lower limit of quantification after the last dose of the 
drug.  
The  primary endpoint is the absolute change from baseline in pre-bronchodilator forced expiratory 
volume in 1 second (FEV1) at week 24, as this is a well-accepted parameter to determine the effect 
of a drug on lung function. Lung function testing is useful in evaluating the progression of ABPA 
since decreased lung function is frequently associated with the disease. In a survey of 126 patients 
with ABPA, 85.7% had abnormal lung function (Agarwal, 2006). Secondary endpoints include:  
annualized rate of severe respiratory exacerbations; ABPA-related exacerbations (in which serum 
IgE doubles compared to the closest pre-exacerbation value); St. George’s Respiratory 
Questionnaire (SGRQ), a widely used, validated questionnaire to assess the impact of the drug on 
HRQoL measures in chronic respiratory diseases; and the Asthma Control Questionnaire (ACQ-
5), a validated measure of asthma control. Systemic drug concentration/anti-drug antibodies 
(ADA) and biomarkers (serum total IgE, A fumigatus-specific IgE, 
 have been used previously in the 
dupilumab program to evaluate the exposure/effect relationship and will help to better understand 
the mechanism of action of dupilumab and IL-4 receptor pathway in patients with ABPA. 
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3.2.2. 
Rationale for Dose Selection 
The proposed dose for this study is dupilumab 300 mg administered subcutaneously (SC) every 
two weeks (Q2W) with a 600 mg loading dose for the first dose. This dose has proven to be 
effective and to have an acceptable safety profile in adult and adolescent patients with 
moderate-to-severe asthma. In addition, dupilumab 300 mg every two weeks (Q2W) has shown a 
significant 
 while significantly reducing exacerbations and improving lung 
function in a population of corticosteroid-dependent patients with severe asthma. This dose 
regimen is approved in the treatment of patients with corticosteroid-dependent asthma. Severity of 
asthma in ABPA is generally greater than in asthma patients without ABPA, and many ABPA 
patients require treatment with chronic systemic corticosteroids. Therefore, to achieve the optimal 
benefit-risk ratio in patients with ABPA, dupilumab 300 mg Q2W dosing regimen is selected for 
this study. 
3.3. 
Risk/Benefit 
Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on 
the conduct of clinical trials, the sponsor does not intend to screen any new patients in this study 
unless the impact of the COVID-19 pandemic is deemed manageable and no longer interfering 
with the conduct of trials at individual sites, and patients can safely participate in this study. The 
sponsor plans to obtain approvals from health authorities/ethics committees to enable continuation 
of study sites for this study, as allowed by local laws and regulations. 
3.3.1. 
Risk/Benefit for Dupilumab 
Dupilumab has shown clinically relevant benefit in several type 2-mediated immune disorders 
including AD, bronchial asthma, CRSwNP, and eosinophilic esophagitis (EoE).  
In adults and adolescents with moderate-to-severe uncontrolled asthma, dupilumab significantly 
reduced the risk of severe exacerbations compared to placebo and consistently improved lung 
function (FEV1), asthma control, and HRQoL in patients with a type 2 inflammatory signature as 
evidenced by a blood eosinophil count of ≥150 cells/µL or a fractional exhaled nitric oxide 
concentration of ≥25 parts per billion (ppb). In OCS-dependent patients with severe asthma, 
dupilumab significantly reduced the need for OCS by ~70% while at the same time reducing 
asthma exacerbations and improving FEV1 compared to placebo.  
Type 2 inflammation plays a critical role in the pathogenesis of ABPA. The hypothesis that 
blocking key mediators of type 2 inflammation will lead to clinical benefit in patients with ABPA 
is supported by a post-hoc subgroup analysis from the completed dupilumab phase 3 pivotal study 
EFC13579 (QUEST) in patients with moderate-to-severe asthma who met the suggested criteria 
for ABPA diagnosis at baseline. The results from a total of 30 patients (n=18 in the combined 
dupilumab group and 12 in the combined placebo group) provide compelling clinical evidence for 
the efficacy of dupilumab in patients with ABPA. Dupilumab treatment compared to placebo 
showed an approximately 80% reduction in annualized severe exacerbation events and a 0.26L 
improvement in change from baseline to week 24 in pre-bronchodilator (BD) FEV1. In clinical 
practice, serum total IgE, which is elevated in patients with ABPA, is monitored to assess ABPA 
disease activity. Dupilumab suppressed serum total IgE by approximately 70% from baseline over 
a 52-week treatment period. Overall, dupilumab was well tolerated in this subgroup of patients 
with ABPA. 
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For dupilumab, the safety data observed so far in completed and currently ongoing studies have 
demonstrated a satisfactory safety profile. As of 28 March 2022 (data lock point of last PBRER), 
approximately 13,577 subjects were enrolled into the development program for dupilumab and are 
included in the safety population:  564 as healthy volunteers, 4998 from atopic dermatitis studies, 
4195 from asthma studies, 880 from rhinosinusitis studies, 468 from eosinophilic esophagitis 
studies, 275 from allergy studies, 1495 from chronic obstructive pulmonary disease studies, 309 
from prurigo nodularis studies, 311 from urticaria studies, 45 from bullous pemphigoid study, and 
37 from an allergic bronchopulmonary aspergillosis study. 
Dupilumab has demonstrated a favorable safety profile in clinical studies across all approved 
indications. The identified adverse drug reactions (ADRs) observed across all indications are 
Injection Site Reactions (ISRs), Sickness-like reaction/Serum Sickness and anaphylactic reaction. 
Though serious serum sickness and serum sickness-like reactions were observed rarely and only 
in AD clinical trials, and dupilumab-related anaphylactic reaction was observed rarely and only in 
an asthma clinical trial, they are considered ADRs across all indications as hypersensitivity is not 
expected to be indication specific. As protein therapeutics, all monoclonal antibodies are 
potentially immunogenic. Systemic hypersensitivity is considered an important identified risk for 
dupilumab. 
Eosinophilia associated with clinical symptoms in asthma patients is an important potential risk, 
based on cases of eosinophilic granulomatosis with polyangiitis and eosinophilic pneumonia 
reported in asthma clinical trials (as well as in adult patients with co-morbid asthma in the 
CRSwNP development program). These events may usually, but not always, be associated with 
the reduction of oral corticosteroid therapy. A causal association between dupilumab and these 
conditions has not been established In the AD clinical studies, Conjunctivitis, Conjunctivitis 
Allergic, Conjunctivitis Bacterial, Blepharitis, Dry Eye, Eye Pruritus, Herpes Simplex (primarily 
mucocutaneous in nature), Eosinophilia and Oral Herpes were identified ADRs. The eye and 
herpes related ADRs appear to be predominantly AD indication specific. Conjunctivitis is also 
considered an ADR for the CRSwNP indication, although it occurred at a lower incidence in these 
studies than in AD studies. Most events were mild in intensity, transient in nature, and did not 
necessitate treatment discontinuation. Conjunctivitis and keratitis related events in AD patients are 
an important identified risk for dupilumab. In the completed AD studies in children 6 to 17 years 
of age, the safety profile was consistent with that reported in adults and there were no new safety 
concerns identified. In a study in participants aged 6 to 11 years with asthma, Enterobiasis and 
Eosinophilia were identified as additional ADRs. Angioedema, Arthralgia, Keratitis, Ulcerative 
Keratitis, and Facial Rash have been identified as ADRs in the post marketing setting. The program 
has a data monitoring committee (DMC), which will review the benefit/risk on a regular basis. A 
complete efficacy and safety profile of dupilumab, with respect to the overall development 
program, is provided in the Investigator’s Brochure.  
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4. 
ENDPOINTS  
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Endpoint 
The primary endpoint of the study is the change from baseline in pre-bronchodilator FEV1 
compared to placebo at week 24. 
4.1.2. 
Secondary Endpoints 
The secondary endpoints are: 
1. Annualized rate of severe respiratory exacerbations, defined as new onset of symptoms or 
clinical worsening of respiratory symptoms requiring systemic corticosteroid treatment 
for ≥3 consecutive days; for patients who are on maintenance systemic corticosteroids, at 
least double the dose of maintenance systemic corticosteroids for ≥3 consecutive days 
(with or without antibiotic therapy if indicated) over the 24- to 52-week treatment period 
2. Annualized rate of ABPA-related exacerbations, defined as severe respiratory 
exacerbations (as defined above) that are associated with a doubling of serum total IgE 
from the prior pre-exacerbation value, over the 24- to 52-week treatment period 
3. Annualized rate of severe respiratory exacerbations requiring either hospitalization or 
observation for >24 hours in an ED/urgent care facility during the 24- to 52-week 
treatment period 
4. Change from baseline in ACQ-5 over the 24- to 52-week treatment period  
5. Change from baseline in SGRQ total score over the 24- to 52-week treatment period  
6. Percentage of participants achieving a reduction in the SGRQ score of 4 points or greater 
from baseline to weeks 12, 24, 36, and 52 
7. Percent change from baseline in total IgE in serum over the 24- to 52-week treatment 
period  
8. Percent change from baseline in A fumigatus-specific IgE in serum over the 24- to 52-
week treatment period  
9. Percent and absolute change from baseline in FeNO over the 24- to 52-week treatment 
period 
10. Incidence of treatment-emergent adverse events (TEAEs) from baseline through the end 
of treatment (week 24 to 52)  
11. Immunogenicity of dupilumab, as determined by the incidence, titer, and clinical impact 
of treatment-emergent ADA to dupilumab over time 
12. Concentrations of functional dupilumab in serum by treatment regimen at each 
assessment time point from baseline to the end of study  
4.1.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
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5. 
STUDY VARIABLES  
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc.), 
disease characteristics, medical/surgical history, medication history, smoking history, spirometry 
and FEV1 reversibility, hepatitis and human immunodeficiency virus (HIV) serology, serum 
pregnancy test for women of childbearing potential (WOCBP), blood eosinophil count, total serum 
IgE, A fumigatus skin testing, serum A fumigatus-specific IgE, serum A fumigatus-specific IgG, 
Aspergillus serum precipitins, and radiological assessment with findings consistent with ABPA. 
5.2. 
Efficacy Variables 
The efficacy variables include counts or measurements for individual patients of the following:  
number of severe respiratory exacerbations over the treatment period, pre- and post-bronchodilator 
FEV1, 
, number of severe respiratory exacerbations over the treatment 
period that are associated with doubling of serum total IgE from the prior pre-exacerbation value, 
number of severe respiratory exacerbations that are associated with hospitalization, ED or urgent 
care visits, assessments of systemic corticosteroid use, 
 
 
. Patient-reported outcome measures to assess HRQoL 
and asthma control include SGRQ total score and ACQ-5 score.  
5.3. 
Safety Variables 
The safety variables include vital signs, physical examination, electrocardiograms (ECGs), 
laboratory evaluations (hematology, chemistry, and urinalysis), urine pregnancy test (females), 
and adverse events (AEs).  
5.4. 
Pharmacokinetic Variables 
Concentrations of functional dupilumab in serum at each time point will be considered to be trough 
values (Ctrough time point). These sampling time points are specified in Table 1. 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, neutralizing antibody (NAb) status, and 
time point/visit. Samples in this study will be collected at the clinic visits specified in Table 1. 
5.6. 
Pharmacodynamic and Other Biomarker Variables 
The pharmacodynamic and biomarker variables are:  
• FeNO 
• Total IgE in serum 
• A fumigatus-specific IgE in serum 
• 
 
• 
 
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This phase 2, global, multicenter, randomized, double-blind, placebo-controlled study of 
dupilumab is designed to evaluate the efficacy and safety of dupilumab in patients with ABPA. 
Approximately 60 patients will be enrolled in the study. The study consists of 3 study periods: 
• Screening period (4 weeks) 
• Randomized treatment period (24- to 52 weeks) 
• Post-treatment follow-up period (12 weeks) 
This study employs a variable treatment duration from 24- to 52 weeks. Patients enrolled in the 
trial will remain in the treatment period for up to a maximum of 52 weeks or until the last patient 
completes a minimum treatment period of 24 weeks. Of note, the accrual and drop-out rates will 
be closely monitored. The maximum treatment duration of 52 weeks will not be changed. For 
further explanation regarding the duration of the randomized treatment period, refer to 
Section 9.1.1. 
Patients who meet the eligibility criteria will be randomized (1:1) to 1 of the following treatment 
groups: 
• Dupilumab 300 mg, after a loading dose of 600 mg on day 1, administered SC Q2W 
• Matching placebo, administered SC Q2W 
Randomization will be stratified by region (pooled country), chronic systemic corticosteroid use 
(yes/no) at screening, and by oral antifungal use (yes/no) at screening. 
Rescue courses of systemic steroids for exacerbations, as determined by the investigators, will be 
permitted during the study. Patients will be required to continue all background asthma controller 
medications (ICS) with or without long-acting beta agonist (LABA), leukotriene receptor 
antagonist (LTRA), or long-acting muscarinic receptor antagonist (LAMA) without any changes 
in the dose or regimen during the study period. However, if 2 or more exacerbations occur during 
the treatment period, changes to background therapy (eg, changes to background asthma controller 
medication or initiation of antifungal therapy) may be made at the investigator’s discretion. 
Patients on Chronic Oral Corticosteroids at Baseline: 
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Patients who experience a severe respiratory exacerbation will have, as soon as possible, an 
unscheduled visit at the site for the collection of a blood sample for serum total IgE measurement. 
Patients who withdraw from the study prematurely will have, at the time of their next regularly 
scheduled visit, an early termination visit. This early termination visit will consist of all 
assessments normally planned for the end of study (EOS) visit. To allow assessment of patient 
outcomes over the stipulated study period, patients who discontinue study treatment but continue 
in the study will be asked and encouraged to complete all remaining study visits and participate in 
all safety follow-up assessments according to the visit schedule (Table 1). 
Patients on Oral Antifungals:  
For patients receiving oral antifungal therapy during the 24- to 52-week treatment period, the dose 
and regimen of the oral antifungal agent should remain stable until the end of the treatment period. 
However, antifungal discontinuation or modification to the dose or regimen is permitted for the 
following reasons: side effects, intolerance, or lack of efficacy (eg, acute exacerbation) as 
determined by the investigator. Initiation of therapy with oral antifungal agents is permitted if 2 or 
more exacerbations occur during the course of the study. 
Blood Immunophenotyping Substudy (Optional): 
A blood phenotypic substudy may be performed at selected sites. Only patients who are not on 
chronic systemic steroids and not on antifungal therapy at baseline and provide a separate written 
informed consent will be eligible to participate in the blood immunophenotyping substudy. A 
blood sample will be collected at time points outlined in the Schedule of Events Table 1. Blood 
may be immunophenotyped and sorted using flow cytometry or other methods and characterized 
using RNA sequencing or other methods to quantitate mRNA. 
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Post-Treatment Follow-Up Period:  
Upon completing the randomized treatment period, patients will continue their background therapy 
and enter a 12-week safety follow-up period. Adjustment of background asthma and ABPA 
medications will be allowed at the discretion of the investigator as clinically indicated during the 
post-treatment follow-up period. 
Figure 1: 
Study Flow Diagram 
 
Note: Upon implementation of amendment 3, the treatment period for all participants will be a minimum of 24 
weeks and a maximum of 52 weeks. The week of EOT and EOS will vary accordingly. 
NOTE: If there are restrictions to the clinical study as a result of the COVID-19 pandemic, it may 
be necessary to adjust the visit schedule, convert in-person visits to telephone contacts, and 
postpone study procedures until the next available study visit. It is necessary that the randomization 
visit (V2) occur in the clinic. All temporary mechanisms utilized, and deviations from planned 
study procedures in response to COVID-19 are to be documented as being related to COVID-19 
and will remain in effect only for the duration of the public health emergency. Once local 
COVID-19 conditions resolve, all study visits and procedures should follow the schedule of events 
as specified in the Schedule of Events (Table 1). 
6.1.1. 
End of Study Definition 
The end of study is defined as the date the last patient completes the last study visit, withdraws 
from the study, or is lost to follow-up (ie, the study patient can no longer be contacted by the 
investigator).  
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6.2. 
Planned Interim Analysis  
No interim analysis is planned. 
6.3. 
Study Committees  
6.3.1. 
Independent Data Monitoring Committee 
An independent data monitoring committee (IDMC), composed of members who are independent 
from the sponsor and the investigators, will monitor patient safety by conducting formal periodic 
reviews of cumulative or periodic safety data that will be blinded by treatment group. The IDMC 
may request and be provided the unblinded safety data, or any other requested data, for the 
purposes of a risk/benefit assessment.  
The IDMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the patients enrolled in the study. The IDMC 
will also recommend any measures that may be required for ensuring the integrity of the study 
results during the study execution. 
All activities and responsibilities of the IDMC are described in the IDMC charter. 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Approximately 60 patients (approximately 30 patients per arm) will be enrolled globally. 
7.2. 
Study Population 
This study will enroll ABPA patients who meet modified ISHAM working group 2013 criteria for 
ABPA (Agarwal, 2013). These diagnostic criteria for ABPA are widely accepted clinically and 
broadly divided into ‘obligatory’ and ‘other’ supportive criteria (Agarwal, 2013). 
The overall goals of treatment of ABPA include reduction of symptoms of ABPA, reducing 
pulmonary inflammation, and treatment of exacerbations to prevent progression of lung disease. 
Systemic corticosteroids have been the mainstay of treatment for ABPA, but toxicities limit their 
use. Approximately 25% to 35% of ABPA patients remain on long-term systemic steroids 
(corticosteroid-dependent). Patients on chronic systemic corticosteroids with a stable dose of up 
to 10 mg/day of prednisolone (or its equivalent) or up to 30 mg of prednisolone (or its equivalent) 
every other day will be allowed to participate in the study to evaluate treatment effects in patients 
with greater disease severity. Antifungal agents, especially triazoles, are prescribed as an adjuvant 
therapy in some cases. However, antifungal agents are not curative, their effects on preventing 
exacerbations are variable, and some of the benefits associated with triazoles may be related to 
impairment of the metabolism of exogeneous corticosteroids by these agents rather than a direct 
antifungal effect. Therefore, to minimize confounding effects of these agents, randomization will 
be stratified by the use of oral antifungal agents (yes/no) at screening. 
Rescue courses of systemic steroids for exacerbations, as determined by the investigators, will be 
permitted during the study. However, to minimize confounding effects of changes in background 
asthma therapies on the outcome measures, changes to background asthma controller therapy 
(other than OCS use as described above) will not be permitted unless the patient has had 2 or more 
severe exacerbations during the treatment period. Once 2 or more severe exacerbations have 
occurred during the treatment period, changes to background asthma controller therapy may be 
made at the investigator’s discretion.  
Patients with post-bronchodilator airflow obstruction (
) will be permitted 
to enroll, since mucus plugging and bronchiectasis may limit bronchodilator reversibility. 
However, patients with severely reduced lung function (
 will not 
be permitted to participate. 
7.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Males and females ≥12 years of age at screening 
2. Diagnosis of ABPA defined by the following criteria at screening: 
Obligatory criteria at screening (must meet all 3 of the following criteria): 
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a. Physician diagnosis of asthma for at least 12 months based on the Global Initiative for 
Asthma (GINA) 2019 guidelines 
b. Evidence of sensitization to A fumigatus by skin testing (at screening or documented 
historical positive skin test in the previous 12 months), or elevated A fumigatus-specific 
IgE in serum (≥0.35 kU/L) at screening 
c. Elevated serum total IgE >1000 IU/mL. If all 3 supportive criteria for ABPA (below) 
are met, IgE ≤1000 IU/mL is acceptable. If the patient is receiving OCS at screening, 
a documented historical IgE > 1000 IU/mL within the previous 12 months is acceptable 
And 2 or more of the following supportive criteria: 
a. For patients on OCS, blood eosinophil count >500 cells/µL at screening or a 
documented historical blood eosinophil count >500 cells/µL within 12 months of 
screening. For patients not on OCS, blood eosinophil count >500 cells/µL at 
screening or blood eosinophil ≥300 to ≤500 cells/µL at screening with a documented 
historical blood eosinophil count >500 cells/µL within 12 months of screening. 
b. The presence of serum precipitating or IgG antibodies to A fumigatus at screening or a 
documented historical positive result for one of these tests within 12 months prior to 
screening 
c. Documented radiological findings consistent with ABPA (such as fleeting pulmonary 
parenchymal opacities, mucoid impaction, high-attenuation mucus, centrilobular 
nodular opacities, atelectasis, bronchiectasis, etc) by historical chest x-ray or chest 
computed tomography (CT) or magnetic resonance imaging (MRI) within the previous 
18 months or at screening 
NOTE: A total of 2 attempts may be made during the screening period until the 
baseline visit to meet the qualifying criteria for blood eosinophils, total serum IgE, 
Aspergillus-specific IgE, Aspergillus-specific IgG, Aspergillus precipitins, and/or 
skin prick test 
3. On a maintenance therapy for their asthma with controller medication which must include 
ICS and may include 1 or more additional controller medications including a LABA, 
LTRA, and/or LAMA, etc for at least 12 weeks, with a stable dose and regimen with no 
change in the dose or frequency of administration for at least 4 weeks prior to the screening 
visit, and between the screening and baseline/randomization visits 
4. For patients on OCS:  must be on a chronic stable dose (no change in the dose) of OCS of 
up to 10 mg/day (for patients taking daily corticosteroids) or up to 30 mg every alternate 
day (for patients taking alternate day corticosteroids) (prednisone/prednisolone or the 
equivalent) for at least 4 weeks prior to the screening visit and between the screening and 
the baseline/randomization visit. In addition, patients must agree to switch to 
study-required prednisone/prednisolone as their OCS at visit 1 and use it per protocol for 
the duration of the study. 
5. Must have experienced ≥1 severe respiratory exacerbation requiring treatment with 
systemic corticosteroids or hospitalization or treatment in ED/urgent care within 12 months 
prior to the screening visit, or must be receiving chronic stable low-dose OCS (see 
inclusion criterion #4) 
6. ACQ-5 score of ≥1.5 at screening and at baseline visit 
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7. For those participating in the blood immunophenotyping substudy, must not have received 
systemic corticosteroids or oral antifungals from 4 weeks prior to screening through 
randomization 
8. Willing and able to comply with clinic visits and study-related procedures 
9. Able to provide signed informed consent/assent (by study patient or legally acceptable 
representative). For adolescents, parent or legal guardian must provide signed informed 
consent (patients must also provide separate informed assent to enroll in the study, and the 
assent documented either in a separate informed assent form or in the informed consent 
form [ICF] signed by the parent(s)/legal guardian(s) [as appropriate based on local 
regulations and requirements]) 
10. For patients receiving oral antifungals at baseline: must be on a stable dose and regimen of 
antifungal agent for at least 4 weeks prior to screening and between the screening and 
baseline visit. 
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Weight less than 30.0 kilograms 
2. Current smoker or e-cigarette user, cessation of smoking or e-cigarette use within 6 months 
prior to randomization, or ≥10 pack-years smoking history   
3. Post-bronchodilator FEV1 <30% predicted normal at screening 
4. (Exclusion criterion #4 was removed in Protocol Amendment 2) 
5. For those receiving OCS at baseline: considered to be at high risk for adverse events due 
to tapering of OCS, in the opinion of the investigator 
6. Respiratory exacerbation requiring systemic corticosteroids within 4 weeks prior to 
screening and between screening and baseline visit (for patients on daily or alternate day 
OCS, exacerbation requiring at least double the maintenance dose of corticosteroids) 
7. Upper or lower respiratory tract infection within the 4 weeks prior to screening (visit 1) or 
between the screening and randomization visits  
8. Significant chronic pulmonary disease other than asthma complicated with ABPA (eg, 
physician-diagnosed bronchiectasis due to a condition other than ABPA; cystic fibrosis; 
sarcoidosis; interstitial lung disease not due to ABPA; chronic obstructive pulmonary 
disease [COPD] not due to ABPA; hypereosinophilic syndrome; etc), a diagnosed 
pulmonary or systemic disease associated with elevated peripheral eosinophil counts 
9. Diagnosis or suspected diagnosis of EGPA (also called Churg-Strauss Syndrome) 
10. Diagnosis of aspergilloma, invasive or disseminated aspergillosis, or chronic pulmonary 
aspergillosis  
11. Severe cor pulmonale with evidence of right cardiac failure 
12. Treatment with supplemental oxygen for >8 hours/day 
13. Hypercapnia requiring non-invasive ventilation (eg, bilevel positive pressure ventilation) 
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14. Patients with a history of clinically significant renal, hepatic, cardiovascular, metabolic, 
neurologic, hematologic, ophthalmologic, respiratory (other than asthma and ABPA), 
gastrointestinal, cerebrovascular, or other significant medical illness or disorder which, in 
the judgment of the investigator, could interfere with the study or require treatment that 
might interfere with the study. Specific examples include but are not limited to 
uncontrolled diabetes, severe uncontrolled hypertension, severe ischemic heart disease, 
unstable angina in the last 6 months, uncontrolled Class III or IV cardiac failure according 
to the New York Heart Association classification, unstable cardiac arrhythmias, 
hepatobiliary conditions (e.g., Child-Pugh class B or C), demyelinating diseases, active 
major autoimmune diseases (eg, lupus, inflammatory bowel disease, rheumatoid arthritis, 
etc)  
15. Acute myocardial infarction <6 months from screening visit 
16. Hospitalization for any cardiovascular or cerebrovascular event <6 months from the 
screening visit 
17. Known or suspected history of immunosuppression or immunodeficiency disorder 
including a history of invasive opportunistic infections (eg histoplasmosis, listeriosis, 
coccidioidomycosis, pneumocystis), despite infection resolution; or unusually frequent, 
recurrent, or prolonged infections, suggesting an immune-compromised status, as judged 
by the investigator 
18. Patients with active autoimmune disease or patients using immunosuppressive therapy for 
autoimmune disease (eg rheumatoid arthritis, inflammatory bowel disease, primary biliary 
cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc) or patients with high titer 
autoantibodies at screening who are considered by the investigator or the sponsor of having 
high risk for developing autoimmune disease  
19. History of malignancy within 5 years before the screening visit, except completely treated 
in situ carcinoma of the cervix or completely treated and resolved non-metastatic squamous 
or basal cell carcinoma of the skin 
20. Previous use of dupilumab 
21. Initiation, discontinuation, or change in the dosage regimen of SC immunotherapy (SCIT) 
within 3 months prior to visit 1 
a. Patients on a stable dose of these medications for at least 1 year prior to visit 1 may be 
included in the study, but must not change the dose during the study 
22. Treatment with sublingual immunotherapy (SLIT) 
23. Patients who have received or initiated bronchial thermoplasty within 3 years prior to 
visit 1 or plan to begin therapy during the screening period or the randomized treatment 
period 
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24. Anti-IgE therapy (eg omalizumab [Xolair®]) within 130 days prior to visit 1 or any other 
biologic therapy (including anti-IL5, anti-IL5R, anti-IL4rα, anti-IL13 monoclonal 
antibodies) or systemic immunosuppressant (eg methotrexate, any anti-TNF drugs, Janus 
kinase inhibitors, B and/or T cell-targeted immunosuppressive therapies) to treat 
inflammatory disease or autoimmune disease (eg rheumatoid arthritis, inflammatory bowel 
disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis) and 
other diseases, within 3 months or 5 half-lives prior to screening, whichever is longer 
25. Exposure to another investigational drug (monoclonal antibodies as well as small 
molecules) within a period prior to screening, as follows:  an interval of less than 6 months 
or at least 5 half-lives for investigational monoclonal antibodies, and an interval of less 
than 30 days for investigational small molecules 
26. History of systemic hypersensitivity or anaphylaxis to any biologic therapy, including any 
excipients, or a contraindication to treatment with dupilumab per the approved local 
prescribing information 
27. Treatment with a live (attenuated) vaccine within 4 weeks prior to the baseline visit or 
planned live attenuated vaccinations during the study 
28. Patients with active tuberculosis or non-tuberculous mycobacterial infection, latent 
untreated tuberculosis, or a history of incompletely treated tuberculosis will be excluded 
from the study unless it is well documented by a specialist that the patient has been 
adequately treated and can now start treatment with a biologic agent in the medical 
judgment of the investigator and/or infectious disease specialist. (Tuberculosis testing will 
be performed on a country-by-country basis according to local guidelines if required by 
regulatory authorities or ethics committees [ECs].) 
29. Diagnosed active parasitic infection (helminths), suspected or high risk of parasitic 
infection, unless clinical and (if necessary) laboratory assessments have ruled out active 
infection before randomization 
30. HIV by clinical or serological history 
31. Established diagnosis of hepatitis B viral infection at the time of screening or positive for 
hepatitis B surface antigen (HBsAg) at the time of screening: 
a. Patients who have gained immunity for hepatitis B virus infection after vaccination 
(patients who are HBsAg-negative, hepatitis B surface antibody [HBsAb]-positive, and 
hepatitis B core antibody [HBcAb]-negative are eligible for the study) 
b. Patients with positive HBcAb are eligible for the study only if hepatitis B virus DNA 
level is undetectable. 
32. Established diagnosis of hepatitis C viral (HCV) infection at the time of screening. Patients 
positive for hepatitis C Ab are eligible for the study only if HCV RNA is negative 
33. Liver injury-related criteria: 
a. Clinically significant/active hepatobiliary disease or evidence of liver disease as 
indicated by persistent (confirmed by repeated tests ≥2 weeks apart) elevated 
transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase 
[AST] more than 3 times the upper limit of normal [ULN] during the screening period) 
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34. Any of the following abnormal lab values at screening: 
a. Creatine phosphokinase (CPK) >10 ULN or 
b. Platelets <100,000 cells/mm3  
NOTE:  If an abnormal value is detected at screening, a repeat test should be performed to 
confirm the abnormality. Only if the repeat test confirms the abnormality would the patient 
be categorized as a screen failure. 
35. Known or suspected alcohol and/or drug abuse within 2 years before the screening visit, or 
evidence of such abuse as documented by a positive result in a laboratory test for alcohol 
and/or drug panel conducted at the screening visit  
NOTE:  If a patient has a positive drug test for a prescription drug being used for medical 
reasons, the patient would still be eligible for enrollment. In such cases, the site would need 
to confirm the medical reason for use with the treating physician. 
36. Any other medical or psychological condition including relevant laboratory abnormalities 
at screening that, in the opinion of the investigator, suggest a new and/or insufficiently 
understood disease, may present an unreasonable risk to the study patient as a result of 
his/her participation in this clinical trial, may make patient’s participation unreliable, or 
may interfere with study assessments. The specific justification for patients excluded under 
this criterion will be noted in study documents 
37. Inability to follow instructions or complete study-related procedures (eg due to language 
problems or psychological disorders) 
38. Individuals accommodated in an institution by virtue of an order issued either by the 
judicial or the administrative authorities; prisoners or patients who are legally 
institutionalized 
39. Patient or his/her immediate family is a member of the dupilumab investigational team  
40. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed 
during the study 
41. WOCBP* who are unwilling to practice highly effective contraception prior to the initial 
dose/start of the first treatment, during the study, and for at least 12 weeks after the last 
dose. Highly effective contraceptive measures include:  
a. stable use of combined (estrogen- and progestogen-containing) hormonal contraception 
(oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of ovulation initiated 2 or more 
menstrual cycles prior to screening 
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS) 
c. bilateral tubal ligation 
d. vasectomized partner (provided that the partner is the sole sexual partner of the 
WOCBP patient and that the vasectomized partner has received medical assessment of 
the surgical success for the procedure) 
e. and/or sexual abstinence†, ‡ 
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*Women of childbearing potential are defined as women who are fertile, following 
menarche until becoming postmenopausal, unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of 
a postmenopausal state. The above definitions are according to Clinical Trial Facilitation 
Group (CTFG) guidance. 
Pregnancy testing and contraception are not required for women with documented 
hysterectomy or tubal ligation. 
† Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient. 
‡ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception. Female condom and male condom should not be 
used together. 
42. Any country-specific regulation that would prevent the participant from entering the study 
NOTE: Patients who do not meet the inclusion criteria or fail the exclusion criteria (eg due to 
a transient reason) may be rescreened once, after consultation with the medical monitor. 
Rescreened patients will be assigned a new patient ID versus the one received for the initial 
screening. There is no requirement for a waiting period between the screen-failure date and the 
rescreening. 
7.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures). An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 9.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.4.2. 
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7.4. 
Replacement of Patients 
Patients prematurely discontinued from study/study drug will not be replaced. 
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8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
Dupilumab drug product is supplied for this study in the following concentration: 
• Dupilumab 150 mg/mL:  Each 2.0 mL single-use prefilled glass syringe with snap-off 
cap delivers 300 mg of study drug (2.0 mL of a 150 mg/mL solution) 
• Placebo-matching dupilumab is prepared in the same formulation without the addition 
of protein (ie active substance, anti-IL-4Rα monoclonal Ab). 
Study drug will be administered by SC injections. Subcutaneous injection sites of study drug 
should be alternated among the different quadrants of the abdomen (avoiding navel and waist 
areas), upper thighs, and upper arms so that the same site is not injected for 2 consecutive 
administrations. 
Dupilumab will be administered as a 600 mg loading dose on day 1, followed by 300 mg 
administered SC Q2W. 
Matching placebo will be administered SC Q2W. 
Instructions on dose preparation are provided in the pharmacy manual. 
8.2. 
Background Treatments 
Prior to screening, patients must be on a stable background therapy for asthma for at least 3 months 
with a stable dose ≥1 month, and all background therapy must remain stable between screening 
and baseline. Asthma controller medications must include ICS and may include 1 or more 
additional controller medications (eg, LABA, LTRA, LAMA). Patients requiring a third controller 
are allowed to participate in this study. The third controller should also be used for at least 3 months 
with a stable dose ≥1 month prior to screening and between screening and baseline.  
Patients requiring systemic corticosteroids (prednisone or equivalent) up to 10 mg per day, or up 
to 30 mg every other day, for ABPA are also permitted. Oral corticosteroid doses will be down-
titrated starting 4 weeks after randomization according to the schedule described in Appendix A. 
Patients receiving oral antifungal therapy at baseline are permitted to enroll. For patients receiving 
antifungal therapy during the 24- to 52-week treatment period, the dose and regimen should remain 
stable until the end of the treatment period. However, antifungal discontinuation or modification 
to the dose or regimen is permitted for the following reasons: side effects, intolerance, or lack of 
efficacy (eg, acute exacerbation) as determined by the investigator.  
Patients will be required to continue all background asthma controller medications (ICS) with or 
without long-acting beta agonist (LABA), leukotriene receptor antagonist (LTRA), or long-acting 
muscarinic receptor antagonist (LAMA) without any changes in the dose or regimen during the 
study period. However, if 2 or more exacerbations occur during the treatment period, changes to 
background therapy (eg, changes to background asthma controller medication or initiation of 
antifungal therapy) may be made at the investigator’s discretion. 
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8.3. 
Rescue Treatments 
Short-acting bronchodilators (SABA) are permitted as rescue therapy throughout the study. Rescue 
therapy with ICS and/or LABAs is not permitted. 
Systemic corticosteroids are allowed as rescue treatment for exacerbation. The need for rescue 
therapy and dosage will be determined by the site investigator. For patients on chronic systemic 
corticosteroids, an increase in the dose of systemic steroids is allowed as rescue treatment.  
If 2 or more exacerbations occur during the treatment period, antifungal therapy may be initiated 
(or the dose may be increased for patients on antifungal therapy) after consultation with the 
medical monitor at the discretion of the investigator. 
Patients receiving rescue therapy permitted by the protocol may continue to receive study drug. 
They will remain blinded and will be asked to return to the clinic for all remaining study visits for 
the double-blind treatment period and the follow-up period, and participate in all assessments for 
these visits according to the Schedule of Events specified in Table 1. 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules 
8.4.1. 
Dose Modification 
Study drug dose modification for an individual patient is not allowed. 
8.4.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug should be encouraged to remain in the 
study. Those who agree and do not withdraw from the study will be asked to return to the clinic 
for all remaining study visits per the visit schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 9.1.2. 
8.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Serious or severe allergic reactions considered related to study drug 
• Specific types of liver dysfunction (eg, Hy’s law is met ([Guidance for Industry Drug 
Induced Liver Injury: Premarketing Clinical Evaluation FDA 2009]) 
• Patient withdraws consent 
• If, in the investigator’s opinion, continuation in the study would be detrimental to the 
patient’s well-being 
• In the event of a critical protocol deviation, at the discretion of the investigator or the 
sponsor 
• At the specific request of the sponsor 
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• Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin. Patient must be withdrawn for these latter 
malignancies if they cannot be adequately treated by local resection. 
• Any opportunistic infection or other infection whose nature or course may suggest an 
immunocompromised status 
• Severe laboratory abnormalities assessed as related to study drug:  
− Neutrophil count ≤0.5 × 103/μL 
− Platelet count ≤50 × 103/μL 
− ALT and/or AST values >3 × ULN with total bilirubin >2 × ULN, excluding 
confirmed Gilbert’s Syndrome 
− Confirmed AST and/or ALT >5 × ULN (for more than 2 weeks)  
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision of permanent discontinuation of study drug for the 
concerned patient. See Table 1 for information on follow-up and any further evaluations 
that need to be completed. 
8.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing may be temporarily discontinued in the event of: 
• Severe laboratory abnormalities (as noted in Section 8.4.2.1) where a causal 
relationship to study drug can be reasonably excluded, (ie, an alternative cause is 
evident):  study drug will be discontinued but may be resumed when the laboratory 
abnormality is sufficiently normalized. At minimum, the laboratory value(s) must 
return to a level that no longer meets the specified criteria for discontinuation, as 
defined in Section 8.4.2.1. A decision to resume study treatment will be made jointly 
by the investigator and medical monitor. 
• Infections or infestations that do not respond to medical treatment 
• Other intercurrent illness or adverse event or major surgery which could, in the opinion 
of the investigator, present an unreasonable risk to the patient as a result of his/her 
continued use of the study drug  
After the condition leading to temporary discontinuation of study drug resolves, study drug dosing 
may resume. A decision to temporarily discontinue study drug and/or resume study drug dosing 
should be discussed with the Regeneron Pharmaceuticals, Inc. medical monitor. Re-initiation of 
treatment with the study drug will be done under close and appropriate clinical and/or laboratory 
monitoring once the investigator will have considered, according to his/her best medical judgment, 
that the AE is sufficiently resolved and unlikely to recur after resuming therapy with the study 
drug. 
The investigator may temporarily discontinue study drug dosing at any time, even without 
consultation with the medical monitor if the urgency of the situation requires immediate action 
and if this is determined to be in the patient’s best interest. However, the Regeneron medical 
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monitor should be contacted as soon as possible. Resumption of study drug dosing requires 
consultation and agreement between the investigator and the Regeneron medical monitor. 
For visits other than the randomization and EOT visits, if a patient is unable to return to the clinic 
for a given visit within the specified visit window, any follow-up procedures scheduled for the 
missed visit should be performed at the subsequent visit. 
If the patient misses more than 4 consecutive doses, the patient will be permanently discontinued 
from the study. 
For all temporary discontinuations of study intervention, duration must be recorded by the 
investigator in the electronic case report form (eCRF). Following a temporary interruption or 
missed dose, the investigational medicinal product (IMP) treatment should be reinitiated at the 
next scheduled visit, maintaining the original dose. 
If a patient requires a prohibited medication at any time during the study, the investigator should 
contact the Regeneron medical monitor (except for illness requiring prompt treatment). Based on 
the discussions, study drug may be continued or temporarily or permanently discontinued. 
8.5. 
Management of Acute Reactions  
8.5.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use. All injection reactions must be reported as AEs (as defined in Section 10.2.1) 
and graded using the grading scales as instructed in Section 10.2.4. 
Acute systemic reactions following SC injection of study drug should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice.  
8.6. 
Method of Treatment Assignment  
Approximately 60 patients will be randomized at baseline/week 0/visit 2 in a 1:1 ratio to receive 
either dupilumab 300 mg Q2W or placebo according to a central randomization scheme provided 
by an interactive voice response system (IVRS)/interactive web response system (IWRS) to the 
designated study pharmacist (or qualified designee). Randomization will be stratified by region 
(pooled country), by chronic systemic corticosteroid use (yes/no) at screening, and by oral 
antifungal use (yes/no) at screening. 
8.7. 
Blinding 
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the study. The Regeneron medical/study director, study 
monitor, and any other Regeneron and contract research organization (CRO) personnel who are in 
regular contact with the study site will remain blinded to all patient randomization assignments. 
Blinded study drug kits coded with a medication numbering system will be used. In order to 
maintain the blind, lists linking these codes with product lot numbers will not be accessible to 
individuals involved in study conduct. 
Anti-drug antibody, drug concentration results, and post-treatment biomarker results (
 
, serum total IgE, and A fumigatus-specific IgEs) will not be communicated to the sites, and 
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the sponsor’s operational team will not have access to results associated with patient identification 
until after the database is locked for the respective study part. 
8.8. 
Emergency Unblinding  
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy) and when a treatment decision is contingent 
on knowing the patient’s treatment assignment. Study drug will be discontinued for patients whose 
treatment has been unblinded/unmasked (Section 8.4.2). 
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
− Only the affected patients will be unblinded. 
− The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist, the 
investigator for the site will unblind/unmask the patient. Unblinding is performed 
using the IVRS/IWRS which will notify Regeneron.  
− The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient. 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency and when a treatment decision is contingent on knowing the patient’s treatment 
assignment. In the event that there is no study pharmacist, the individual at the site fulfilling that 
role will be the only unblinded member of the site personnel. 
8.9. 
Treatment Logistics and Accountability 
8.9.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label blinded investigational study drug. Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.9.2. 
Supply and Disposition of Treatments  
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed or returned to the 
sponsor or designee. 
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8.9.3. 
Treatment Accountability 
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. 
8.9.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.10. 
Concomitant Medications and Procedures 
Any treatment administered from the time of informed consent to the final study visit will be 
considered concomitant medication. This includes medications that were started before the study 
and are ongoing during the study. 
8.10.1. 
Prohibited Medications and Procedures 
Treatment with the following concomitant medications is prohibited during the study: 
• Systemic immunosuppressive/immunomodulating drugs (including, but not limited to:  
omalizumab, cyclosporine, mycophenolate-mofetil, azathioprine, methotrexate, IFN-γ, 
or other biologics) other than protocol-defined use of corticosteroids 
• Treatment with an investigational drug (other than dupilumab) 
• Initiation of SCIT, or change in dose for those patients on a stable dose of SCIT within 
1 year prior to screening  
• SLIT 
• Oral immunotherapy 
• Treatment with a live (attenuated) vaccine: 
− Chickenpox (varicella)  
− FluMist-influenza 
− Intranasal influenza 
− Measles (rubeola)  
− Measles-mumps-rubella combination  
− Measles-mumps-rubella-varicella combination 
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− Mumps 
− Oral polio (Sabin) 
− Oral typhoid 
− Rubella 
− Smallpox (vaccinia)  
− Yellow fever  
− Bacille Calmette-Guerin 
− Rotavirus 
− Varicella zoster (shingles) 
• The following concomitant procedures are prohibited during the study period: 
− Major elective surgical procedures 
− Bronchial thermoplasty  
8.10.2. 
Permitted Medications  
Other than the prohibited medications listed in Section 8.10.1, treatment with concomitant 
medications are permitted during the study. This includes topical and systemic anti-infective 
medications for any duration, use of contraceptives, nasal and inhaled corticosteroids, and oral 
antihistamines for any duration. Antifungal therapy to treat ABPA is described in Section 8.2.  
Medications used to treat chronic diseases such as diabetes, hypertension, and asthma (ICS plus 1 
or more additional controller medications [eg, LABA, LTRA, LAMA, etc], and/or systemic 
steroids [see Section 8.2]) are permitted during the study. 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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9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms. 
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures are to be 
documented as being related to COVID-19 and will remain in effect only for the duration of the 
public health emergency. 
Study assessments and procedures are presented by study period and visit in Table 1.  
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Table 1: 
Schedule of Events 
 
 
Randomized treatment period** 
 
 
 
Study Procedure 
Screening Visita 
Randomization/ 
Baseline Visitb 
 
EOT visit 
EOS visit 
Unscheduled Visitz 
 
 
 
 
 
 
 
 
 
 
 
Phone call 
visits 
 
Phone call visits 
 
Phone call 
visits 
 
Phone call 
visits 
 
 
 
Week 
-4 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
24-
52** 
36-
64 
 
Visit 
1 
2c 
3 
4 
5* 
6 
7* 
8 
9* 10*
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
14-
28 
15-
29 
 
Window (days) 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
 
Screening/Baseline: 
Inclusion/ 
Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre- and post-
bronchodilator 
spirometryd,e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Qualifying ACQ-5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ANCA, Hepatitis 
and HIV serologyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis 
testingg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
testh,i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A fumigatus skin 
testing  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum IgG and 
precipitins against A 
fumigatus 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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REGENERON CONFIDENTIAL 
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Randomized treatment period** 
 
 
 
Study Procedure 
Screening Visita 
Randomization/ 
Baseline Visitb 
 
EOT visit 
EOS visit 
Unscheduled Visitz 
 
 
 
 
 
 
 
 
 
 
 
Phone call 
visits 
 
Phone call visits 
 
Phone call 
visits 
 
Phone call 
visits 
 
 
 
Week 
-4 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
24-
52** 
36-
64 
 
Visit 
1 
2c 
3 
4 
5* 
6 
7* 
8 
9* 10*
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
14-
28 
15-
29 
 
Window (days) 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
 
Urine toxicology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior & concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
Call IVRS/IWRSk 
X 
X 
X 
X 
X* 
X 
X* 
X 
X* X* 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Administer study 
drugl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense /Review 
home dosing paper 
diary 
X 
X 
X 
X 
X* 
X 
X* 
X 
X* X* 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
OCS dose titration 
for pts on OCS at 
baseline 
 
 
 
X 
X* 
X 
X* 
X 
X* X* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy: 
Spirometryd 
 
X 
X 
X 
X* 
X 
X* X X* X* 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Post-BD 
spirometryd 
 
X 
X 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
ACQ-5 scorem 
 
X 
X 
X 
X* 
X 
X* X X* X* 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
SGRQ Scorem 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
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Clinical Study Protocol 
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REGENERON CONFIDENTIAL 
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Randomized treatment period** 
 
 
 
Study Procedure 
Screening Visita 
Randomization/ 
Baseline Visitb 
 
EOT visit 
EOS visit 
Unscheduled Visitz 
 
 
 
 
 
 
 
 
 
 
 
Phone call 
visits 
 
Phone call visits 
 
Phone call 
visits 
 
Phone call 
visits 
 
 
 
Week 
-4 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
24-
52** 
36-
64 
 
Visit 
1 
2c 
3 
4 
5* 
6 
7* 
8 
9* 10*
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
14-
28 
15-
29 
 
Window (days) 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
 
Safety: 
Vital Signsn 
X 
X 
X 
X 
X* 
X 
X* 
X 
X* X* 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Physical 
examinationo 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
Electro-cardiogramp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing: 
Hematologyq 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Blood chemistryr 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Urinalysiss  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Urine pregnancy 
testt 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Pharmacokinetics and ADA Sampling 
Drug concentration 
sampleu 
 
X 
 
  
 
 
 
X 
 
  
 
 
 
X 
 
 
 
 
 
  
 
 
 
  
 
 
 
X 
X 
  
ADA sampleu 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
  
 
 
 
 
 
 
 
X 
X 
 
Biomarkers: 
FeNOv 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Serum total IgEw 
Xe 
X 
 
X  
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
Serum A fumigatus 
specific IgE 
Xe  
X 
 
X 
 
 
 
X 
 
 
 
 
 
X  
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
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REGENERON CONFIDENTIAL 
Page 59 of 99 
 
 
Randomized treatment period** 
 
 
 
Study Procedure 
Screening Visita 
Randomization/ 
Baseline Visitb 
 
EOT visit 
EOS visit 
Unscheduled Visitz 
 
 
 
 
 
 
 
 
 
 
 
Phone call 
visits 
 
Phone call visits 
 
Phone call 
visits 
 
Phone call 
visits 
 
 
 
Week 
-4 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
24-
52** 
36-
64 
 
Visit 
1 
2c 
3 
4 
5* 
6 
7* 
8 
9* 10*
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
14-
28 
15-
29 
 
Window (days) 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
 
Pharmacogenomics and future biomedical research: 
Blood samples for 
future Biomedical 
research  
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Whole blood RNAx 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for 
DNAx 
(optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood 
immunophenotyping 
substudyy (optional) 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
NOTE:  EOS is end of study; the follow-up period begins at the EOT visit and ends at the EOS visit.  
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9.1.1. 
Footnotes for the Schedule of Events Table 
Footnotes for Table 1 Schedule of Events 
*Visits 5, 7, 9, and 10 will be performed as phone visits for patients not receiving OCS at baseline. 
For patients receiving OCS at baseline, these visits should be performed in-clinic if the patient 
remains on OCS on the day of the clinic visit. If OCS has been discontinued, these visits can be 
either in-clinic or performed as a phone visit at the discretion of the investigator. 
Assessments/procedures marked with an asterisk should only be performed if the visit occurs 
in-clinic.  
**After the last patient has completed visit 14/week 24 of the treatment period or withdrawn from 
the study, all patients still currently in the treatment period (between visit 15/week 26 and visit 
27/week 50) should return to the clinic 2 weeks from their last dose/treatment administration to 
complete their EOT visit and all its applicable assessments. For patients who have withdrawn from 
the study treatment but remain in the study, the EOT visit will take place 2 weeks from their last 
visit. All patients must have their EOS visit 12 weeks after their EOT visit. 
 
a. Prior to screening, patients must be on a stable background therapy for asthma which may 
include ICS in combination with a second controller medication (eg, LABA, LTRA, 
theophylline, etc) for at least 3 months with a stable dose ≥1 month prior to baseline. 
Patients requiring a third controller are allowed to participate in this study. The third 
controller should also be used for at least 3 months with a stable dose ≥1 month prior to 
visit 1. Patients requiring systemic steroids of up to 10 mg per day (or up to 30 mg every 
alternate day) as controller medication are permitted.  
b. Randomization/baseline visit is defined as day 1. The visit schedule should be adhered to 
within ±1 week for the screening period, ±3 days for the randomized IMP treatment period, 
and ±7 days for the post-IMP treatment period. 
c. All assessments at visit 2 (day 1) are to be conducted pre-IMP dose except for the 
assessment of local tolerability of SC injections. 
d. Spirometry will be done locally according to European Respiratory Society 
(ERS)/American Thoracic Society (ATS) guidance, but measured by a central laboratory. 
Spirometry will be performed during a trough period of bronchodilators according to their 
action duration, for example, withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of ipratropium 
for at least 8 hours, withholding the last dose of LABA for at least 12 hours (ultra-long-
acting LABA-like vilanterol should be withheld for at least 24 hours), and withholding the 
last dose of LAMA for at least 24 hours. This will be verified before performing the 
measurements. Post-bronchodilator FEV1 will be determined at the designated treatment 
visits.  
e. Three attempts may be made during the screening period until the baseline visit to meet 
the qualifying criteria for FEV1. A total of 2 attempts may be made during the screening 
period until the baseline visit to meet the qualifying criteria for blood eosinophils, total 
serum IgE, Aspergillus-specific IgE, Aspergillus-specific IgG, Aspergillus precipitins, 
and/or skin prick test. 
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f. Clinical laboratory testing at screening visit 1 will include hepatitis screen covering 
HBsAg, HBsAb, HBcAb), hepatitis C virus antibodies, HIV screen (anti-HIV-1 and 
anti-HIV-2 antibodies). In case of results showing HBsAg (negative), and HBcAb 
(positive), an HBV DNA testing will be performed prior to randomization to rule out a 
false positivity if the investigator believes the result is a false positive, or to clarify the 
serological status if the investigator finds it unclear to interpret in absence of known HBV 
infection. In case of results showing HCV Ab (positive), an HCV RNA testing may be 
performed to rule out a false positivity, if the investigator believes the patient is a false 
positive. 
g. Patients with active tuberculosis or non-tuberculous mycobacterial infection, latent 
untreated tuberculosis, or a history of incompletely treated tuberculosis will be excluded 
from the study unless it is well documented by a specialist that the patient has been 
adequately treated, and can now start treatment with a biologic agent in the medical 
judgment of the investigator and/or infectious disease specialist. (Tuberculosis testing will 
be performed on a country-by-country basis according to local guidelines if required by 
regulatory authorities or ethics committees [ECs].) 
h. Only for women of childbearing potential. Pregnancy will lead to definitive treatment 
discontinuation in all cases. In case of positive urinary test, a serum pregnancy test should 
be performed as soon as possible to confirm the pregnancy.  
i. Serum pregnancy test will be conducted at visit 1 and urine dipstick pregnancy tests will 
be conducted at other visits. A negative result must be obtained at visits 1 and 2 prior to 
randomization.  
j. 
 
 
 
 
  
k. IVRS/IWRS will be utilized during screening to assign screening IDs, during baseline to 
provide treatment assignments to the investigator, and to dispense study drug. 
l. Every 2 weeks, study drug administrations must be separated by at least 11 days. IMP can 
be administered in clinic at scheduled visits or at home (patient, caregiver, or health care 
professional). Patients and parents/caregivers who prefer to have clinic staff administer 
study drug may choose to have injections administered in the clinic. Due to the COVID-19 
pandemic, study drug may be shipped from the clinical site to the patient's home if 
necessary. 
m. ACQ-5 and SGRQ are completed in the electronic diary during clinic visits and prior to 
spirometry at each visit. NOTE: If COVID-19 restrictions limit the availability of staff or 
the patient to have in-clinic visits, site staff should make every effort to conduct telephone 
interviews to complete these questionnaires. Site staff should conduct the telephone 
interviews on the date of scheduled site visit by following an interview guide provided by 
the sponsor. Patient responses from the interviewer administered questionnaires will be 
captured by the site staff. 
n. Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per 
minute), body temperature (°C), and respiratory rate will be measured at screening, 
baseline, and every subsequent on-site visit. For adults, height (cm) will be measured only 
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at screening (visit 1), and body weight (kg) will be measured at screening (visit 1) and at 
EOT/EOS visits. For adolescents, height and body weight will be measured at the screening 
and randomization visits (visits 1 and 2) and every subsequent visit.  
o. Complete physical examinations will include skin, nasal cavities, eyes, ears, and 
respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal 
systems. 
p. 12-lead ECG is to be read centrally. 
q. Hematology will include hemoglobin, hematocrit, platelet count, total white blood cell 
(WBC) count, differential count, and total red blood cell (RBC) count.  
r. Hematology will include hemoglobin, hematocrit, platelet count, total white blood cell 
count, differential count, and total red blood cell count.  
s. Urinalysis will include specific gravity, pH, glucose, ketones, blood, protein, nitrate, 
leukocyte esterase, urobilinogen, and bilirubin. If any parameter on the dipstick is 
abnormal, a urine sample should be sent to the central laboratory for quantitative 
measurement. If positive for protein and/or red blood cells, microscopic analysis will be 
performed by the central laboratory. 
t. Serum pregnancy test will be conducted at visit 1 and urine dipstick pregnancy tests will 
be conducted at other visits. A negative result must be obtained at visits 1 and 2 prior to 
randomization. 
u. Pharmacokinetic (PK) and ADA samples are to be collected prior to the administration of 
the drug. In the event of suspected serious adverse events (SAEs), such as anaphylaxis or 
hypersensitivity, additional samples for the analysis of ADA and dupilumab drug 
concentration may be collected as close to the event as practically possible. 
v. Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast of 
≥1 hour. 
w. If the patient experiences an exacerbation, an unscheduled visit is to be performed for the 
collection of an additional blood sample for serum total IgE at the time of, or as soon as 
possible after, the exacerbation. 
x. If collection is not completed at randomization, sample can be taken at a following visit. 
To be collected prior to IMP administration 
y. Blood samples will be collected at selected sites. Only patients who are not on chronic 
systemic corticosteroids and not on oral antifungal therapy at baseline will be allowed to 
participate in the blood immunophenotyping substudy. 
z. Unscheduled visits may be necessary to repeat testing following abnormal laboratory 
results, for follow-up of AEs, or for any other reason as warranted. If the patient develops 
a respiratory exacerbation, he/she will be required to have an unscheduled visit as soon as 
possible, and a blood sample for serum total IgE needs to be collected. 
9.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study will be asked to return to the clinic once at the time of 
the next regularly scheduled visit for an early termination visit consisting of the end of study 
assessments described in Table 1. 
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9.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, during 
respiratory exacerbation, or for any other reason as warranted. 
9.1.4. 
End of Treatment Visit 
After the last patient has completed visit 14/week 24 of the treatment period or withdrawn from 
the study, all patients still currently in the treatment period (between visit 15/week 26 and visit 
27/week 50) should return to the clinic 2 weeks from their last dose/treatment administration to 
complete an EOT visit consisting of the assessments described in Table 1. For patients who have 
withdrawn from the study drug but remain in the study, the EOT visit will take place 2 weeks from 
their last visit. 
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed at the Screening/Baseline Visit 
The following procedures will be performed for the purpose of determining study eligibility or 
characterizing the baseline population: informed consent/assent, medical and surgical history, 
demographics, smoking history, qualifying ACQ-5, pre- and post-bronchodilator spirometry, 
hepatitis and HIV serology, serum IgG against A fumigatus, serum precipitins to A fumigatus, A 
fumigatus skin testing, serum pregnancy testing, urine toxicology for drug screening, 
randomization, and tuberculosis testing as guided by country local authorities. 
Eligible patients must meet all of the inclusion criteria and none of the exclusion criteria to 
participate in the study.  
9.2.2. 
Efficacy Procedures  
9.2.2.1. 
Severity of Respiratory Exacerbations 
The number of severe respiratory exacerbations will be recorded by the investigator and defined 
as new onset symptoms or clinical worsening that requires systemic corticosteroid treatment for 
≥3 consecutive days, and, for patients who are on maintenance systemic corticosteroids, at least 
double the dose of maintenance systemic corticosteroids for ≥3 consecutive days plus antibiotic 
therapy if indicated. 
Clinical signs and symptoms of respiratory exacerbation will be captured in the eCRF, including, 
but not limited to, new onset or increase in cough, wheezing, chest tightness, shortness of breath, 
sputum volume, and/or change in sputum appearance, etc.  
Two events will be considered different if the interval between their start dates is ≥ 28 days. 
The reasons (eg, infections including viral and bacterial, allergen exposure, exercise, and others) 
for the exacerbation events will be collected in eCRF. 
9.2.2.2. 
Lung Function 
The following lung function parameters will be measured using spirometry at the clinical site: 
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REGENERON CONFIDENTIAL 
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• FEV1 (pre- and post-bronchodilator) 
• percent predicted FEV1, 
  
Spirometry should be performed prior to administration of study drug and in accordance with 
ATS/ERS guidelines (Miller, 2005). 
For pre-bronchodilator measured parameters, including FEV1, 
 
spirometry will be performed after a washout period of bronchodilators according to their action 
duration. Examples of washout periods include withholding the last dose of salbutamol/albuterol 
or levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for at least 
12 hours (ultra-long-acting LABA, such as vilanterol, should be withheld for at least 24 hours), 
withholding the last dose of ipratropium for at least 8 hours, and withholding the last dose of 
LAMA for at least 24 hours. Withholding times will be verified before performing the 
measurements. Note that when both pre- and post-bronchodilator spirometry are assessed, the post-
bronchodilator spirometry should be performed 30 minutes after administration of 2 to 4 puffs of 
albuterol or another SABA.  
At all visits, spirometry should be performed in the morning if possible, but if the test can only be 
done at a different time of the day, the testing should be done at approximately the same time of 
the day at each visit throughout the study.  
A spirometer that meets the ATS/ERS recommendations will be used. The same spirometer and 
standard spirometric techniques, including calibration, will be used to perform spirometry at all 
visits and, whenever possible, the same person should perform the measurements. Three 
measurements fulfilling the ATS acceptability and repeatability criteria should be obtained at 
every visit, if possible.  
The acceptability criteria must be applied before the repeatability criteria. Unacceptable 
maneuvers must be discarded before applying the repeatability criteria. If a patient fails to provide 
repeatable and/or acceptable maneuvers, an explanation should be documented. 
 
 
 
 
  
Further details on spirometry will be available in a separate operational manual provided to the 
sites. 
9.2.2.3. 
Allergic Bronchopulmonary Aspergillosis-Related Exacerbations 
Allergic bronchopulmonary aspergillosis-related exacerbations will be recorded by the 
investigator and are defined as a severe respiratory exacerbation (as defined in Section 9.2.2.1) 
associated with a doubling of serum total IgE value compared to the closest value before the onset 
of the exacerbation. For all respiratory exacerbations, patients will be required to have, as soon as 
possible, an unscheduled visit at the site for the collection of a blood sample for serum total IgE 
measurement.  
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9.2.2.4. 
Patient-Reported Outcome Questionnaires 
Health-related quality of life and disease control will be recorded by patients using patient-reported 
outcome questionnaires. The questionnaires will be completed in an electronic diary during clinic 
visits, prior to spirometry.  
St. George’s Respiratory Questionnaire (SGRQ) 
This questionnaire will be completed by the patient at the time points specified in Table 1 The 
SGRQ is a 50-item questionnaire designed to measure and quantify health status in adult patients 
with chronic airflow limitation (Nelsen, 2017a). 
A total score ranges from 0 to 100. Scores by dimension are calculated for three domains:  
Symptoms, Activity, and Impacts (Psychosocial). Lower score indicates better QoL. 
The first part (Symptoms) evaluates symptomatology, including frequency and severity of cough, 
sputum production, wheeze, breathlessness, and the duration and frequency of attacks of 
breathlessness or wheeze.  
The second part has 2 components:  Activity and Impacts. The Activity section addresses 
disturbances to patients’ daily physical activities. The Impacts section covers a range of effects 
that chest troubles may have on patients’ daily life and psychosocial functions (eg, daily life 
activities and functioning, employment, physical functioning, emotional impact, stigmatization, 
and patients’ perceptions when treated). The recall period of the questionnaire is over the past 
4 weeks. 
Psychometric testing has demonstrated its repeatability, reliability, and validity. Sensitivity has 
been demonstrated in clinical trials (Nelsen, 2017b). A minimum change in score of 4 units was 
established as clinically relevant after patient and clinician testing. The SGRQ has been used in a 
range of disease groups including asthma, COPD, and bronchiectasis.  
Asthma Control Questionnaire (ACQ-5) 
The ACQ-5 questionnaire will be completed by the patient at the time points specified in Table 1. 
The ACQ was designed to measure both the adequacy of asthma control and change in asthma 
control, which occurs either spontaneously or as a result of treatment. 
The ACQ-5 is a short version of ACQ-7. The ACQ-5 score is the mean of the first 5 questions, 
between 0 (totally controlled) and 6 (severely uncontrolled). A higher score indicates lower asthma 
control. Patients with a score below 1.0 reflect adequately controlled asthma and patients with 
scores above 1.0 reflect inadequately controlled asthma. The optimal cut-point score of 1.50 should 
be used to be confident that a patient has inadequately controlled asthma. On the 7-point scale of 
the ACQ-5, a change or difference in score of 0.5 is the smallest change that can be considered 
clinically important, corresponding to the minimal clinically important difference defined by the 
developer. 
Systemic Corticosteroid Use for Patients on Chronic Corticosteroids at Baseline 
Systemic corticosteroid use (including reduction or elimination) during the study will be 
recorded for patients on chronic OCS at baseline. 
 
 
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If a patient experiences a severe exacerbation during the OCS dose reduction, the exacerbation 
should be treated with the use of oral or parenteral steroids at least double the dose of the current 
OCS maintenance dose. Following exacerbation treatment, the patient should be placed on the 
OCS dose 1 step higher than the dose they were on when the exacerbation occurred.  
 
 
 
 
 
 
 
 
 
 
 
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9.2.3. 
Safety Procedures 
9.2.3.1. 
Vital Signs 
Vital signs, including systolic and diastolic blood pressure, pulse rate, body temperature, 
respiratory rate, height, and weight will be measured at time points according to Table 1. 
9.2.3.2. 
Physical Examination 
A thorough and complete physical, including skin, nasal cavities, eyes, ears, respiratory, and 
cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems 
examination will be performed at time points according to Table 1. Care should be taken to 
examine and assess any abnormalities that may be present, as indicated by the patient’s medical 
history. 
9.2.3.3. 
Electrocardiogram 
A standard 12-lead ECG will be performed at time points according to Table 1. Heart rate will be 
recorded from the ventricular rate and the PR, QRS, and QT (QTcF) intervals will be recorded. 
The ECG strips or reports will be retained with the source. 
9.2.3.4. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory. Detailed instructions for blood sample collection are in the laboratory manual provided 
to study sites. 
Samples for laboratory testing will be collected at visits according to Table 1. Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK) 
Glucose 
Alkaline phosphatase 
  
Albumin 
Lactate dehydrogenase (LDH) 
 
 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
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Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
Additional laboratory tests to be performed include: 
• Antineutrophil cytoplasmic antibodies (ANCA) at screening 
• Hepatitis screen including HBsAg, HbsAb, HbcAb, HCVAb 
• HIV (Anti-HIV-1 and anti-HIV-2 antibodies) serology 
• Serum IgG against A fumigatus 
• A fumigatus skin testing  
• Serum A fumigatus-specific IgE 
• Urine toxicology for drug screening 
• Pregnancy test: For WOCBP, pregnancy testing will include a serum pregnancy test at 
screening and urine pregnancy tests at subsequent time points as specified in Table 1. 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the medical/study director must 
be consulted.  
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 10.1.1. 
9.2.4. 
Drug Concentration and Measurements 
Samples for dupilumab trough concentration measurements will be collected at visits listed in 
Table 1.  
9.2.5. 
Immunogenicity Measurements and Samples 
Samples for ADA and NAb assessment will be collected at time points listed in Table 1. Samples 
positive in the ADA assay will be analyzed for the presence of neutralizing antibody in the NAb 
assay. 
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9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
In this study, research assessments will be performed to explore how dupilumab may modify the 
mechanism of action underlying the disease process in ABPA patients. In particular, the role of 
the IL-4Rα pathway and the effect of dupilumab on FeNO, 
, and 
total and specific IgE in serum will be explored.  
Biomarker samples will be collected at time points according to Table 1. Pharmacodynamic 
marker/biomarker measurements will be performed to determine effects on biomarkers of ABPA 
or relevant physiological and pathogenic processes. The biomarkers studied are believed to be 
relevant to the pathophysiology of ABPA, target engagement, mechanism of action of dupilumab, 
and possible toxicities. 
Several biomarkers related to type 2 inflammation will be assessed for their value in predicting 
therapeutic response and/or in documenting the time course of drug response:  concentrations of 
FeNO (a marker of airway inflammation), serum total IgE (a product of immunoglobulin class 
switching driven by IL-4), serum A fumigatus-specific IgE, 
 
 
 
Data analyses will be described in the statistical analysis plan (SAP) and the results will be 
described in the clinical study report (CSR).  
9.2.6.1. 
Fractional Exhaled Nitric Oxide  
Fractional exhaled nitric oxide is a measure of lung inflammation. FeNO will be performed 
according to the timepoints in Table 1. FeNO will be analyzed using a NIOX instrument 
(Aerocrine AB, Solna, Sweden), or similar analyzer using a flow rate of 50 mL/s, and reported in 
parts per billion. This assessment should be conducted prior to spirometry and following a fast of 
at least 1 hour. Further details on the procedure for measuring fractional exhaled nitric oxide with 
NIOX will be provided in a separate instruction manual. 
9.2.6.2. 
Serum Total IgE 
Patients with ABPA have elevated IgE, and levels are clinically monitored to assess disease 
activity. Changes in total IgE reflect not only on ABPA but atopy in general. Baseline IgE levels 
will be assessed for potential predictive value for treatment response. Post-treatment samples will 
be evaluated for PD effects of study treatment on total IgE. 
Total IgE will be collected according to the time points in Table 1 and measured in serum with a 
quantitative method (eg, Phadia ImmunoCAP) approved for diagnostic testing.  
Detailed instructions for blood sample collection are provided in the study reference manual/site 
binder or file.  
9.2.6.3. 
Serum A Fumigatus-Specific IgE  
A fumigatus-specific IgE will be measured in serum from samples collected according to the time 
points in Table 1 and measured in serum using a method (eg, Phadia ImmunoCAP) approved for 
diagnostic testing.  
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Detailed instructions for blood sample collection are provided in the study reference manual/site 
binder or file.  
9.2.6.4. 
 
 
 
 
 
  
 
 
9.2.6.5. 
 
 
 
 
 
 
 
 
9.2.6.6. 
Blood Immunophenotypying Substudy (Optional) 
A subset of study sites may be selected to perform evaluations of circulating cells before and after 
dupilumab treatment. Only patients who are not on chronic systemic corticosteroids and not on 
oral antifungal therapy at baseline will be allowed to participate in the blood immunophenotyping 
substudy. 
Blood will be collected from patients in the substudy. Circulating immune cells, including 
eosinophils, will be analyzed to assess changes in frequency, activation status, and 
 
. Collection for the blood immunophenotyping substudy will be performed according 
to the Schedule of Events in Table 1. The results of the substudy will not be included in the CSR. 
9.2.7. 
Future Biomedical Research (Optional) 
Patients who agree to participate in the future biomedical research substudy will be required to 
consent to this optional substudy before samples are banked in long-term storage. Additional 
samples for future biomedical research will be collected according to the Schedule of Events in 
Table 1. These unused biomarker samples for study-related research, as well as unused PK and 
ADA samples, will be stored for up to 15 years after the final date of the database lock. The unused 
samples may be utilized for future biomedical research related to the study, as reference samples 
for other studies, or for other research including development and validation of new assays. After 
15 years, any residual samples will be destroyed. The results of these future biomedical research 
analyses will not be presented in the CSR. 
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9.2.7.1. 
Pharmacogenomic Analysis (Optional) 
Patients who agree to participate in the genomics substudy will be required to consent to this 
optional substudy before collection of the samples. Whole blood samples for DNA extraction 
should be collected on day 1/baseline (pre-dose) but can be collected at a later study visit. Whole 
blood samples for RNA extraction will be collected at time points indicated in Table 1. 
DNA and RNA samples will be collected for the pharmacogenomic analyses to understand the 
genetic determinants of efficacy and safety associated with the treatments in this study and the 
molecular basis of ABPA and related diseases. These samples will be single-coded as defined by 
the ICH guideline E15. Samples will be stored for up to 15 years after the final date of the database 
lock. If there are specific site or country requirements involving the pharmacogenomics analyses 
which the sponsor is unable to comply with, samples will not be collected from patients at the site.  
Research findings from the optional genomic substudy will not be disclosed to the patient or 
principal investigator, even if they have implications for a patient’s health and management. 
Genetic results from this substudy are for research purposes only and not for medical diagnosis or 
for reproductive decision-making. 
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to dupilumab, other ABPA clinical outcome measures, and possible AEs. In 
addition, associations between genomic variants and prognosis or progression of ABPA, as well 
as related allergic/atopic diseases, may also be studied. These data may be used or combined with 
data collected from other studies to identify and validate genomic markers related to the study drug 
or ABPA, asthma, and related diseases. 
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions. Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome 
sequencing (or other methods for quantitating RNA expression) may also be performed. The list 
of methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period. Results from the genomic analyses will not be 
reported in the CSR. 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events  
10.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data collection 
period (see Section 11.4.5.1). Medical conditions that existed or were diagnosed prior to the 
signing of the ICF will be recorded as part of medical history. Abnormal laboratory values and 
vital signs observed at the time of informed consent should also be recorded as medical history. 
Any subsequent worsening (ie, any clinically significant change in frequency and/or intensity) of 
a pre-existing condition that is temporally associated with the use of the study drug should also be 
recorded as an AE. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
patient. Adverse events may be directly observed, reported spontaneously by the patient or by 
questioning the patient at each study visit. Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms. The investigator must assess all AEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2. 
The investigator’s assessment must be clearly documented in the site’s source documentation with 
the investigator’s signature. The investigator should follow up on SAEs (and adverse events of 
special interest [AESIs]) until they have resolved or are considered clinically stable; AEs should 
be followed until they are resolved or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available. If the signs and symptoms are distinct and do not suggest a 
common diagnosis, report them as individual entries of AE or SAE.  
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
investigator to determine their clinical significance. Isolated abnormal laboratory results, vital sign 
findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported as 
AEs if they are symptomatic, lead to study drug discontinuation or dose reduction, require 
corrective treatment, or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization). A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE. Pre-planned (prior to signing the ICF) 
procedures, treatments requiring hospitalization for pre-existing conditions that do not worsen in 
severity, and admission for palliative or social care should not be reported as SAEs (see 
Section 10.2 for Definitions).  
For deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Any SAE that may occur subsequent to the reporting period (end of the follow-up period) that the 
investigator assesses as related to study drug should also be reported. 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.3.  
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10.1.2. 
Reporting Procedure  
All events (serious and non-serious) must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the (when applicable:  blinded) study drug. For SAEs and 
AESIs, a detailed narrative summarizing the course of the event, including its evaluation, 
treatment, and outcome should be provided on the AE CRF. Specific or estimated dates of event 
onset, treatment, and resolution should be included, when available. Medical history, concomitant 
medications, and laboratory data that are relevant to the event should also be summarized in the 
narrative. For fatal events, the narrative should state whether an autopsy was or will be performed, 
and include the results if available. Information not available at the time of the initial report must 
be documented in a follow-up report. Source documents (including hospital or medical records, 
diagnostic reports, etc) will be summarized in the narrative on the AE CRF, and retained at the 
study center and available upon request.  
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
• SAEs. 
• AESIs; serious and nonserious:  Adverse events of special interest for this study 
include the following:   
− Anaphylactic reactions 
− Systemic hypersensitivity reactions 
− Helminthic infections 
− Any severe type of conjunctivitis or blepharitis 
− Keratitis 
− Clinically symptomatic eosinophilia (or eosinophilia associated with clinical 
symptoms) 
• Pregnancy:  Although pregnancy is not considered an AE, it is the responsibility of 
the investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female, during the study or within 12 weeks of the last 
dose of study drug. Any complication of pregnancy affecting a female study patient 
and/or fetus and/or newborn that meets the SAE criteria must be reported as an SAE. 
Outcome for all pregnancies should be reported to the sponsor.  
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10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug (ICH 
E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
In-patient hospitalization is defined as a hospital admission (any duration) or an 
emergency room visit for longer than 24 hours. Prolongation of existing hospitalization 
is defined as a hospital stay that is longer than was originally anticipated for the event, 
or is prolonged due to the development of a new AE as determined by the investigator 
or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).  
• Is a congenital anomaly/birth defect 
• Is an important medical event. Important medical events may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the patient or may 
require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Adverse Events of Special Interest 
An AESI (serious or non-serious) is one of scientific and medical interest specific to the sponsor’s 
product or program, for which ongoing monitoring and rapid communication by the investigator 
to the sponsor can be appropriate. Such an event might warrant further investigation in order to 
characterize and understand it. For a list of AESIs, see Section 10.1.3.  
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10.2.4. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild:  Does not interfere in a significant manner with the patient’s normal functioning level. It 
may be an annoyance. Prescription drugs are not ordinarily needed for relief of symptoms, but may 
be given because of personality of the patient. 
Moderate:  Produces some impairment of functioning but is not hazardous to health. It is 
uncomfortable or an embarrassment. Treatment for symptom may be needed. 
Severe:  Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the patient’s health. Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of grade): 
Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires 
emergency room visit or hospitalization; necrosis or exfoliative dermatitis 
10.2.5. 
Causality 
The investigator must provide causality assessment as to whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions. The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
For double-blinded studies using an active comparator, the investigator should consider all study 
drugs in determining event causality.  
The following factors should be considered when assessing causality: 
• Temporal relationship:  time to onset versus time drug was administered 
• Nature of the reactions:  immediate versus long term 
• Clinical and pathological features of the events  
• Existing information about the drug and same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
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• Response to dechallenge (drug discontinuation) or dose reduction, if applicable  
• Response to rechallenge (re-introduction of the drug) or dose increase, if applicable  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
state (eg, disease under study, concurrent diseases, concomitant medications), or 
other external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its class of drugs, or is predicted 
by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol-specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol-specified 
procedure, and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical state (eg, disease under study, concurrent diseases, and 
concomitant medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol-specified procedure, 
or can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
10.3. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The medical/study director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments 
(eg, Pharmacovigilance; Risk Management; Biostatistics and Data Management). Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic, cumulative aggregate basis. 
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10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, ECs or institutional 
review boards (IRBs), and the participating investigators of any SUSARs (suspected unexpected 
serious adverse reactions) occurring in other study centers or other studies of the active study drug 
(REGN668; dupilumab), as appropriate per local reporting requirements. In addition, the sponsor 
and/or CRO will comply with any additional local safety reporting requirements. All notifications 
to investigators will contain only blinded information.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the IRB/EC unless delegated to the sponsor. 
Event expectedness for study drug (dupilumab) is assessed against the Reference Safety 
Information section of the current Investigator’s Brochure that is effective for expedited safety 
reporting.  
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the CSR to health authorities and ECs/IRBs as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides the basis for the SAP for the study. The SAP will be revised prior to the end 
of the study to accommodate amendments to the clinical study protocol and to make changes to 
adapt to unexpected issues in study execution and data that may affect the planned analyses. The 
final SAP will be issued before the first database lock. 
Endpoints are listed in Section 4. Analysis variables are listed in Section 5.  
Data collected through the implementation of new CRFs regarding the impact of the COVID-19 
pandemic on patients will be summarized (eg, discontinuation due to COVID-19). Any additional 
analyses and methods required to investigate the impact of COVID-19 on the efficacy (eg, missing 
data due to COVID-19) and safety evaluation will be specified in the SAP. 
11.1. 
Statistical Hypothesis  
The primary analyses of the study compare the treatment effect of dupilumab 300 mg Q2W against 
placebo on the absolute change from baseline in pre-bronchodilator FEV1. 
The statistical hypotheses to test dupilumab 300 mg Q2W against placebo on having a greater 
increase from baseline in pre-bronchodilator FEV1 at week 24 are as follows: 
• Null hypothesis:  ΔDupilumab - ΔPbo = 0 
• Alternative hypothesis: ΔDupilumab - ΔPbo ≠ 0 
where ΔDupilumab and ΔPbo represent the absolute change from baseline in pre-bronchodilator FEV1 
at week 24 in the dupilumab and placebo groups, respectively. 
11.2. 
Justification of Sample Size 
The power calculation for this study is based on a comparison between dupilumab 300 mg Q2W 
and placebo with regard to the primary efficacy endpoint of the absolute change from baseline in 
pre-bronchodilator FEV1 at week 24. Assuming a 1:1 randomization ratio, a standard deviation 
(SD) for the change from baseline in pre-bronchodilator FEV1 at week 24 of 
 in both 
groups, a 2-sided Type 1 error of 0.05, and a dropout rate of 
 by week 24, with approximately 
60 randomized patients (~30 patients per group), the study will have approximately 96% power to 
detect a difference of 
 in the change from baseline in pre-bronchodilator FEV1 at week 24 
between the dupilumab and placebo groups, based on the 2-sample t-test. 
 
 
. 
11.3. 
Analysis Sets  
11.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized patients. It is based on the treatment allocated 
(as randomized), regardless of whether the treatment kit was used or not. Efficacy endpoints will 
be analyzed using the FAS. 
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11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated). Treatment compliance/administration and all clinical 
safety variables will be analyzed using the SAF. 
11.3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis population includes all patients who received any study drug and who had at least 
1 non-missing drug concentration result following the first dose of study drug. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all patients who received any study drug and who had at least 
1 non-missing ADA result following the first study dose.  
The NAb analysis set includes all patients who received any study drug and who are negative in 
the ADA assay or with at least 1 non-missing result in the NAb assay (patients who are 
ADA-negative are set to negative in the NAb analysis set). 
11.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information:  the number 
of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum.  
For categorical data, frequencies and percentages will be displayed for each category. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the ICF 
• The total number of randomized patients:  received a randomization number 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.  
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11.4.3. 
Primary Efficacy Analysis 
The absolute change from baseline in pre-bronchodilator FEV1 at week 24 will be analyzed using 
a mixed-effects model with repeated measures (MMRM) approach. The vector of responses will 
consist of the absolute change from baseline in pre-bronchodilator FEV1 at weeks 2, 4, 8, 12, and 
24. For patients who discontinue study treatment prior to week 24, any off-study treatment pre-
bronchodilator FEV1 values collected after the discontinuation of study treatment through week 
24 will be included in the analysis. The MMRM model will include OCS use at screening, OAF 
use at screening, region, age, sex, height, baseline eosinophil count, treatment, visit, treatment-by-
visit interaction, baseline pre-bronchodilator FEV1 value, and baseline pre-bronchodilator FEV1 
value-by-visit interaction as covariates. An unstructured covariance matrix will be used to model 
the correlations between repeated measurements. Parameters will be estimated using the restricted 
maximum likelihood (REML) method and the Newton-Raphson algorithm. Statistical inference 
for the treatment comparison of the absolute change from baseline in pre-bronchodilator FEV1 at 
week 24 will be derived from the MMRM model using the Kenward Roger method for calculation 
of the denominator degrees of freedom for the tests of the fixed effects. If the model does not 
converge, alternative model specifications (eg, a different covariance structure or reduction in the 
number of covariates) will be applied; details will be provided in the SAP. 
For the primary estimand of interest for the primary endpoint, the intercurrent events, strategies, 
and the corresponding missing data handling approaches are provided as below: 
Primary Efficacy Endpoint 
Intercurrent event(s) handling 
strategies 
Missing data handling 
approaches 
Change from baseline in 
pre-bronchodilator FEV1 at 
week 24 
 
The intercurrent events will be handled 
using the treatment policy strategy as 
follows:  
-        Taking rescue medications with 
systemic corticosteroids and/or oral 
antifungal drugs (including an 
increase in dose) for asthma or 
ABPA for any reason: all endpoint 
data collected after use of rescue 
medication will be used in the 
analysis 
-        Taking prohibited medications: all 
endpoint data will be included in the 
analysis irrespective of use of 
prohibited medications 
-        Discontinuing the study treatment: all 
endpoint data collected after 
discontinuation will be used in the 
analysis 
 
Two types of missing data: 1) 
Patients discontinuing from the 
study prior to the analysis time 
point (week 24) will have missing 
data from the time of 
discontinuation through week 24; 
2) Some intermittently missing 
data are expected because of 
occasionally missing a study visit 
while continuing with the 
randomized treatment 
Missing data handling: for both 
types of missing data, the primary 
analysis MMRM model assumes 
that missing data are MAR, that is, 
that patients with missing data 
would have efficacy outcomes like 
those in similar patients in their 
treatment group who continue their 
randomized treatment through the 
time point at which data are 
missing 
 
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Sensitivity Analyses 
Sensitivity analyses, such as tipping point analyses, may be conducted. Details of the analyses will 
be specified in the SAP. 
Subgroup Analyses 
Subgroup analysis will not be performed due to the small study sample size. 
11.4.4. 
Control of Multiplicity 
Control of multiplicity is not applicable. 
11.4.5. 
Safety Analysis 
The summary of safety results will be presented by treatment group. All safety analyses will be 
performed on the SAF.  
11.4.5.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
• The pre-treatment period is defined as the time from signing the ICF to prior to the 
first dose of study drug. 
• The on-treatment period is defined as the time from day 1 (on or after administration 
of the first dose of study drug) to the date of last dose of study drug +14 days or the 
date of patient last contact, whichever is earlier 
• The follow-up period is defined as the time from the date of last dose of study drug 
+15 days to the EOS visit or the date of patient last contact, whichever is earlier 
The treatment-emergent period is comprised of the on-treatment and follow-up periods. 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the treatment-emergent period. 
Analysis 
All AEs reported in this study will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). 
Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.4), 
presented by SOC and PT 
• TEAEs related to treatment presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group. 
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Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
11.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Number and percentage of patients with a treatment-emergent potentially clinically significant 
value (PCSV) will be summarized for each vital sign variable. The criteria for treatment-emergent 
PCSV will be defined in the SAP. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a PCSV at any post-randomization time point will be 
summarized for each clinical laboratory test for all patients and separately for patients in whom 
the PCSV criterion was normal or missing at baseline.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out-of-laboratory range values. 
12-Lead ECG 
Summaries of 12-lead ECG parameters by treatment will include: 
• Each ECG parameter and change from baseline 
• The number (n) and percentage (%) of patients with PCSV 
• ECG status (ie, normal or abnormal); abnormal ECG status will be classified as 
clinically significant or non-clinically significant  
Listings will be provided with flags indicating the PCSV values and ECG status. 
11.4.5.3. Treatment Exposure 
The duration of exposure during the study will be presented by treatment group and calculated as: 
(Date of last study drug administration – date of first study drug administration) + 14 days 
The number (%) of patients randomized and exposed to double-blind study drug will be presented 
by specific time periods for each treatment group. The time periods of interest will be specified in 
the SAP. 
In addition, duration of exposure during the study will be summarized for each treatment group 
using number of patients, mean, SD, minimum, Q1, median, Q3, and maximum. 
11.4.5.4. Treatment Compliance 
The compliance with study drug will be calculated as follows: 
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Treatment Compliance = 
(Number of study drug injections during exposure period)/(Number of planned study drug 
injections during exposure period) x 100% 
The treatment compliance will be presented by specific ranges. The ranges of interest will be 
specified in the SAP. 
11.4.5.5. Analysis of Drug Concentration Data 
The concentrations of functional dupilumab over time will be summarized by descriptive statistics.  
No formal statistical hypothesis testing will be performed.  
11.4.6. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized into ADA and NAb responses as described below:  
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 4-fold over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative or missing 
− Treatment-emergent ADA response may be further characterized as persistent, 
transient, or indeterminate  
• Treatment-boosted ADA response, defined as any post-dose positive ADA assay 
response that is 4-fold over baseline titer levels when baseline is positive in the ADA 
assay  
• Maximum ADA Titer values 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000)  
• NAb status for samples that are positive in the ADA assay depending on the study  
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers, 
and NAb positivity presented by patient, time point, and dose cohort will be provided. Incidence 
of treatment-emergent ADA, persistent response, and NAb will be assessed as absolute occurrence 
(N) and percent of patients (%), grouped by study cohorts and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on individual 
PK profiles evaluated. Assessment of impact of ADA and NAbs on safety and efficacy may be 
provided. 
11.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
Data analyses of biomarkers (Section 5.6) will be described in the SAP, and the results will be 
described in the CSR.  
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11.5. 
Statistical Considerations Surrounding the Premature Termination 
of a Study  
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are described in this section.  
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management  
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical/surgical history, and spirometry) will be 
done using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) tool. 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system – assign screening IDs, randomization, study drug supply 
• EDC system – data capture 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
12.2. 
Study Monitoring 
12.2.1. 
Monitoring of Study Sites  
The study monitor and/or designee (eg, CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study. This study will use the principles of risk-based 
monitoring (ICH). This means that the number of visits for any given site may vary based on site 
risk indicators. The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
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12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). The site is responsible to ensure quality within their records and systems and is 
accountable for ensuring that all source data and CRF data are timely, accurate, and complete. 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
12.2.3. 
Case Report Form Requirements  
Study data obtained in the course of the clinical study will be recorded on eCRFs within the EDC 
system by trained site personnel. All required CRFs must be completed for each and every patient 
enrolled in the study. The investigator must ensure the accuracy, completeness, and timeliness of 
the data reported to the sponsor in the CRFs. After review of the clinical data for each patient, the 
investigator must provide an electronic signature. A copy of each patient CRF casebook is to be 
retained by the investigator as part of the study record, and must be available at all times for 
inspection by authorized representatives of the sponsor and regulatory authorities. 
Corrections to the eCRF will be entered in the eCRF by the investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system. For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
Audits and Inspections  
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities. Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities. Conditions of study material storage are also subject to inspection. In addition, 
representatives of the sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator’s institution. 
In all instances, the confidentiality of the data must be respected. 
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12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient’s final 
eCRF that will be provided to the sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the investigator’s personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
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13. 
ETHICAL AND REGULATORY CONSIDERATIONS  
13.1. 
Good Clinical Practice Statement  
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
13.2. 
Informed Consent  
ADULT PATIENTS: 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand. The ICF should be signed and dated by the patient and by the 
investigator or authorized designee who reviewed the ICF with the patient.  
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF read 
to them in the presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately. All study patients must be informed of the new information and provide their written 
consent if they wish to continue in the study. The original, signed revised ICF must be maintained 
in the patient’s study record and a copy must be given to the patient. 
PEDIATRIC PATIENTS: 
The principles of informed consent are described in ICH guidelines for Good Clinical Practice. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient and his/her parent(s) or legal guardian(s) prior to the 
patient’s participation in the study and after the aims, methods, objectives, and potential hazards 
of the study have been explained to the fullest possible extent in language that the patient and the 
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parent(s) or legal guardian(s) can understand. The ICF should be signed and dated by the patient’s 
parent(s) or legal guardian(s) and the same investigator or designee who explained the ICF. 
Local law must be observed in deciding whether 1 or both parents’/guardians’ consent is required. 
If only 1 parent or guardian signs the consent form, the investigator must document the reason the 
other parent or guardian did not sign. The patient may also be required to sign and date the ICF, 
as determined by the IRB/EC and in accordance with the local regulations and requirements. 
• Patients who can write but cannot read will have the assent form read to them before 
writing their name on the form. 
• Patients who can understand but who can neither write nor read will have the ICF read 
to them in the presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient’s parent(s) or legal guardian(s). 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately. All study patients and their parent(s) or legal guardian(s) must be informed of the 
new information and provide their written consent if they wish the patient to continue in the study. 
The original, signed revised ICF must be maintained in the patient’s study record and a copy must 
be given to the patient’s parent(s) or legal guardian(s). 
13.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor. Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator’s personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB/EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
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A copy of the IRB/EC approval letter, with a current list of the IRB/EC members and their 
functions, must be received by the sponsor prior to shipment of drug supplies to the investigator. 
The approval letter should include the study number and title, the documents reviewed, and the 
date of the review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations. Treatment codes will be disseminated to each investigation site 
thereafter. 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment. Where required per local legislation, regulatory authority approval 
will also be sought.  
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15. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, safety, 
or futility, among others. Should the sponsor decide to terminate the study, the investigator(s) will 
be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the sponsor. 
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing. Reasons 
may include the following, among others:  
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study is enrolled earlier than expected 
In all cases, the appropriate IRB/EC and health authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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19. 
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Schwartz HJ, Citron KM, Chester EH, Kaimal J, Barlow PB, Baum GL, et al. A comparison of 
the prevalence of sensitization to Aspergillus antigens among asthmatics in Cleveland and 
London. J Allergy Clin Immunol 1978; 62(1):9-14. 
 
Stevens DA, Schwartz HJ, Lee JY, Moskovitz BL, Jerome DC, Catanzaro A, et al. A randomized 
trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 2000; 
342(11):756-762. 
 
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Voskamp AL, Gillman A, Symons K, Sandrini A, Rolland JM, O'Hehir RE, et al. Clinical 
efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis. J 
Allergy Clin Immunol Pract 2015; 3(2):192-199. 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: “A Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Efficacy and Safety of Dupilumab in Patients with Allergic 
Bronchopulmonary Aspergillosis” and agree to abide by all provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved. I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC. I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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APPENDIX A. ORAL CORTICOSTEROIDS (OCS) DOSE REDUCTION 
SCHEDULE DURING THE RANDOMIZED TREATMENT 
PERIOD FOR PATIENTS WHO ENTER THE STUDY ON 
OCS AT BASELINE 
The OCS dose should be down-titrated during this phase following a predetermined schedule that 
is based upon the OCS dose patient was receiving at baseline visit (week 0). During this period, 
patients will continue taking their background controller medication(s) (ICS +/- LABA, LTRA, 
LAMA, theophylline, etc) without any changes. The reduction in OCS dose should occur per the 
schedule unless the patient meets defined criteria indicating that it is not acceptable for the patient 
to reduce the dose. A clinical assessment should be completed prior to each dose reduction. 
Primary reasons for not following the scheduled dose reduction include: 
1. FEV1 >15% reduction from the baseline value 
2. Need for rescue short-acting bronchodilator medication by metered dose inhaler or dry 
powder inhaler use more than 4 puffs/day (or 2 or more nebulized doses/day) above the 
mean baseline value for any 2 consecutive days in the prior week; or 12 puffs or more of a 
short-acting bronchodilator metered dose inhaler or dry powder inhaler (or more than 
6 uses of a nebulizer) on any 1 day in the prior week 
3. Increase in ACQ-5 score ≥+0.5 from the prior OCS dose assessment visit 
4. Clinically significant respiratory exacerbation 
5. Requiring hospitalization or treatment in the ED/urgent care due to asthma related or 
ABPA-related symptoms  
6. Clinically significant event, based on investigator judgment, that requires treatment by 
OCS dose adjustment 
The investigator will decide, depending on the reason for not reducing the OCS dose per schedule, 
whether to maintain or increase patient’s current OCS dose by 1 step. 
Table 2: 
 
 
 
 
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Table 3: 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
 A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Efficacy and Safety of Dupilumab in Patients with Allergic Bronchopulmonary 
Aspergillosis 
 
Protocol Number: 
R668-ABPA-1923 
Protocol Version:   
R668-ABPA-1923 Amendment 4  
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
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Signature Page for VV-RIM-00295189 v1.0
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Approval/eSignature
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Approval/eSignature
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Approval/eSignature
24-Mar-2023 19:16:50 GMT+0000
                                        VV-RIM-00295189-1.0 Approved - 24 Mar 2023 GMT-5:00