Conditions: Allergic Rhinitis Due to Cat Allergy
Keywords: Cat allergy induced allergic rhinitis Allergic conjunctivitis Asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 446
Healthy volunteers: no

Brief summary:
The primary objective of the study is to determine the efficacy of REGN1908-1909, as compared to placebo, to reduce allergic rhinitis/conjunctivitis symptoms and allergy rescue medication use during natural cat exposure.

The Secondary Objectives are:

* To assess the reduction of allergic symptoms and use of allergy rescue medications after treatment with REGN1908-1909 versus placebo, as measured by the individual components of the CSMS
* To assess health-related quality of life (HRQoL) as measured by the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ\[S\])
* To determine the efficacy of REGN1908-1909, as compared to placebo, to inhibit a wheal-and-flare response to a skin prick test with cat allergen
* To assess the durability of effect in allergic rhinitis and conjunctivitis symptom and medication scores after multiple doses of REGN1908-1909 compared to placebo given every 12 weeks (Q12W)
* To determine the efficacy following multiple doses of REGN1908-1909 compared to placebo at inhibiting a wheal-and-flare response to a skin prick test with cat allergen
* To estimate the effect of REGN1908-1909 on lung function, as compared to placebo, in patients with asthma
* To determine the efficacy of REGN1908-1909 as compared to placebo to reduce asthma symptoms in patients with asthma
* To assess whether there is a difference in asthma rescue medication use in patients with asthma who are treated with REGN1908-1909 compared to placebo
* To assess whether there is a difference in nighttime awakenings in patients with asthma treated with REGN1908-1909 compared to placebo
* To evaluate the short-term and long-term safety and tolerability of REGN1908-1909, including the incidence of hypersensitivity reactions, local injection site reactions, and asthma exacerbations
* To determine systemic exposure of total (free and antigen-bound) antibodies as measured by concentration of REGN1908 and REGN1909
* To assess the immunogenicity of REGN1908 and REGN1909

Detailed description:

Arms:
arm 1: Randomized 1:1 arm 2: Randomized 1:1

Interventions: intervention 1: REGN1908-1909 intervention 2: Matching Placebo
Intervention descriptions: intervention 1: Subcutaneous (SC) for a total of 5 administrations intervention 2: SC for a total of 5 administrations

Protocol document:
Prot_000.pdf: 
EudraCT: 2021-002089-42 
IND Number:117093 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY IN CAT-ALLERGIC PATIENTS WITH ALLERGIC 
RHINITIS WHO LIVE WITH A CAT TO ASSESS THE 
EFFICACY AND SAFETY OF ANTI-FEL D 1 ANTIBODIES 
DURING NATURAL CAT EXPOSURE IN THE HOME 
Compound: 
REGN1908-1909 
Clinical Phase: 
3 
Protocol Number: 
R1908-1909-ALG-2102 
Protocol Version: 
R1908-1909-ALG-2102 Amendment 3 
Date of Issue: 
See appended electronic signature page 
Amendment 2 DE Date of Issue: 
01 Oct 2021 
Amendment 1 Admin Date of Issue: 
19 May 2021 
Original Date of Issue: 
30 Apr 2021 
Medical /Study Director: 
 
  
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACQ-5 
Asthma Control Questionnaire 5 Question Version 
ADA 
Anti-drug antibody 
ADSD 
Asthma Daytime Symptom Diary 
ADSS 
Asthma Daily Symptom Score 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANSD 
Asthma Nighttime Symptom Diary 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CSMS 
Combined symptom and medication score 
DMS 
Daily medication score 
EAR 
Early asthmatic response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EEU 
Environmental exposure unit 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FDA 
United States Food and Drug Administration 
Fel d 1 
Felis domesticus allergen 1 
GCP 
Good Clinical Practice 
GINA 
Global Imitative for Asthma 
GPS 
Global Patient Safety 
HDM 
House dust mite 
HRQoL 
Health related quality of life 
IA 
Interim analysis 
IAF 
Informed assent form 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
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IgE 
Immunoglobulin E 
INCS 
Intranasal corticosteroids 
IRB 
Institutional Review Board 
LABA 
Long-acting beta 2-agonist 
LAMA 
Long-acting muscarinic antagonist 
mAb 
Monoclonal antibody 
NAb 
Neutralizing antibody 
pERK 
Phosphorylated extracellular signal-regulated kinase 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PT 
Preferred term 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RBQM 
Risk-Based Quality Monitoring 
RQLQ(S) 
Rhinoconjunctivitis Quality of Life Questionnaire for Ages 12+ 
SABA 
Short-acting beta 2-agonist 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAMA 
Short-acting muscarinic antagonist 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SIT 
Specific immunotherapy 
SOC 
System organ class 
SPT 
Skin prick test 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TNSS 
Total nasal symptom score 
TOSS 
Total ocular symptom score 
TSS 
Total symptom score 
WBC 
White blood cell 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................2 
AMENDMENT HISTORY ...........................................................................................................10 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................22 
1. 
INTRODUCTION ......................................................................................................29 
2. 
STUDY OBJECTIVES ..............................................................................................32 
2.1. 
Primary Objective .......................................................................................................32 
2.2. 
Secondary Objectives .................................................................................................32 
2.3. 
Exploratory Objectives ...............................................................................................33 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................34 
3.1. 
Hypotheses ..................................................................................................................34 
3.2. 
Rationale .....................................................................................................................34 
3.2.1. 
Rationale for Study Design .........................................................................................34 
3.2.2. 
Rationale for Dose Selection ......................................................................................36 
3.3. 
Risk-Benefit ................................................................................................................36 
4. 
ENDPOINTS ..............................................................................................................38 
4.1. 
Primary Endpoint ........................................................................................................38 
4.2. 
Secondary Endpoints ..................................................................................................38 
4.3. 
Exploratory Endpoints ................................................................................................40 
5. 
STUDY VARIABLES................................................................................................42 
5.1. 
Demographic and Baseline Characteristics ................................................................42 
5.2. 
Efficacy Variables ......................................................................................................42 
5.3. 
Safety Variables ..........................................................................................................42 
5.4. 
Pharmacokinetic Variables .........................................................................................42 
5.5. 
Immunogenicity Variables ..........................................................................................42 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................42 
6. 
STUDY DESIGN .......................................................................................................43 
6.1. 
Study Description and Duration .................................................................................43 
6.1.1. 
Study Stopping Rules .................................................................................................46 
6.1.1.1. 
Study Stopping Criteria ..............................................................................................46 
6.1.2. 
End of Study Definition ..............................................................................................46 
6.2. 
Planned Interim Analysis ............................................................................................46 
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6.3. 
Study Committees .......................................................................................................47 
6.3.1. 
Independent Data Monitoring Committee ..................................................................47 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............48 
7.1. 
Number of Patients Planned .......................................................................................48 
7.2. 
Study Population .........................................................................................................48 
7.2.1. 
Inclusion Criteria ........................................................................................................48 
7.2.2. 
Exclusion Criteria .......................................................................................................49 
7.3. 
Premature Withdrawal from the Study .......................................................................52 
7.4. 
Replacement of Patients .............................................................................................52 
8. 
STUDY TREATMENTS............................................................................................53 
8.1. 
Investigational and Reference Treatments ..................................................................53 
8.2. 
Rescue Treatments ......................................................................................................53 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................54 
8.3.1. 
Dose Modification ......................................................................................................54 
8.3.2. 
Study Drug Discontinuation .......................................................................................54 
8.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................54 
8.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................54 
8.4. 
Management of Acute Reactions ................................................................................55 
8.4.1. 
Acute Injection Reactions ...........................................................................................55 
8.4.1.1. 
Systemic Injection Reactions ......................................................................................55 
8.4.1.2. 
Local Injection Site Reactions ....................................................................................55 
8.5. 
Method of Treatment Assignment ..............................................................................55 
8.6. 
Blinding ......................................................................................................................56 
8.7. 
Emergency Unblinding ...............................................................................................56 
8.8. 
Treatment Logistics and Accountability .....................................................................56 
8.8.1. 
Packaging, Labeling, and Storage ..............................................................................56 
8.8.2. 
Supply and Disposition of Treatments .......................................................................57 
8.8.3. 
Treatment Accountability ...........................................................................................57 
8.8.4. 
Treatment Compliance ................................................................................................57 
8.9. 
Concomitant Medications ...........................................................................................57 
8.9.1. 
Prohibited Medications ...............................................................................................57 
8.9.2. 
Permitted Medications ................................................................................................60 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................61 
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9.1. 
Schedule of Events .....................................................................................................61 
9.1.1. 
Footnotes for the Schedule of Events .........................................................................66 
9.1.2. 
Early Termination Visit ..............................................................................................67 
9.1.3. 
Unscheduled Visits .....................................................................................................67 
9.2. 
Study Procedures ........................................................................................................67 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................68 
9.2.2. 
Efficacy Procedures for All Patients ...........................................................................68 
9.2.2.1. 
Total Nasal Symptom Score .......................................................................................68 
9.2.2.2. 
Total Ocular Symptom Score .....................................................................................68 
9.2.2.3. 
Total Symptom Score .................................................................................................68 
9.2.2.4. 
Daily Medication Score ..............................................................................................68 
9.2.2.5. 
Combined Symptom and Medication Score ...............................................................68 
9.2.2.6. 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire for Ages 
12+ ..............................................................................................................................68 
9.2.2.7. 
Patient Global Impression of Severity ........................................................................69 
9.2.2.8. 
Patient Global Impression of Change .........................................................................69 
9.2.2.9. 
Skin Prick Test ............................................................................................................69 
9.2.2.10. 
Spirometry ..................................................................................................................69 
9.2.2.11. 
Evaluation of Cat Exposure ........................................................................................70 
9.2.2.12. 
Patient Experience Assessment ..................................................................................70 
9.2.3. 
Efficacy Procedures for Patients with Asthma ...........................................................70 
9.2.3.1. 
Asthma Nighttime Symptom Diary Score ..................................................................70 
9.2.3.2. 
Asthma Daytime Symptom Diary Score ....................................................................70 
9.2.3.3. 
Asthma Daily Symptom Score ...................................................................................71 
9.2.3.4. 
Nighttime Awakenings ...............................................................................................71 
9.2.3.5. 
Rescue Medication Use ..............................................................................................71 
9.2.3.6. 
Juniper Asthma Control Questionnaire ......................................................................71 
9.2.4. 
Safety Procedures for All Patients ..............................................................................71 
9.2.4.1. 
Body Weight ...............................................................................................................71 
9.2.4.2. 
Vital Signs ..................................................................................................................71 
9.2.4.3. 
Physical Examination .................................................................................................71 
9.2.4.4. 
Electrocardiogram .......................................................................................................72 
9.2.4.5. 
Laboratory Testing ......................................................................................................72 
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9.2.5. 
Drug Concentration and Measurements .....................................................................73 
9.2.6. 
Immunogenicity Measurements and Samples ............................................................73 
9.2.7. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................73 
9.2.8. 
Future Biomedical Research (Optional) .....................................................................73 
9.2.9. 
Pharmacogenomic Analysis (Optional) ......................................................................74 
10. 
SAFETY EVALUATION AND REPORTING .........................................................75 
10.1. 
Recording and Reporting Adverse Events ..................................................................75 
10.1.1. 
General Guidelines .....................................................................................................75 
10.1.2. 
Reporting Procedure ...................................................................................................76 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................76 
10.2. 
Definitions ..................................................................................................................77 
10.2.1. 
Adverse Event .............................................................................................................77 
10.2.2. 
Serious Adverse Event ................................................................................................77 
10.2.3. 
Adverse Events of Special Interest .............................................................................78 
10.2.4. 
Severity .......................................................................................................................78 
10.2.5. 
Causality .....................................................................................................................78 
10.3. 
Safety Monitoring .......................................................................................................80 
10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics Committee, 
and Investigators .........................................................................................................80 
11. 
STATISTICAL PLAN................................................................................................81 
11.1. 
Statistical Hypothesis ..................................................................................................81 
11.2. 
Justification of Sample Size........................................................................................81 
11.3. 
Analysis Sets ...............................................................................................................82 
11.3.1. 
Efficacy Analysis Sets ................................................................................................82 
11.3.2. 
Safety Analysis Set .....................................................................................................82 
11.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................82 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................82 
11.4. 
Statistical Methods ......................................................................................................83 
11.4.1. 
Patient Disposition ......................................................................................................83 
11.4.2. 
Demography and Baseline Characteristics .................................................................83 
11.4.3. 
Efficacy Analyses .......................................................................................................83 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................83 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................85 
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11.4.4. 
Control of Multiplicity ................................................................................................87 
11.4.5. 
Timing of Statistical Analyses ....................................................................................88 
11.4.6. 
Safety Analysis ...........................................................................................................88 
11.4.6.1. 
Adverse Events ...........................................................................................................88 
11.4.6.2. 
Other Safety ................................................................................................................89 
11.4.6.3. 
Treatment Exposure ....................................................................................................90 
11.4.7. 
Pharmacokinetics ........................................................................................................90 
11.4.7.1. 
Analysis of Drug Concentration Data .........................................................................90 
11.4.8. 
Analysis of Immunogenicity Data ..............................................................................90 
11.4.9. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................91 
11.4.10. 
Analysis of Quality of Life Data ................................................................................91 
11.5. 
Statistical Considerations Surrounding the Premature Termination of a Study .........91 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................92 
12.1. 
Data Management and Electronic Systems ................................................................92 
12.1.1. 
Data Management .......................................................................................................92 
12.1.2. 
Electronic Systems ......................................................................................................92 
12.2. 
Study Monitoring ........................................................................................................92 
12.2.1. 
Monitoring of Study Sites ...........................................................................................92 
12.2.2. 
Source Document Requirements ................................................................................93 
12.2.3. 
Case Report Form Requirements ................................................................................93 
12.3. 
Audits and Inspections ................................................................................................93 
12.4. 
Study Documentation .................................................................................................94 
12.4.1. 
Certification of Accuracy of Data ...............................................................................94 
12.4.2. 
Retention of Records ..................................................................................................94 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................95 
13.1. 
Good Clinical Practice Statement ...............................................................................95 
13.2. 
Informed Consent .......................................................................................................95 
13.3. 
Patients Confidentiality and Data Protection ..............................................................96 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................96 
13.5. 
Clinical Study Data Transparency ..............................................................................96 
14. 
PROTOCOL AMENDMENTS ..................................................................................97 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................98 
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15.1. 
Premature Termination of the Study ...........................................................................98 
15.2. 
Close-out of a Site ......................................................................................................98 
16. 
CONFIDENTIALITY ................................................................................................98 
17. 
FINANCING AND INSURANCE .............................................................................98 
18. 
PUBLICATION POLICY ..........................................................................................98 
19. 
REFERENCES ...........................................................................................................99 
20. 
INVESTIGATOR’S AGREEMENT ........................................................................103 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................104 
 
LIST OF TABLES 
Table 1: 
Medications Prohibited Prior to Screening and Throughout the Study ......................57 
Table 2: 
Medications Prohibited During Specific Periods of the Study ...................................59 
Table 3: 
Schedule of Events .....................................................................................................62 
Table 4: 
Summary of Statistical Assumptions and Power for Selected Secondary 
Endpoints ....................................................................................................................82 
Table 5: 
Summary of Estimand for Primary Endpoint .............................................................84 
Table 6: 
Summary of Estimands for Key Secondary Endpoints and Selected Other 
Secondary Endpoints ..................................................................................................86 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................45 
 
 
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AMENDMENT HISTORY 
Amendment 3 
Note: Amendment 2 was a country-specific amendment. Amendment 3 is a global amendment. All 
changes made in Amendment 2 are implemented globally in Amendment 3.  
The main purpose of this amendment is to add safety assessments and to change the timing of the 
primary efficacy endpoint assessment from the initial to the last 12 weeks of the treatment period, 
per health authority requests. Instructions for the skin prick test were modified to ensure that this 
measurement of efficacy is performed in a manner to prevent accidental unblinding starting during 
the treatment period. In countries where local regulations or approvals permit enrollment of adults 
only, enrollment was restricted to patients who are ≥18 years of age. The percent change from 
baseline in daily combined symptom and medication score (CSMS) and symptom scores, averaged 
over the initial 12 weeks (weeks 0 to 12) and the last 12 weeks (weeks 48 to 60) of the treatment 
period, in patients who receive REGN1908-1909 versus placebo, were added as secondary 
endpoints. A non-binding interim futility analysis will now be performed when at least 40% of 
randomized patients have completed the week 12 visit or discontinued before week 12. Other, 
more minor changes were also implemented. 
The following table outlines the changes made to the protocol and the rationale. 
Description of Change 
Brief Rationale 
Sections Changed 
The following safety assessments were 
added as study procedures: 
• 
Physical examination will now 
also be performed at the week 
24 and 36 visits 
• 
Samples for hematology and 
blood chemistry will now also 
be collected at the week 24, 36, 
and 48 visits 
Additional safety assessments were 
added per Health Authority 
request.  
Table 3: Schedule of Events 
The timing of the primary efficacy 
assessment period was changed such that 
the daily CSMS will be averaged over the 
last 12 weeks of the treatment period 
(weeks 48 to 60) instead of the initial 12 
weeks of the treatment period (weeks 0 to 
12) in patients who received REGN1908-
1909 versus placebo.  
The analysis of the daily CSMS averaged 
over the initial 12 weeks of the treatment 
period (weeks 0 to 12) will now be 
considered 
a 
secondary 
efficacy 
endpoint.  
Per health authority suggestion, the 
timing of the primary endpoint was 
changed in acknowledgement that 
REGN1908-1909 is proposed as a 
chronic therapy.  
Clinical Study Protocol 
Synopsis, Primary Endpoint 
Clinical Study Protocol 
Synopsis, Secondary Endpoints 
Clinical Study Protocol 
Synopsis, Statistical Plan 
Section 3.1 Hypotheses 
Section 3.2.1 Rationale for 
Study Design 
Section 4.1 Primary Endpoint 
Section 4.2 Secondary 
Endpoints 
Section 6.1 Study Description 
and Duration 
Table 2: Medications 
Prohibited During Specific 
Periods of the Study 
Figure 1: Study Flow Diagram 
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Description of Change 
Brief Rationale 
Sections Changed 
Table 3: Schedule of Events 
Section 9.1.2 Early 
Termination Visit 
Section 11.1 Statistical 
Hypothesis 
Section 11.4.3.1 Primary 
Efficacy Analysis 
Table 5: Summary of Estimand 
for Primary Endpoint 
In addition to changing the primary 
endpoint timing, other endpoints under 
“key secondary,” “other secondary,” and 
“exploratory” were re-categorized.  
Categorization of endpoints was 
reconsidered based on the change 
in timing for the primary endpoint 
and to more accurately reflect the 
analyses intended by the sponsor.  
Clinical Study Protocol 
Synopsis, Primary Endpoint 
Clinical Study Protocol 
Synopsis, Secondary Endpoints 
Section 4.2 Secondary 
Endpoints 
Section 4.3 Exploratory 
Endpoints 
The percent change from baseline in 
daily combined symptom and medication 
score (CSMS) and symptom scores, 
averaged over the initial 12 weeks (weeks 
0 to 12) and last weeks (weeks 48 to 60) 
of the treatment period in patients who 
receive REGN1908-1909 versus placebo 
were added as secondary endpoints. 
The daily CSMS, averaged over 
the last 12 weeks of the treatment 
period in patients who receive 
REGN1908-1909 versus placebo is 
the primary endpoint of the study 
and symptom and medication 
scores analyzed in a similar 
manner are secondary endpoints 
during weeks 0 to12 and weeks 48 
to 60 in the current protocol; the 
percent change from pre-treatment 
baseline in these parameters were 
added as secondary endpoints.  
Clinical Study Protocol 
Synopsis, Secondary Endpoints 
Clinical Study Protocol 
Synopsis, Statistical Plan 
Section 4.2 Secondary 
Endpoints 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Table 6: Summary of 
Estimands for Key Secondary 
Endpoints and Select Other 
Secondary Endpoint 
Percent 
change 
from 
pre-treatment 
baseline over the initial 12 weeks and the 
last 12 weeks of the treatment period in 
patients with asthma who receive 
REGN1908-1909 versus placebo for 
average asthma daily symptom score 
(ADS), average frequency of asthma 
rescue medication use, and average 
frequency in nighttime awakenings will 
be analyzed as exploratory endpoints.  
The data for these analyses will be 
collected and percent change in 
these parameters from 
pre-treatment baseline over the 
initial 12 weeks and the last 12 
weeks of the treatment period can 
analyzed for exploratory research.  
Clinical Study Protocol 
Synopsis, Other Secondary 
Endpoints 
Section 4.2 Secondary 
Endpoints 
Section 4.3 Exploratory 
Endpoints 
Instructions for the skin prick test (SPT) 
post-randomization were modified to 
ensure that this measurement of efficacy 
is performed in a manner to prevent 
accidental unblinding starting during the 
treatment period. 
The SPTs (cat, saline, histamine, and 
house dust mites) will be run in replicate 
(8 total) with a blinded code. The allergen 
wells will be blinded by the unblinded 
The anti-Fel d 1 antibodies 
suppress SPT based on the 
mechanism of action of the drug by 
binding to the allergen and 
inhibition of type I, immediate, 
IgE-mediated response. A blinding 
strategy for the skin prick test was 
added to ensure the integrity of the 
clinical study results by preventing 
accidental unblinding in some 
Table 3: Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events, footnote #3  
Section 9.2.2.9 Skin Prick Test 
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Description of Change 
Brief Rationale 
Sections Changed 
pharmacist (or qualified designee) and 
provided with labels (allergen #1 to 
allergen #7) to the blinded personnel. 
One positive control histamine skin prick 
test will not be blinded.  
House dust mite SPT will be added at 
weeks 12, 60, and 72 to be performed 
with the cat SPT testing. 
patients that may have a large 
suppression of SPT to cat allergen.  
Patients with allergic rhinitis are 
frequently poly-allergic and 
symptoms due to house dust mite 
allergy could potentially overlap 
during the efficacy assessment 
periods for the study. Therefore, 
house dust mite SPT has been 
added at additional timepoints 
during the study due to the longer 
trial duration to identify any new 
sensitizations that may potentially 
impact efficacy and to help 
maintain the blind for the cat SPT. 
Eligibility criteria were modified to 
specify that for those countries where 
local regulations or approvals permit 
enrollment of adults only, subject 
recruitment will be restricted to those 
who are ≥18 years of age.*  
Additional language to further support 
the rationale for inclusion of adolescents 
was added to Rationale for Study Design.   
These modifications were made to 
accommodate local regulations or 
approvals in countries where 
enrollment of adolescents was not 
permitted.  
Clinical Study Protocol 
Synopsis, Study Design 
Clinical Study Protocol 
Synopsis, Target Population 
Clinical Study Protocol 
Synopsis, Sample Size 
Section 3.2.1 Rationale for 
Study Design 
Section 6.1 Study Description 
and Duration 
Section 7.2 Study Population 
Section 7.2.1 Inclusion Criteria, 
criterion #1 
A non-binding interim futility analysis 
will be performed when at least 40% of 
randomized patients have completed the 
week 12 visit or discontinued before 
week 12. The details of the analysis will 
be described in the Statistical Analysis 
Plan. 
The results of the interim futility 
analysis will inform internal 
business decisions regarding this 
study and the clinical development 
program.   
Clinical Study Protocol 
Synopsis, Control of 
Multiplicity 
Section 6.2 Planned Interim 
Analysis 
Section 6.3.1 Independent Data 
Monitoring Committee 
Section 11.4.4 Control of 
Multiplicity 
Section 11.4.5 Timing of 
Statistical Analyses 
Text was added to clarify that in-class 
equivalents of the protocol-specified 
rescue medications may be used, if 
discussed and agreed upon with the 
sponsor.  
This clarification was made to 
allow flexibility regarding rescue 
medication.  
Section 8.2 Rescue Treatments 
Section 8.9.2 Permitted 
Medications 
Section 9.2.2.4 Daily 
Medication Score 
Additional criteria were added for 
permanent 
and 
temporary 
discontinuation of study drug. 
The safety precaution for asthmatic 
patients was added to the criteria 
for permanent study drug 
discontinuation per Ethics 
Section 8.3.2.1 Reasons for 
Permanent Discontinuation of 
Study Drug 
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Permanent Discontinuation 
• 
A serious or severe asthma 
event deemed related to 
study drug that in the 
opinion of the investigator 
would result in an 
increased risk to the patient 
or a ≥50% decline in FEV1 
from pre-treatment 
baseline. 
• 
If, in the investigator’s 
opinion or at the specific 
request of the sponsor, 
continuation of study drug 
would be detrimental to the 
patient’s well-being, there 
is no longer any potential 
for benefit, or if 
continuation would 
undermine the scientific 
integrity of the study 
• 
In the event of a critical 
protocol deviation, at the 
discretion of the 
investigator or the sponsor 
Temporary Discontinuation 
• 
An asthmatic patient 
experiencing an asthma 
exacerbation and/or a 
clinically relevant decrease 
in FEV1 ≥20% below 
baseline at a visit during 
which study drug was 
scheduled to be dosed, per 
investigator judgement. In 
this case, the patient may 
return to the clinic within 
the dosing visit window to 
be re-assessed for 
eligibility to receive study 
drug.  
• 
Other intercurrent illness 
or adverse event or major 
surgery that could, in the 
opinion of the investigator, 
present an unreasonable 
Committee (EC) and regulatory 
agency recommendation. 
The additional criteria for 
permanent or temporary study drug 
discontinuation were added to 
prevent administration of study 
drug when not advisable.  
The increased window for study 
drug dosing allows patients 
additional time to avoid missed 
doses. 
Section 8.3.2.2 Reasons for 
Temporary Discontinuation of 
Study Drug 
 
Changes pertaining to increased 
dosing window: 
Section 9.1.1 Footnotes for the 
Schedule of Events, footnote #6  
Section 9.2.2.10 Spirometry 
Table 3: Schedule of Events 
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Description of Change 
Brief Rationale 
Sections Changed 
risk to the patient as a 
result of his/her continued 
use of the study drug 
To avoid redundancy with the newly 
added criterion, “surgical procedure” was 
removed 
from 
the 
Temporary 
Discontinuation list.   
To accommodate the increased window 
for study drug administration, the dosing 
visit windows for visits during which 
study 
drug 
is 
scheduled 
to 
be 
administered was changed from ±7 to 
±14 days. 
A statement was added to further clarify 
that specific asthma medications - 
bronchodilators 
(beta-agonists 
and 
muscarinic antagonists) - will be washed 
out prior to spirometry assessments to 
prevent interference with spirometry and 
the recommended washout periods.  
Washout 
for 
bronchodilators 
was 
removed 
from 
the 
Medications 
Prohibited During Specific Periods of the 
Study table and added to the study 
procedures section describing spirometry 
with examples of washout timeframes 
(less restrictive).  
This text was added to ensure 
accurate spirometry results and to 
ensure patient safety, EC 
recommendation.  
Table 2: Medications 
Prohibited During Specific 
Periods of the Study 
Section 9.2.2.10 Spirometry 
Modifications and clarifications were 
made to prohibited medications.  
Modifications include the following:  
• 
Systemic calcineurin inhibitors 
were added as medications 
prohibited prior to screening 
and 
throughout 
the 
study. 
Topical calcineurin inhibitors 
have been removed from the list 
of prohibited medications 
• 
Decongestants 
are 
now 
prohibited from the baseline 
assessment period up to week 12 
and from weeks 48 to 60 with a 
3-day 
washout 
period. 
Previously 
there 
was 
no 
restriction 
on 
the 
use 
of 
decongestants.  
General clarification was added that 
anti-allergic 
medications 
(such 
as 
antihistamines, anti-allergic eye drops, 
These medications may impact 
efficacy endpoint measurements.  
Table 1: Medications 
Prohibited Prior to Screening 
and Throughout the Study 
Table 2: Medications 
Prohibited During Specific 
Periods of the Study 
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Description of Change 
Brief Rationale 
Sections Changed 
anti-allergic nasal sprays) outside of 
study-related anti-allergic medications 
are prohibited during baseline and 
efficacy assessment periods (baseline to 
week 12 and weeks 48 to 60). 
Eligibility criteria were modified to 
exclude participation of any patient 
committed to an institution by virtue of 
an order issued either by the judicial or 
the administrative authorities.  
This exclusion criterion is an 
addition to the sponsor’s protocol 
template aimed to increase the 
ethical integrity of clinical studies.  
Section 7.2.2 Exclusion 
Criteria, criterion #27 
Language was added to clarify that the 
total 
rhinitis/conjunctivitis 
symptom 
score  is based on total symptom score 
(TSS), which will be measured to 
determine whether a patient has a daily 
total 
rhinitis/conjunctivitis 
symptom 
score of at least 8 of 18 during at least 8 
days of the 15-day baseline assessment 
period.  
Clarification was added per Health 
Authority suggestion.  
Section 6.1 Study Description 
and Duration 
Section 7.2.1 Inclusion Criteria, 
criterion #5 
Language was added to clarify that 
whether a patient has significant multiple 
and/or severe allergies is to be assessed 
by the investigator in the criterion 
excluding 
patients 
from 
study 
participation who have a history of 
significant 
multiple 
and/or 
severe 
allergies that would potentially interfere 
with the assessments during the baseline 
and 12-week efficacy assessment periods 
or confound results.  
This clarification was made per 
health authority suggestion.  
Section 7.2.2 Exclusion 
Criteria, criterion #1 
Text was added to specify that if, during 
the screening period, missing data are 
reported due to documented e-diary 
malfunction (eg, technical issues that are 
reported to the vendor), then the baseline 
assessment period may be extended 
accordingly, allowing the 15-day period 
to be re-started, to ensure that a 
consecutive 15-day period can be 
obtained. In such a circumstance, the 
medical monitor should be consulted, and 
agreement must be obtained with the 
sponsor. 
This was added to ensure that 
otherwise eligible patients are not 
deemed ineligible for study 
participation due to technical 
issues that may arise with e-diary 
usage.  
Section 6.1 Study Description 
and Duration 
Section 9.1.1 Footnotes for the 
Schedule of Events, footnote #2 
Text was added specifically to state the 
in-clinic observation period of 2 hours 
post-drug administration after each dose 
of study drug.*  
More specific text was added for 
clarity surrounding the in-clinic 
observation period that is in place 
to ensure patient safety, per EC and 
Health Authority recommendation.  
Table 3: Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events, footnote #5 
(added; subsequent footnotes 
were re-numbered accordingly) 
The number of vital sign measurements 
to be performed was clarified and vital 
These changes clarify the number 
of vital sign measurements to be 
performed. Additional vital sign 
Section 9.1.1 Footnotes for the 
Schedule of Events, footnote #8  
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Description of Change 
Brief Rationale 
Sections Changed 
sign measurements were added post drug 
administration on visits 6 and 12.  
measurements added for patient 
safety, per Health Authority 
recommendation.  
In addition to the current evaluation of cat 
exposure at the screening, baseline, and 
randomization 
visits 
(via 
the 
inclusion/exclusion criteria), patients will 
now also be asked about their exposure to 
cat(s) at study visits 6, 8, 10, 12, 14, and 
at any unscheduled visit.* 
In addition, from week 48 through week 
60, as part of the patient reported e-diary, 
patients will be asked to report exposure 
to their cat(s). 
These questions are important to 
understand a patient’s continued 
exposure to cat(s), per Health 
Authority recommendation.  
Clinical Study Protocol 
Synopsis, Procedures and 
Assessments 
Table 3: Schedule of Events 
Section 9.2.2.11 Evaluation of 
Cat Exposure 
Patients will answer questions (Patient 
Experience Assessment) at end of 
treatment (week 60) to assess changes 
that patients experienced over the course 
of the study regarding the amount of time 
they spent with their cat(s) and the impact 
on their health status.  
These changes may support 
assessment of impact of drug on 
efficacy outcomes.  
Clinical Study Protocol 
Synopsis, Procedures and 
Assessments 
Table 3: Schedule of Events 
Section 9.2.2.11 Patient 
Experience Assessment 
Patients with comorbid asthma will now 
complete the Asthma Daytime Symptom 
Diary (ADSD), questions on asthma 
rescue medication use, the Asthma 
Nighttime Symptom Diary (ANSD) and 
questions on nighttime awakening during 
the last 12 weeks of the treatment period 
(weeks 48 to 60), in addition to the 
previously specified timeframe of weeks 
0 to 12.  
This change allows the efficacy 
analyses for patients with asthma 
to be performed during the primary 
efficacy analysis period.  
Section 3.2.1 Rationale for 
Study Design 
Section 4.2 Secondary 
Endpoints 
Section 4.3 Exploratory 
Endpoints 
Section 6.1 Study Description 
and Duration 
Table 3: Schedule of Events 
Instructions 
for 
the 
body 
weight 
assessment that specified that patients 
should void (empty bladder) prior to 
weight assessment and that patients 
should be wearing undergarments only 
and no shoes during 
the 
weight 
assessment were removed.  
This change allows flexibility for 
performing this assessment, per 
feasibility at each study site.  
Section 9.2.4.1 Body Weight 
A statement was added to allow sample 
size re-estimation in a blinded fashion 
after greater than 50% of patients have 
baseline data available using observed 
values of CSMS to determine the 
baseline PBO mean (SD) and assuming 
the same 20% difference between 
REGN1908-1909 versus placebo. If the 
re-estimated number is higher than the 
current estimation of 315 per arm, then 
the sample size may be increased. 
This will ensure adequate sample 
size for the planned analyses.  
Clinical Study Protocol 
Synopsis, Justification of 
Sample Size 
Section 11.2 Justification of 
Sample Size 
Table 4: Summary of Statistical 
Assumptions and Power for 
Selected Secondary Endpoints 
Modifications and clarifications were 
made specifying how to handle the 
The composite approach allows the 
analysis to include observed values 
Section 11.4.3.1  
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Description of Change 
Brief Rationale 
Sections Changed 
intercurrent 
event 
of 
prohibited 
medications.  
The primary estimand for the relevant 
prohibited medications will utilize the 
observed TNSS, TOSS, and DMS prior 
to receiving prohibited medication or the 
worst score of all observations in 
corresponding treatment group if a 
patient has no single value of CSMS 
during the 12-week assessment period 
(composite 
strategy) 
to 
handle 
intercurrent 
events. 
Previously, 
a 
hypothetic strategy was proposed.  
prior to receiving prohibited 
medications.  
Primary Efficacy Analysis 
Table 5: Summary of Estimand 
for Primary Endpoint 
Table 6: Summary of 
Estimands for Key Secondary 
Endpoints and Select Other 
Secondary Endpoint 
 
A modification was made to specify that 
the worst score to impute the missing data 
should be the worst one of the 
observations 
in 
the 
corresponding 
treatment group if a patient does not have 
any observed value of the endpoint 
during the 12-week assessment period 
because of the patients’ discontinuation 
from study due to AEs and lack of 
efficacy. 
The change supports the 
imputation considering treatment 
groups. 
Section 11.4.3.1  
Primary Efficacy Analysis 
Table 5: Summary of 
Estimands for Primary 
Endpoint 
Table 6: Summary of 
Estimands for Key Secondary 
Endpoints and Select Other 
Secondary Endpoint 
 
Language was added specifying that if a 
pregnancy occurs during the study, 
information about the progress and 
outcome of the pregnancy will be 
collected. This should include the date 
that the subject became pregnant, 
information about the health of the 
subject, 
any 
medication 
treatments 
received during the pregnancy, any 
medical problems affecting or related to 
the pregnancy and/or the baby, whether 
the pregnancy came to term, the date of 
the child’s birth, and the health of the 
child 
after 
birth. 
To 
collect 
this 
information, the study staff should 
contact the subject every trimester for 
updates on the pregnancy. The subject 
should also be asked to contact the site as 
soon as possible in the event of any 
medical problem affecting or related to 
the pregnancy and/or baby. Once the 
baby is born, the study staff will ask for a 
final update after one well-baby visit with 
the pediatrician. 
More specific instructions were 
added regarding the collection of 
information related to a pregnancy 
in order to standardize the type of 
information collected.  
Section 10.1.1 General 
Guidelines 
A statement was added noting that 
anaphylaxis 
will 
be 
prospectively 
analyzed using the criteria discussed in 
the statement paper from the Second 
This statement and reference were 
added based on health authority 
suggestion.  
Section 10.1.3 Events that 
Require Expedited Reporting to 
the Sponsor 
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Description of Change 
Brief Rationale 
Sections Changed 
Symposium on the definition and 
Management of Anaphylaxis (Summary 
Report-Second National Institute of 
Allergy and Infectious Disease/Food 
Allergy 
and 
Anaphylaxis 
Network 
Symposium. J Allergy Clin Immunol 
2006;117(2):391-97).  
Exclusion criterion number 13 was 
modified to “SIT with any allergen other 
than cat at screening visit 1. Patients who 
plan to initiate SIT during the trial period 
will be excluded.” The prior criterion 
excluded patients on SIT with any 
allergen other than cat within 6 months 
prior to screening visit 1.  
This change was made to allow 
more flexibility for patients to 
enroll in the trial if they were not 
on allergen specific 
immunotherapy other than cat at 
screening visit 1 without the 
requirement for a 6-month washout 
prior to screening, based on health 
authority feedback. 
Section 7.2.2 Exclusion 
Criteria, criterion #13 
Treatment-emergent 
adverse 
events 
(TEAEs) will be defined as those that are 
not present at baseline or represent the 
exacerbation of a pre-existing condition 
during the on-treatment and follow-up 
periods.  
This definition within the safety 
analysis section was updated to 
align with the endpoints.  
Section 11.4.6.1 Adverse 
Events 
The 3 locations for subcutaneous (SC) 
injection (upper arms, abdomen, and 
thighs) for a single dose was added to the 
description of investigational treatments, 
along with the recommendation not to 
administer all 3 injections in the same 
site. A statement that there will be 5 visits 
during the treatment period during which 
study drug will be administered for a total 
of 15 injections was also added.  
Additional instructional and 
descriptive information regarding 
study drug administration was 
provided in the protocol for 
convenience and clarity.  
Section 8.1 Investigational and 
Reference Treatments 
Text was added to clarify that treatment 
of cat allergy includes removal of the cat 
from the home and that this study is 
intended for those who continue to have 
cat exposure in the home.  
Additionally, text was added to support 
the persistence of cat allergen even after 
removal of a cat from the home.  
These modification were added per 
EC request and to support that 
treatment of cat allergy can be 
challenging in patients who 
continue to have cat allergen 
exposure. 
Section 1 Introduction 
Section 3.3 Risk-Benefit 
Clarification of clinical pharmacology 
data for study dosing was added to 
support multiple administration.  
Additional text was added to 
support the study drug dosing for 
this study. 
Section 3.2.2 Rationale for 
Dose Selection 
Instructions consistent with the sponsor’s 
latest guidelines for receipt of a 
COVID-19 vaccine (initial series or 
booster) by a study participant during the 
study were added.  
The sponsor has issued guidance 
on receipt of the COVID-19 
vaccine in relation to the conduct 
of its clinical studies.  
Section 8.9.2 Permitted 
Medications 
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Description of Change 
Brief Rationale 
Sections Changed 
The statement that shift tables based on 
baseline normal/abnormal and other 
tabular graphical methods may be used to 
present the results for laboratory tests of 
interest was removed from the protocol.  
Analysis and presentation of these 
data will be discussed, as relevant, 
in the Statistical Analysis Plan.  
Section 11.4.6.2 Other Safety 
Minor editorial changes, clarifications, 
and updates to align with the current 
sponsor template were made.  
These changes were made to 
increase clarity and improve 
readability.  
Throughout the protocol.  
*Note that this change was implemented in the country-specific protocol amendment 2.  
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Amendment 2 DE 
Amendment 2 was a country-specific amendment. All changes made in Amendment 2 were 
implemented globally in Amendment 3. 
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Amendment 1 
The purpose of this protocol amendment is to correct a typo and provide a clarification within the 
inclusion criteria. 
Description of Change 
Rationale 
Section Changed 
The phrase “augmented rental clearance” was 
corrected to say “allergic rhinoconjunctivitis.” 
Correction of a typo. 
Section 7.2.1 Inclusion Criteria, #5 
A clarification was made that, for adolescents, 
a parent or legal guardian must also provide 
informed consent.  
Additionally, the row for “informed consent” 
was modified to say “informed 
consent/assent” within the schedule of events 
table. 
 
 
For clarification. 
Section 7.2.1 Inclusion Criteria, #7 
Table 3 Schedule of Events 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-Blind, Placebo-Controlled Study in Cat-Allergic 
Patients with Allergic Rhinitis Who Live with a Cat to Assess the Efficacy 
and Safety of Anti-Fel d 1 Antibodies during Natural Cat Exposure in the 
Home 
Site Locations 
Approximately 630 adult and adolescent patients will be enrolled at multiple 
sites across North America and Europe. 
Principal Investigator 
To be determined 
Objectives 
Primary Objective  
The primary objective of the study is to determine the efficacy of 
REGN1908-1909, 
as 
compared 
to 
placebo, 
to 
reduce 
allergic 
rhinitis/conjunctivitis symptoms and allergy rescue medication use during 
natural cat exposure. 
Note: The combined symptom and medication score (CSMS) is defined as 
the daily combined allergic rhinitis and conjunctivitis total symptom score 
(TSS: calculated as the sum of total nasal symptom score [TNSS] and total 
ocular symptom score [TOSS]) plus daily medication score (DMS). 
Secondary Objectives 
The secondary objectives are: 
• To assess the reduction of allergic symptoms and use of allergy rescue 
medications after treatment with REGN1908-1909 versus placebo, as 
measured by the individual components of the CSMS 
• To assess health-related quality of life (HRQoL) as measured by the 
Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ[S])  
• To determine the efficacy of REGN1908-1909, as compared to 
placebo, to inhibit a wheal-and-flare response to a skin prick test with 
cat allergen 
• To assess the durability of effect in allergic rhinitis and conjunctivitis 
symptom and medication scores after multiple doses of REGN1908-
1909 compared to placebo given every 12 weeks (Q12W) 
• To 
determine 
the 
efficacy 
following 
multiple 
doses 
of 
REGN1908-1909 compared to placebo at inhibiting a wheal-and-flare 
response to a skin prick test with cat allergen 
• To estimate the effect of REGN1908-1909 on lung function, as 
compared to placebo, in patients with asthma  
• To determine the efficacy of REGN1908-1909 as compared to placebo 
to reduce asthma symptoms in patients with asthma 
• To assess whether there is a difference in asthma rescue medication use 
in patients with asthma who are treated with REGN1908-1909 
compared to placebo  
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• To assess whether there is a difference in nighttime awakenings in 
patients with asthma treated with REGN1908-1909 compared to 
placebo  
• To evaluate the short-term and long-term safety and tolerability of 
REGN1908-1909, including the incidence of hypersensitivity 
reactions, local injection site reactions, and asthma exacerbations  
• To determine systemic exposure of total (free and antigen-bound) 
antibodies as measured by concentration of REGN1908 and 
REGN1909  
• To assess the immunogenicity of REGN1908 and REGN1909  
Study Design 
This is a phase 3, randomized, double-blind, parallel-group, multi-dose study 
in approximately 630 cat-allergic adult (≥18 years of age) and adolescent 
patients (ages ≥12 to <18 years), where permitted, with allergic rhinitis with 
or without conjunctivitis and with or without asthma. 
• Cat allergic patients living with a cat who are significantly 
symptomatic while using standard of care anti-allergy medications will 
be enrolled in the study. The study includes a screening period of up to 
12 weeks to ensure sensitization and medication use requirements are 
met during the baseline period. 
• Randomization to 1 of 2 treatment arms (1:1)  
o 
REGN1908-1909 600 mg (300 mg per monoclonal 
antibody [mAb])  
o 
Placebo that replaces REGN1908-1909 
• Study drug will be administered Q12W for a total of 5 administrations 
• End of treatment visit at week 60 
• End of study safety follow-up visit at week 72 
The screening period is set up to be a long enough duration so that the 
baseline assessment will occur outside of relevant pollen seasons for patients 
who are pollen allergic. Efficacy assessments will be done during the initial 
12 weeks (weeks 0 to 12) after the first dose and during the last 12-week 
period (weeks 48 to 60) after last dose (dose 5) of REGN1908-1909 or 
placebo. For those individuals with seasonal allergies, efficacy assessments 
will be timed by the investigational site to ensure that the assessments are 
outside of any relevant pollen seasons. 
Study Duration 
The duration of the study for a patient is approximately 72 weeks, excluding 
the screening period of up to 12 weeks. 
End of Study Definition 
The end of study is defined as the date the last patient completes the last 
study visit or 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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Target Population 
Male and female patients 12 years of age and older (≥12 to <18 years of age, 
where permitted) living with at least 1 cat who have allergic rhinitis with or 
without conjunctivitis symptoms and with or without asthma with cat 
sensitization confirmed at screening will be enrolled after they meet a 
symptom and medication requirement at baseline. Other inclusion and 
exclusion criteria apply. 
 
Sample Size: 
Approximately 630 patients will be enrolled.  
Treatment 
Study Drug and Placebo 
Dose/Route/Schedule: 
• REGN1908-1909 600 mg (300 mg per mAb), administered by 
subcutaneous (SC) injections Q12W for a total of 5 doses 
• Matching placebo that replaces REGN1908-1909 SC Q12W 
Endpoints 
Primary Endpoint 
The primary endpoint is the daily CSMS, averaged over the last 12 weeks of 
the treatment period (weeks 48 to 60), in patients who receive REGN1908-
1909 versus placebo. 
Note: CSMS is defined as the daily combined allergic rhinitis and 
conjunctivitis TSS (calculated as the sum of TNSS and TOSS) plus daily 
medication score (DMS). 
Key Secondary Endpoints  
The key secondary endpoints, specified without order, are: 
• 
Daily TNSS, averaged over the last 12 weeks of treatment period 
(weeks 48 to 60), in patients who receive REGN1908-1909 versus 
placebo 
• 
Percent change from pre-treatment baseline in average CSMS, over 
the last 12 weeks of the treatment period (weeks 48 to 60), in 
patients who receive REGN1908-1909 versus placebo  
• 
Percent change from pre-treatment baseline in average TNSS, over 
the last 12 weeks of the treatment period (weeks 48 to 60), in 
patients who receive REGN1908-1909 versus placebo 
• 
Daily TSS, averaged over the last 12 weeks of the treatment period 
(weeks 48 to 60), in patients who receive REGN1908-1909 versus 
placebo 
• 
Percent change from pre-treatment baseline in average TSS, over 
the last 12 weeks of the treatment period (weeks 48 to 60), in 
patients who receive REGN1908-1909 versus placebo 
• 
Percent change from baseline to the end of treatment (week 60) in 
cat SPT mean wheal diameter in patients who receive REGN1908-
1909 versus 
Other Secondary Endpoints 
Other secondary endpoints, specified without order, are: 
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• 
Daily CSMS, averaged over the initial 12 weeks of the treatment 
period (weeks 0 to 12), in patients who receive REGN1908-1909 
versus placebo 
• 
Daily TNSS, averaged over the initial 12 weeks of treatment period 
(weeks 0 to 12), in patients who receive REGN1908-1909 versus 
placebo 
• 
Percent change from pre-treatment baseline in average CSMS, over 
the initial 12 weeks of the treatment period (weeks 0 to 12), in 
patients who receive REGN1908-1909 versus placebo 
• 
Percent change from pre-treatment baseline in average TNSS, over 
the initial 12 weeks of the treatment period (weeks 0 to 12), in 
patients who receive REGN1908-1909 versus placebo 
• 
Percent change from pre-treatment baseline in average TSS, over 
the initial 12 weeks of the treatment period (weeks 0 to 12), in 
patients who receive REGN1908-1909 versus placebo 
• 
Daily TSS score, averaged over the initial 12 weeks of the treatment 
period (weeks 0 to 12), in patients who receive REGN1908-1909 
versus placebo 
• 
Percent change from pre-treatment baseline in average TOSS, over 
the initial 12 weeks of the treatment period (weeks 0 to 12), in 
patients who receive REGN1908-1909 versus placebo 
• 
Daily TOSS, averaged over the last 12 weeks of the treatment 
period (weeks 48 to 60), in patients who receive REGN1908-1909 
versus placebo 
• 
Percent change from pre-treatment baseline in average TOSS, over 
the last 12 weeks of the treatment period (weeks 48 to 60), in 
patients who receive REGN1908-1909 versus placebo 
• 
Percent change from baseline to week 12 in FEV1 in patients with 
asthma who receive REGN1908-1909 versus placebo 
• 
Percent change from baseline to week 60 in FEV1 in patients with 
asthma who receive REGN1908-1909 versus placebo 
• 
Percent change from baseline to week 12 in cat skin prick test (SPT) 
mean wheal diameter in patients who receive REGN1908-1909 
versus placebo 
• 
Change from baseline to week 12 in FEV1 in patients with asthma 
who receive REGN1908-1909 versus placebo 
• 
Change from baseline to week 60 in FEV1 in patients with asthma 
who receive REGN1908-1909 versus placebo 
• 
Change from baseline to week 60 in RQLQ(S)+12 in patients who 
receive REGN1908-1909 versus placebo 
• 
DMS, averaged over the initial 12 weeks of the treatment period 
(weeks 0 to 12), in patients who receive REGN1908-1909 versus 
placebo 
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• 
DMS, averaged over the last 12 weeks of the treatment period 
(weeks 48 to 60), in patients who receive REGN1908-1909 versus 
placebo 
• 
Percent change from pre-treatment baseline in average DMS, 
averaged over the last 12 weeks of the treatment period (weeks 48 
to 60), in patients who receive REGN1908-1909 versus placebo 
• 
Percent change from baseline to end of study (week 72) in cat SPT 
mean wheal diameter in patients who receive REGN1908-1909 
versus placebo 
• 
Asthma daily symptom (ADS) score, averaged over the initial 12 
weeks of the treatment period (weeks 0 to 12), using Asthma 
Daytime Symptom Diary (ADSD) and the Asthma Nighttime 
Symptom Diary (ANSD), in patients with asthma who receive 
REGN1908-1909 versus placebo 
• 
Asthma daily symptom (ADS) score, averaged over the last 12 
weeks of the treatment period (weeks 48 to 60), using Asthma 
Daytime Symptom Diary (ADSD) and the Asthma Nighttime 
Symptom Diary (ANSD), in patients with asthma who receive 
REGN1908-1909 versus placebo 
• 
Daily TOSS, averaged over the initial 12 weeks of the treatment 
period (weeks 0 to 12), in patients who receive REGN1908-1909 
versus placebo 
• 
Change from baseline to week 60 in ACQ-5 in patients with asthma 
who receive REGN1908-1909 versus placebo 
• 
Daily number of nighttime awakenings, averaged over the initial 
12 weeks of the treatment period (weeks 0 to 12), in patients with 
asthma who receive REGN1908-1909 versus placebo 
• 
Daily number of nighttime awakenings, averaged over the last 
12 weeks of the treatment period (weeks 48 to 60), in patients with 
asthma who receive REGN1908-1909 versus placebo 
• 
Incidence of treatment-emergent adverse events (TEAEs), AESIs, 
and serious TEAEs throughout the study (weeks 0 to 72)  
• 
Total REGN1908 and REGN1909 concentration in serum over the 
study duration (weeks 0 to 72)  
• 
Incidence of treatment-emergent anti-drug antibodies (ADAs) to 
REGN1908 and REGN1909 throughout the study (weeks 0 to 72) 
Procedures and Assessments 
Efficacy assessments will include: TNSS, TOSS, TSS (calculated as 
TNSS+TOSS), DMS, CSMS (calculated as TSS+DMS), ANSD score, 
ADSD score, nighttime awakenings and asthma rescue medication use, 
ACQ-5, RQLQ(S), Patient Global Impression of Severity (PGIS), Patient 
Global Impression of Change (PGIC), spirometry, SPT with cat allergen and 
other relevant allergen extracts, and serum for sIgE for cat and other 
allergens. 
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Patients will be asked throughout the study about their continued exposure 
to cat(s). Patients will also be asked questions in the Patient Experience 
Assessment at week 60 to characterize exposure to their cat(s) in order to 
further inform interpretation of efficacy results.   
Safety assessments will include monitoring laboratory tests (hematology, 
blood chemistry, urinalysis, pregnancy tests), weight, vital signs, physical 
examination, ECG, adverse events (AEs), and concomitant medications. 
Samples will be collected for pharmacokinetic (PK), immunogenicity, and 
exploratory research. 
Statistical Plan 
Justification of Sample Size 
The sample size will be approximately 315 patients per arm, for a total of 
630 patients. This study is powered to detect differences between 
REGN1908-1909 and placebo on the primary endpoint of daily average 
CSMS averaged over the last 12 weeks of the treatment period (weeks 48 to 
60 primary) when considering a 20% dropout rate by week 60.  
A sample size of 251 patients per arm gives 90% power to detect a mean 
difference in daily average CSMS of 1.8 (20% reduction from placebo) 
between REGN1908-1909 (mean CSMS = 7.3) and placebo (mean CSMS = 
9.1), assuming a common standard deviation in CSMS of 6.2. Assuming a 
20% dropout rate (~64 per arm) by the last 12 weeks (weeks 48 to 60), the 
sample size is 315 patients per arm. A 2-sample t-test with 2-sided alpha of 
0.05 was assumed. Calculations were performed using nQuery+nTerim 4.0.  
A sample size of 315 patients per arm also gives the power of 91% and 96% 
to detect a 20% reduction from placebo in TSS (SD=3.0 and mean in 
placebo=4.2) and TNSS (SD=2.3 and mean in placebo=3.3) during the 
primary efficacy period, respectively.  
Estimates of mean in the placebo and common variability are based on the 
house dust mite (HDM) SLIT-tablet data for combined rhinoconjunctivitis 
score during 8-week assessment period. A treatment difference of 20% 
relative to placebo is based on a previous phase 1b study (R1908-1909-ALG-
1325) of the same molecules and the treatment effect observed for reduction 
in symptoms after a nasal allergen challenge over a 12-week period.  
Primary Efficacy Analysis 
The primary analysis of the efficacy endpoint, the daily CSMS averaged over 
the last 12 weeks of the treatment period (weeks 48 to 60), will be analyzed 
on the full analysis set (FAS), which consists of all randomized patients. 
The 
primary 
analysis 
will 
focus 
on 
the 
comparison 
between 
REGN1908-1909 and placebo in the FAS. The analysis will be performed 
using an analysis of covariance (ANCOVA) model, with the treatment 
group, randomization stratification factors, and cat sIgE (<17.5 kUa/L versus 
≥17.5 kUa/L) as fixed effects and the baseline CSMS as a covariate.  
The average CSMS (max score 38/day) will be calculated based on the sum 
of daily TNSS (max score 12/day), daily TOSS (max score 6/day), and daily 
medication scores (DMS, max of 20/day) recorded over the duration of the 
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last 12 weeks. Only days with observed data will be included in the 
calculation of average score. Additional details are provided in Table 5 
within the protocol body. 
The intercurrent events, strategies, and the corresponding missing data 
handling approaches for the estimand for the primary endpoint are 
summarized in the Primary Efficacy Analysis section of the Statistical 
Methods section within the protocol body. 
Secondary Efficacy Analyses 
The secondary efficacy endpoints will be analyzed using an ANCOVA 
model in the same fashion as the primary analysis of the primary efficacy 
endpoint.  
The intercurrent events, strategies, and the corresponding missing data 
handling approaches for the estimand for the secondary endpoint is similar 
to the primary endpoint,  summarized in the Secondary Efficacy Analysis 
section of the Statistical Methods section within the protocol body. 
Control of Multiplicity  
Multiplicity is considered for testing multiple endpoints. The overall type-I 
error rate will be controlled at the 2-sided 0.05 level.  
A non-binding futility interim analysis (IA) is planned in this study and an 
administrative penalty of 0.001 will be taken from the significance level used 
at final analysis, and thus 2-sided 0.049 will be used. No further multiplicity 
adjustment will be performed for the IA.  
At the final analysis, hierarchical testing procedure is proposed to strongly 
control the family wise type-I error rate for testing the primary and key 
secondary endpoints. Two-sided alpha of 0.049 will be allocated to the 
endpoints relating to the 12 weeks of the treatment period. The detailed 
hierarchical order will be specified in the study SAP. 
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1. 
INTRODUCTION 
Cat allergens are among the most important indoor allergens and a common cause of IgE-mediated 
allergic disease worldwide, affecting approximately 26% of patients consulting for suspected 
allergy to inhalant allergens in Europe (Heinzerling, 2009). Approximately 12% to 15% of the 
United States (US) population has a known sensitivity to cat allergen (Salo, 2011). About 25% to 
34% of households in Europe and the US reported owning a cat in the home 
(Humane Society of United States, 2021) (The European Pet Food Industry, 2019). 
Felis domesticus allergen 1 (Fel d 1) is produced by the skin and by salivary and lacrimal glands 
of the cat (Kleine-Tebbe, 1993) (Grönlund, 2009). Dried saliva and dandruff are spread from the 
cat hair as small airborne particles into the surrounding environment that readily adhere to surfaces 
such as walls, carpets, and furniture. About 90% to 95% of cat allergic individuals are sensitized 
to Fel d 1, which is the immunodominant allergen (van Ree, 1999). While the highest amount of 
Fel d 1 allergen is found in households with cats and the concentration correlates with the number 
of cats kept in a home (Bollinger, 1996) (Bollinger, 1998) (Niesler, 2016), this allergen can also 
be carried on clothes and shoes into homes and schools without cats and may persist in these areas 
for months to years (Karlsson, 2004). Additionally, cat allergen is also challenging to remove since 
it is buoyant and tends to be “sticky” and can remain in homes for months after cat removal 
(Bateman, 1999) (Chapman, 2001) (Wood, 1989). Therefore, it is difficult to avoid exposure to 
cat allergen in the environment. 
Nasal and eye symptoms are the most frequently reported and most bothersome of all cat allergy 
symptoms. While treatment of cat allergy includes a recommendation for removal of the cat from 
the home, often patients or families will refuse to remove the cat from the home due to emotional 
attachment.  As such, despite recommendations, patients continue to live with their cat(s) 
(Coren, 1997). Rhinoconjunctivitis is treated with antihistamines and intranasal corticosteroids 
(INCS), which are only moderately effective for nasal symptoms (Ciprandi, 2011). The best 
reported treatment effects for antihistamines and INCS are 5% to 11% relative reduction of total 
nasal symptoms compared to placebo (Durham, 2016). Allergic conjunctivitis symptoms are 
typically treated with topical antihistamines that are sometimes combined with mast cell stabilizers 
(Mounsey, 2016). Although nasal symptoms are often considered most bothersome, eye symptoms 
commonly occur with rhinitis. Epidemiologically, it is challenging to define an exact prevalence 
of eye symptoms (Bousquet, 2001). However, available reports indicate that the majority of 
allergic rhinitis patients do experience ocular symptoms that result in significant impact on quality 
of life (Bielory, 2007) (Gomes, 2014) (Riedi, 2010).  
The association between cat allergy and asthma is significant. Approximately 30% of allergic 
asthmatics reportedly have a concomitant allergy to cats (Arbes, 2007). More than 50% of 
cat-sensitized patients have a diagnosis of co-morbid asthma, ranging from intermittent mild to 
potentially life-threatening asthmatic exacerbations requiring treatment with short- and 
long-acting bronchodilators, inhaled corticosteroids, and broader immune-targeting agents 
(Giavina-Bianchi, 2016). Patients with high concentrations of cat allergen-specific IgE are at 
higher risk for oculo-nasal and/or asthma symptoms, or both (Olivieri, 2016) (Perzanowski, 2016).  
Specific immunotherapy (SIT) is a disease-modifying, standard-of-care treatment option for 
patients with allergic rhinoconjunctivitis triggered by cat allergen when pharmacological therapies 
are insufficient (Walker, 2011) (Zuberbier, 2010). Allergen-specific polyclonal IgG4 titers 
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increase during SIT and may inhibit effector cell activation by blocking binding of IgE-allergen 
complex to high-affinity IgE receptors on mast cell and basophil surfaces, thereby effectively 
preventing early phase allergic symptoms (James, 2011) (Kündig, 2010). Clinical symptom 
improvement correlates with the ability of blocking IgG4s to compete with IgE for allergen 
binding. Although SIT can provide long-lasting protection from allergic disease, SIT carries a risk 
of local and systemic adverse reactions (especially in uncontrolled or severe asthma), is variably 
effective among different patients, and can take 3 to 5 years to induce permanent immune tolerance 
(Durham, 2012) (Leung, 2010) (Scadding, 2017). 
REGN1908 and REGN1909 are human IgG4 monoclonal antibodies (mAbs), which bind 
independently, non-competitively, and with high affinity to the Fel d 1 allergen and are being 
developed as an antibody cocktail (REGN1908-1909) for the treatment of allergic disease 
triggered by exposure to cats or cat hair. Fel d 1 is the major cat allergen which is recognized in 
more than 90% of cat-allergic patients (van Ree, 1999) and accounts for 60% to 90% of the total 
allergenic activity in cat dander (Kleine-Tebbe, 1993). 
These human high-affinity IgG4 mAbs targeted to the major cat allergen are designed to block Fel 
d 1 from binding to IgE, as well as or better than those naturally produced during SIT 
(Orengo, 2018). 
In a phase 1b proof-of-mechanism (POM) study (R1908-1909-ALG-1325), a single 600 mg 
subcutaneous (SC) dose of REGN1908-1909 (300 mg each of REGN1908 and REGN1909) 
prophylactically blocked the early allergic response to nasal challenge with cat allergen, and 
resulted in a 29% improvement in total nasal symptom score (TNSS) following a nasal challenge 
8 days after REGN1908-1909 administration (which was the earliest time point assessed), 
compared with placebo. REGN1908-1909 treatment reduced TNSS AUC(0–1 h) by 56%, 61%, 
51%, and 51% on days 8, 29, 57, and 85 respectively; resulting in 29%, 33%, 14%, and 23% 
reduction vs placebo and achieving nominal statistical significance vs placebo at every time point 
except day 57 (ANCOVA, p = 0.0005, 0.0004, 0.1321, 0.0187, respectively).  
In a phase 2 trial in cat allergic patients with Global Initiative for Asthma (GINA) I asthma, 
(R1908-1909-ALG-1703), a single 600 mg SC dose of REGN1908-1909 (300 mg each of 
REGN1908 and REGN1909) prophylactically blocked the early asthmatic response (EAR) in an 
Environmental Exposure Unit (EEU) as early as day 8 and through day 85 (the last time point 
evaluated). All patients included in the study demonstrated an EAR within 2 hours of the 
Controlled Cat Allergen Challenge at screening. EAR was defined as a reduction in FEV1 by 
≥20% upon exposure to controlled cat allergen in an EEU. A single dose of REGN1908-1909 
provided a rapid and durable reduction in cat allergen induced acute bronchoconstriction, as shown 
by the increased time to EAR in cat-allergic, mild asthmatic patients upon EEU exposure to cat 
allergen at 8 days (earliest time evaluated) and up to day 85 (latest time evaluated). Compared with 
placebo, REGN1908-1909 significantly increased the median time to EAR from 51 minutes 
(baseline) to >4 hours on days 8 (hazard ratio [HR]=0.36; p <0.0083), 29 (HR = 0.24; p <0.0001), 
and 85 (HR = 0.27; p = 0.0003) and to 232 mins on day 57 (HR = 0.45; p = 0.0222). As compared 
with placebo, REGN1908-1909 significantly prevented cat allergen induced declines in FEV1 over 
0 to 2 hours during the Controlled Cat Allergen Challenge in the EEU up to 85 days after a single 
dose. The difference from placebo was 13.6% at day 8 and was consistent through day 85. As 
compared to placebo, an approximately 3-fold higher cumulative allergen quantity was tolerated 
relative to baseline after single-dose REGN1908-1909 at days 8 (p = 0.003), 29 (p <0.001), 
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57 (p = 0.023), and 85 (p = 0.003). Additionally, REGN1908-1909 significantly reduced skin test 
reactivity (mean wheal diameter) provoked by a skin prick test (SPT) with serial cat allergen 
titration at these same time points, suggesting that inhibition of immediate IgE-mediated responses 
may be a key mechanism by which REGN1908-1909 ameliorated the acute bronchoconstriction 
in this study. 
In all studies to date (R1908-HV-1240, R1908-1909-ALG-1325, and R1908-1909-ALG-1703), 
REGN1908-1909 was generally well tolerated with an acceptable safety profile. There were no 
deaths, systemic hypersensitivity reactions, or anaphylaxis reported.  
Targeted, passive immunotherapy of cat allergy with REGN1908-1909 may provide rapid 
systemic relief of the constellation of “unified airway” respiratory (upper and lower) and ocular 
symptoms. As compared to SIT, REGN1908-1909 may potentially: 1) be safer as the allergic 
patient is not exposed to actual allergen, 2) offer more convenience, as a single SC dose may 
prevent allergic symptoms for months, 3) broaden the pool of patients to derive benefit including 
asthmatics who may have previously been contraindicated for SIT, and 4) have a faster onset of 
action, as demonstrated in the study R1908-1909-ALG-1325, which achieved clinical efficacy 
8 days after a single dose of 600 mg/kg, the earliest time point at which efficacy was assessed. 
Furthermore, in study R1908-1908-ALG-1703, REGN1908-1909 was able to increase the median 
time to early asthma reaction (EAR) in an EEU by day 8. The effect persisted through day 85 (the 
last time point evaluated). Additionally, REGN1908-1909 significantly prevented cat allergen 
induced reductions in FEV1 during the EEU sessions. The amount of allergen tolerated was 
3 times higher in the active group compared to the placebo group. 
This phase 3 study (R1908-1909-ALG-2102) aims to investigate the effect of REGN1908-1909 
on the treatment of cat allergic patients with allergic rhinitis with or without conjunctivitis and 
with or without asthma. Additionally, given that it is expected that at least 30% of the population 
enrolled will have concomitant asthma, the effect on asthma symptoms, asthma rescue medication 
use, lung function, and overall asthma control will be evaluated. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to determine the efficacy of REGN1908-1909, as compared 
to placebo, to reduce allergic rhinitis/conjunctivitis symptoms and allergy rescue medication use 
during natural cat exposure. 
Note: The combined symptom and medication score (CSMS) is defined as the daily combined 
allergic rhinitis and conjunctivitis total symptom score (TSS: calculated as the sum of total nasal 
symptom score [TNSS] and total ocular symptom score [TOSS]) plus daily medication score 
(DMS). 
2.2. 
Secondary Objectives 
The secondary objectives are: 
• To assess the reduction of allergic symptoms and use of allergy rescue medications 
after treatment with REGN1908-1909 versus placebo, as measured by the individual 
components of the CSMS 
• To assess health-related quality of life (HRQoL) as measured by the 
Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ[S])  
• To determine the efficacy of REGN1908-1909, as compared to placebo, to inhibit a 
wheal-and-flare response to a skin prick test with cat allergen 
• To assess the durability of effect in allergic rhinitis and conjunctivitis symptom and 
medication scores after multiple doses of REGN1908-1909 compared to placebo given 
every 12 weeks (Q12W) 
• To determine the efficacy following multiple doses of REGN1908 1909 compared to 
placebo at inhibiting a wheal-and-flare response to a skin prick test with cat allergen 
• To estimate the effect of REGN1908-1909 on lung function, as compared to placebo, 
in patients with asthma  
• To determine the efficacy of REGN1908-1909 as compared to placebo to reduce 
asthma symptoms in patients with asthma 
• To assess whether there is a difference in asthma rescue medication use in patients with 
asthma who are treated with REGN1908-1909 compared to placebo  
• To assess whether there is a difference in nighttime awakenings in patients with asthma 
treated with REGN1908-1909 compared to placebo  
• To evaluate the short-term and long-term safety and tolerability of REGN1908-1909, 
including the incidence of hypersensitivity reactions, local injection site reactions, and 
asthma exacerbations  
• To determine systemic exposure of total (free and antigen-bound) antibodies as 
measured by concentration of REGN1908 and REGN1909  
• To assess the immunogenicity of REGN1908 and REGN1909  
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2.3. 
Exploratory Objectives 
• To evaluate “well days”  
Note: “Well days” are defined as days when the TSS is ≤2 without the use of anti-allergy 
rescue medications.  
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
A cocktail of 2 anti-Fel d 1 (mAbs) (REGN1908-1909) is more effective at reducing allergic 
rhinitis and conjunctivitis symptoms and medication scores when compared to placebo during 
weeks 48 to 60 of the treatment period. 
Treatment Q12W will result in a durable treatment effect that persists through the approximate 
1-year treatment period. 
Refer to Section 11.1 for the statistical hypothesis. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
REGN1908-1909, fully human IgG4 anti Fel d 1 mAbs, bind specifically, non-competitively, and 
with high affinity to different epitopes on Fel d 1, the major cat allergen. By the mAbs attaching 
to this relevant allergen, there will be interference of Fel d 1 binding to and crosslinking IgE, 
resulting in a blockade of the subsequent allergic cascade in cat allergic subjects when exposed to 
cat allergen. The purpose of this study is to demonstrate that REGN1908-1909 reduces the 
symptoms associated with cat allergy. The focus of the trial will be on allergic rhinitis and 
conjunctivitis symptoms. Efficacy will be evaluated by assessing the reduction of allergic nasal 
and ocular symptoms, and the reduction in the use of allergy rescue medications in patients 
exposed to cat in their home. However, given that more than 50% of cat-allergic patients can have 
a diagnosis of co-morbid asthma (Giavina-Bianchi, 2016), an evaluation of the effect on asthma 
will also be conducted. 
Patients with cat allergy who are ≥12 to <18 years of age, where permitted based on local 
regulations, and older (≥18 years of age) will be considered for this trial. Allergic rhinitis is a 
common condition in adolescents, with ~80% of patients developing allergic rhinitis symptoms 
before age 20 years (Gentile, 2013). The pathophysiology, diagnosis and treatment of allergic 
rhinitis in adolescents is thought to be similar to adults (Izquierdo-Domínguez, 2013) 
(Dykewicz, 2020). Similar to adults, adolescents experience symptoms of allergic 
rhinoconjunctivitis and related impact on quality of life (Blaiss, 2018). In addition, the diagnostic 
considerations and treatment recommendations do not differ between adolescents and adults with 
allergic rhinitis and/or asthma (Dykewicz, 2020) (Krishnan, 2021). The cumulative 
pharmacokinetic (PK) data from the 3 completed clinical studies were assessed to support the 
inclusion of adolescents in this phase 3 field study. The PK of REGN1908 and REGN1909 has 
been consistent across all clinical trials, exhibiting linear, dose proportional PK. Given that 
REGN1908 and REGN1909 are monoclonal antibodies mAbs directed at an exogenous target, 
administration of REGN1908 and REGN1909 is not expected to affect endogenous pathways, and 
physiological differences between adolescent and adult populations would not affect target 
availability or engagement. As is typical for a monoclonal antibody, exposure to REGN1908 and 
REGN1909 is inversely proportional to body weight, as body weight is often the most influential 
covariate affecting PK of mAbs (Temrikar, 2020) (Shi, 2010) (Xu, 2020). However, the exposure 
difference by body weight does not appear to translate into meaningful differences in efficacy or 
safety at the proposed dose, which has generally been well tolerated. The lower end of the proposed 
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body weight range (≥40 kg) falls within the range of expected body weights for the majority of 
adolescent subjects and given the overlapping body weight ranges in adults and adolescents, a 600 
mg SC dose is expected to yield comparable exposures to REGN1908 and REGN1909 in 
adolescent populations to those observed in adults. A body weight criterion of ≥40 kg was included 
in the phase 3 protocol to ensure drug exposure will be in a range that has been previously 
measured in humans; therefore, only those adolescent patients who fall within the weight 
parameters already tested in the adult population (≥40 kg) will be included in this study. 
The study consists of up to a 12-week screening period. A baseline 15-day assessment of symptoms 
and medication use is required to ensure that patients are significantly symptomatic despite use of 
standard of care anti-allergy rescue medications (provided as part of the study). Importantly, the 
baseline symptom/ medication assessment and 12-week efficacy assessments should occur outside 
of the relevant pollen season in patients with concomitant seasonal allergies. The extended 
screening period will allow for these procedures and assessments to occur at temporally 
appropriate times.  
After meeting all inclusion and no exclusion criteria, patients will be randomized to receive 
REGN1908-1909 or placebo administered SC Q12W. Efficacy will be evaluated over a 12-week 
period following the initial dosing of REGN1908-1909 or placebo and following the final dose of 
REGN1908-1909. Twelve-week periods represent a significant time period of a year to measure 
effectiveness of study drug. The second 12-week period following the last dose of medication, 
considered the primary efficacy endpoint assessment for this study, will provide evidence of 
durability of effect for this medication which is intended for chronic use. Due to the various pollens 
that are prevalent during the spring through the autumn seasons, efficacy assessment will occur 
over the winter months for those patients with relevant pollen allergies to reduce potential 
confounding factors that may impact nasal and ocular symptoms.  
During the initial 12-week period following the first treatment dose with either REGN1908-1909 
or placebo, daily symptoms of allergic rhinitis and conjunctivitis will be captured as well as the 
use of study provided allergy rescue medication for the treatment of allergic rhinitis and 
conjunctivitis. In patients with co-morbid asthma, the asthma daytime and nighttime symptom 
questionnaires, nighttime awakening, asthma rescue medication use, spirometry, and the Asthma 
Control Questionnaire 5 Question Version (ACQ-5) will also be collected.  
Following the initial 12-week assessment period, all patients will continue to receive 
REGN1908-1909 or placebo Q12W with the last dose administered at approximately week 48. 
Following the last dose, daily symptoms of allergic rhinitis and conjunctivitis will be captured as 
well as the use of study provided allergy-relieving rescue medication for the treatment of allergic 
rhinitis and conjunctivitis for an additional 12 weeks (weeks 48 to 60). In patients with asthma, 
the ACQ-5, spirometry, ANSD and nighttime awakenings, and ADSD and asthma rescue 
medication usage will be collected. The assessments collected during the last 12 weeks of the 
treatment period will be utilized to demonstrate durability of the treatment effect.  
Evaluations of efficacy will occur during pre-specified 12-week periods (weeks 0 to 12 and weeks 
48 to 60). Given that the majority of patients are expected to have sensitizations to allergens other 
than cat, the efficacy assessment periods will be planned to occur at times of year when there will 
be limited interference by other allergens for those patients with other co-morbid clinically relevant 
allergies.  
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3.2.2. 
Rationale for Dose Selection  
Preclinical: 
Blocking potency of the cocktail of anti-Fel d 1 mAbs was characterized in a preclinical basophil 
activity test using fresh basophils from cat allergic patients. The utilization of both antibodies 
(REGN1908-1909) was more effective than either REGN1908 or REGN1909 alone, in the 
majority of patients in blocking Fel d 1 binding to polyclonal human IgE and inhibiting activation 
of basophils, as measured by flow cytometry by percent inhibition of phosphorylated extracellular 
signal-regulated kinase (pERK) responses, from cat allergic patients.  
Clinical: 
The PK of REGN1908 and REGN1909 has been consistent across all clinical trials, exhibiting 
linear PK and a terminal half-life of approximately 31.0±5.9 days and 22.4±3.8 days for 
REGN1908 and REGN1909, respectively. In a phase 1b study (R1908-1909-ALG-1325) designed 
to reduce nasal symptoms after a nasal allergen challenge and a phase 2 study (R1908-1909-ALG-
1703) that evaluated efficacy of preventing asthma in an EEU, a dose of 600 mg (300 mg/mAb) 
was well tolerated and maintained efficacy for up to 12 weeks, suggesting that this dose will be 
safe and efficacious in a phase 3 field study, including after repeat administration. PK data from 
previous clinical trials in cat allergic humans were used to estimate PK parameters and then 
simulate repeat SC doses for 300 mg/mAb every 3 months. Maximum (Cmax) and trough (Ctrough) 
total antibody concentrations in serum are within approximately 10% of single dose Cmax and 
Ctrough values, indicating that accumulation is expected to be minimal, while also maintaining a 
Ctrough concentration that is associated with efficacy. 
3.3. 
Risk-Benefit 
REGN1908 and REGN1909 are human mAbs of the IgG4 isotype that bind different epitopes on 
Fel d 1 simultaneously, non-competitively, and with high affinity. REGN1908 and REGN1909 are 
being developed as an antibody cocktail (designated as REGN1908-1909). REGN1908-1909 
blocks Fel d 1 from binding and crosslinking receptor bound IgE on the surface of allergic effector 
cells, thus preventing initiation of the cat allergic response. The clinical proof-of-mechanism study 
(R1908-1909-ALG-1325) examined the potential of REGN1908-1909 to block acute allergic 
symptoms triggered by nasal provocation with cat extract in cat allergic patients. The majority of 
patients receiving REGN1908-1909 experienced symptom amelioration, with at least 50% of 
patients achieving 60% improvement in TNSS at every time point assessed during nasal allergen 
challenges up to 12 weeks post-treatment (day 85, last time point assessed) with efficacy 
demonstrated as early as the first time point evaluated (day 8). This suggests that a majority of cat 
allergic patients who were treated with REGN1908-1909 may derive benefit by experiencing 
reduced rhinitis symptoms upon challenge with cat allergen. Additionally, in a proof-of-concept 
study (R1908-1909-ALG-1703) in cat allergic patients with GINA 1 asthma, REGN1908-1909 
increased the time to EAR in the majority of patients and increased the cumulative cat allergen 
tolerated during cat allergen EEU challenge by 3 fold. These effects were first noted on day 8 
(initial time point evaluated post study drug administration) and persisted up to 12 weeks 
post-treatment, suggesting a potential benefit in cat allergic individuals with mild asthma. Taken 
together, these results support that a single dose of the REGN1908-1909 cocktail demonstrated a 
rapid and clinically meaningful effect in reducing the allergic airway response in cat allergic 
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patients. The treatment may offer a rapid and potentially effective approach for the treatment of 
cat allergy in patients where there is ongoing exposure to cat allergen or cats cannot be avoided. 
REGN1908-1909 has been used to treat 83 subjects in 3 completed clinical studies with no 
significant clinical safety findings observed to date, including no deaths, and no cases of systemic 
hypersensitivity, or anaphylaxis. No important identified risks have been established. The 
important potential risks with REGN1908-1909 (based on preclinical evaluation, mechanism of 
action targeting an exogeneous antigen, and risks associated with mAbs in general) include 
systemic hypersensitivity reactions and immunogenicity. REGN1908-1909 has been generally 
well tolerated and risks have been adequately managed. 
To date, no significant safety information with regard to the important potential risks of systemic 
hypersensitivity reactions and immunogenicity has been reported. Currently, the available safety 
data along with the risk minimization and monitoring activities support the continued development 
of REGN1908-1909. 
As with most other protein therapeutics that are administered SC, injection site reactions may occur 
and may be treated symptomatically. Among the 3 completed studies, injection site reactions were 
reported in 6 patients that received REGN1908-1909, compared to 2 patients in the placebo groups, 
and all were mild in severity. Allergy/hypersensitivity reactions may develop; the most concerning 
are those that may develop immediately or within a few hours of administration of 
REGN1908-1909. Because REGN1908-1909 is composed of antibodies whose sequence is fully 
human, the risk of these immediate reactions is considered to be extremely low. Emergency 
equipment and medication for the treatment of these potential adverse effects (including but not 
limited to antihistamines, corticosteroids, acetaminophen, and/or epinephrine) are available for 
immediate use in this study. Considering the safety data and the exogenous nature of the target 
antigen, the risk of other adverse reactions is considered to be low. A risk-benefit statement with 
respect to the overall development program is provided in the Investigator’s Brochure.  
An Independent Data Monitoring Committee (IDMC) will be involved in the review of unblinded 
data in an ongoing manner (refer to Section 6.3.1). 
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 patients in this study until 
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. Until then, the 
Sponsor plans to obtain approvals from Health Authorities/Ethics Committees (ECs) to enable 
initiation of study sites for this study, as allowed by local laws and regulations. 
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4. 
ENDPOINTS 
4.1. 
Primary Endpoint 
The primary endpoint is the daily CSMS, averaged over the last 12 weeks of the treatment period 
(weeks 48 to 60), in patients who receive REGN1908-1909 versus placebo.  
Note: CSMS is defined as the daily combined allergic rhinitis and conjunctivitis TSS (calculated 
as the sum of TNSS and TOSS) plus daily medication score (DMS). 
4.2. 
Secondary Endpoints 
The key secondary endpoints, specified without order, are: 
• Daily TNSS, averaged over the last 12 weeks of treatment period (weeks 48 to 60), in 
patients who receive REGN1908-1909 versus placebo 
• Percent change from pre-treatment baseline in average CSMS, over the last 12 weeks 
of the treatment period (weeks 48 to 60), in patients who receive REGN1908-1909 
versus placebo 
• Percent change from pre-treatment baseline in average TNSS, over the last 12 weeks 
of the treatment period (weeks 48 to 60), in patients who receive REGN1908-1909 
versus placebo 
• Daily TSS, averaged over the last 12 weeks of the treatment period (weeks 48 to 60), 
in patients who receive REGN1908-1909 versus placebo 
• Percent change from pre-treatment baseline in average TSS, over the last 12 weeks of 
the treatment period (weeks 48 to 60), in patients who receive REGN1908-1909 versus 
placebo 
• Percent change from baseline to the end of treatment (week 60) in cat SPT mean wheal 
diameter in patients who receive REGN1908-1909 versus 
Other secondary endpoints, specified without order, are: 
• Daily CSMS, averaged over the initial 12 weeks of the treatment period (weeks 0 to 
12), in patients who receive REGN1908-1909 versus placebo 
• Daily TNSS, averaged over the initial 12 weeks of treatment period (weeks 0 to 12), in 
patients who receive REGN1908-1909 versus placebo 
• Percent change from pre-treatment baseline in average CSMS, over the initial 12 weeks 
of the treatment period (weeks 0 to 12), in patients who receive REGN1908-1909 
versus placebo 
• Percent change from pre-treatment baseline in average TNSS, over the initial 12 weeks 
of the treatment period (weeks 0 to 12), in patients who receive REGN1908-1909 
versus placebo 
• Percent change from pre-treatment baseline in average TSS, over the initial 12 weeks 
of the treatment period (weeks 0 to 12), in patients who receive REGN1908-1909 
versus placebo 
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• Daily TSS score, averaged over the initial 12 weeks of the treatment period (weeks 0 
to 12), in patients who receive REGN1908-1909 versus placebo 
• Percent change from pre-treatment baseline in average TOSS, over the initial 12 weeks 
of the treatment period (weeks 0 to 12), in patients who receive REGN1908-1909 
versus placebo 
• Daily TOSS, averaged over the last 12 weeks of the treatment period (weeks 48 to 60), 
in patients who receive REGN1908-1909 versus placebo 
• Percent change from pre-treatment baseline in average TOSS, over the last 12 weeks 
of the treatment period (weeks 48 to 60), in patients who receive REGN1908-1909 
versus placebo. 
• Percent change from baseline to week 12 in FEV1 in patients with asthma who receive 
REGN1908-1909 versus placebo 
• Percent change from baseline to week 60 in FEV1 in patients with asthma who receive 
REGN1908-1909 versus placebo 
• Percent change from baseline to week 12 in cat skin prick test (SPT) mean wheal 
diameter in patients who receive REGN1908-1909 versus placebo 
• Change from baseline to week 12 in FEV1 in patients with asthma who receive 
REGN1908-1909 versus placebo 
• Change from baseline to week 60 in FEV1 in patients with asthma who receive 
REGN1908-1909 versus placebo 
• Change from baseline to week 60 in RQLQ(S)+12 in patients who receive REGN1908-
1909 versus placebo 
• DMS, averaged over the initial 12 weeks of the treatment period (weeks 0 to 12), in 
patients who receive REGN1908-1909 versus placebo 
• DMS, averaged over the last 12 weeks of the treatment period (weeks 48 to 60), in 
patients who receive REGN1908-1909 versus placebo 
• Percent change from pre-treatment baseline in average DMS, averaged over the last 12 
weeks of the treatment period (weeks 48 to 60), in patients who receive REGN1908-
1909 versus placebo 
• Percent change from baseline to end of study (week 72) in cat SPT mean wheal 
diameter in patients who receive REGN1908-1909 versus placebo 
• Asthma daily symptom (ADS) score, averaged over the initial 12 weeks of the 
treatment period (weeks 0 to 12), using Asthma Daytime Symptom Diary (ADSD) and 
the Asthma Nighttime Symptom Diary (ANSD), in patients with asthma who receive 
REGN1908-1909 versus placebo 
• Asthma daily symptom (ADS) score, averaged over the last 12 weeks of the treatment 
period (weeks 48 to 60), using Asthma Daytime Symptom Diary (ADSD) and the 
Asthma Nighttime Symptom Diary (ANSD), in patients with asthma who receive 
REGN1908-1909 versus placebo 
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• Daily TOSS, averaged over the initial 12 weeks of the treatment period (weeks 0 to 12), 
in patients who receive REGN1908-1909 versus placebo 
• Change from baseline to week 60 in ACQ-5 in patients with asthma who receive 
REGN1908-1909 versus placebo 
• Daily number of nighttime awakenings, averaged over the initial 12 weeks of the 
treatment period (weeks 0 to 12), in patients with asthma who receive REGN1908-
1909 versus placebo 
• Daily number of nighttime awakenings, averaged over the last 12 weeks of the 
treatment period (weeks 48 to 60), in patients with asthma who receive REGN1908-
1909 versus placebo 
• Incidence of treatment-emergent adverse events (TEAEs), AESIs, and serious TEAEs 
throughout the study (weeks 0 to 72)  
• Total REGN1908 and REGN1909 concentration in serum over the study duration 
(weeks 0 to 72)  
• Incidence of treatment-emergent anti-drug antibodies (ADAs) to REGN1908 and 
REGN1909 throughout the study (weeks 0 to 72) 
4.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• The number of “well days” in those who received REGN1908-1909 versus placebo, 
over the initial 12 weeks (weeks 0 to 12) of the treatment period; “well days” are 
defined as days when rescue medication is not utilized and the TSS is ≤2/18 
• The number of “well days” in those who received REGN1908-1909 versus placebo, 
over the last 12 weeks of the treatment period (weeks 48 to 60); “well days” are defined 
as days when rescue medication is not utilized and the TSS is ≤2/18 
• Percent change from pre-treatment baseline in average ADS score, over the initial 12 
weeks of the treatment period (weeks 0 to 12), using ADSD and the ANSD in patients 
with asthma who receive REGN1908-1909 versus placebo 
• Percent change from pre-treatment baseline in average frequency of asthma rescue 
medication use, over the initial 12 weeks of the treatment period (weeks 0 to 12), in 
patients with asthma who receive REGN1908-1909 versus placebo 
• Percent change from pre-treatment baseline in average frequency of nighttime 
awakenings, over the initial 12 weeks of the treatment period (weeks 0 to 12), in 
patients with asthma who receive REGN1908-1909 versus placebo 
• Percent change from pre-treatment baseline in average DMS, over the initial 12 weeks 
of the treatment period (weeks 0 to 12), in patients who receive REGN1908-1909 
versus placebo 
• Change from baseline to week 12 in RQLQ(S)+12 in patients who receive REGN1908-
1909 versus placebo 
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• Change from baseline to week 12 in Asthma Control Questionnaire 5 Question Version 
(ACQ-5) in patients with asthma who receive REGN1908-1909 versus placebo 
• Daily frequency of asthma rescue medication use, averaged over the initial 12 weeks 
of the treatment period (weeks 0 to 12), in patients with asthma who receive 
REGN1908-1909 versus placebo  
• Daily frequency of asthma rescue medication use, averaged over the last 12 weeks of 
the treatment period (weeks 48 to 60), in patients with asthma who receive REGN1908-
1909 versus placebo 
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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), 
medical history (including allergy history), medication history, asthma history, SPT mean wheal 
diameter for cat and other allergens, and cat and Fel d 1 sIgE levels for each patient. 
5.2. 
Efficacy Variables 
Efficacy variables include TNSS, TOSS, TSS (which results from adding the TNSS and TOSS), 
DMS, CSMS (which results from adding the DMS and TSS), mean wheal diameter of cat SPT, 
and RQLQ(S) and spirometry (in all patients at screening and randomization, and only in patients 
with asthma after randomization). For patients with asthma, ACQ-5, asthma symptoms, and rescue 
medication use for asthma will also be evaluated.  
5.3. 
Safety Variables 
Safety variables include AEs, vital signs, physical examinations, electrocardiogram (ECG), and 
laboratory safety tests.  
5.4. 
Pharmacokinetic Variables 
The pharmacokinetic variables are total concentration of REGN1908 and total concentration of 
REGN1909 in serum at each time point. Samples in this study will be collected using a sparse 
sampling schedule, eg, only 1 blood sample for drug concentration measurement is collected at 
any single clinic visit. These sampling time points are specified in Table 3. 
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 3. 
5.6. 
Pharmacodynamic and Other Biomarker Variables 
Exploratory biomarker variables include, but are not limited to serum sIgE for cat and Fel d 1, 
serum sIgE for other relevant allergens (such as but not limited to Fel d 2, 4, and 7), SPT results 
for cat, and other relevant allergens. 
Exploratory aims of biomarkers analyses include, but are not limited to: 
• To identify genomic associations with clinical or biomarker response to treatment 
with REGN1908-1909 
• To identify genomic variants associated with the prognosis or progression of cat 
allergy, asthma and related diseases 
These results may be reported outside of the clinical study report (CSR). 
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6. 
STUDY DESIGN  
6.1. 
Study Description and Duration 
This is a phase 3, randomized, double-blind, parallel-group, multi-dose study in approximately 
630 cat-allergic adult and adolescent patients (ages ≥12 to <18 years), where permitted, with 
allergic rhinitis with or without conjunctivitis and with or without asthma. 
• Cat allergic patients living with a cat who are significantly symptomatic while using 
standard of care anti-allergy medications will be enrolled in the study. The study 
includes a screening period of up to 12 weeks to ensure sensitization, symptom and 
medication use requirements are met during the baseline period. 
• Randomization to 1 of 2 treatment arms (1:1) 
o REGN1908-1909 600 mg (300 mg per mAb) 
o Placebo that replaces REGN1908-1909 
• Study drug will be administered Q12W for a total of 5 administrations  
• End of treatment visit at week 60 
• End of study safety follow-up visit at week 72 
The screening period is set up to be a long enough duration so that the baseline assessment will 
occur outside of relevant pollen seasons for patients who are pollen allergic. Efficacy assessments 
will be done during the initial 12 weeks (weeks 0 to 12) after the first dose and during the last 
12-week period (weeks 48 to 60) after last dose (dose 5) of REGN1908-1909 or placebo. For those 
individuals with seasonal allergies, efficacy assessments will be timed by the investigational site 
to ensure that the assessments are outside of any relevant pollen seasons. The study flow diagram 
is depicted in Figure 1. For prohibited medications and washout durations for different study 
procedures and assessment periods, see Section 8.9.1. 
Screening:  
During screening at 1 or more visits, patients undergo assessments of eligibility, including skin 
testing to cat allergen as well as serum specific IgE assessment to cat and Fel d 1. In-clinic 
spirometry will also be completed during screening. Provided that the initial eligibility criteria at 
screening are met, patients will be given an electronic diary to capture their allergic rhinitis and 
conjunctivitis symptoms as well as anti-allergy rescue medication use to capture symptoms and 
medication use for a 15-day baseline assessment (outside of any relevant pollen seasons for 
individuals with other seasonal allergies), which occurs as part of the screening period. Asthma 
daytime and nighttime symptom diaries, nighttime awakenings, and asthma rescue medication use 
will also be collected in patients with asthma during the baseline assessment.  
Rescreening is allowed up to 1 time. Patients cannot be rescreened based on skin testing or sIgE 
to cat not meeting eligibility. Baseline period assessment for symptom and medication 
requirements may not be repeated if patients do not meet eligibility criteria. 
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Baseline Period within Screening:  
The baseline assessment period is up to 21 days, and should be completed for a minimum of 15 
consecutive days during the approximately 12-week screening period. This period is utilized to 
demonstrate that patients are sufficiently symptomatic due to cat exposure while taking standard 
of care anti-allergy rescue medications provided during the study (oral antihistamine, 
antihistamine eye drops, intranasal corticosteroid; Section 8.2). Patients will complete an e-diary 
to record their nasal, ocular, and asthma symptoms as well as anti-allergy rescue medication use 
up to a 3-week period during screening (the 3-week period allows for up to 6 days of training or 
troubleshooting, if required). Patients will be required to have experienced allergic 
rhinoconjunctivitis symptoms, as measured by the TSS, and to have used anti-allergy rescue 
medications, as specified, for at least 8 days of a consecutive 15-day period during this time. 
Patients must meet a daily total rhinitis and conjunctivitis symptom threshold of at least 8 of 18 on 
at least 8 days of the consecutive 15-day baseline assessment period and use standard therapeutic 
doses of the anti-allergy rescue medications on 8 of the consecutive 15 days during the baseline 
assessment period. Adequate standard of care treatment is defined as currently approved doses of 
antihistamines and intranasal corticosteroids provided during the study.  
The baseline assessment will occur outside of relevant pollen season for those patients with 
seasonal allergies. 
Patients will complete baseline Patient Global Impression of Severity (PGIS) and RQLQ(S) during 
the baseline assessment period. Additionally, patients with asthma will complete the Asthma 
daytime and nighttime symptom diaries (ADSD and ANSD), ACQ-5, nighttime awakenings, and 
asthma rescue medication use during the baseline assessment period.  
If missing data are reported due to documented e-diary malfunction (eg, technical issues that are 
reported to the vendor), then the baseline assessment period may be extended accordingly, 
allowing the 15-day period to be re-started, to ensure that a consecutive 15 day period can be 
obtained. In such a circumstance, the medical monitor should be consulted, and agreement must 
be obtained with the sponsor. 
Treatment Period:  
Patients meeting eligibility criteria and symptom threshold will be randomized to either 
REGN1908-1909 or placebo. Patients will be administered either REGN1908-1909 or placebo for 
a total of 5 study drug administrations which will be given Q12W. The initial 12 weeks (weeks 0 
to 12) and the last 12 weeks (weeks 48 to 60) following the first dose of study drug will be the 
efficacy assessment periods. The primary efficacy assessment period is the last 12 weeks of the 
treatment period (after the fifth administration of study drug). 
The allergic rhinitis symptoms are measured by the total nasal symptom score (TNSS), based on 
nasal congestion, sneezing, runny nose, and itching of the nose; each symptom is graded 0 (none), 
1 (mild), 2 (moderate), and 3 (severe) for a maximum score of 12. Allergic conjunctivitis is 
measured by the TOSS, based on itching/redness/gritty feeling and tearing/watering; each of the 2 
symptoms is graded 0 (none), 1 (mild), 2 (moderate), and 3 (severe) for a maximum score of 6. A 
TSS results from adding the TNSS and TOSS, yielding a minimum score of 0 and a maximum 
score of 18. The allergic nasal and ocular symptoms will be recorded daily by the patients using 
the e-diary.  
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Patients will be provided with open-label allergy-relieving rescue medications (oral antihistamine, 
antihistamine eye drops, intranasal corticosteroid; Section 8.2) starting at the baseline assessment 
period (during screening), visit 3 (day 1), and during the study, which they may take as needed in 
standard therapeutic doses during the study to treat their allergic rhinitis/conjunctivitis symptoms. 
Patients will be asked to record their daily anti-allergy rescue medication use using an e-diary, 
including the specific medication name and dose. This information will be used to calculate the 
DMS as follows: desloratadine 5 mg 6 points/dose; maximum daily score 6 points, olopatadine 1 
mg/mL each drop 1.5 points/drop; maximum daily score 6 points, mometasone furoate 50 ug/dose 
2.0 points/spray; maximum daily score 8 points. The maximum DMS score is 20 (Calderon, 2014).  
The CSMS (combined symptom and medication score) is calculated by adding the TSS 
(TNSS+TOSS) and DMS together, with scores ranging between 0 and 38. RQLQ(S) will also be 
collected at baseline and during the initial 12-week efficacy assessment period as well as during 
the last 12 weeks of the treatment period.  
During the efficacy assessment periods, from the first day of dosing through the initial 12 weeks 
of the study and during the final efficacy assessment period (weeks 48 to 60), patients with 
comorbid asthma will complete the Asthma Daytime Symptom Diary (ADSD) and questions on 
asthma rescue medication use; this will occur each evening. Every morning, patients with 
co-morbid asthma will complete the Asthma Nighttime Symptom Diary (ANSD), and questions 
on nighttime awakening. In-clinic spirometry and ACQ-5 will be collected in patients with 
co-morbid asthma to compare any changes between baseline and the end of the initial 12-week 
efficacy assessment and the last 12 weeks of the treatment period.  
Figure 1: 
Study Flow Diagram 
 
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6.1.1. 
Study Stopping Rules 
6.1.1.1. 
Study Stopping Criteria 
There are no pre-specified stopping rules; however, appropriate action, if needed, will be taken 
based upon data review and in consultation with an IDMC (described in Section 6.3). Applicable 
regulatory procedures will be adhered to as required by local laws in relation to any decisions 
related to a change in study conduct, temporary halt, study termination, or study restart.  
6.1.2. 
End of Study Definition 
The end of study is defined as the date the last patient completes the last study visit or withdraws 
from the study, or is lost to follow-up (ie, the study patient can no longer be contacted by the 
investigator).  
6.2. 
Planned Interim Analysis  
A non-binding futility interim analysis (IA) in the study is planned to be performed when at least 
40% of randomized patients have completed the week 12 visit or discontinued before week 12. 
There is no plan to change the conduct of this trial except a possibility to stop the trial due to 
unfavorable benefit-risk. The IA will be performed by independent statisticians that support the 
IDMC and who are separate from personnel involved in the trial conduct. The IDMC will review 
the unblinded IA results and recommend action based on the non-binding futility criteria based on 
CSMS and TNSS that will be specified in the IDMC charter and SAP.  
Unblinded results can only be viewed by a small group of senior sponsor individuals, who are 
separate from sponsor personnel involved in the conduct of the study, if the non-binding futility 
criterion is met. A detailed plan will be defined in the IDMC charter and SAP, including plans to 
describe the processes intended to control access to comparative interim results to preserve trial 
integrity. Individuals involved in the conduct of the study (ie, patients, Investigators, Study Team, 
and Project Team, etc.) will have no access to the IA results.  
For the IA, the efficacy endpoints will be analyzed using the same methods described in the 
efficacy analyses section (Section 11.4.3.1). The analysis population for the interim futility 
analysis will include at least the first 40% of the randomized patients. The analysis of the endpoints 
will use all the data collected for the analysis population up to the IA cutoff time. An administrative 
penalty of 0.001 will be taken from the significance level used at final analysis (ie, 2-sided 0.049 
will be used for the final analysis).  
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6.3. 
Study Committees  
6.3.1. 
Independent Data Monitoring Committee 
An IDMC will actively review data throughout the study to monitor patient safety and efficacy 
data. The IDMC is composed of members who are independent from the sponsor and the study 
investigators. The IDMC will provide oversight of patient safety by conducting formal reviews of 
accumulated safety data that will be blinded by treatment group; if requested, the IDMC may have 
access to the treatment allocation code or any other requested data for the purposes of a risk-benefit 
assessment. As described in Section 6.2, an IA will be performed by independent statisticians that 
support the IDMC. 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 these 
studies. 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 630 adult and adolescent patients will be enrolled at multiple sites across North 
America and in Europe. 
7.2. 
Study Population 
Male and female patients ≥12 to <18 years of age, where permitted, and older (≥18 years of age) 
living with at least 1 cat who have allergic rhinitis with or without conjunctivitis symptoms and 
with or without asthma with cat sensitization confirmed at screening will be enrolled after they 
meet a symptom and medication requirement at baseline. 
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Generally healthy males and females who are 12 years and older at the time of screening. 
• Note that for those countries where local regulations or approvals permit enrollment 
of adults only, subject recruitment will be restricted to those who are ≥18 years of 
age. 
2. Weight must be ≥40 kg at the time of screening  
3. Documented or patient reported history (for at least 2 years) of symptomatic cat 
allergen-triggered allergic rhinitis with or without conjunctivitis and with or without 
asthma as defined by all of the following criteria: 
a. Positive skin prick test (SPT) with cat hair extract (mean wheal diameter at least 
5 mm greater than a negative control) at screening 
b. Positive allergen-specific IgE (sIgE) tests for cat and Fel d 1 (both ≥0.7 kUa/L at 
screening) 
c. Documented or patient reported history of nasal and/or ocular symptoms upon cat 
exposure 
d. Symptomatic despite the use of medications to treat their nasal and/or ocular 
symptoms 
4. At least 1 generally healthy cat (that is unlikely to die during the study) living in the home 
resulting in regular exposure 
5. A daily total rhinitis/conjunctivitis symptom score (total symptom score [TSS]) of at least 
8 of 18 during at least 8 days of the 15-day baseline assessment period and use of standard, 
therapeutic doses of pharmacotherapy for the treatment of allergic rhinoconjunctivitis on 
at least 8 days of the 15-day baseline assessment period.  
6. Willing and able to comply with clinic visits and study-related procedures. 
7. Provide informed consent signed by study patient or legally acceptable representative. For 
adolescents, a parent or legal guardian must provide signed informed consent (patients 
must also provide separate informed assent to enroll in the study, and the assent 
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documented either in a separate informed assent form [IAF] or in the informed consent 
form [ICF] signed by the parent(s)/legal guardian [as appropriate based on local regulations 
and requirements]). 
8. Able to understand and complete study-related questionnaires.  
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. History of significant multiple and/or severe allergies, as assessed by the investigator, that 
would potentially interfere with the assessments during the baseline and 12-week efficacy 
assessment periods or confound results, per investigator discretion, including significant 
rhinitis or sinusitis due to daily contact with other allergens causing symptoms that are 
expected to coincide with the baseline period or any of the efficacy assessment periods  
2. Received REGN1908-1909 in a prior REGN1908-1909 clinical trial (receipt of placebo in 
a previous trial is allowed) 
3. Active lung disease other than asthma 
4. FEV1 less than 70% of predicted at screening or randomization 
5. Treatment with an investigational drug within 2 months or within 5 half-lives (if known), 
whichever is longer, prior to screening 
6. Persistent chronic or recurring acute infection requiring treatment with antibiotics, 
antivirals, or antifungals, or any untreated respiratory infections within 4 weeks prior to 
screening. Patients may be re-evaluated after resolution of symptoms and specified time 
duration 
7. Any laboratory findings showing evidence of organ dysfunction or any clinically 
significant deviation from the normal range, as decided by the Investigator at the screening 
visit, including but not limited to  
a. Clinically significant/ active hepatobiliary disease 
b. Abnormal laboratory values at screening, such as  
• Platelets <100 ×103/μL 
• Neutrophils <1.5 × 103/μL 
• Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 
NOTE: If an abnormal value is detected at screening, a repeat test can be performed to 
confirm the abnormality to categorize the patient as a screen failure. 
8. Any medical illness, which in the judgment of the investigator could preclude participation 
in the study or in whom treatment with epinephrine or beta-2 agonists or systemic 
corticosteroids would pose an increased risk (eg, history of clinically significant 
cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, 
psychiatric, or neurological disease, etc) 
9. Patients taking any prohibited treatment (see Section 8.9.1) 
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10. Use of systemic corticosteroids within 30 days prior to screening visit 1, if used for the 
treatment of asthma symptoms. Patients may be re-evaluated after resolution of symptoms 
and specified time duration 
11. Use of anti-IgE or other biological therapy (including but not limited to anti IL-5, anti IL-4) 
that interferes with type 2 disease within 6 months prior to screening visit 1 
12. Specific immunotherapy (SIT) with cat allergen or cat vaccine within 6 months prior to 
screening visit 1. Patients with symptomatic cat allergy despite previous history of SIT 
(more than 6 months prior to screening visit 1) with cat allergen or vaccine may enroll if 
SIT was assessed as ineffective, per principal investigator discretion  
13. SIT with any allergen other than cat at screening visit 1. Patients who plan to initiate SIT 
during the trial period will be excluded. 
14. Patients who have recently started (within 12 weeks prior to screening visit 1) and plan to 
continue or plan to start their cat(s) on an anti-allergen cat food (eg, Purina Pro Plan® 
LiveClear) or other anti-allergen treatment during the study 
15. Patients who anticipate major changes in allergen exposure in their home or work 
environments during baseline and efficacy assessment periods, as assessed by the 
investigator 
16. History of life-threatening asthma, defined as an asthma episode that required intubation, 
and/or was associated with hypercapnia, respiratory arrest, and/or hypoxic seizures  
17. History of intensive care hospitalization for asthma within past 2 years 
18. History of intolerance to systemic or topical corticosteroids or antihistamines, or drug 
treatment excipient  
19. History of hypersensitivity to drug treatment excipient or allergies that could represent a 
substantial risk to the patient in the opinion of the investigator 
20. History of nasal polyps 
21. History of drug or alcohol abuse within a year prior to screening 
22. Any malignancy within the past 5 years, except for basal cell or squamous epithelial cell 
carcinomas of the skin or carcinoma in situ of the cervix or anus that have been resected, 
with no evidence of local recurrence or metastatic disease for 3 years  
23. Positive serum human chorionic gonadotropin pregnancy test at the screening visit or 
randomization visit for women of childbearing potential (WOCBP)  
NOTE: Pregnancy testing and contraception are not required for women with documented 
hysterectomy, bilateral oophorectomy, or tubal ligation 
24. Members of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the sponsor 
25. Pregnant or breastfeeding women 
26. Women of childbearing potential (WOCBP)* who are unwilling to practice highly 
effective contraception prior to the initial dose/start of the first treatment, during the study, 
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and for at least 24 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 male vasectomized partner is the sole sexual 
partner of the WOCBP study participant and that the vasectomized partner has obtained 
medical assessment of surgical success for the procedure); and/or 
e. sexual abstinence†, ‡  
* WOCBP 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 the 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 
27. Is committed to an institution by virtue of an order issued either by the judicial or the 
administrative authorities 
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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 8.3.2. 
7.4. 
Replacement of Patients 
Patients prematurely discontinued from the study will not be replaced. 
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8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
REGN1908 and REGN1909 are each formulated in a buffered, aqueous solution at pH 5.8. 
REGN1908 and REGN1909 drug product will be supplied separately as lyophilized cakes in 
20 mL glass vials.  
REGN1908 and REGN1909 are provided individually in open-label vials in cartons. A medication 
numbering system will be used to label unblinded investigational study drug. Lists linking 
medication numbers with product lot numbers will be maintained by the groups (or companies) 
responsible for study drug packaging; these lists will not be accessible to individuals involved in 
study conduct. The unblinded pharmacist will prepare the unblinded investigational product and 
dispense it in a blinded manner to the blinded study staff for administration to the patient. Study 
drug will be stored at the site at a temperature of 2ºC to 8ºC. Storage instructions will be provided 
in the pharmacy manual.  
For SC administration, these drug products are each reconstituted with 2.3 mL of sterile water for 
injection, yielding a final concentration of 100 mg/mL REGN1908 or 100 mg/mL REGN1909 in 
histidine, polysorbate 80, and sucrose. A total volume of 2.0 mL of the reconstituted liquid can be 
withdrawn from the glass vial. The reconstituted liquids will be mixed as a 1:1 cocktail. The 
resulting mixture will have a concentration of 100 mg/mL total of REGN1908-1909 (50 mg/mL 
REGN1908 and 50 mg/mL REGN1909). A 2.0 mL injection of the cocktail will provide a total 
dose of 200 mg REGN1908-1909. Three 2.0 mL SC injections will be administered for 600 mg 
total (300 mg per mAb). It is recommended that the 3 SC injections be given in separate locations, 
either the abdomen, thighs, or upper arms. During the treatment period, there will be 5 visits during 
which study drug will be administered for a total of 15 injections. 
This is a multiple dose study. Study drug will be administered at study site Q12W for a total of 5 
administrations. Patients will be randomized in a 1:1 ratio to receive 600 mg REGN1908-1909 or 
matching placebo that replaces REGN1908-1909. 
Instructions on dose preparation are provided in the pharmacy manual. 
8.2. 
Rescue Treatments 
Patients will be provided with the following medications (or an in-class equivalent, agreed upon 
with the sponsor) to treat allergic symptoms during the study:  
• desloratadine 5 mg (second generation antihistamine) 
• olopatadine 1 mg/mL (antihistamine eye drop) 
• mometasone furoate 50 ug/dose (intranasal steroid) 
From the time of baseline assessment period, patients can utilize the study provided allergy rescue 
medications (desloratadine, olopatadine and mometasone as specified above) to treat their allergic 
rhinitis and allergic conjunctivitis symptoms. During the baseline assessment and the efficacy 
assessment periods of the trial (weeks 0 to 12 and 48 to 60), daily use of rescue medications will 
be documented in the patient diary. At other non-efficacy periods (weeks 12 to 48), the rescue 
medication use can be documented in the concomitant medications.  
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Patients will be asked to refrain from taking specific prohibited medications during the study 
periods or within the specified time periods, preceding screening, baseline symptom and 
medication assessment, efficacy periods and at specific time points when skin testing or in-clinic 
spirometry will be conducted to prevent interference with the procedure (see Section 8.9.1). 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules 
8.3.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
8.3.2. 
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. 
8.3.2.1. 
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 
• A serious or severe asthma event deemed related to study drug that in the opinion of 
the PI would result in increased risk to the patient or a ≥50% decline in FEV1 from 
pre-treatment baseline  
• If, in the investigator’s opinion or at the specific request of the sponsor, continuation 
of study drug would be detrimental to the patient’s well-being, or there is no longer any 
potential for benefit, or if continuation would undermine the scientific integrity of the 
study 
• Specific types of liver dysfunction (eg, Hy’s law is met (FDA, 2009)) 
• Patient withdraws consent/ assent 
• In the event of an important protocol deviation, at the discretion of the investigator or 
the sponsor 
8.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing will be temporarily discontinued in the event of: 
• An asthmatic patient experiencing an asthma exacerbation and/or has a clinically 
relevant decrease in FEV1 ≥20% below baseline at a visit during which study drug was 
scheduled to be dosed, per investigator judgement. In this case, the patient may return 
to the clinic within the dosing visit window to be re-assessed for eligibility to receive 
study drug.  
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• Neutrophil count ≤1.0 x 103/µL 
• Sustained ALT/AST values greater than 3x the ULN plus total bilirubin >2x ULN or 
isolated AST/ALT >5x ULN 
• Hospitalization  
• Other intercurrent illness or adverse event or major surgery that 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 medical monitor. 
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 
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. 
If a patient requires a prohibited medication at any time during the study, the principal 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. 
8.4. 
Management of Acute Reactions  
8.4.1. 
Acute Injection Reactions 
8.4.1.1. 
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.  
8.4.1.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.2.4. 
8.5. 
Method of Treatment Assignment  
Approximately 630 patients will be randomized in a 1:1 ratio to receive either 600 mg (300 mg 
per mAb) REGN1908-1909 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 according to 
age (adolescents vs adults), asthma status (yes vs no), and house dust mite (HDM) sensitivity 
(<0.7 kUa/L versus ≥0.7 kUa/L).  
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8.6. 
Blinding 
Study patients, the principal investigators, and study site personnel (excluding the unblinded 
pharmacy staff) will remain blinded to all randomization assignments and blinded procedures 
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. 
Selected individuals not involved in the conduct of the study may have access to unblinded data 
as needed for safety review or other data review. 
8.7. 
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 (Section 8.3.2). 
• 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 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. 
8.8. 
Treatment Logistics and Accountability 
8.8.1. 
Packaging, Labeling, and Storage  
A medication numbering system will be used to label unblinded open-label investigational study 
drug. Lists linking medication numbers with product lot numbers will be maintained by the groups 
(or companies) responsible for study drug packaging; these lists will not be accessible to 
individuals involved in study conduct. 
The unblinded pharmacist will prepare the unblinded investigational product and dispense it in a 
blinded manner to the blinded study staff for administration to the patient. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual.  
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8.8.2. 
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 (requires sponsor 
approval) or returned to the sponsor or designee. 
8.8.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug/rescue 
medication. These records should contain the dates, quantity, and study drug 
• 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. 
8.8.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.9. 
Concomitant Medications  
Any treatment administered from the time of informed consent to the final study visit will be 
recorded. Any treatment administered from the time of first dose of study drug 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. 
8.9.1. 
Prohibited Medications  
Medications prohibited throughout the entire study are presented in Table 1 and medications 
prohibited for specific study periods are presented in Table 2.  
Table 1: 
Medications Prohibited Prior to Screening and Throughout the Study 
Medication Group 
Time Prohibited Before 
Study (Washout) 
Corticosteroids (intra-muscular/ intra-articular/ extended duration implants 
such as intravitreal etc) 
Prohibited (3 months) 
Tricyclic antidepressants/ typical antipsychotics 
Prohibited (14 days) 
Specific immunotherapy (SIT) with cat allergen or vaccines against cat allergy 
Prohibited (6 months) 
SIT with any allergen other than cat 
Prohibited (6 months) 
Immune directed biologics and/or therapies that would interfere with Type 2 
allergic disease or suppress the immune system, including but not limited to 
anti-IgE, anti IL-5, anti Il-4 
Prohibited (6 months) 
Methylxanthines 
Prohibited (3 days) 
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Medication Group 
Time Prohibited Before 
Study (Washout) 
Systemic calcineurin inhibitors 
Prohibited (14 days) 
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Table 2: 
Medications Prohibited During Specific Periods of the Study 
Medication Group 
Medication Subgroup 
Baseline Assessment Period up to Week 12 and 
Weeks 48 to 60 
(Washout)* 
Antihistamines 
1st gen, 2nd gen oral antihistamines/ intranasal antihistamines/ ocular antihistamines 
Prohibited except study provided anti-allergy 
rescue medications (desloratadine, olopatadine) 
Longer acting antihistamines (eg, Hydroxyzine/ Cyproheptadine) 
Prohibited (10 days) 
Decongestants 
Topical/ oral 
Prohibited (3 days) 
Leukotreine modifiers 
  
Prohibited (30 days) 
Anti cholinergics 
Intranasal anticholinergics 
Prohibited (12 h) 
Corticosteroids 
Intranasal 
Prohibited except study provided anti-allergy 
rescue medications (mometasone nasal spray) 
Ocular 
Prohibited (14 days) 
Oral/ IV 
Prohibited (30 days) 
Cromoglycates 
Ocular/ intranasal 
Prohibited (14 days) 
*NOTE: Patients will be provided the study rescue medications starting at their baseline assessment visit during screening. Once the patients start their baseline 
assessment, they should continue to use the study provided rescue medications and avoid any prohibited medications until the completion of the initial efficacy 
assessment period (weeks 0 to 12). Similarly, the patients should continue to use the study provided rescue medications and avoid any prohibited medications 
during the final efficacy assessment period (48 to 60 weeks). Prohibited medications (with specific washout durations) are specified in this table for these time 
periods. Anti-allergic medications (such as antihistamines, anti-allergic eye drops, anti-allergic nasal sprays) outside of study-related anti-allergic medications are 
prohibited during baseline and efficacy assessment periods (baseline to week 12 and weeks 48 to 60).  
Skin prick testing: Antihistamines should be withheld for 5 days prior to SPT (longer acting antihistamines such as hydroxyzine, 
cyproheptadine should be withheld for 10 days) 
 
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8.9.2. 
Permitted Medications 
Study provided rescue medications (desloratadine, olopatadine, and mometasone furoate, or 
in-class equivalent) can be used, as needed, throughout the study. The use of medications not listed 
as prohibited, will be allowed outside of the baseline and efficacy assessment periods (see 
Section 8.2).Treatment for acute reactions is allowed during the study (see Section 8.2).  
If a patient intends to receive a COVID-19 vaccine (initial series or booster) before the start of 
study drug administration, day 1 of the study and the events associated with day 1, should not 
occur until at least 1 week after any COVID-19 vaccination dosing.  
COVID-19 vaccination, either as an initial series or as a booster dose, received during the study, 
will be treated as a concomitant medication. As noted, administration of a COVID-19 vaccination 
should be separated from the time of administration of the investigational product (at least 
72 hours, ideally by at least 1 week) in order to avoid confounding the effects (eg, adverse effects) 
of the vaccine/booster with the effects of study drug. 
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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 3. 
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Table 3: 
Schedule of Events  
 
Screening Period1 
Randomization 
Double-Blind Treatment Period 
Follow Up Period 
 
Initial 
Efficacy 
Assessment 
 
Final 
(Primary) 
Efficacy 
Assessment 
End of 
Treatment 
(EOT)/ 
Early 
Term. 
End 
of 
Study 
(EOS) 
 
Visit 
Screening 
Visit 11 
Baseline 
V22 
R  
V34 
Tel 
V4 
Tel 
V5 
V6 
Tel 
V7 
V8 
Tel  
V9 
V10 
Tel 
V11 
V12 
Tel 
V13 
EOT  
V14 
EOS  
V15 
Un-
scheduled 
Visit13 
Day 
-85 to -1 
1 
8 
43 
85 
127 
169 
211 
253 
302 
337 
365 
421 
505 
 
Window (day) 
 
 
±3 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±7 
±7 
 
Week 
- 12  
0 
1 
6 
12 
18 
24 
30 
36 
43 
48 
52 
60 
72 
 
Screening/Baseline: 
Inclusion/exclusion 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics (age, 
race, height, 
weight) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skin prick test for 
cat and HDM3 
X3 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Skin prick test for 
other allergens3 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense e-diary 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Collect e-diary 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Dispense rescue 
meds 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Randomization4 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
Administer study 
drug5 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Concomitant meds 
and treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Screening Period1 
Randomization 
Double-Blind Treatment Period 
Follow Up Period 
 
Initial 
Efficacy 
Assessment 
 
Final 
(Primary) 
Efficacy 
Assessment 
End of 
Treatment 
(EOT)/ 
Early 
Term. 
End 
of 
Study 
(EOS) 
 
Visit 
Screening 
Visit 11 
Baseline 
V22 
R  
V34 
Tel 
V4 
Tel 
V5 
V6 
Tel 
V7 
V8 
Tel  
V9 
V10 
Tel 
V11 
V12 
Tel 
V13 
EOT  
V14 
EOS  
V15 
Un-
scheduled 
Visit13 
Day 
-85 to -1 
1 
8 
43 
85 
127 
169 
211 
253 
302 
337 
365 
421 
505 
 
Window (day) 
 
 
±3 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±7 
±7 
 
Week 
- 12  
0 
1 
6 
12 
18 
24 
30 
36 
43 
48 
52 
60 
72 
 
Efficacy: 
TNSS, TOSS, DMS 
 
X 
Nightly in e-diary 
 
 
 
 
 
Nightly in e-diary 
 
 
PGIS  
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
PGIC 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
RQLQ(S) 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
Evaluation of cat 
exposure 
 
 
 
 
 
X 
 
X 
 
X 
 
Daily in e-diary 
 
X 
Patient Experience 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Spirometry6,7 
X6 
 
X6 
 
 
X7 
 
 
 
 
 
X7 
 
X7 
 
 
ACQ-5 for asthma 
patients7 
 
 
X6 
 
 
X7 
 
 
 
 
 
X7 
 
X7 
 
 
ANSD and 
nighttime 
awakening for 
asthma patients7 
 
X7 
Daily in e-diary7 
 
 
 
 
 
Daily in e-diary7 
 
 
ADSD and asthma 
rescue med use for 
asthma patients7 
 
X7 
Nightly in e-diary7 
 
 
 
 
 
Nightly in e-diary7 
 
 
Safety: 
Vital signs8 
X 
X 
X8 
 
 
X8 
 
X8 
 
X8 
 
X8 
 
X 
X 
X 
Physical 
examination 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events 
X 
 
X 
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Screening Period1 
Randomization 
Double-Blind Treatment Period 
Follow Up Period 
 
Initial 
Efficacy 
Assessment 
 
Final 
(Primary) 
Efficacy 
Assessment 
End of 
Treatment 
(EOT)/ 
Early 
Term. 
End 
of 
Study 
(EOS) 
 
Visit 
Screening 
Visit 11 
Baseline 
V22 
R  
V34 
Tel 
V4 
Tel 
V5 
V6 
Tel 
V7 
V8 
Tel  
V9 
V10 
Tel 
V11 
V12 
Tel 
V13 
EOT  
V14 
EOS  
V15 
Un-
scheduled 
Visit13 
Day 
-85 to -1 
1 
8 
43 
85 
127 
169 
211 
253 
302 
337 
365 
421 
505 
 
Window (day) 
 
 
±3 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±7 
±7 
 
Week 
- 12  
0 
1 
6 
12 
18 
24 
30 
36 
43 
48 
52 
60 
72 
 
Laboratory Testing: 
Hematology 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Blood chemistry 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum pregnancy 
test for WOCBP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy for 
WOCBP9 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
FSH test for 
postmenopausal 
women only10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum for specific 
IgE for Fel d 1 and 
cat 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for sIgE for 
Fel d 2, 4, and 7  
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Serum for sIgE for 
other allergens (eg, 
HDM, etc) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK and ADA: 
Drug conc. sample11 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
ADA sample11 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
Biomarkers: 
Research sample for 
serum  
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Research sample for 
plasma 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
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Screening Period1 
Randomization 
Double-Blind Treatment Period 
Follow Up Period 
 
Initial 
Efficacy 
Assessment 
 
Final 
(Primary) 
Efficacy 
Assessment 
End of 
Treatment 
(EOT)/ 
Early 
Term. 
End 
of 
Study 
(EOS) 
 
Visit 
Screening 
Visit 11 
Baseline 
V22 
R  
V34 
Tel 
V4 
Tel 
V5 
V6 
Tel 
V7 
V8 
Tel  
V9 
V10 
Tel 
V11 
V12 
Tel 
V13 
EOT  
V14 
EOS  
V15 
Un-
scheduled 
Visit13 
Day 
-85 to -1 
1 
8 
43 
85 
127 
169 
211 
253 
302 
337 
365 
421 
505 
 
Window (day) 
 
 
±3 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±7 
±7 
 
Week 
- 12  
0 
1 
6 
12 
18 
24 
30 
36 
43 
48 
52 
60 
72 
 
Pharmacogenomics: 
Optional DNA 
sample (whole 
blood)12 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional Research 
Samples: whole 
blood for RNAseq  
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
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9.1.1. 
Footnotes for the Schedule of Events 
1. All screening-related procedures and assessments should be performed between day -85 to 
-1. During this window, rescreening is allowed up to 1 time. Patients cannot be rescreened 
based on skin testing or sIgE to cat not meeting eligibility. Baseline period assessment for 
symptom and medication requirements may not be repeated if patients do not meet 
eligibility criteria.  
2. The baseline assessment period is up to 21 days, and should be completed for a minimum 
of 15 consecutive days during the approximately 12-week screening period. This period is 
utilized to demonstrate that patients are sufficiently symptomatic due to cat exposure while 
taking study provided standard of care anti-allergy rescue medications in standard 
therapeutic doses. Patients will complete an e-diary to record their nasal, ocular and asthma 
symptoms as well as anti-allergy rescue medication use during up to a 3-week period 
during screening. Patients will be required to be have experienced allergic 
rhinoconjunctivitis symptoms and to have used their anti-allergy rescue medications, as 
specified, for at least 8 days of a consecutive 15-day period during this time. Patients must 
meet a daily total rhinitis and conjunctivitis symptom threshold of at least 8 of 18 on at 
least 8 days of the consecutive 15-day baseline assessment period and use standard 
therapeutic doses of anti-allergy rescue medications on 8 of the consecutive 15 days during 
the baseline assessment period. If missing data are reported due to documented e-diary 
malfunction (eg, technical issues that are reported to the vendor), then the baseline 
assessment period may be extended accordingly, allowing the 15-day period to be re-
started, to ensure that a consecutive 15 day period can be obtained. In such a circumstance, 
the medical monitor should be consulted, and agreement must be obtained with the sponsor. 
3. Screening skin prick test for cat hair and skin prick test for other relevant allergens (such 
as house dust mite [HDM] and other relevant allergens) is performed as described in the 
study manual. If screening skin prick test for cat hair is negative at screening visit 1 (mean 
wheal diameter less than at least 5 mm greater than a negative control), then other screening 
visit 1 procedures do not need to be performed as the patient will have failed screening 
based upon cat hair skin prick testing (eg, perform skin prick testing prior to other 
procedures such as blood draw, spirometry, etc). Appropriate measures will be taken to 
prevent accidental unblinding during the treatment period when skin prick tests are 
performed.  
4. Randomization may occur within 1 day prior to study drug administration. All safety 
assessments performed at screening must be normal and checked against the 
inclusion/exclusion criteria prior to study drug administration. 
5. Patients will remain in the clinic for 2 hours post-drug administration after receiving the 
first dose of study drug and after all subsequent doses.  
6. All patients will undergo in-clinic spirometry during screening and at randomization. After 
randomization, spirometry will only be done in patients with asthma. Washout of 
bronchodilator medications will be discussed by investigator with the patient and verified 
before performing the measurements as specified in Section 9.2.2.10. During the treatment 
period, at a visit for which study drug dosing is scheduled, any patient with asthma 
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experiencing an asthma exacerbation and/or has a clinically relevant decrease in FEV1 
≥20% below baseline will not be dosed, per investigator judgement. In this case, the patient 
may return to the clinic within the permitted dosing window to be re-assessed for eligibility 
to receive study drug. 
7. Only in patients with asthma: ANSD, ADSD, nighttime awakenings, asthma rescue 
medication use, ACQ-5, and post-randomization spirometry assessments will be collected. 
8. For all in-clinic visits where study drug is administered at visit 3, visit 6, visit 8, visit 10, 
and visit 12 vital signs are taken twice: (1) prior to study drug administration, and (2) at 
approximately 2 hours after completion of the injections. 
9. On day 1 and at subsequent visits, urine pregnancy test is completed prior to administration 
of study drug in women of childbearing potential. Postmenopausal women do not need 
urine pregnancy testing. If a urine pregnancy test is positive, a serum pregnancy test should 
be sent for confirmation. Drug should not be administered if a patient has a positive test. 
10. FSH test to be performed in postmenopausal women only, if postmenopausal status is in 
question. 
11. PK and ADA samples are to be collected prior to study drug administration. In the event 
of suspected AESIs, such as anaphylaxis or systemic hypersensitivity, additional samples 
for PK and ADA analyses may be collected as close to the event as practically possible. 
12. Genomic analysis is optional for all patients enrolling in the study. One DNA sample is to 
be collected on day 1/randomization, but if this sample collection was omitted at baseline, 
it can be collected at any subsequent visit.  
13. Assessments and procedures at unscheduled visits are to be performed at the discretion of 
the principal investigator. 
9.1.2. 
Early Termination Visit 
Patients who permanently discontinue study drug but who do not withdraw from the study will be 
asked to return to the clinic for all remaining study visits per the visit schedule (Table 3). Patients 
who are withdrawn from the study will be asked to return to the clinic for Early Termination 
assessments only. 
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, or for any 
other reason, as warranted. 
9.2. 
Study Procedures 
All study procedures should be performed and/or collected at time points according to Table 3. 
For adolescent patients, parent(s)/caregiver(s) may assist in filling out questionnaires as needed. 
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9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed only at screening/baseline to determine study 
eligibility or to characterize the baseline population: demographics, medical history, ECG, SPT 
for other allergens, and FSH determination (in postmenopausal women if postmenopausal status 
is in question). 
9.2.2. 
Efficacy Procedures for All Patients 
9.2.2.1. 
Total Nasal Symptom Score 
The TNSS ranges from 0 to 12 and is based on assessment of 4 nasal symptoms graded on a Likert 
scale ranging from 0 (none) to 3 (severe) for nasal congestion, itching, and runny nose, and 
sneezing. The TNSS will be recorded before going to bed for the night using an e-diary.  
9.2.2.2. 
Total Ocular Symptom Score 
The TOSS ranges from 0 to 6 and is based on 2 eye symptoms: itching/redness/gritty feeling and 
tearing/watering. Each of the 2 symptoms is graded on a Likert scale ranging from 0 (none) to 3 
(severe). The TOSS will be recorded before going to bed for the night using an e-diary.  
9.2.2.3. 
Total Symptom Score 
The TSS is calculated by adding the TNSS (see Section 9.2.2.1) and TOSS (see Section 9.2.2.2) 
together, for a combined TSS of 0 to 18.  
9.2.2.4. 
Daily Medication Score 
For the DMS, before going to bed for the night, patients will be asked to record their daily rescue 
medication use using an e-diary, including which medications and the amount of these 
pre-specified medications. This information will be used to calculate the DMS for the following 
medications or the approved in-class equivalents, as follows: desloratadine 5 mg 6 points/dose; 
maximum daily score 6 points, olopatadine 1 mg/mL each drop 1.5 points/drop; maximum daily 
score 6 points, mometasone furoate 50 ug/dose 2.0 points/spray; maximum daily score 8 points). 
The maximum DMS score is 20 (Calderon, 2014). 
9.2.2.5. 
Combined Symptom and Medication Score 
The CSMS is defined as TSS (see Section 9.2.2.3) plus DMS (see Section 9.2.2.4). 
9.2.2.6. 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire for Ages 12+ 
The RQLQ(S) is a self-administered questionnaire to measure HRQoL in those 12 years of age 
and above, as a result of perennial or seasonal allergic rhinitis. There are 28 items on the RQLQ(S) 
in 7 domains: activity limitation, sleep problems, nasal symptoms, eye symptoms, non-nasal/eye 
symptoms, practical problems, and emotional function. The RQLQ(S) responses are based on a 
7-point Likert scale with responses ranging from 0 (not troubled) to 6 (extremely troubled). The 
overall RQLQ(S) score is the mean of all 28 responses and the individual domain scores are the 
means of the items in those domains. Higher scores indicated more HRQoL impairment (lower 
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scores were better). A change of 0.5 point or more in total score is considered to be clinically 
meaningful. 
9.2.2.7. 
Patient Global Impression of Severity 
The PGIS assesses the severity of the cat allergy symptoms over the past 1 week. Symptom 
severity ranges from 0 (no symptoms), 1 (mild), 2 (moderate), and 3 (severe) symptoms. 
9.2.2.8. 
Patient Global Impression of Change 
The PGIC assesses the overall change in cat allergy symptoms since the start of taking the study 
injection. It is measured with a 7‑point Likert-type response scale, with values ranging from 
0 = “Very Much Better” to 6 = “Very Much Worse”.  
9.2.2.9. 
Skin Prick Test 
An SPT with cat allergen extract, other relevant allergens, a negative control (such as saline/ 
diluent), and a histamine positive control will be performed to assess sensitization status. A 
positive response for cat is defined by a mean wheal diameter at least 5 mm greater than a negative 
control, in which SPT mean wheal diameter is defined as ([longest diameter + longest 
perpendicular]/2). For other allergens, a positive sensitization is defined as a mean wheal diameter 
of at least 3 mm greater than a negative control. 
Allergen exposure can induce immediate or late allergic reactions, such as allergic conjunctivitis, 
allergic rhinitis, asthma symptoms, or rarely anaphylaxis, in sensitized patients, which will be 
treated appropriately at the discretion of the investigator. With the exception of severe or clinically 
concerning reactions (as judged by the investigator), rescue treatments should be given after study 
endpoint data collection is obtained (eg, after the skin wheals are measured after application of 
allergen). 
Starting at week 12, the SPTs will be performed in a manner to prevent accidental unblinding. The 
skin prick tests (cat, saline, histamine, and house dust mites) will be run in replicate (8 total) with 
a blinded code. The allergen wells will be blinded by the unblinded pharmacist (or qualified 
designee) and provided with labels (allergen #1 to allergen #7) to the blinded personnel (described 
in Section 8.6). One positive control histamine skin prick test will not be blinded. 
Specific medications to be withheld prior to SPT are described in Prohibited Medications 
(Section 8.9.1). 
9.2.2.10. Spirometry 
Spirometry measurements include FVC (L), FEV1 (L), FEV1/FVC (%), PEF (L/s), 
FEF 25-75 (L/s). Spirometry (American Thoracic Society [ATS]/European Respiratory Society 
[ERS]-compliant) (Graham, 2019), as adjudicated by the site investigator, will be performed 
locally during the study at specified time points (Table 3). Spirometry details will be available in 
a separate operational manual provided to the sites. 
Spirometry will be performed in-clinic at screening and randomization for all patients to exclude 
any patients with abnormal lung function and/or poorly controlled asthma. FEV1 eligibility criteria 
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are specified in exclusion criteria (Section 7.2.2). After randomization, spirometry will only be 
done in patients with co-morbid asthma.  
Spirometry will be performed after a washout period of bronchodilators according to their action 
duration to avoid interference with spirometry assessments and the investigator will discuss this 
with the patients. Examples of washout periods that investigator can discuss with the patient 
include withholding the last dose of short acting bronchodilator (SABA, such as  
salbutamol/albuterol or levosalbutamol/levalbuterol) for at least 6 hours, long acting 
bronchodilator (LABA, such as formoterol or salmeterol) for at least 12 hours, ultra-long-acting 
LABA (such as vilanterol, indacaterol) for at least 24 hours, short acting muscarinic antagonist 
(SAMA, such as ipratropium) for at least 8 hours, and long acting muscarinic antagonist (LAMA, 
such as tiotropium, umeclidinium) for at least 24 hours. Withholding times will be verified before 
performing the measurements.  
9.2.2.11. Evaluation of Cat Exposure 
Patients will be asked about their exposure to cat(s) at study visits as outlined in Table 3. From 
week 48 through week 60, as part of the patient reported e-diary, patients will be asked to report 
exposure to their cat(s). At the screening, baseline, and randomization visits, exposure to cat(s) is 
assessed via the inclusion/exclusion criteria.  
9.2.2.12. Patient Experience Assessment 
Patients will complete questions at week 60 (Table 3) to assess various parameters that may impact 
efficacy assessments. Questions will assess changes that patients experienced over the course of 
the study regarding the amount of time spent with their cat(s) and the impact on their perceived 
health status.  
9.2.3. 
Efficacy Procedures for Patients with Asthma 
9.2.3.1. 
Asthma Nighttime Symptom Diary Score  
Only for patients with asthma, upon waking up in the morning, patients will complete the e-dairy 
to report asthma symptoms experienced during the nighttime using the Asthma Nighttime 
Symptom Diary (ANSD). The ANSD score will be based on 6 patient-reported symptoms 
(difficulty breathing, wheezing, shortness of breath, chest tightness, chest pain, and cough at their 
worst using an 11-point numeric rating scale (NRS) ranging from 0 (‘None’) to 10 (‘As bad as you 
can imagine’). 
9.2.3.2. 
Asthma Daytime Symptom Diary Score  
Only for patients with asthma, before going to bed for the night, patients will complete the e-diary 
to report asthma symptoms experienced during the day using the Asthma Daytime Symptom Diary 
(ADSD). The ADSD score will be based on 6 patient-reported symptoms (difficulty breathing, 
wheezing, shortness of breath, chest tightness, chest pain, and cough at their worst using an 
11-point numeric rating scale (NRS) ranging from 0 (‘None’) to 10 (‘As bad as you can imagine’). 
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9.2.3.3. 
Asthma Daily Symptom Score 
Only for patients with asthma, average of daily scores of the ANSD score and the ADSD score 
will be used to generate an Asthma Daily Symptom Score (ADSS) ranging from 0 (‘None’) to 10 
(‘As bad as you can imagine’). 
9.2.3.4. 
Nighttime Awakenings  
Only for patients with asthma, patients will report the number of nighttime awakenings by 
completing the e-diary every morning.  
9.2.3.5. 
Rescue Medication Use 
Only for patients with asthma, patients will report the number of rescue medication puffs 
(example- short-acting bronchodilator) by completing the e-diary every evening.  
9.2.3.6. 
Juniper Asthma Control Questionnaire 
Only for patients with asthma, the ACQ-5, (5-question version of the Juniper ACQ), is a validated 
questionnaire to evaluate asthma control. The ACQ-5 score is the mean of the scores of the 5 items 
and ranges from 0 (totally controlled) to 6 (severely uncontrolled). Scores less than 1.0 reflect 
adequately controlled asthma, and scores 1.0 or greater reflect inadequately controlled asthma. 
Higher score indicates lower asthma control and 0.5 is the smallest change that can be considered 
clinically important.  
9.2.4. 
Safety Procedures for All Patients 
9.2.4.1. 
Body Weight 
Body weight will be assessed using calibrated scales. Body weight will be recorded to the nearest 
0.1 kg. 
9.2.4.2. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, pulse, and respiration, will be collected 
predose. 
9.2.4.3. 
Physical Examination 
A thorough and complete physical examination will be performed. Care should be taken to 
examine and assess any abnormalities that may be present, as indicated by the patient’s medical 
history. 
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9.2.4.4. 
Electrocardiogram 
A standard 12-lead ECG will be performed. Heart rate will be recorded from the ventricular rate 
and the PR, QRS, and QT (identify QTcB or QTcF) intervals will be recorded. The ECG strips or 
reports will be retained with the source. 
9.2.4.5. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed. Detailed 
instructions for blood sample collection are in the laboratory manual provided to study sites. 
Samples for laboratory testing will be collected. Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Aspartate aminotransferase (AST) 
Potassium 
Creatinine 
Alanine aminotransferase (ALT) 
Chloride 
Blood urea nitrogen (BUN) 
Alkaline phosphatase 
Carbon dioxide 
Total bilirubin  
Albumin 
Calcium 
Glucose  
 
Hematology 
Hemoglobin 
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
WBC 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Yeast 
Protein 
 
 
Other Laboratory Tests 
Patients will be tested for FSH levels (if postmenopausal status is in question) and will undergo 
serum and urine pregnancy testing (women of childbearing potential only); pregnancy testing is 
not required of women confirmed to be menopausal. Samples will be collected for quantitative 
assessment of allergen specific IgE. 
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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 drug 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 adverse event (AE) are provided in Section 10.1.1. 
9.2.5. 
Drug Concentration and Measurements 
Samples for drug concentration measurement will be collected at visits listed in Table 3.  
9.2.6. 
Immunogenicity Measurements and Samples 
Samples for ADA assessment for REGN1908 and REGN1909 will be collected at time points 
listed in Table 3. Anti-REGN1908 and anti-REGN1909 neutralizing antibody (NAb) analysis may 
be performed on ADA positive serum samples. The overall immunogenicity risk will be taken into 
consideration to assess the need for NAb analysis. Serum samples will be banked if NAb analysis 
is to be conducted at a later time. Detailed instructions for blood sample collection are included in 
the laboratory manual provided. 
9.2.7. 
Pharmacodynamic and Exploratory Biomarker Procedures 
Blood samples will be obtained for additional exploratory research to better understand the effects 
of various anti-Fel d 1 antibodies on cat allergy. This will include the assessment of effective 
competition between REGN1908 and REGN1909 (either alone or in combination) and endogenous 
sIgE in serum for allergen binding in an in vitro interference/ inhibition assay.  
These results will be part of exploratory research analysis and will be included in an exploratory 
biomarker report, which will not be described in the clinical study report.  
9.2.8. 
Future Biomedical Research (Optional) 
Patients who agree to participate in the future biomedical research (FBR) sub-study will be 
required to consent to this optional sub-study before samples are banked for FBR. Residual 
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 (or for a shorter time period if 
required per regional laws and regulations). The samples may be utilized for FBR that may or may 
not be directly related to the study, including being used as reference samples and assay 
development or validation. The results of these future biomedical research analyses will not be 
presented in the CSR. 
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9.2.9. 
Pharmacogenomic Analysis (Optional) 
Patients who agree to participate in the genomics sub-study will be required to consent to this 
optional sub-study before collection of the samples. Whole blood samples for DNA extraction 
should be collected on day 1/baseline (predose), but can be collected at a later study visit. Whole 
blood samples for RNA extraction will be collected at time points according to Table 3. DNA and 
RNA samples will be collected for pharmacogenomics analyses to understand the genetic 
determinants of efficacy and safety associated with the treatments in this study and the molecular 
basis of cat allergy and related diseases. These samples will be single-coded as defined by the 
International Council for Harmonisation (ICH) guideline E15. Samples will be stored for up to 
15 years after the final date of the database lock (or for a shorter time period if required per regional 
laws and regulations). If there are specific site or country requirements involving the 
pharmacogenomic analyses which the sponsor is unable to comply with, samples will not be 
collected at those sites.  
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to REGN1908-1909 treatment, cat allergy or related allergic diseases, clinical 
outcome measures, and possible AEs. In addition, associations between genomic variants and 
prognosis or progression of cat allergy as well as related allergic 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, target pathway, or cat 
allergy 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, from the time of signing the ICF to the end of on-treatment period (see 
Section 11.4.6.1). Medical conditions that existed or were diagnosed prior to the signing of the 
Informed Consent 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 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.  
Although not considered an adverse event, if a pregnancy occurs during the study, information 
about the progress and outcome of the pregnancy will be collected. This should include the date 
that the subject became pregnant, information about the health of the subject, any medication 
treatments received during the pregnancy, any medical problems affecting or related to the 
pregnancy and/or the baby, whether the pregnancy came to term, the date of the child’s birth, and 
the health of the child after birth. To collect this information, the study staff should contact the 
subject every trimester for updates on the pregnancy. The subject should also be asked to contact 
the site as soon as possible in the event of any medical problem affecting or related to the 
pregnancy and/or baby. Once the baby is born, the study staff will ask for a final update after one 
well-baby visit with the pediatrician.  
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, 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 serious adverse event (SAE; diagnosis or symptom requiring hospitalization). A procedure 
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is not an AE or SAE, but the reason for the procedure may be an AE or SAE. Pre-planned (prior 
to signing the Informed Consent Form) 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 on-treatment 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.  
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 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 case report form (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 
• Selected Adverse Events of Special Interest (AESI; serious and nonserious): Adverse 
events of special interest for this study include the following:  
− Severe or systemic hypersensitivity reactions 
NOTE: Anaphylaxis will be prospectively analyzed using the criteria discussed in 
the statement paper from the Second Symposium on the definition and Management 
of Anaphylaxis (Sampson, 2006) 
− Asthma exacerbations, defined as asthma symptoms requiring treatment with 
systemic corticosteroids or resulting in an emergency room visit or hospitalization 
• 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, 
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any pregnancy occurring in a female during the study or within 24 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. 
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.  
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10.2.3. 
Adverse Events of Special Interest 
An adverse event of special interest (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.  
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 AE, 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 
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• Clinical and pathological features of the events  
• Existing information about the drug and same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
• Response to rechallenge (re-introduction of the drug) or dose increase, when 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, 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. 
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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, 
Global Patient Safety (GPS); 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. 
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, Institutional Review 
Boards (IRBs)/Ethics Committees (ECs), and the participating investigators of any Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring in other study centers or other studies 
of the active study drug (REGN1908-1909), 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 (REGN1908-1909) is assessed against the Reference Safety 
Information section of the 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 Clinical Study Report to health authorities and IRB/EC as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (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.  
Handling of missing data due to the COVID-19 pandemic and any additional analyses required to 
investigate the impact of COVID-19 to understand estimated treatment effect and safety will be 
detailed in the SAP. 
11.1. 
Statistical Hypothesis 
For comparison of REGN1908-1909 to placebo, the following hypothesis of the primary endpoint 
(the average daily CSMS over the last 12 weeks of the treatment period [weeks 48 to 60]) will be 
tested:  
H0: There is no difference in CSMS, averaged over the last 12 weeks of the treatment period (weeks 
48 to 60), in patients receiving REGN1908-1909 and placebo.   
H1: The CSMS, averaged over the last 12 weeks of the treatment period (weeks 48 to 60, is 
significantly different in patients receiving REGN1908-1909 and placebo.  
The statistical hypothesis specified above can be tested on the selected secondary endpoints. The 
study will be declared positive if at least the null hypothesis for the primary efficacy endpoint for 
REGN1908-1909 versus placebo is rejected. 
11.2. 
Justification of Sample Size 
The sample size will be approximately 315 patients per arm, for a total of 630 patients. This study 
is powered to detect the difference between REGN1908-1909 and placebo on the primary endpoint 
of daily CSMS averaged over the last 12 weeks of the treatment period (weeks 48 to 60) when 
considering a 20% dropout rate by week 60. 
A sample size of 251 patients per arm gives 90% power to detect a mean difference in daily average 
CSMS of 1.8 (20% reduction from placebo) between REGN1908-1909 (mean CSMS=7.3) and 
placebo (mean CSMS=9.1), assuming a common standard deviation in CSMS of 6.2. Assuming a 
20% dropout rate (~64 per arm), the sample size is 315 per arm. A 2-sample t-test with 2-sided 
alpha of 0.05 was assumed. Calculations were performed using nQuery+nTerim 4.0 
The sample size of 315 patients per arm also gives the power of 91% and  96% to detect a 20% 
reduction from placebo in TSS (SD=3.0 and mean in placebo=4.2) and daily TNSS (SD=2.3 and 
mean in placebo=3.3) averaged over the last 12 weeks (weeks 48 to 60), respectively. Details are 
displayed in Table 4.  
The assumptions of mean in the placebo  and common standard deviation for the above endpoints 
are based on the house dust mite (HDM) SLIT-tablet data (Demoly, 2016) for combined 
rhinoconjunctivitis score during 8-week assessment period. A treatment difference of 20% relative 
to placebo is based on a previous phase 1b study (R1908-1909-ALG-1325) of the same molecules 
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and the treatment effect observed for reduction in symptoms after a nasal allergen challenge over 
a 12-week period.  
Table 4: 
Summary of Statistical Assumptions and Power for Selected Secondary 
Endpoints 
Daily Score, 
Averaged over 12 
weeks 
Mean 
Anti-Fel d 1 vs PBO 
Power with 
n=315/arm  
PBO 
Anti-Fel d 1 
% Reduction 
from PBO 
Reduction from 
PBO (SD)  
TNSS 
3.3 
2.6 
-20% 
-0.7 (2.3) 
96% 
TSS 
4.2 
3.4 
-20% 
-0.8 (3.0) 
91% 
The sample size may be re-estimated in a blinded fashion after greater than 50% of patients have 
baseline data available using observed values of CSMS to determine the baseline PBO mean (SD) 
and assuming the same 20% difference between REGN1908-1909 versus placebo. If the 
re-estimated number is higher than the current estimation of 315 per arm, then the sample size may 
be increased.  
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). Efficacy endpoints will be analyzed using the FAS. 
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 result following the first dose of study drug. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set includes all patients who received study drug and 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 positive for ADA 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). 
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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 or ordinal 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 who signed the ICF 
• The total number of randomized patients: received a randomization number 
• The total number of randomized patients who discontinue the study, and the reasons 
for discontinuation 
• The total number of randomized patients who discontinued from study treatment, and 
the 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.  
11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis 
The primary endpoint, the daily CSMS averaged over the last 12 weeks of the treatment period 
(weeks 48 to 60), will be analyzed on the full analysis set (FAS), which consists of all 
randomized patients.  
The primary analysis will focus on the comparison between REGN1908-1909 and placebo in the 
FAS. The analysis will be performed using an analysis of covariance (ANCOVA) model, with the 
treatment group, randomization stratification factors, and cat sIgE (<17.5 kUa/L versus ≥17.5 
kUa/L) as fixed effects and the baseline CSMS as a covariate. The least squares means estimates 
for the average CSMS during the last 12 weeks of the treatment period for each treatment group, 
as well as the difference between the REGN1908-1909 and placebo will be provided along with 
the corresponding 2-sided p-value and associated 95% confidence interval.  
Only days with observed data will be included in the calculation of average score. The average 
CSMS (max score 38/day) will be calculated based on the sum of daily total nasal symptom scores 
(TNSS, max score 12/day), daily TOSS (max score 6/day) and daily medication scores (DMS, max 
of 20/day) recorded over the last 12 weeks of the treatment period (weeks 48 to 60).  
Any data collected after rescue medication use will be used in the analysis for the CSMS. Since 
the relevant prohibited medication use may have an impact on symptom measurements, the CSMS 
data will be set to missing at the time of and after receiving the prohibited medication. The details 
of the relevant prohibited medications will be specified in the SAP. The primary estimand will 
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utilize the CSMS calculated by observed components prior to receiving relevant prohibited 
medication or the worst score of all observations in corresponding treatment group if a patient has 
no single value of CSMS during the last 12 weeks of the treatment period (composite strategy).  
If a patient has no single available value of CSMS during the last 12-week assessment period, a 
hybrid approach of the worst score and the multiple imputation (MI) will be used to impute the 
missing data for the primary analysis. Missing data because of patients’ discontinuation from study 
due to AEs and lack of efficacy will be imputed using the worst score of all the observations in 
corresponding treatment group, and multiple imputation (MI) will be applied to impute missing 
values due to all other reasons. With respect to the missing data handling of daily entries, 
sensitivity analyses may be performed to confirm robustness of the conclusion drawn based on the 
main model for primary analysis. Details of these sensitivity analyses will be provided in the SAP. 
The intercurrent events, strategies, and the corresponding missing data handling approaches for 
the estimand for the primary endpoint are summarized in Table 5.  
Table 5: 
Summary of Estimand for Primary Endpoint 
Endpoint 
Category 
Estimand 
Endpoint(s) 
Population 
Intercurrent event(s) handling strategy 
and missing data handling 
Population-level 
summary 
Primary endpoint 
– Continuous 
Daily 
combined 
symptom and 
medication 
scores (CSMS) 
averaged over 
the last 12 
weeks of the 
treatment 
period 
FAS 
The intercurrent events will be handled as 
follows: 
• 
Discontinuing the study 
intervention: all data collected 
after discontinuation will be used 
in the analysis (treatment policy 
strategy) 
• 
Rescue treatment to treat allergic 
symptoms during the efficacy 
assessment period: data after 
rescue medication will be used in 
the analysis (treatment policy 
strategy)  
• 
Relevant prohibited medications 
taken during the efficacy 
assessment period: the daily 
average CSMS will be calculated 
by observed components prior to 
receiving prohibited medication or 
the worst score of all observations 
in corresponding treatment group 
if a patient has no single value of 
CSMS during the last 12 weeks of 
the treatment period (composite 
strategy) 
In addition, if a patient has no available 
values of CSMS during the last 12 weeks of 
the treatment period, the missing data 
imputation rules are as follows: 
• 
Missing data because of patients’ 
discontinuation from study due to 
AEs and lack of efficacy will be 
ANCOVA model 
with treatment group, 
stratification factors, 
and cat sIgE (<17.5 
kUa/L versus ≥17.5 
kUa/L) as fixed 
factors and baseline 
CSMS as a covariate 
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Endpoint 
Category 
Estimand 
Endpoint(s) 
Population 
Intercurrent event(s) handling strategy 
and missing data handling 
Population-level 
summary 
imputed using worst score of all 
the observations in corresponding 
treatment group (largest number) 
and missing data due to any other 
reason will be imputed using 
multiple imputation (MI).  
To assess the consistency in treatment effects across different subgroup levels, subgroup analyses 
will be performed for the primary efficacy endpoint with respect to age group, gender, region, and 
other factors that will be specified in the SAP. 
11.4.3.2. Secondary Efficacy Analysis 
The secondary efficacy endpoints will be analyzed using an ANCOVA model in the same fashion 
as the primary analysis of the primary endpoint.  
The average symptom score or medication score over the initial or last 12 weeks of the treatment 
period will be calculated in similar way as the primary endpoint. 
The intercurrent events, strategies, and the corresponding missing data handling approaches for 
the estimands for key secondary endpoints and selected other secondary endpoints are summarized 
in Table 6. 
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Table 6: 
Summary of Estimands for Key Secondary Endpoints and Selected Other 
Secondary Endpoints 
Endpoint 
Category 
Estimands 
Endpoint(s) 
Population 
Intercurrent event(s) handling strategy and 
missing data handling 
Population-level 
summary 
Secondary 
endpoint – 
Continuous, 
daily 
measurements 
Daily TNSS, 
TSS, TOSS, 
and DMS over 
the last 12 
weeks of the 
efficacy 
assessment 
period (weeks 
48 to 60) and 
the percent 
change from 
baseline in 
these 
endpoints 
Daily TNSS, 
CSMS, TSS, 
DMS, and 
TOSS over the 
initial 12 
weeks of the 
efficacy 
assessment 
period (weeks 
0 to 12) and 
the percent 
change from 
baseline in 
these 
endpoints 
FAS 
The intercurrent events will be handled as follows: 
• Discontinuing the study intervention: all data 
collected after discontinuation will be used 
in the analysis (treatment policy strategy) 
• Rescue treatment to treat allergic symptoms 
during the efficacy assessment period: data 
after rescue medication will be used in the 
analysis (treatment policy strategy)  
• Relevant prohibited medications taken 
during the efficacy assessment period: the 
daily average symptom or medication score 
will be calculated by observed score prior to 
receiving relevant prohibited medication or 
the worst score of all observations in 
corresponding treatment group if a patient 
has no single value of the score during the 
12-week assessment period (composite 
strategy).  
In addition, if a patient has no available values of 
the relevant measurement during the 12-week 
assessment period, the missing data imputation 
rules are as follows: 
• 
Missing data because of patients’ 
discontinuation from study due to AEs and 
lack of efficacy will be imputed using the 
worst score of all the observations in 
corresponding treatment group and missing 
data due to any other reason will be imputed 
using MI.  
ANCOVA model 
with treatment 
group, stratification 
factors, and cat 
sIgE (<17.5 kUa/L 
versus ≥17.5 
kUa/L) as fixed 
factors and relevant 
baseline 
measurement as a 
covariate 
Secondary 
endpoint – 
Continuous, 
SPT 
Percent 
change from 
baseline to 
week 12 cat 
SPT mean 
wheal 
diameter 
Percent 
change from 
baseline to end 
of treatment 
(week 60) cat 
SPT mean 
wheal 
diameter 
FAS 
The intercurrent events will be handled as follows: 
• Discontinuing the study intervention: all data 
collected after discontinuation will be used 
in the analysis (treatment policy strategy) 
• Rescue treatment to treat allergic symptoms 
during the efficacy assessment period: data 
after allergy-relieving rescue medication will 
be used in the analysis (treatment policy 
strategy)  
• Relevant prohibited medications taken 
during the defined window leading up to 
SPT at the relevant visit (week 12 or week 
60): data prior to receiving prohibited 
medication or the worst value of all 
observations in corresponding treatment 
group if a patient has no single value of the 
value during the 12-week assessment period 
(composite strategy) will be utilized.  
In addition, if a patient has no available values of 
the relevant measurement during the 12-week 
ANCOVA model 
with treatment 
group, stratification 
factors, and cat 
sIgE (<17.5 kUa/L 
versus ≥17.5 
kUa/L) as fixed 
factors and baseline 
SPT mean wheal 
diameter as a 
covariate 
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Endpoint 
Category 
Estimands 
Endpoint(s) 
Population 
Intercurrent event(s) handling strategy and 
missing data handling 
Population-level 
summary 
assessment period, the imputation rules are as 
follows: 
• Missing data because of patients’ 
discontinuation from study due to AEs and 
lack of efficacy will be imputed using worst 
score of all the observations in 
corresponding treatment group and missing 
data due to any other reason will be imputed 
using MI. 
Secondary 
endpoint – 
Continuous, 
FEV1 
Percent 
change from 
baseline to 
week 12 FEV1  
Percent 
change from 
baseline to 
week 60 FEV1 
All 
randomized 
patients 
with 
asthma 
The intercurrent events will be handled as follows: 
• Discontinuing the study intervention: all data 
collected after discontinuation will be used 
in the analysis (treatment policy strategy) 
• Rescue treatment to treat allergic symptoms 
during the efficacy assessment period: data 
after rescue medication will be used in the 
analysis (treatment policy strategy)  
• Relevant prohibited medications taken 
during the defined window leading up to 
spirometry at the relevant visit (week 12 or 
week 60): data prior to receiving prohibited 
medication or the worst value of all 
observations in corresponding treatment 
group if a patient has no single value of the 
score during the 12-week assessment period 
(composite strategy) will be utilized.  
In addition, if a patient has no available values of 
the relevant measurement during the 12-week 
assessment period, the imputation rules are as 
follows: 
• Missing data because of patients’ 
discontinuation from study due to AEs and 
lack of efficacy will be imputed using worst 
score of all the observations in 
corresponding treatment group and missing 
data due to any other reason will be imputed 
using MI. 
ANCOVA model 
with treatment 
group, stratification 
factors, and cat 
sIgE (<17.5 kUa/L 
versus ≥17.5 
kUa/L) as fixed 
factors and baseline 
FEV1 measurement 
as a covariate 
11.4.4. 
Control of Multiplicity 
Multiplicity is considered for testing multiple endpoints. The overall type-I error rate will be 
controlled at the 2-sided 0.05 level.  
A non-binding futility interim analysis (IA) is planned in this study (details are provided in 
Section 6.2), and an administrative penalty of 0.001 will be taken from the significance level used 
at final analysis, and thus 2-sided 0.049 will be used. No further multiplicity adjustment will be 
performed for the IA.  
At the final analysis, a hierarchical testing procedure is proposed to strongly control the family 
wise type-I error rate for testing the primary and key secondary endpoints. Two-sided alpha of 
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0.049 will be allocated to the endpoints. The detailed hierarchical order will be specified in the 
study SAP. 
11.4.5. 
Timing of Statistical Analyses 
A non-binding futility IA will be performed when at least 40% of all randomized patients complete 
week 12 or discontinue before week 12. The IA will be performed by independent statisticians 
who support the IDMC and who are separate from personnel involved in the trial conduct.  
The unblinded primary analysis will be performed when all randomized participants have 
completed the last 12 weeks of the treatment period (week 60). This unblinded primary analysis 
will be considered the final analysis for the efficacy endpoints. Additional data between this 
database lock and last patient completing the last visit will be summarized in a CSR.  
11.4.6. 
Safety Analysis 
The analysis population for the safety endpoints (SAF) includes all randomized patients who 
receive at least 1 injection of study drug and will be analyzed according to the intervention they 
actually received. The SAF will be the basis for the analyses for the study period. The safety 
analyses will be based on descriptive statistics using the observed data. The number and percentage 
of patients with at least 1 treatment-emergent adverse event (TEAE), treatment-emergent SAE, 
treatment-emergent AESI, treatment-related TEAE, and TEAE leading to treatment 
discontinuation will be tabulated by treatment group. Descriptive statistics of values and change 
from baseline values for each laboratory and vital signs parameters will be summarized by 
treatment group at each time point. The number and percentage of patients with at least 1 incidence 
of potentially clinically significant abnormality at any time during the treatment-emergent period 
will be summarized by treatment group.  
The SAP for the study will be developed and finalized before database lock. Statistical analyses 
were conducted with SAS software version 9.4 or above. 
11.4.6.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The on-treatment period is defined as the day from first dose of study drug to the last 
dose of study drug plus 12 weeks (weeks 0 to 60). 
• The follow-up period is defined as the end of the on-treatment period to 12 weeks after 
the end of the on-treatment period (weeks 60 to 72). 
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 on-treatment and follow-up periods.  
Adverse events of special interest (Section 10.2.3 and Section 10.1.3) for this study include:  
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• Severe or systemic hypersensitivity reactions defined using the narrow SMQ for 
hypersensitivity, with manual adjudication of relevant PTs by medical monitor before 
database lock. 
• Asthma exacerbations defined using the narrow SMQ for asthma and further manually 
adjudicated for events requiring treatment with systemic corticosteroids or resulting in 
an emergency room visit or hospitalization. 
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 system organ 
class (SOC) and preferred term (PT) 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.4), 
presented by SOC and PT 
• Treatment related TEAEs, presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be 
summarized by treatment group.  
Safety AE outcomes such as time to the first AESIs or TEAE leading to permanent treatment 
discontinuation, will be assessed by Kaplan-Meier estimates (K-M plot). In order to detect any AE 
signals, the hazard ratio (HR) will be provided together with the corresponding 95% confidence 
interval (CI) for the selected adverse events during the 60-week treatment period. Hazard ratios 
will be calculated using a Cox model including factors of treatment group and randomization 
strata. For patients with events, the time to events is defined as the date of first event – the date of 
first dose + 1. Patients without an event will be censored at the end of study period. 
11.4.6.2. 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. 
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 potentially clinically significant value (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.  
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11.4.6.3. Treatment Exposure 
The duration of exposure during the study will be calculated as follows: 
• (date of last dose of study drug in the specific study part – date of first dose of study 
drug in the specific study part) + 84 days  
In addition, duration of cumulative exposure to REGN1908-1909 across study parts will be 
calculated as follows: 
• (date of last dose of study drug – date of first dose of study drug in the study) + 84 
days.  
Number and percentage of patients exposed to study drug will be summarized by time periods of 
specific lengths for each treatment group. The lengths of interest will be specified in the SAP.  
In addition, duration of exposure will be summarized as a continuous variable for each treatment 
group with the number of patients reflected in the calculation (n), mean, median, SD, minimum, 
the first and third quartiles, and maximum. 
A summary of the number of doses for each treatment group will be provided. 
11.4.7. 
Pharmacokinetics 
11.4.7.1. Analysis of Drug Concentration Data 
The concentrations of total REGN1908 and total REGN1909 over time will be summarized by 
descriptive statistics for each of the treatment groups. 
No formal statistical hypothesis testing will be performed.  
11.4.8. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA response, titer, and NAb response observed:  
• 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 9-fold over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative 
− 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 9-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)  
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• NAb status for samples that are positive in the ADA assay 
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers 
and NAb positivity presented by patient, time point, and dose will be provided separately for 
REGN1908 and REGN1909. Incidence of treatment-emergent ADA 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 separately for REGN1908 and REGN1909. Assessment of impact of ADA 
and NAbs on safety and efficacy may be provided. 
11.4.9. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
Biomarker results will be summarized by baseline, measured values, change from baseline, and 
percent change from baseline to each scheduled assessment time point with descriptive statistics. 
11.4.10. 
Analysis of Quality of Life Data 
Quality of life data will be analyzed using the same method as specified for the continuous 
secondary efficacy variables.  
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 history) will be done using internationally 
recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) system: 
Medidata Rave. 
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 – randomization, study drug supply 
• EDC system – data capture – Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
12.2. 
Study Monitoring 
12.2.1. 
Monitoring of Study Sites 
Regeneron uses a study-specific risk-based approach to study monitoring and oversight, aligned 
with risk-based quality principles, outlined in ICH E6 (R2) Guideline for Good Clinical Practice. 
Risk-Based Quality Monitoring (RBQM) methodology focuses on employing a fit-for-purpose 
monitoring strategy, supported either directly by Regeneron as sponsor, or via our CRO partners. 
RBQM strategies include: reduced source data verification (SDV), targeted source data review 
(SDR), the use of off-site/remote and triggered on-site monitoring visits, and Centralized 
Monitoring to identify site level risks and study level trends. The investigator must allow study-
related monitoring activities to occur. 
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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. 
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 are 
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 electronic CRFs 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 CRF will be entered in the CRF 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 
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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. 
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 final 
eCRFs 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 
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- or 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 adult patient, and written informed consent or assent from 
each adolescent patient and written informed consent from his/her parent(s) or legal guardian(s), 
prior to patient’s participation in the study and after the aims, methods, objectives, and potential 
hazards of the study have been explained to the patient and adolescent patient’s parent(s) or legal 
guardian(s) in language that he/she can understand. The ICF should be signed and dated by the 
adult patient, and the ICF/IAF by adolescent patient and his/her parent(s) or legal guardian(s), and 
by the investigator or authorized designee who reviewed the ICF/IAF with the patient/patient’s 
parent(s) or legal guardian(s).  
For adolescent patients, local law must be observed in deciding whether the consent of 1 or both 
parents/guardians 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 or EC and in accordance with the local 
regulations and requirements. 
Patients/parents/guardians who can write but cannot read will have the ICF/IAF read to them 
before signing and dating the ICF/IAF. 
Patients who can understand but who can neither write nor read will have the ICF/IAF read to 
them in presence of an impartial witness, who will sign and date the ICF/IAF to confirm that 
informed consent/assent was given. 
The original ICF/IAF 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 adult patient, or to the adolescent patient and his/her 
parent(s) or legal guardian(s). 
If new safety information results in significant changes in the risk/benefit assessment, the ICF/IAF 
must be reviewed and updated appropriately. All study patients (and adolescent patients’ parent[s] 
or legal guardian[s]) must be informed of the new information and provide their written 
consent/assent if they wish to continue in the study. The original signed revised ICF/IAF must be 
maintained in the patient’s study record and a copy must be given to the adult patient, and the 
adolescent patient and his/her parent(s) or legal guardian(s). 
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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. 
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 are 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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Durham SR, Emminger W, Kapp A, de Monchy JG, Rak S, Scadding GK, et al. SQ-standardized 
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Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. 
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Grönlund H, Saarne T, Gafvelin G,van Hage M. The Major Cat Allergen, Fel d 1, in Diagnosis 
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and adults. Curr Allergy Asthma Rep 2013; 13(2):142-151. 
 
James LK, Shamji MH, Walker SM, Wilson DR, Wachholz PA, Francis JN, et al. Long-term 
tolerance after allergen immunotherapy is accompanied by selective persistence of blocking 
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Karlsson AS, Renstrom A, Hedren M,Larsson K. Allergen avoidance does not alter airborne cat 
allergen levels in classrooms. Allergy 2004; 59(6):661-667. 
 
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Kleine-Tebbe J, Kleine-Tebbe A, Jeep S, Schou C, Løwenstein H,Kunkel G. Role of the Major 
Allergen Fel d I in Patients Sensitized to Cat Allergens. International Archives of Allergy and 
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Krishnan JA, Cloutier MM,Schatz M. National Asthma Education and Prevention Program 2020 
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Conjunctivitis. Am Fam Physician 2016; 93(11):915-916. 
 
Niesler A, Ścigała G,Łudzeń-Izbińska B. Cat (Fel d 1) and dog (Can f 1) allergen levels in cars, 
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Challenge at 3 Years Among Patients With Moderate to Severe Seasonal Allergic Rhinitis: The 
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2(4):389-418. 
 
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Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs 2020; 22(2):199-216. 
 
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van Ree R, van Leeuwen WA, Bulder I, Bond J,Aalberse RC. Purified natural and recombinant 
Fel d 1 and cat albumin in in vitro diagnostics for cat allergy. Journal of Allergy and Clinical 
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allergic rhinitis. Clinical & Experimental Allergy 2011; 41(9):1177-1200. 
 
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content in household-dust samples. J Allergy Clin Immunol 1989; 83(4):730-734. 
 
Xu Y, Langevin BA, Zhou H,Xu Z. Model-Aided Adults-to-Children Pharmacokinetic 
Extrapolation and Empirical Body Size-Based Dosing Exploration for Therapeutic Monoclonal 
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Zuberbier T, Bachert C, Bousquet PJ, Passalacqua G, Walter Canonica G, Merk H, et al. 
GA2LEN/EAACI pocket guide for allergen-specific immunotherapy for allergic rhinitis and 
asthma. Allergy 2010; 65(12):1525-1530. 
 
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20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Randomized, Double-Blind, Placebo-Controlled Study in Cat-
Allergic Patients with Allergic Rhinitis Who Live with a Cat to Assess the Efficacy and Safety of 
Anti-Fel d 1 Antibodies during Natural Cat Exposure in the Home 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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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 Study in Cat-Allergic Patients 
with Allergic Rhinitis Who Live with a Cat to Assess the Efficacy and Safety of Anti-Fel d 1 
Antibodies during Natural Cat Exposure in the Home 
Protocol Number: R1908-1909-ALG-2102 
Protocol Version:  R1908-1909-ALG-2102 Amendment 3 
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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Approval/eSignature
20-Dec-2021 20:38:15 GMT+0000
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 79 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: AMENDMENT 1 
Clinical Study Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Study in Cat-
Allergic Patients with Allergic Rhinitis Who Live with a Cat to Assess the Efficacy and Safety of 
Anti-Fel d 1 Antibodies during Natural Cat Exposure in the Home 
Compound: 
REGN1908-1909 
Protocol Number: 
R1908-1909-ALG-2102 
Clinical Phase:  
Phase 3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
 
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date: 
Amendment 1 / 18 August, 2022 
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Statistical Analysis Plan 
 
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
See appended electronic signature page 
 
 
See appended electronic signature page 
   
 
See appended electronic signature page 
 
 
See appended electronic signature page 
 
 
See appended electronic signature page 
   
 
See appended electronic signature page 
 
 
 
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Statistical Analysis Plan 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background and Rationale ............................................................................................9 
1.2. 
Study Objectives .........................................................................................................11 
1.2.1. 
Primary Objective .......................................................................................................11 
1.2.2. 
Secondary Objectives .................................................................................................11 
1.2.3. 
Exploratory Objectives ...............................................................................................12 
1.2.4. 
Modifications from the Statistical Section in the Protocol Amendment 3 .................12 
1.2.5. 
Revision History for SAP Amendments .....................................................................12 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design and Randomization ..............................................................................13 
2.2. 
Statistical Hypothesis ..................................................................................................14 
2.3. 
Sample Size and Power Considerations .....................................................................14 
2.4. 
Study Plan ...................................................................................................................15 
3. 
ANALYSIS POPULATIONS ....................................................................................16 
3.1. 
The Full Analysis Set (FAS) .......................................................................................16 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................16 
3.3. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................16 
3.4. 
The Immunogenicity Analysis Set..............................................................................16 
3.5. 
Subgroups ...................................................................................................................17 
4. 
ANALYSIS VARIABLES .........................................................................................19 
4.1. 
Demographic and Baseline Characteristics ................................................................19 
4.2. 
Medical History ..........................................................................................................20 
4.3. 
Pre-Treatment / Concomitant Medication/Procedure .................................................20 
4.4. 
Rescue Medication and Prohibited Medication During Study ...................................21 
4.5. 
Efficacy Variable ........................................................................................................22 
4.5.1. 
Primary Efficacy Variable ..........................................................................................22 
4.5.2. 
Key Secondary Efficacy Variables .............................................................................22 
4.5.3. 
Other Secondary Efficacy Variables ..........................................................................23 
4.5.4. 
Exploratory Variables .................................................................................................24 
4.5.5. 
Definitions ..................................................................................................................25 
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4.6. 
Safety Variables ..........................................................................................................27 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................27 
4.6.2. 
Adverse Events of Special Interest .............................................................................27 
4.6.3. 
Laboratory Safety Variables .......................................................................................28 
4.6.4. 
Vital Signs ..................................................................................................................29 
4.6.5. 
Physical Examination Variables .................................................................................29 
4.6.6. 
Spirometry ..................................................................................................................29 
4.7. 
Pharmacokinetic Variables .........................................................................................29 
4.8. 
Immunogenicity Variables ..........................................................................................29 
4.9. 
Biomarker Variables ...................................................................................................30 
5. 
STATISTICAL METHODS .......................................................................................31 
5.1. 
Demographics and Baseline Characteristics ...............................................................31 
5.2. 
Medical History ..........................................................................................................31 
5.3. 
Prior/Concomitant Medications/Procedures ...............................................................31 
5.4. 
Subject Disposition .....................................................................................................32 
5.5. 
Extent of Study Treatment Exposure ..........................................................................32 
5.5.1. 
Exposure to Investigational Product ...........................................................................32 
5.6. 
Analyses of Efficacy Variables ..................................................................................33 
5.6.1. 
Analysis of Primary Efficacy Variable .......................................................................33 
5.6.2. 
Analysis of Secondary Efficacy Variables .................................................................37 
5.6.3. 
Adjustment for Multiple Comparisons .......................................................................39 
5.6.4. 
Subgroup analysis .......................................................................................................40 
5.6.5. 
Analysis of Exploratory Efficacy Variables ...............................................................40 
5.7. 
Analysis of Safety Data ..............................................................................................41 
5.7.1. 
Adverse Events ...........................................................................................................41 
5.7.2. 
Clinical Laboratory Measurements.............................................................................42 
5.7.3. 
Analysis of Vital Signs ...............................................................................................43 
5.8. 
Analysis of Pharmacokinetic Data ..............................................................................43 
5.9. 
Analysis of Immunogenicity Data ..............................................................................43 
5.9.1. 
Analysis of ADA Data ................................................................................................43 
5.9.2. 
Analysis of NAb Data .................................................................................................44 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................45 
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5.10.1. 
Immunogenicity and Exposure ...................................................................................45 
5.10.2. 
Immunogenicity and Safety and Efficacy ...................................................................45 
5.11. 
Analysis of Biomarker Data .......................................................................................45 
5.12. 
Sample Size Adjustment .............................................................................................46 
6. 
DATA CONVENTIONS ............................................................................................47 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................47 
6.2. 
Data Handling Conventions ........................................................................................47 
6.3. 
Data Handling Convention for Spirometry Data ........................................................47 
6.4. 
Data Handling Convention for Missing Data .............................................................48 
6.5. 
Visit Windows ............................................................................................................50 
6.6. 
Statistical Technical Issues .........................................................................................51 
7. 
INTERIM ANALYSIS ...............................................................................................52 
7.1. 
Futility Interim Analysis .............................................................................................52 
7.2. 
Interim Futility Criteria ...............................................................................................52 
7.3. 
Timing of Unblinded Primary Analysis .....................................................................53 
8. 
SOFTWARE ...............................................................................................................54 
9. 
REFERENCES ...........................................................................................................55 
10. 
APPENDIX.................................................................................................................58 
10.1. 
Summary of Statistical Analyses ................................................................................58 
10.1.1. 
Summary of Efficacy Analyses ..................................................................................58 
10.1.2. 
Summary of Safety Analyses ......................................................................................59 
10.2. 
Schedule of Time and Events .....................................................................................60 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................66 
10.4. 
Search Criteria for TEAE of Special Interest .............................................................74 
10.5. 
Prohibited Medications Relevant for Analysis ...........................................................75 
10.6. 
Additional Details on Sample Size Adjustment .........................................................79 
 
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LIST OF TABLES 
Table 1: 
Summary of Statistical Assumptions and Power for Select Secondary 
Endpoints ....................................................................................................................14 
Table 2: 
Medications Prohibited Prior to Screening and Throughout the Study ......................21 
Table 3: 
Medications Prohibited During Specific Periods of the Study ...................................21 
Table 4: 
Summary of Estimand for Primary Endpoint .............................................................33 
Table 5: 
Summary of Estimands for Secondary Endpoints of Clinical Importance .................38 
Table 6: 
Schedule of Events .....................................................................................................60 
Table 7: 
Prohibited medication categories for CSMS, TNSS, TOSS, DMS and 
RQLQ(S)+12 endpoints ..............................................................................................76 
Table 8: 
Prohibited medication categories for asthma-related endpoints .................................77 
Table 9: 
Prohibited medication categories for SPT endpoints..................................................78 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................15 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACQ-5 
Asthma Control Questionnaire 5 Question Version 
ADA 
Anti-drug antibody 
ADSD 
Asthma Daytime Symptom Diary 
ADSS 
Asthma Daily Symptom Score 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANSD 
Asthma Nighttime Symptom Diary 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form (electronic or paper) 
CSMS 
Combined symptom and medication score 
DMS 
Daily medication score 
Df 
Dermatophagoides farina 
Dp 
Dermatophagoides pteronyssinus 
EAR 
Early asthmatic response 
ECG 
Electrocardiogram 
EEU 
Environmental exposure unit 
FAS 
Full analysis set 
FDA 
United States Food and Drug Administration 
Fel d 1 
Felis domesticus allergen 1 
GINA 
Global Imitative for Asthma 
HDM 
House dust mite 
HRQoL 
Health related quality of life 
IA 
Interim analysis 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IgE 
Immunoglobulin E 
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Statistical Analysis Plan 
 
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INCS 
Intranasal corticosteroids 
mAb 
Monoclonal antibody 
MWD 
Mean wheal diameter 
NAb 
Neutralizing antibody 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PT 
Preferred term 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RQLQ(S) 
Rhinoconjunctivitis Quality of Life Questionnaire for Ages 12+ 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SIT 
Specific immunotherapy 
SOC 
System organ class 
SPT 
Skin prick test 
TEAE 
Treatment-emergent adverse event 
TNSS 
Total nasal symptom score 
TOSS 
Total ocular symptom score 
TSS 
Total symptom score 
WBC 
White blood cell 
 
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Statistical Analysis Plan 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to any database 
lock. The SAP is intended to be a comprehensive and detailed description of the strategy and 
statistical methods to be used in the analysis of data from the R1908-1909-ALG-2102 study. 
This plan may be revised during the study to accommodate protocol amendments and/or to make 
changes to adapt to unexpected issues in study execution and/or data that affect planned analyses. 
These revisions will be based on blinded review of the study and data, and a final plan will be 
issued prior to data lock and before code breaking. 
1.1. 
Background and Rationale 
Cat allergens are among the most important indoor allergens and a common cause of IgE-mediated 
allergic disease worldwide, affecting approximately 26% of patients consulting for suspected 
allergy to inhalant allergens in Europe. Approximately 12% to 15% of the United States (US) 
population has a known sensitivity to cat allergen . About 25% to 34% of households in Europe 
and the US reported owning a cat in the home. 
Felis domesticus allergen 1 (Fel d 1) is produced by the skin and by salivary and lacrimal glands 
of the cat. Dried saliva and dandruff are spread from the cat hair as small airborne particles into 
the surrounding environment that readily adhere to surfaces such as walls, carpets, and furniture. 
About 90% to 95% of cat allergic individuals are sensitized to Fel d 1, which is the 
immunodominant allergen. While the highest amount of Fel d 1 allergen is found in households 
with cats and the concentration correlates with the number of cats kept in a home, this allergen can 
also be carried on clothes and shoes into homes and schools without cats and may persist in these 
areas for months to years.  
Nasal and ocular symptoms are the most frequently reported cat allergy symptoms; although nasal 
symptoms are often considered most bothersome, ocular symptoms commonly occur with rhinitis. 
Treatment of cat allergy includes a recommendation for removal of the cat from the home.  Despite 
this recommendation, often patients continue to live with their cat(s) due to emotional attachment. 
Rhinoconjunctivitis is treated with antihistamines and intranasal corticosteroids (INCS), which are 
only moderately effective for nasal symptoms. The best reported treatment effects for 
antihistamines and INCS are 5% to 11% relative reduction of total nasal symptoms compared to 
placebo. Allergic conjunctivitis symptoms are typically treated with topical antihistamines that are 
sometimes combined with mast cell stabilizers .  
The association between cat allergy and asthma is significant. Approximately 30% of allergic 
asthmatics reportedly have a concomitant allergy to cats. More than 50% of cat-sensitized patients 
have a diagnosis of co-morbid asthma, ranging from intermittent mild to potentially life-
threatening asthmatic exacerbations requiring treatment with short- and long-acting 
bronchodilators, inhaled corticosteroids, and broader immune-targeting agents. 
Specific immunotherapy (SIT) is a disease-modifying, standard-of-care treatment option for 
patients with allergic rhinoconjunctivitis triggered by cat allergen when pharmacological therapies 
are insufficient. Allergen-specific polyclonal IgG4 titers increase during SIT and may inhibit 
effector cell activation by blocking binding of IgE-allergen complex to high-affinity IgE receptors 
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on mast cell and basophil surfaces, thereby effectively preventing early phase allergic symptoms . 
Although SIT can provide long-lasting protection from allergic disease, SIT carries a risk of local 
and systemic adverse reactions (especially in uncontrolled or severe asthma), is variably effective 
among different patients, and can take 3 to 5 years to induce permanent immune tolerance. 
REGN1908 and REGN1909 are human IgG4 monoclonal antibodies (mAbs), which bind 
independently, non-competitively, and with high affinity to the Fel d 1 allergen and are being 
developed as an antibody cocktail (REGN1908-1909) for the treatment of allergic disease 
triggered by exposure to cats or cat hair. Fel d 1 is the major cat allergen which is recognized in 
more than 90% of cat-allergic patients  and accounts for 60% to 90% of the total allergenic activity 
in cat dander . 
In a phase 1b proof-of-mechanism (POM) study (R1908-1909-ALG-1325), a single 600 mg 
subcutaneous (SC) dose of REGN1908-1909 (300 mg each of REGN1908 and REGN1909) 
prophylactically blocked the early allergic response to nasal challenge with cat allergen and 
resulted in a 29% improvement in total nasal symptom score (TNSS) following a nasal challenge 
8 days after REGN1908-1909 administration (which was the earliest time point assessed), 
compared with placebo. REGN1908-1909 treatment reduced TNSS AUC (0 to 1 h) by 56%, 61%, 
51%, and 51% on days 8, 29, 57, and 85 respectively; resulting in 29%, 33%, 14%, and 23% 
reduction vs placebo and achieving nominal statistical significance vs placebo at every time point 
except day 57 (ANCOVA, p = 0.0005, 0.0004, 0.1321, 0.0187, respectively).  
In a phase 2 trial in cat allergic patients with Global Initiative for Asthma (GINA) I asthma, 
(R1908-1909-ALG-1703), a single 600 mg SC dose of REGN1908-1909 (300 mg each of 
REGN1908 and REGN1909) prophylactically blocked the early asthmatic response (EAR) in an 
Environmental Exposure Unit (EEU) as early as day 8 and through day 85 (the last time point 
evaluated). Compared with placebo, REGN1908-1909 significantly increased the median time to 
EAR from 51 minutes (baseline) to >4 hours on days 8 (hazard ratio [HR]=0.36; p <0.0083), 
29 (HR = 0.24; p <0.0001), and 85 (HR = 0.27; p = 0.0003), and to 232 mins on day 57 
(HR = 0.45; p = 0.0222). As compared to placebo, an approximately 3-fold higher cumulative 
allergen quantity was tolerated relative to baseline after single-dose REGN1908-1909 at days 8 
(p = 0.003), 29 (p <0.001), 57 (p = 0.023), and 85 (p = 0.003). Additionally, REGN1908-1909 
significantly reduced skin test reactivity (mean wheal diameter) provoked by a skin prick test 
(SPT) with serial cat allergen titration at these same time points, suggesting that inhibition of 
immediate IgE-mediated responses may be a key mechanism by which REGN1908-1909 
ameliorated the acute bronchoconstriction in this study. 
In all studies to date (R1908-HV-1240, R1908-1909-ALG-1325, and R1908-1909-ALG-1703), 
REGN1908-1909 was generally well tolerated with an acceptable safety profile. There were no 
deaths, systemic hypersensitivity reactions, or anaphylaxis reported.  
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure and study protocol. 
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1.2. 
Study Objectives  
1.2.1. 
Primary Objective 
The primary objective of the study is to determine the efficacy of REGN1908-1909, as compared 
to placebo, to reduce allergic rhinitis/conjunctivitis symptoms and allergy rescue medication use 
during natural cat exposure. 
1.2.2. 
Secondary Objectives 
The secondary objectives are: 
• To assess the reduction of allergic symptoms and use of allergy rescue medications 
after treatment with REGN1908-1909 versus placebo, as measured by the individual 
components of the CSMS 
• To assess health-related quality of life (HRQoL) as measured by the 
Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ[S])  
• To determine the efficacy of REGN1908-1909, as compared to placebo, to inhibit a 
wheal-and-flare response to a skin prick test with cat allergen 
• To assess the durability of effect in allergic rhinitis and conjunctivitis symptom and 
medication scores after multiple doses of REGN1908-1909 compared to placebo given 
every 12 weeks (Q12W) 
• To determine the efficacy following multiple doses of REGN1908-1909 compared to 
placebo at inhibiting a wheal-and-flare response to a skin prick test with cat allergen 
• To estimate the effect of REGN1908-1909 on lung function, as compared to placebo, 
in patients with asthma  
• To determine the efficacy of REGN1908-1909 as compared to placebo to reduce 
asthma symptoms in patients with asthma 
• To assess whether there is a difference in asthma rescue medication use in patients with 
asthma who are treated with REGN1908-1909 compared to placebo  
• To assess whether there is a difference in nighttime awakenings in patients with asthma 
treated with REGN1908-1909 compared to placebo  
• To evaluate the short-term and long-term safety and tolerability of REGN1908-1909, 
including the incidence of hypersensitivity reactions, local injection site reactions, and 
asthma exacerbations  
• To determine systemic exposure of total (free and antigen-bound) antibodies as 
measured by concentration of REGN1908 and REGN1909 in serum 
• To assess the immunogenicity of REGN1908 and REGN1909  
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1.2.3. 
Exploratory Objectives 
• To evaluate “well days”  
Note: “Well days” are defined as days when the TSS is ≤2 without the use of anti-allergy 
rescue medications.  
1.2.4. 
Modifications from the Statistical Section in the Protocol Amendment 3 
• Additional intercurrent events for the loss of all cat(s) in the patient’s home and 
significant change in cat allergen exposure during the efficacy assessment period have 
been added for the primary estimand of interest efficacy endpoints for the primary 
analysis.  These details are specified in Section 5.6.1. 
• The data handling for the intercurrent event of relevant prohibited medication use will 
utilize a composite strategy, combining observed data prior to prohibited medication 
use and imputation with the patient’s worst score after prohibited medication use.  
This is outlined in Section 5.6.1. 
1.2.5. 
Revision History for SAP Amendments 
The primary purpose of this amendment is to update the intercurrent events strategy for use of 
prohibited medications and change in cat exposure per regulatory agency feedback.  The major 
changes made include the following: 
• Additional details were added regarding the analysis methods for the interim futility 
analysis in Section 7.2  
• The categories of prohibited medication for the purposes of analysis have been 
updated in Appendix Section 10.5 Table 7, Table 8, and Table 9 
• A treatment policy strategy will be used for all scenarios of changes in cat allergen 
exposure, other than travel away from cat for more than 6 weeks where hypothetical 
strategy will be used in this case 
• A supplemental analysis will be performed using a treatment policy strategy for all 
intercurrent events 
Additional minor updates that were made include the following: 
• Additional details were added regarding the sample size adjustment in Appendix 
Section 10.6  
• Editorial changes and additional details were added throughout. 
 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a phase 3, randomized, double-blind, parallel-group, multi-dose study in approximately 
630 cat-allergic adult and adolescent patients (ages ≥12 to <18 years), where permitted, with 
allergic rhinitis with or without conjunctivitis and with or without asthma. 
• Screening period of up to 12 weeks: Cat allergic patients living with a cat who are 
significantly symptomatic while using standard of care anti-allergy medications will be 
enrolled in the study. The study includes a screening period of up to 12 weeks to ensure 
sensitization, symptom and medication use requirements are met during the baseline period. 
• Randomization to 1 of 2 treatment arms (1:1) 
o REGN1908-1909 600 mg Q12W (300 mg per mAb)  
o Placebo that replaces REGN1908-1909 
• Study drug period (60 weeks +/- 7 days): to administer patients with R1908-1909 or placebo 
dose regimen every 12 weeks (Q12W) for a total of 5 administrations  
• Post treatment period (12 weeks +/- 7 days): to continue to collect safety data (PK, 
immunogenicity, etc.) after patients have completed the study drug treatment 
Efficacy will be evaluated by assessing the reduction of allergic nasal and ocular symptoms and 
the reduction in the use of allergy rescue medications during the initial 12 weeks and the last 
12 weeks. The primary efficacy endpoint will be assessed during the last 12 weeks of treatment 
(weeks 48-60).   
The initial 12 weeks of the treatment period are defined as the date of Visit 3 through Visit 6. 
The last 12 weeks of the treatment period are defined as the date of Visit 12 through Visit 14.   
The incidence and severity of TEAEs, including hypersensitivity reactions and local injection site 
reactions, will also be assessed throughout the study. Total drug concentration in serum and 
immunogenicity of REGN1908, and REGN1909 will also be measured throughout the study. 
There will be a non-binding futility interim analysis (IA) in the study planned to be performed 
when at least 40% of randomized patients have completed the week 12 visit or discontinued before 
week 12. 
Randomization will be stratified by IVRS based on the following: 
• Age (adolescents vs adults) 
• Asthma status (yes vs no) 
• House dust mite (HDM) sensitivity (<0.7 kUa/L versus ≥0.7 kUa/L) 
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2.2. 
Statistical Hypothesis 
For comparison of REGN1908-1909 to placebo, the following hypothesis of the primary endpoint 
(the average daily CSMS over the last 12 weeks of the treatment period [weeks 48 to 60]) will be 
tested:  
• H0: There is no difference in CSMS, averaged over the last 12 weeks of the treatment 
period (weeks 48 to 60), in patients receiving REGN1908-1909 and placebo. 
• H1: The CSMS, averaged over the last 12 weeks of the treatment period (weeks 48 to 
60), is different in patients receiving REGN1908-1909 and placebo. 
The statistical hypothesis specified above can be tested on the secondary endpoints of clinical 
interest. The study will be declared positive if the null hypothesis for the primary efficacy endpoint 
for REGN1908-1909 versus placebo is rejected. 
2.3. 
Sample Size and Power Considerations 
The sample size will be approximately 315 patients per arm, for a total of 630 patients in two 
treatment groups. This study is powered to detect the difference between REGN1908-1909 and 
placebo on the primary endpoint of daily CSMS averaged over the last 12 weeks of the treatment 
period (weeks 48 to 60) when considering a 20% dropout rate by week 60. 
A sample size of 251 patients per arm gives 90% power to detect a mean difference in daily CSMS, 
averaged over weeks 48-60, of 1.8 (20% reduction from placebo) between REGN1908-1909 
(mean CSMS=7.3) and placebo (mean CSMS=9.1), assuming a common standard deviation in 
CSMS of 6.2. Assuming a 20% dropout rate (~64 per arm), the sample size is 315 per arm. A 2-
sample t-test with 2-sided alpha of 0.049 was assumed (an administrative penalty of 0.001 will be 
taken from the significance level used at final analysis due to a planned interim analysis; details 
are provided in Section 7). Calculations were performed using nQuery+nTerim 4.0. 
The sample size of 315 patients per arm also gives the power of 91% and 96% to detect a 20% 
reduction from placebo in TSS (SD=3.0 and mean in placebo=4.2) and daily TNSS (SD=2.3 and 
mean in placebo=3.3) averaged over the last 12 weeks (weeks 48 to 60), respectively. Details are 
displayed in Table 1.  
Table 1: 
Summary of Statistical Assumptions and Power for Select Secondary 
Endpoints 
Daily Score, 
Averaged 
over last 
12 weeks 
Mean 
Anti-Fel d 1 vs Placebo 
Power with 
n=315/arm*  
Power with 
n=251/arm* 
Placebo 
Anti-Fel d 1 
% Reduction 
from Placebo 
Reduction from 
Placebo (SD) 
TNSS 
3.3 
2.6 
-20% 
-0.7 (2.3) 
96% 
92% 
TSS 
4.2 
3.4 
-20% 
-0.8 (3.0) 
91% 
84% 
*: Two-sided t-test with alpha = 0.049, assuming 20% reduction from PBO 
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The assumptions of mean in the placebo and common standard deviation for the above endpoints 
are based on the house dust mite (HDM) SLIT-tablet data for combined rhinoconjunctivitis score 
during 8-week assessment period. A treatment difference of 20% relative to placebo is based on a 
previous phase 1b study (R1908-1909-ALG-1325) of the same molecules and the treatment effect 
observed for reduction in symptoms after a nasal allergen challenge over a 12-week period. 
The sample size may be re-estimated in a blinded fashion after greater than 50% of patients have 
baseline data available using observed values of CSMS to determine the baseline placebo mean 
(SD) and assuming the same 20% difference between REGN1908-1909 versus placebo. If the re-
estimated number is higher than the current estimation of 315 per arm, then the sample size may 
be increased.  Further details are provided in Section 5.12.  
2.4. 
Study Plan 
The total study duration is approximately 72 weeks excluding screening (Figure 1). Efficacy 
assessments will be done during the initial 12 weeks (weeks 0 to 12) after the first dose and during 
the last 12-week period (weeks 48 to 60) after last dose (dose 5) of REGN1908-1909 or placebo. 
For those individuals with seasonal allergies, efficacy assessments will be timed by the 
investigational site to ensure that the assessments are outside of any relevant pollen seasons. 
Approximately 630 cat-allergic subjects will be randomized 1:1 to REGN1908-1909 or placebo. 
A non-binding futility interim analysis (IA) in the study is planned to be performed when at least 
40% of randomized patients have completed the week 12 visit or discontinued before week 12. 
More details are specified in Section 7. 
The Schedule of Events table is presented in Section 10.2. 
Figure 1: 
Study Flow Diagram 
 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analysis: 
3.1. 
The Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized patients; it is based on the treatment allocated 
(as randomized). Efficacy endpoints will be analyzed using the FAS. 
3.2. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated). Treatment administration and all clinical safety 
variables will be analyzed using the SAF. 
For patients randomized to either placebo or REGN1908-1909, a patient will be considered as 
treated with REGN1908-1909 if they received at least one dose of REGN1908-1909.  If the patient 
receives no doses of REGN1908-1909 throughout the study, the patient will be considered as 
treated with placebo.   
3.3. 
The Pharmacokinetic Analysis Set (PKAS) 
The PK analysis set (PKAS) includes all patients who received any study drug and who had at 
least 1 non-missing concentration result following the first dose of study drug. The PK analysis 
set is based on the actual treatment received (as treated) rather than as randomized. 
For patients randomized to either placebo or REGN1908-1909, a patient will be considered as 
treated with REGN1908-1909 if they received at least one dose of REGN1908-1909.  If the patient 
receives no doses of REGN1908-1909 throughout the study, the patient will be considered as 
treated with placebo.   
3.4. 
The Immunogenicity Analysis Set 
The ADA analysis set (AAS) includes all treated patients who received any amount of study drug 
(active or placebo [safety analysis set]) and had at least one non-missing ADA result following the 
first dose of study drug or placebo. The ADA analysis set is based on the actual treatment received 
(as treated) rather than as randomized. 
The NAb analysis set (NAbAS) includes all treated patients (active or placebo) that are included 
in the ADA analysis set and that tested negative at all ADA sampling times or tested positive at 
one or more post-dose ADA sampling times and had at least one non-missing post-dose NAb result 
(either imputed or analysis result). Samples that tested negative for ADA are not assayed in the 
NAb assay and the corresponding NAb results are imputed as negative and included as such in the 
NAb analysis set. Patients in the NAbAS with multiple post-dose ADA results which consist of 
both imputed NAb-negative result(s) for ADA negative samples and only missing NAb results for 
all ADA-positive result(s), are set to NAb negative. Patients in the NAbAS that have at least one 
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post-dose positive NAb analysis result are set to NAb positive even if other NAb results are 
missing. 
3.5. 
Subgroups 
Subgroups are defined by key baseline factors recorded on the eCRF (unless otherwise specified) 
and listed as follows. The analysis for the subgroups defined may not be performed if the number 
of patients within the subgroup is small, e.g., <10 patients per treatment arm.  
Subgroups to be considered for both efficacy and selected safety endpoints: 
• Age group (≥12 to <18 years (Adolescents), ≥18 to < 65 years, ≥ 65 years)  
• Sex (Male, Female) 
• Ethnicity (Hispanic or Latino: Yes, No) 
• Race (White, Black, Asian, Other) 
• Baseline cat dander IgE level (<17.5 kUa/L, ≥17.5 kUa/L) 
• Asthma status (based on collected medical history:  Yes, No) 
Subgroups to be considered for primary and key secondary efficacy endpoints: 
• House dust mite (HDM) sensitivity (Dermatophagoides farina (Df) and 
Dermatophagoides pteronyssinus (Dp) sIgE <0.7 kUa/L, Either Df or Dp sIgE 
≥0.7 kUa/L) 
• Region (Canada, United States, Europe) 
• Number of cats at baseline (1, 2, > 2) 
• Patient Global Impression of Severity (PGIS) at baseline (no symptoms/mild, 
moderate, severe) 
• Prior cat immunotherapy (Yes, No) 
• Baseline sensitization status based on sIgE or SPT (only sensitized to cat allergens 
(mono-sensitized), and those sensitized to other allergens including seasonal and 
perennial allergens) 
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Note: Cat allergens and other allergens are listed as below for SPT and sIgE: 
  
Cat allergens 
Other allergens 
SPT 
Cat Hair 
Seasonal allergens: 
Tree (mix) 
Grass (mix) 
Ragweed 
Perennial allergens: 
House Dust Mite (mix) 
Mold (mix) 
Dog 
sIgE 
Cat Dander 
Fel d 1 
Fel d 2 
Fel d 4 
Fel d 7 
Seasonal allergens: 
Timothy Grass 
Perennial allergens: 
Dog Dander 
Mite Df 
Mite Dp 
Alternaria tenus 
Cladosporium herbarum 
Cockroach German 
 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics variables will be summarized 
descriptively: 
• Demographic variables: 
− Age at screening as a continuous variable 
− Age group (Adolescents, Adults) 
− Sex (Male, Female) 
− Race (White, Black, Asian, Other) 
− Ethnicity (Hispanic/Latino: Yes or No) 
− Baseline Weight (kg) 
− Baseline Height (cm) 
− BMI (kg/m2) 
− Region (Canada, United States, Europe) 
• Baseline characteristics: 
− Skin prick test (SPT) for cat (mm) 
− Serum cat dander sIgE and Fel d 1 sIgE at screening and baseline (≥0.7 to <3.5 
kUa/L, ≥3.5 to <17.5 kUa/L, ≥17.5 kUa/L) 
− Serum house dust mite Df and Dp sIgE at screening and baseline (< 0.7 kUa/L, 
≥0.7 kUa/L) 
− Baseline sensitization status based on sIgE or SPT (e.g., sensitization to cat 
allergens only, only sensitized to cat allergens and seasonal allergens, only 
sensitized to cat allergens and perennial allergens, or sensitized to cat allergens, 
seasonal and perennial allergens) 
− Baseline sensitization status based on sIgE or SPT (mono-sensitized to cat, poly-
sensitized) 
− Baseline allergy symptom status for tree, grass, and weeds (as recorded in eCRF) 
− Baseline TNSS, TOSS, TSS, DMS, CSMS 
− Baseline RQLQ(S) 
− Baseline FEV1(L and percent predicted) 
− History of Asthma (yes/no, as recorded in eCRF) 
− Baseline ANSD, ADSD, ADSS, ACQ-5, asthma rescue medication use, and 
nighttime awakening for asthma patients 
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− Baseline PGIS 
− Duration of allergic symptoms to cat 
− Number of cats in home (1, 2, ≥3) 
Sensitization status based on sIgE or SPT 
An SPT with cat allergen extract, other relevant allergens, a negative control (such as saline/ 
diluent), and a histamine positive control will be performed to assess sensitization status. A 
positive response for cat is defined by a mean wheal diameter at least 5 mm greater than a negative 
control, in which SPT mean wheal diameter is defined as ([longest diameter + longest 
perpendicular]/2). For other allergens, a positive sensitization by SPT is defined as a mean wheal 
diameter of at least 3 mm greater than a negative control. 
For allergens that are not cat-related, sensitization by sIgE is defined as sIgE ≥0.35. 
SPT and sIgE values will be presented as both summaries of continuous measurements and 
categorically as specified above. Patients will be considered sensitized to an allergen if they meet 
the criteria defined above for either SPT or sIgE. 
4.2. 
Medical History 
Medical history (including general medical history, allergic disease history and history related to 
aero-allergens) will be coded using Medical Dictionary for Regulatory Activities (MedDRA®). 
Information on conditions related to cat allergy will be summarized in medical history, including 
asthma, allergic conjunctivitis, allergic rhinitis, etc. 
4.3. 
Pre-Treatment / Concomitant Medication/Procedure 
Medications/Procedures will be recorded from the day of informed consent until the end-of-study 
(EOS) visit. Medications will be coded using WHO Drug Dictionary (WHODD). Procedure will 
be performed based on medical history, adverse event, prophylaxis, and others. Subjects will be 
counted once in each medication class linked to the medication. 
Prior medications/procedures: medications taken, or procedures performed prior to administration 
of the first dose of study drug. 
Concomitant medications/procedures (CMs/CPs): medications taken or procedures performed 
following the dose of study drug through the EOS visit. 
• Concomitant medications/procedures during the 60-week treatment period are 
medications/procedures taken after the first dose up to the week 60 visit date or date of 
study day 421 if the week 60 visit date is missing. Medications/procedures taken during 
the 60-week treatment period and continued afterwards into the follow-up period will 
be counted only once as concomitant medications/procedures during the 60-week 
treatment period. 
• Concomitant 
medications/procedures 
during 
the 
follow-up 
period 
are 
medications/procedures taken after the week 60 visit date or date of study day 421 if 
the week 60 visit date is missing to end of study. 
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4.4. 
Rescue Medication and Prohibited Medication During Study 
Medications prohibited throughout the entire study are presented in Table 2 and medications 
prohibited for specific study periods are presented in Table 3.  
Table 2: 
Medications Prohibited Prior to Screening and Throughout the Study 
Medication Group 
Time Prohibited Before Study 
(Washout) 
Corticosteroids (intra-muscular/ intra-articular/ extended duration implants such 
as intravitreal etc.) 
Prohibited (3 months) 
Tricyclic antidepressants/ typical antipsychotics 
Prohibited (14 days) 
Specific immunotherapy (SIT) with cat allergen or vaccines against cat allergy 
Prohibited (6 months) 
SIT with any allergen other than cat 
Prohibited 
Immune directed biologics and/or therapies that would interfere with Type 2 
allergic disease or suppress the immune system, including but not limited to 
anti-IgE, anti IL-5, anti Il-4 
Prohibited (6 months) 
Methylxanthines 
Prohibited (3 days) 
Systemic calcineurin inhibitors 
 
Prohibited (14 days) 
Table 3: 
Medications Prohibited During Specific Periods of the Study 
Medication 
Group 
Medication Subgroup 
Baseline Assessment Period up 
to Week 12 and Weeks 48 to 60 
(Washout)* 
Antihistamines 
1st gen, 2nd gen oral antihistamines/ intranasal antihistamines/ 
ocular antihistamines 
Prohibited except study provided 
anti-allergy rescue medications 
(desloratadine, olopatadine) 
Longer acting antihistamines (e.g., Hydroxyzine/ 
Cyproheptadine) 
Prohibited (10 days) 
Decongestants 
Topical/ oral 
Prohibited (3 days) 
Leukotreine 
modifiers 
  
Prohibited (30 days) 
Anti 
cholinergics 
Intranasal anticholinergics 
Prohibited (12 h) 
Corticosteroids 
Intranasal 
Prohibited except study provided 
anti-allergy rescue medications 
(mometasone nasal spray) 
Ocular 
Prohibited (14 days) 
Oral/ IV 
Prohibited (30 days) 
Cromoglycates 
Ocular/ intranasal 
Prohibited (14 days) 
* NOTE: Patients will be provided the study rescue medications (desloratidine, olopatadine, mometasone furoate, or in-
class equivalent) starting at their baseline assessment visit during screening. Once the patients start their baseline 
assessment, they should continue to use the study provided rescue medications and avoid any prohibited medications until 
the completion of the initial efficacy assessment period (weeks 0 to 12). Similarly, the patients should continue to use the 
study provided rescue medications and avoid any prohibited medications during the final efficacy assessment period (48 
to 60 weeks). Prohibited medications (with specific washout durations) are specified in this table for these time periods. 
Anti-allergic medications (such as antihistamines, anti-allergic eye drops, anti-allergic nasal sprays) outside of study-
related anti-allergic medications are prohibited during baseline and efficacy assessment periods (baseline to week 12 and 
weeks 48 to 60).  
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Skin prick testing: Antihistamines should be withheld for 5 days prior to SPT (longer acting 
antihistamines such as hydroxyzine, cyproheptadine should be withheld for 10 days). 
Prohibited medications as specified above have been further categorized into groups based on their 
expected impact on the efficacy variables.  Appropriate data handling methods for analysis for 
each category are described in Section 5.6.  Categories of prohibited medications based on their 
expected impact on efficacy assessment are defined in Section 10.5. 
Medications that fall into each of the categories as specified in Section 10.5 are specified in Table 7 
(for CSMS, TNSS, TOSS, DMS and RQLQ(S)+12), Table 8 (for asthma-related endpoints), and 
Table 9 (for SPT endpoints). For medications that fall into Category 2, blinded adjudication by the 
study medical director will be implemented before the database lock to determine the potential 
impact of the use of the prohibited medication on the efficacy assessments. The adjudication 
procedure will be documented. 
4.5. 
Efficacy Variable 
4.5.1. 
Primary Efficacy Variable 
The primary efficacy endpoint in the study is the daily CSMS defined in Section 4.5.5, averaged 
over the last 12 weeks of the treatment period (weeks 48 to 60).  
4.5.2. 
Key Secondary Efficacy Variables 
The key secondary endpoints, specified without order, are: 
• Daily TNSS, averaged over the last 12 weeks of treatment period (weeks 48 to 60) 
• Percent change from pre-treatment baseline in average CSMS, over the last 12 weeks 
of the treatment period (weeks 48 to 60) 
• Percent change from pre-treatment baseline in average TNSS, over the last 12 weeks 
of the treatment period (weeks 48 to 60) 
• Daily TSS, averaged over the last 12 weeks of the treatment period (weeks 48 to 60) 
• Percent change from pre-treatment baseline in average TSS, over the last 12 weeks of 
the treatment period (weeks 48 to 60) 
• Percent change from baseline to the end of treatment (week 60) in cat SPT mean 
wheal diameter  
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4.5.3. 
Other Secondary Efficacy Variables 
Other secondary endpoints, specified without order, are: 
• Daily CSMS, averaged over the initial 12 weeks of the treatment period (weeks 0 to 
12) 
• Daily TNSS, averaged over the initial 12 weeks of treatment period (weeks 0 to 12) 
• Percent change from pre-treatment baseline in average CSMS, over the initial 12 
weeks of the treatment period (weeks 0 to 12) 
• Percent change from pre-treatment baseline in average TNSS, over the initial 
12 weeks of the treatment period (weeks 0 to 12) 
• Percent change from pre-treatment baseline in average TSS, over the initial 12 weeks 
of the treatment period (weeks 0 to 12) 
• Daily TSS score, averaged over the initial 12 weeks of the treatment period (weeks 0 
to 12) 
• Percent change from pre-treatment baseline in average TOSS, over the initial 
12 weeks of the treatment period (weeks 0 to 12) 
• Daily TOSS, averaged over the last 12 weeks of the treatment period (weeks 48 to 60) 
• Percent change from pre-treatment baseline in average TOSS, over the last 12 weeks 
of the treatment period (weeks 48 to 60) 
• Percent change from baseline to week 12 in FEV1 in patients with asthma 
• Percent change from baseline to week 60 in FEV1 in patients with asthma 
• Percent change from baseline to week 12 in cat skin prick test (SPT) mean wheal 
diameter 
• Change from baseline to week 12 in FEV1 in patients with asthma 
• Change from baseline to week 60 in FEV1 in patients with asthma 
• Change from baseline to week 60 in RQLQ(S)+12 
• DMS, averaged over the initial 12 weeks of the treatment period (weeks 0 to 12) 
• DMS, averaged over the last 12 weeks of the treatment period (weeks 48 to 60) 
• Percent change from pre-treatment baseline in average DMS, averaged over the last 
12 weeks of the treatment period (weeks 48 to 60) 
• Percent change from baseline to end of study (week 72) in cat SPT mean wheal 
diameter 
• Asthma daily symptom score (ADSS), averaged over the initial 12 weeks of the 
treatment period (weeks 0 to 12), using Asthma Daytime Symptom Diary (ADSD) 
and the Asthma Nighttime Symptom Diary (ANSD), in patients with asthma 
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• Asthma daily symptom score (ADSS), averaged over the last 12 weeks of the 
treatment period (weeks 48 to 60), using Asthma Daytime Symptom Diary (ADSD) 
and the Asthma Nighttime Symptom Diary (ANSD), in patients with asthma 
• Daily TOSS, averaged over the initial 12 weeks of the treatment period (weeks 0 to 
12) 
• Change from baseline to week 60 in ACQ-5 in patients with asthma 
• Daily number of nighttime awakenings, averaged over the initial 12 weeks of the 
treatment period (weeks 0 to 12), in patients with asthma 
• Daily number of nighttime awakenings, averaged over the last 12 weeks of the 
treatment period (weeks 48 to 60), in patients with asthma 
4.5.4. 
Exploratory Variables 
The exploratory endpoints are: 
• The number of “well days” over the initial 12 weeks (weeks 0 to 12) of the treatment 
period; “well days” are defined as days when rescue medication is not utilized and the 
TSS is ≤2/18 
• The number of “well days” over the last 12 weeks of the treatment period (weeks 48 
to 60); “well days” are defined as days when rescue medication is not utilized and the 
TSS is ≤2/18 
• Percent change from pre-treatment baseline in average ADSS, over the initial 
12 weeks of the treatment period (weeks 0 to 12), using ADSD and the ANSD 
• Percent change from pre-treatment baseline in average frequency of asthma rescue 
medication use, defined as the number of puffs of a short-acting bronchodilator and 
an inhaled steroid over the past 24 hours, over the initial 12 weeks of the treatment 
period (weeks 0 to 12), in patients with asthma 
• Percent change from pre-treatment baseline in average frequency of nighttime 
awakenings, over the initial 12 weeks of the treatment period (weeks 0 to 12), in 
patients with asthma 
• Percent change from pre-treatment baseline in average DMS, over the initial 
12 weeks of the treatment period (weeks 0 to 12) 
• Change from baseline to week 12 in RQLQ(S)+12 
• Change from baseline to week 12 in Asthma Control Questionnaire 5 Question 
Version (ACQ-5) in patients with asthma 
• Daily frequency of asthma rescue medication use, averaged over the initial 12 weeks 
of the treatment period (weeks 0 to 12), in patients with asthma  
• Daily frequency of asthma rescue medication use, averaged over the last 12 weeks of 
the treatment period (weeks 48 to 60), in patients with asthma 
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4.5.5. 
Definitions 
The definition and details of the efficacy variables are listed as follows: 
Total Nasal Symptom Score (TNSS) 
The TNSS ranges from 0 to 12 and is based on assessment of 4 nasal symptoms graded on a Likert 
scale ranging from 0 (none) to 3 (severe) for nasal congestion, itching, and runny nose, and 
sneezing. The TNSS will be recorded before going to bed for the night using an e-diary.  
Total Ocular Symptom Score (TOSS) 
The TOSS ranges from 0 to 6 and is based on 2 eye symptoms: itching/redness/gritty feeling and 
tearing/watering. Each of the 2 symptoms is graded on a Likert scale ranging from 0 (none) to 3 
(severe). The TOSS will be recorded before going to bed for the night using an e-diary.  
Total Symptom Score (TSS) 
The daily TSS is calculated by adding the TNSS and TOSS together, for a combined TSS of 0 to 
18.  
Daily Medication Score (DMS) 
For the DMS, before going to bed for the night, patients will be asked to record their daily rescue 
medication use using an e-diary, including which medications and the amount of these pre-
specified medications. This information will be used to calculate the DMS for the following 
medications or the approved in-class equivalents, as follows: desloratadine 5 mg 6 points/dose; 
maximum daily score 6 points, olopatadine 1 mg/mL each drop 1.5 points/drop; maximum daily 
score 6 points, mometasone furoate 50 ug/dose 2.0 points/spray; maximum daily score 8 points). 
The maximum DMS score is 20 (Calderon, 2014). 
Combined Symptom and Medication Score (CSMS) 
The daily CSMS is calculated by adding the DMS and TSS together, with scores ranging between 
0 and 38. The method for calculating average CSMS is described in Section 5.6.1.   
Skin Prick Test  
An SPT with cat allergen extract, other relevant allergens, a negative control (such as saline/ 
diluent), and a histamine positive control will be performed to assess sensitization status. A 
positive response for cat is defined by a mean wheal diameter (MWD) at least 5 mm greater than 
a negative control, in which SPT MWD is defined as ([longest diameter + longest 
perpendicular]/2). (Note: For other allergens, a positive sensitization is defined as a MWD of at 
least 3 mm greater than a negative control.) 
The negative control mean wheal diameter will be subtracted from the SPT mean wheal diameter 
for presentation as a normalized MWD. In the case that the negative control MWD is larger than 
the allergen SPT MWD, the value of 0 mm will be used as the normalized MWD. 
After week 12, the cat, house dust mite, and negative control SPT will be performed in replicate.  
Averages of the MWDs will be calculated for each allergen at the same visit and then the average 
of the two negative control MWDs will be subtracted to compute the normalized MWD. 
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Standardized Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ(S)] for Ages 12+ 
The RQLQ(S) is a self-administered questionnaire to measure HRQoL in those 12 years of age 
and above, as a result of perennial or seasonal allergic rhinitis. There are 28 items on the RQLQ(S) 
in 7 domains: activity limitation, sleep problems, nasal symptoms, eye symptoms, non-nasal/eye 
symptoms, practical problems, and emotional function. The RQLQ(S) responses are based on a 7-
point Likert scale with responses ranging from 0 (not troubled) to 6 (extremely troubled). The 
overall RQLQ(S) score is the mean of all 28 responses and the individual domain scores are the 
means of the items in those domains. Higher scores indicated more HRQoL impairment (lower 
scores were better). A change of 0.5 point or more in total score is considered to be clinically 
meaningful. 
Asthma Nighttime Symptom Diary Score  
Only for patients with asthma, upon waking up in the morning, patients will complete the e-dairy 
to report asthma symptoms experienced during the nighttime using the Asthma Nighttime 
Symptom Diary (ANSD). The ANSD score will be based on 6 patient-reported symptoms 
(difficulty breathing, wheezing, shortness of breath, chest tightness, chest pain, and cough at their 
worst using an 11-point numeric rating scale (NRS) ranging from 0 (‘None’) to 10 (‘As bad as you 
can imagine’). 
Asthma Daytime Symptom Diary Score  
Only for patients with asthma, before going to bed for the night, patients will complete the e-diary 
to report asthma symptoms experienced during the day using the Asthma Daytime Symptom Diary 
(ADSD). The ADSD score will be based on 6 patient-reported symptoms (difficulty breathing, 
wheezing, shortness of breath, chest tightness, chest pain, and cough at their worst using an 11-
point numeric rating scale (NRS) ranging from 0 (‘None’) to 10 (‘As bad as you can imagine’). 
Asthma Daily Symptom Score 
Only for patients with asthma, average of daily scores of the ANSD score and the ADSD score 
will be used to generate an Asthma Daily Symptom Score (ADSS) ranging from 0 (‘None’) to 10 
(‘As bad as you can imagine’).  
Juniper Asthma Control Questionnaire 
Only for patients with asthma, the ACQ-5, (5-question version of the Juniper ACQ), is a validated 
questionnaire to evaluate asthma control. The ACQ-5 score is the mean of the scores of the 5 items 
and ranges from 0 (totally controlled) to 6 (severely uncontrolled). Scores less than 1.0 reflect 
adequately controlled asthma, and scores 1.0 or greater reflect inadequately controlled asthma. 
Higher score indicates lower asthma control and 0.5 is the smallest change that can be considered 
clinically important. 
FEV1 
Before randomization, in-clinic spirometry will be performed on all patients to determine FEV1 
(forced expiratory volume in 1 second) in liters (L).  After randomization, in-clinic spirometry will 
only be performed for patients with asthma. 
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4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of the study. All adverse events are to be coded to a 
“Preferred Term (PT)” and associated primary “System Organ Class (SOC)” according to the 
Medical Dictionary for Regulatory Activities (MedDRA). 
An Adverse Event 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. Laboratory results, vital 
signs, or ECG abnormalities are to be recorded as AEs if they are medically relevant: symptomatic, 
requiring corrective therapy, leading to treatment discontinuation and/or fulfilling a seriousness 
criterion. 
For safety variables, 4 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The on-treatment period is defined as the day from first dose of study drug to the last 
dose of study drug plus 12 weeks (visit 3 to visit 14). 
• The follow-up period is defined as the end of the on-treatment period to 12 weeks after 
the end of the on-treatment period (visit 14 to visit 15). 
• The overall study period is defined as the day from first dose of study drug to the end 
of study visit (on-treatment period plus follow-up period) 
Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition during the on-treatment and follow-up 
periods. 
A Serious Adverse Event is an adverse event (AE) that is classified as serious according to the 
criteria specified in the study protocol 10.2.2.  
4.6.2. 
Adverse Events of Special Interest 
An adverse event of special interest (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. List of AESI and AESI criteria is 
specified in Section 10.4. 
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Adverse events of special interest for this study include:  
• Severe or systemic hypersensitivity reactions (including anaphylaxis) defined using the 
narrow SMQ for hypersensitivity, with blinded manual adjudication of relevant PTs by 
medical monitor before database lock. 
− For SMQ “anaphylactic reaction”, an algorithmic approach will be used.  
Details are provided in Section 10.4.  
• Asthma exacerbations defined using the narrow SMQ for asthma and further manual 
blinded adjudication before database lock for events requiring treatment with systemic 
corticosteroids or resulting in an emergency room visit or hospitalization. 
4.6.3. 
Laboratory Safety Variables 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed. Detailed 
instructions for blood sample collection are in the laboratory manual provided to study sites. 
Samples for laboratory testing will be collected. Tests will include: 
Blood chemistry 
Sodium 
Total protein, serum 
Aspartate aminotransferase (AST) 
Potassium 
Creatinine 
Alanine aminotransferase (ALT) 
Chloride 
Blood urea nitrogen (BUN) 
Alkaline phosphatase 
Carbon dioxide 
Total bilirubin  
Albumin 
Calcium 
Glucose  
 
Hematology 
Hemoglobin 
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
WBC 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Yeast 
Protein 
 
 
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Other laboratory tests 
4.6.4. 
Vital Signs 
Vital signs include systolic and diastolic blood pressure, respiratory rate, and heart rate. Vital signs 
will be collected in a seated position. On the day of study drug administration, vital signs are taken 
prior to PK blood draw, prior to study drug administration, and at 2 hours (±10 min) after 
completion of the injection.  
Weight and height are measured at screening visit 1 only. 
4.6.5. 
Physical Examination Variables 
A thorough and complete physical examination will be performed. Care should be taken to 
examine and assess any abnormalities that may be present, as indicated by the patient’s medical 
history. 
4.6.6. 
Spirometry 
Spirometry measurements include FVC (L), FEV1 (L), FEV1/FVC, PEF (L/s), FEF 25-75 (L/s). 
Spirometry (American Thoracic Society [ATS]/European Respiratory Society [ERS]-compliant) 
(Graham, 2019), as adjudicated during the centralized OverRead review, will be performed locally 
during the study at specified time points. Spirometry details will be available in a separate 
operational manual provided to the sites. Additional data handling conventions are presented in 
Section 6.3. 
4.7. 
Pharmacokinetic Variables  
Concentrations in serum of total (free+antigen bound) REGN1908 and REGN1909 will be 
determined at time points specified in the study schedule of events in Appendix Section 10.2. 
Pharmacokinetic variables consist concentrations individual drug (REGN1908 and REGN1909), 
and total drug (REGN1908+REGN1909) in serum, and time (both nominal and actual time).  
4.8. 
Immunogenicity Variables  
The immunogenicity variables include ADA status, titer and NAb status at nominal sampling 
time/visit. Serum samples for ADA will be collected at the clinic visits specified in Appendix 10.2. 
Samples positive in the REGN1908-1909 ADA assay will be further characterized for ADA titers. 
Anti-REGN1908, and anti-REGN1909 neutralizing antibodies (NAb) analysis may be performed 
on ADA-positive serum samples. The overall immunogenicity risk will be taken into consideration 
to assess the need for NAb analysis. Serum samples will be banked, if NAb analysis is to be 
conducted at a later time.  
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4.9. 
Biomarker Variables  
Exploratory biomarker variables include: 
• Serum for specific IgE for Fel d 1  
• Serum for specific IgE for cat dander 
• Serum for sIgE for Fel d 2, 4, and 7 at baseline, week 12 (V6), week 60 (V14) 
• Serum for sIgE for other allergens (e.g., HDM, etc.)  
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
Missing values at baseline will not be imputed unless otherwise specified. 
5.1. 
Demographics and Baseline Characteristics 
Demographics and Baseline Characteristics will be summarized by treatment groups and overall 
based on the FAS. 
5.2. 
Medical History 
Medical history will be summarized by primary SOC and PT for each treatment group and for 
study total based on the SAF. The table will be sorted by decreasing frequency of SOC followed 
by PT based on the overall incidence across treatment groups. Number/proportion of each medical 
history, listing all the values in allergy form. 
5.3. 
Prior/Concomitant Medications/Procedures  
The number and proportion of subjects taking prior medications will be summarized, as well as 
the number and proportion taking concomitant medications during the treatment and follow-up 
periods (separately) based on the FAS.  Similar tables will be provided for the number and 
proportion of subjects taking prohibited medications.  Prohibited medications taken in the first and 
last 12 weeks of the treatment period may also be presented separately.   Each table will be sorted 
by decreasing frequency of Anatomical Therapeutic Chemical (ATC) level 2 and ATC level 4 
based on the overall incidence. Subjects will be counted only once for each medication class (ATC 
levels 2 and 4) linked to the medication. 
Number of patients taking rescue medications will be summarized by medication name based on 
rescue medication e-diary based on the FAS. The frequency of rescue medication use during the 
efficacy assessment periods may also be summarized.  
Number and proportion of patients taking prior/concomitant procedures will be summarized for 
study total based on the SAF, sorted by decreasing frequency of SOC and PT based on the overall 
incidence. Patients will be counted only once for each SOC and PT linked to the procedure. 
Number of patients receiving prior immunotherapy (SLIT, SCIT) will be summarized separately.  
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5.4. 
Subject Disposition 
The following summaries will be provided for each treatment group and total (unless otherwise 
specified): 
• The total number of screened subjects who signed ICF, along with reasons for screen 
failure (for study total only) 
• The total number of randomized patients: received a randomization number from 
IWRS 
• The total number of patients in each analysis set 
• The total number of randomized patients who discontinued the study and the reasons 
for discontinuation (including COVID-19 related reasons) 
• The total number of randomized patients who completed the study treatment and 
discontinued the study treatment with the reason of discontinuation (including 
COVID-19 related reasons) 
5.5. 
Extent of Study Treatment Exposure  
5.5.1. 
Exposure to Investigational Product 
The duration of exposure during the study will be calculated as follows: 
(date of last dose of study drug– date of first dose of study drug) + 84 days  
The calculations do not take into account temporary dosing interruption including due to COVID-
19. The summary of exposure to study drug will include the number of study drug doses and 
injections administered and the duration of exposure. Duration of exposure will be summarized 
for each treatment group using the number of patients, mean, SD, minimum, median, Q1, Q3, and 
maximum. 
In addition, the duration of exposure will be summarized categorically by counts and percentages 
for each of the following categories cumulatively by these categories: ≥ 85 days (> 12 weeks), 
≥ 169 days (> 24 weeks), ≥ 253 days (> 36 weeks), ≥ 337 days (> 48 weeks), and ≥ 365 days 
(> 52 weeks). 
The duration of observation period during the study in days is calculated as: 
(Date of the last visit – date of the first study drug injection) +1. 
The duration of observation period will be summarized descriptively using number of 
patients, mean, SD, median, Q1, Q3, minimum and maximum. In addition, the number (%) of 
subjects with observation periods will be presented by specific time periods. The time periods of 
interest are specified as: 
< 85 days, ≥ 85 days, ≥ 169 days, ≥ 253 days, ≥ 337 days, ≥ 421 days, and ≥ 505 days. 
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5.6. 
Analyses of Efficacy Variables 
5.6.1. 
Analysis of Primary Efficacy Variable 
The analyses of efficacy variables are described in the subsections below and summarized in 
Section 10.1.1 of the Appendix. The intercurrent events, strategies, and the corresponding missing 
data handling approaches for the primary estimands of interest for the primary endpoint are 
provided in Table 4. 
Table 4: 
Summary of Estimand for Primary Endpoint 
Endpoint 
Category 
Estimand 
Endpoint(s) 
Population 
Intercurrent event(s) handling strategy and missing data 
handling 
Population-level 
summary 
Primary 
endpoint  
Daily 
combined 
symptom 
and 
medication 
scores 
(CSMS) 
averaged 
over the last 
12 weeks of 
the 
treatment 
period 
FAS 
The intercurrent events will be handled as follows1: 
1. 
Discontinuing the study intervention: all data collected 
after discontinuation will be used in the analysis 
(treatment policy strategy) 
2. 
Rescue treatment and select prohibited medications2,3 
taken to treat allergic symptoms during the last 12 
weeks of the efficacy assessment period: data after 
medication will be used in the analysis (treatment 
policy strategy) 
3. 
Prohibited medications taken during the efficacy 
assessment period which are adjudicated to be handled 
using a composite strategy3:  
a. 
The daily CSMS, starting from the day the 
prohibited medication was taken through the end 
of the last 12 weeks of efficacy assessment, will 
be imputed by worst CSMS score (largest 
observed TNSS+TOSS+DMS) observed before 
prohibited medications were taken from the same 
patient. The average CSMS will be calculated 
using observed components prior to receiving 
prohibited medication and imputed values after 
prohibited medication.   
b. 
If no values of CSMS4 are available during the 
last 12 weeks of the efficacy assessment period 
prior to the patient taking prohibited medication, 
the daily CSMS will be imputed using the worst 
average CSMS score during the last 12 weeks of 
all observations in the corresponding treatment 
group 
4. 
Prohibited medications taken during the efficacy 
assessment period which are adjudicated to be handled 
using a hypothetical strategy3:  data during use of 
medication and during washout period will be set to 
missing 
5. 
Change in cat allergen exposure: 
a. 
If no cat is living in the patient’s home during all or 
part of the last 12 weeks of the treatment period: all 
available data will be used in analysis (treatment 
policy) 
b. 
If patient travels away from home for less than 42 
consecutive days:  all available data will be used in 
ANCOVA model 
with treatment 
group, stratification 
factors, and cat 
sIgE (<17.5 kUa/L 
versus ≥17.5 
kUa/L) as fixed 
factors and baseline 
CSMS as a 
covariate. 
The least squares 
means (LS-means) 
estimates for the 
average CSMS 
during the last 12 
weeks of the 
treatment period for 
each treatment 
group, as well as 
the difference 
between the 
REGN1908-1909 
and placebo will be 
provided along 
with the 
corresponding 2-
sided p-value and 
associated 95% 
confidence interval. 
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Endpoint 
Category 
Estimand 
Endpoint(s) 
Population 
Intercurrent event(s) handling strategy and missing data 
handling 
Population-level 
summary 
analysis (treatment policy); otherwise, for travel ≥ 
42 consecutive days, a hypothetical strategy will be 
used where data during patient travel will be set to 
missing 
In addition, the missing data imputation rules for patients who 
have no available values of CSMS4 during the last 12 weeks 
of the treatment period are as follows: 
• 
Missing data due to patients’discontinuation from 
study due to AEs and lack of efficacy will be imputed 
using worst average CSMS score during the last 12 
weeks of all observations in the corresponding 
treatment group 
• 
Missing data due to any other reason will be imputed 
using MI 
[1] If a data point or missing value falls into multiple categories of intercurrent events as specified above, the following priority 
order for handling of data will be applied: ICE 3), ICE 4), ICE 5b) ICE 5a),  ICE 1), ICE 2).  For example, if data or missing 
value fall into both ICE 3) and 5a), the strategy for ICE 3) should be followed, as it takes priority over 5a). 
[2] Select prohibited medications that will be handled using a treatment policy are listed in Category 1 of Table 7  
[3] Additional prohibited medications listed in Category 2 Table 7 will undergo blinded adjudicated by study medical monitor 
before the database lock to determine if they will be handled by treatment policy, composite strategy, or hypothetical strategy 
[4] No available values of CSMS means no available TNSS, TOSS, or DMS during the last 12 weeks of the efficacy assessment 
period 
The primary analysis will focus on the comparison between REGN1908-1909 and placebo in the 
FAS. The analysis will be performed using an analysis of covariance (ANCOVA) model, with the 
treatment group, randomization stratification factors (as stratified), and cat sIgE (<17.5 kUa/L 
versus ≥17.5 kUa/L) as fixed effects and the baseline CSMS as a covariate. The baseline CSMS 
will be calculated as the average CSMS during the first 15 consecutive days of the baseline 
assessment period where eligibility criteria (for TSS and rescue medication use) were met, as 
specified based on the following two criteria: 
1. Must have at least 8 unique days of a TSS score ≥ 8 within a 15 consecutive day period. 
2. Must have a least 8 unique days of a DMS score >0 within the same 15 consecutive day 
period as Criteria 1.  The 8 unique days do not have to occur on the same days as Criteria 1; 
however, they must be within the same 15 consecutive days. 
If less than 15 days of data are available during the baseline assessment period, the baseline will 
be the average CSMS over all available days (if duplicate entries of CSMS are available on the 
same day, the worst score will be used). 
Only days with observed data will be included in the calculation of average score. The average 
CSMS (max score 38/day) will be calculated based on the sum of average daily TNSS (max score 
12/day), average daily TOSS (max score 6/day) and average daily medication scores (DMS, max 
of 20/day) recorded over the last 12 weeks of the treatment period (weeks 48 to 60).  
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For the MI procedure, missing data (the average CSMS) will be imputed 50 times to generate 
50 complete data sets utilizing the SAS procedure PROC MI.  Note that any imputation by worst 
CSMS score as specified in Table 4 will occur prior to MI.  The 2 steps below will be followed for 
MI: 
Step 1:  The Markov Chain Monte Carlo (MCMC) method will be used to fill in missing 
values of average CSMS during weeks 0-12  by treatment group so that a monotone 
missing pattern will be formed. 
Step 2:  Using the data sets from Step 1, missing values of average CSMS from weeks 
48-60 will be imputed using a monotone regression method.  The imputation model will 
include the covariates in the ANCOVA model and the average CSMS from weeks 0-12. 
For steps 1 and 2, any score imputed outside the range of CSMS (0-38) will be truncated to 
the nearest value of CSMS according to the following algorithm: 
− If the imputed score > 38, then the final imputed score will be 38. 
− If the imputed score < 0, then the final imputed score will be 0. 
 
Sample SAS syntax code for MI: 
proc mi data=mi1 out=mi3 noprint nimpute=50 seed=190819; 
mcmc impute=monotone; 
var BASELINE CSMS012 CSMS4860; 
by TRTP; 
run; 
proc mi data=mi3 out=mi4 nimpute=1 seed=190819; 
class TRTP STRAT1 STRAT2 STRAT3 CATIGE; 
monotone reg; 
var TRTP STRAT1 STRAT2 STRAT3 CATIGE BASELINE CSMS012; 
by _imputation_; 
run; 
Each imputed data set will then be analyzed by ANCOVA as previously described. The SAS 
procedure PROC MIANALYZE will be used to generate valid statistical inferences by combining 
results from these 50 ANCOVA analyses using Rubin’s formula. The least squares means (LS-
means) estimates for the average CSMS during the last 12 weeks of the treatment period for each 
treatment group, as well as the difference between the REGN1908-1909 and placebo will be 
provided along with the corresponding 2-sided p-value and associated 95% confidence interval. 
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Sensitivity analysis:  
With respect to the missing data handling of daily entries, sensitivity analyses will be performed 
to confirm robustness of the conclusion drawn based on the main model for primary analysis. 
Tipping Point Analysis 
Sensitivity analysis using a tipping point approach with MI will be performed to assess the 
robustness of the results due to data that may be missing not-at-random (MNAR).  The impact 
from missing data on comparisons of average CSMS during the last 12 weeks between 
REGN1908-1909 and placebo will be examined. 
This approach will introduce a sensitivity parameter, δ.  Estimations will be performed using MI 
methodology.  Missing data will be imputed 50 times to generate 50 complete data sets utilizing 
the SAS procedure PROC MI for each δ following the 2 steps as previously described, where δ 
will be added to each of the imputed values (of average of last 12 weeks) for patients in the 
REGN1908-1909 arm.  (Note that when δ=0, this aligns with the standard MI analysis assuming 
missing at random (MAR).)  Scores that are adjusted to outside the range of CSMS will be 
truncated in the same manner as previously described for the MI method.   
Each imputed data set will then be analyzed by ANCOVA as previously described. For each δ, the 
SAS procedure PROC MIANALYZE will be used to generate valid statistical inferences by 
combining results from these 50 ANCOVA analyses using Rubin’s formula.  By progressively 
increasing δ, the sensitivity analysis will explore the “tipping point”, where the result is no longer 
statistically significant (i.e., p-value>0.049).  
Additional Sensitivity Analyses 
An additional sensitivity analysis may be performed when determining asthma status from medical 
history and house dust mite sensitization status from lab data, rather than as stratified. 
Supplemental Analyses   
Additional sensitivity analysis will also be performed for the handling of data after relevant 
prohibited medications. After use of prohibited medication, daily CSMS will be imputed by the 
worst score in the corresponding treatment group, and with the worst 5th percentile score in the 
corresponding treatment group, as a way to consider a reasonable range of “poor” scores to impute 
the missing data. 
A supplemental analysis will also be performed where all intercurrent events are handled via a 
treatment policy, regardless of type of prohibited medication taken or change in cat exposure. 
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5.6.2. 
Analysis of Secondary Efficacy Variables 
The secondary efficacy endpoints will be analyzed using an ANCOVA model in the same fashion 
as the primary analysis of the primary endpoint.  
Average Daily Symptom Score Endpoints (TOSS, TNSS, DMS, TSS) 
The average TOSS, TNSS, and DMS will be calculated using all observed daily scores during the 
specified time period (initial 12 weeks or last 12 weeks of the treatment period). 
The average TSS will be calculated by adding average TNSS and average TOSS during the 
specified time period (initial 12 weeks or the last 12 weeks of the study).  
The intercurrent events, strategies, and the corresponding missing data handling approaches for 
these endpoints will follow the same strategy as for the primary endpoint, outlined in Table 4. 
Supplemental analyses using non-parametric methods, such as Wilcoxon ranked sum test or 
Hodges-Lehmann analysis of median differences, may be performed in the event of a violation of 
the normality assumption. 
Asthma-related endpoints (ADSS, FEV1, ACQ-5) 
All asthma endpoints will be analyzed on patients in the FAS with asthma (all randomized patients 
with ongoing asthma in medical history).  Supplemental analyses may be performed in the subset 
of ongoing asthma patients who were also on asthma medication at baseline. 
All available daily ADSS will be averaged over the specified time period (initial 12 weeks or last 
12 weeks of the treatment period). If ADSD or ANSD is missing on any given day, ADSS score 
for that day will be considered missing and no value will be calculated. In addition, ANSD will be 
shifted by one day, i.e., ADSD on Day 1 and ANSD on Day 2 will be used to get the ADSS on 
Day 1, ADSD on Day 2 and ANSD on Day 3 will be used to get the ADSS on Day 2, and so on.  
The day before Visit 6 or Visit 14 for the initial 12 weeks and last 12 weeks, respectively, will be 
the last day that contributes to the average ADSS (since there will generally be no ANSD 
measurement corresponding to the date of Visit 6 or 14). 
The estimand for ADSS will follow the same approach as for the primary endpoint, described in 
Table 4.  Separate analyses of average ADSD and average ANSD may also be performed. 
Estimands for FEV1 and ACQ-5 are specified in Table 5.  A supplemental analysis may be 
performed for the change from baseline ACQ-5 endpoint only in patients with baseline ACQ-5 
> 1.5. 
Supplemental analyses using non-parametric methods, such as Wilcoxon ranked sum test or 
Hodges-Lehmann analysis of median differences, may be performed in the event of a violation of 
the normality assumption.   
Prohibited medications and corresponding data utilization methods relevant for asthma endpoints 
are specified in Table 8  
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SPT endpoints 
The intercurrent events, strategies, and the corresponding missing data handling approaches for 
the SPT endpoints are outlined in Table 5. 
Prohibited medications and corresponding data utilization methods relevant for SPT endpoints are 
specified in Table 9  
Table 5: 
Summary of Estimands for Secondary Endpoints of Clinical Importance 
Endpoint 
Category 
Estimands 
Endpoint(s) 
Population 
Intercurrent event(s) handling strategy and 
missing data handling 
Population-level 
summary 
Secondary 
endpoint – 
Continuous, 
SPT, and 
RQLQ(S)+12 
Percent change 
from baseline to 
week 12 and 
end of treatment 
(week 60) cat 
SPT mean 
wheal diameter 
Change from 
baseline to 
week 60 in 
RQLQ(S)+12 
FAS 
The intercurrent events will be handled as 
follows5: 
1. Discontinuing the study intervention: all data 
collected after discontinuation will be used 
in the analysis (treatment policy strategy) 
2. Rescue treatment1 and select prohibited 
medications2,4 to treat allergic symptoms 
during the efficacy assessment period: data 
after allergy-relieving rescue medication will 
be used in the analysis (treatment policy 
strategy)  
3. Prohibited medications taken during the 
protocol defined window leading up to the 
relevant visit (week 12 or week 60) which 
are adjudicated to be handled using a 
composite strategy4: data will be set to 
missing and imputed using the worst value 
of all observations in corresponding 
treatment group.  
4. Prohibited taken during the protocol defined 
window leading up to the relevant visit 
(week 12 or week 60) which are adjudicated 
to be handled using a hypothetical 
strategy3,4: data will be set to missing and 
multiple imputation will be used.  
5. Patient does not have exposure to cat leading 
up to assessment6: 
a. If no cat is living in the patient’s home 
leading up to assessment: all available 
data will be used in analysis (treatment 
policy) 
b. If patient is traveling away from home 
for less than 42 consecutive days prior 
to the assessment: all available data will 
be used in the analysis (treatment 
policy); otherwise (for travel  ≥42 
consecutive days), data will set to 
missing and multiple imputation will be 
used (hypothetical strategy) 
ANCOVA model with 
treatment group, 
stratification factors, 
and cat sIgE (<17.5 
kUa/L versus ≥17.5 
kUa/L) as fixed factors 
and relevant baseline 
measurement as a 
covariate. 
LS-means estimates 
will be provided for 
each treatment group, 
as well as the 
difference between 
REGN1908-1909 and 
placebo with 
corresponding 95% 
confidence interval and 
2-sided p-value. 
Secondary 
endpoint – 
Continuous, 
FEV1, and 
ACQ-5 
Percent change 
from baseline to 
week 12, week 
60 FEV1  
Change from 
baseline to 
week 60 in 
ACQ-5 
 
FAS with 
asthma 
 
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Endpoint 
Category 
Estimands 
Endpoint(s) 
Population 
Intercurrent event(s) handling strategy and 
missing data handling 
Population-level 
summary 
In addition, if a patient has no available value of 
the relevant measurement at the specified visit, 
the imputation rules are as follows: 
• 
Missing data because of patients’ 
discontinuation from study due to AEs and 
lack of efficacy will be imputed using 
worst score of all the observations in 
corresponding treatment group 
• 
Missing data due to any other reason will 
be imputed using MI. 
[1] Note that for SPT endpoints, oral antihistamines are considered as prohibited medication, as specified in Table 9  
[2] Category 1 of Table 7 (RQLQ), Table 8 (asthma), Table 9 (SPT) lists prohibited medications that will be handled using a 
treatment policy 
[3] Additional prohibited medications listed in Category 2 of Table 7, Table 8, and Table 9 will undergo blinded adjudication by 
study medical monitor before the database lock to determine they will be handled by treatment policy, composite strategy, or 
hypothethical strategy 
[4] Prohibited medications that are not indicative of treatment failure and will be handled by hypothethical strategy are defined 
in Category 3 of Table 8 and Table 9 
[5] If a data point or missing value falls into multiple categories of intercurrent events as specified above, the following priority 
order for handling of data will be applied: ICE 3), ICE 4), ICE 5b), ICE 5a), ICE 1), ICE 2).  For example, if data or missing 
value fall into both ICE 3) and 4), the strategy for ICE 3) should be followed, as it takes priority over ICE 4). 
[6] This intercurrent event is not relevant for the SPT endpoints 
5.6.3. 
Adjustment for Multiple Comparisons 
A non-binding futility interim analysis (IA) is planned in this study (details are provided in 
Section 7) and an administrative penalty of 0.001 will be taken from the significance level used at 
final analysis, and thus 2-sided 0.049 will be used. No further multiplicity adjustment will be 
performed for the IA.  
The following multiplicity adjustment approach, a hierarchical procedure, will be used to control 
the overall Type-1 error rate at 0.049 for the primary endpoint and the secondary endpoints of 
R1908-1909 versus placebo. Each hypothesis will be formally tested only if the preceding one is 
significant at the 2-sided 0.049 significance level. The hierarchical testing order is shown in below 
table (all comparisons are with the placebo).  
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Level 
Endpoints 
Testing 
Order  
Primary 
endpoint 
Daily CSMS, averaged over the last 12 weeks of the treatment period (weeks 48 to 60)  
1 
Secondary 
endpoints 
Daily TNSS, averaged over the last 12 weeks of treatment period (weeks 48 to 60) 
2 
Percent change from baseline to the end of treatment (week 60) in cat SPT mean wheal 
diameter 
3 
Percent change from pre-treatment baseline in average TNSS, over the last 12 weeks of 
the treatment period (weeks 48 to 60) 
4 
Daily CSMS, averaged over the initial 12 weeks of the treatment period (weeks 0 to 12) 
5 
Daily TNSS, averaged over the initial 12 weeks of treatment period (weeks 0 to 12) 
6 
Daily TSS, averaged over the last 12 weeks of the treatment period (weeks 48 to 60) 
7 
Daily TSS, averaged over the initial 12 weeks of the treatment period (weeks 0 to 12) 
8 
Percent change from pre-treatment baseline in average CSMS, over the last 12 weeks of 
the treatment period (weeks 48 to 60) 
9 
Change from baseline to week 60 in RQLQ(S)+12 
10 
DMS, averaged over the last 12 weeks of the treatment period (weeks 48 to 60) 
11 
Daily TOSS, averaged over the last 12 weeks of the treatment period (weeks 48 to 60) 
12 
Percent change from pre-treatment baseline in average TSS, over the last 12 weeks of 
the treatment period (weeks 48 to 60) 
13 
 
5.6.4. 
Subgroup analysis 
Subgroups defined in Section 3.5 for the primary endpoint will be analyzed based on the FAS. 
The analysis method for the subgroups will be the same as the primary analysis described in 
Section 5.6.1, as appropriate. If for any reason, such as small number of patients in a subgroup, 
the model-based inferential statistics cannot be computed, or deemed inappropriate, only 
descriptive statistics will be provided.  
Forest plots of the primary efficacy endpoint across subgroups will be provided. 
5.6.5. 
Analysis of Exploratory Efficacy Variables 
For continuous exploratory efficacy variables, e.g., percent change in ADSS, they will be analyzed 
by using an ANCOVA model similar to the analyses of primary endpoint. 
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5.7. 
Analysis of Safety Data 
The analysis of safety will be performed on the SAF, as defined in Section 3.2. 
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations, and vital signs).  
Thresholds for treatment-emergent Potential Clinically Significant Values (PCSV) in laboratory 
variables and vital signs are defined in Section 10.3. Treatment-emergent PCSV is any PCSV that 
developed or worsened in severity compared to the baseline during the on-treatment and follow-
up period. The baseline when determining treatment-emergent PCSV refers to the baseline value 
of the study. 
The summary of safety results will be presented for each treatment group. The time interval to 
detect any event or abnormality is between the first injection of study medication and EOS. 
In addition, the summary of safety results (including TEAEs, clinical laboratory, vital signs, and 
ECG) will be performed for subjects who were impacted by COVID-19 pandemic and not 
impacted by COVID-19 pandemic in each study part, respectively if deemed appropriate. The 
summary will be performed for pre-, during, and post-COVID-19 periods for patients impacted by 
COVID-19, if deemed appropriate.  
5.7.1. 
Adverse Events  
The number and proportion of subjects reporting TEAEs will be summarized on SAF overall 
during the study, during the week 60 treatment period, during the follow-up period, and during the 
study, separately. The TEAE search criteria is described in Section 3.2. 
AE incidence tables will be presented by treatment group for the SAF as well as subgroups for 
safety. TEAE summaries will present the number (n) and percentage (%) of subjects experiencing 
a TEAE by SOC, HLT, and PT, sorted by decreasing frequency of SOC, HLT, and PT for the 
REGN 1908-1909 treatment group. Multiple occurrences of AEs of the same PT (or SOC) in the 
same subject will be counted only once for that PT (or SOC). For tables presenting severity of 
events, the worst severity will be chosen for subjects with multiple instances of the same event. 
The denominator for computation of percentage is the number of subjects in each treatment group 
for safety analysis. 
An overall summary of TEAEs will be provided with number and proportion of subjects with any: 
• TEAE 
• Serious TEAE 
• TEAE of special interest (AESI) 
• Serious TEAE leading to death 
• Study drug related TEAE 
• TEAE leading to study treatment discontinuation 
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Detailed summaries of TEAEs will include: 
• TEAEs 
− TEAEs by primary SOC/PT 
− TEAEs by PT 
− TEAEs by severity and by primary SOC/PT 
− TEAEs related to study drug as assessed by the investigator by primary SOC/PT 
− Severe TEAEs by SOC/PT 
− Severe TEAEs related to study drug as assessed by the investigator by SOC/PT  
− Injection site reactions by HLT/PT 
• Serious TEAE 
− Serious TEAEs by primary SOC/PT 
− Serious TEAEs related to study drug as assessed by the investigator by SOC/PT  
• Fatal TEAEs by primary SOC/PT 
• TEAE leading to study treatment discontinuation by primary SOC/PT 
• AESI by AESI category (see Section 10.4), primary SOC/HLT/PT 
In order to detect any AE signals, the hazard ratio (HR) may be provided together with the 
corresponding 95% confidence interval (CI) for the selected adverse events during the 60-week 
treatment period. Hazard ratios will be calculated using a Cox model including factors of treatment 
group and randomization strata. For patients with events, the time to events is defined as the date 
of first event – the date of first dose + 1. Patients without an event will be censored at the end of 
study period. Graphs of cumulative incidence rate over time may be provided by treatment group 
for selected TEAEs leading to permanent discontinuation of study treatment. 
5.7.2. 
Clinical Laboratory Measurements  
Laboratory measurements include clinical chemistry, hematology, and urinalysis results, and will 
be converted to standard international units and US conventional units. Summaries of laboratory 
variables will include: 
• Descriptive statistics of laboratory result and change from baseline by visit 
• The number (n) and percentage (%) of subjects with treatment emergent PCSVs. This 
summary will be provided based on all patients in the SAF as well as in the subgroup 
of SAF, patients who did not meet the PCSV criterion at baseline. 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
The graph of mean change and/or percent change from baseline value for lab parameters by visit 
will be provided. 
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5.7.3. 
Analysis of Vital Signs 
Summary of vital sign variables (pulse rate, blood pressures, respiratory rate, and temperature) 
will include: 
• Descriptive statistics of vital sign variable and change from baseline by visit 
• The number (n) and percentage (%) of subjects with treatment-emergent PCSV 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
The last measurement will be used in the analysis if multiple data collected at the same time 
point. 
5.8. 
Analysis of Pharmacokinetic Data 
Descriptive 
statistics 
of 
total 
REGN1908, 
total 
REGN1909, 
and 
total 
drug 
(REGN1908+REGN1909) concentrations in serum at each sampling timepoint will be provided. 
Plots of mean concentration versus nominal time may be presented. Select PK parameters may be 
calculated. 
Exposure-response analysis for biomarkers, efficacy, and safety endpoints may be conducted as 
appropriate, and presented in separate reports. 
5.9. 
Analysis of Immunogenicity Data 
5.9.1. 
Analysis of ADA Data 
The immunogenicity variables described in Section 4.8 will be summarized using descriptive 
statistics. Immunogenicity will be characterized per drug molecule by ADA status, ADA category 
and maximum titer observed in patients in the ADA analysis sets. For samples confirmed as drug 
specific ADA positive, but found negative at the lowest titer dilution, the lowest dilution in the 
titer assay is imputed. 
The ADA status of each patient may be classified as one of the following:  
• Positive 
• Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as < 9-fold the baseline titer value 
• Negative - If all samples are found to be negative in the ADA assay. 
• The ADA category of each positive patient is classified as: 
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥9-fold the baseline titer value  
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• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Patients that are treatment-emergent 
will be further categorized as follows: 
− Persistent - A positive result in the ADA assay detected in at least 2 consecutive 
post baseline samples separated by at least a 16-week post baseline period [based 
on nominal sampling time], with no ADA-negative results in-between, regardless 
of any missing samples 
− Transient - Not persistent or indeterminate, regardless of any missing samples 
− Indeterminate - A positive result in the ADA assay at the last collection time point 
only, regardless of any missing samples 
• The maximum titer category of each patient is classified as: 
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer >10,000) 
• The following will be summarized by treatment group and ADA titer level: 
− Number (n) and percent (%) of ADA-negative patients 
− Number (n) and percent (%) of pre-existing patients 
− Number (n) and percent (%) of treatment-emergent ADA positive patients 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of transient treatment-emergent ADA positive patients 
− Number (n) and percent (%) of treatment-boosted ADA positive patients 
• Listing of all ADA titer levels will be provided for patients with pre-existing, 
treatment-emergent, and treatment-boosted ADA response. 
5.9.2. 
Analysis of NAb Data 
The absolute occurrence (n) and percent of patients (%) with NAb status in the NAb analysis set 
will be provided by treatment groups.  The NAb status is categorized as follows: 
• Negative: Samples tested negative in the ADA assay, or samples positive in the ADA 
assay but tested negative in the NAb assay. 
• Positive: Samples tested positive in the NAb assay. 
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5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.10.1. 
Immunogenicity and Exposure 
Potential association between immunogenicity and systemic exposure to REGN1908 and 
REGN1909 will be explored by treatment groups. Plots of individual REGN1908 and REGN1909 
concentration time profiles may be provided to examine the potential impact of ADA category, 
maximum titer category and NAb status on these profiles. 
5.10.2. 
Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
• Injection site reaction (serious or severe) 
• Hypersensitivity (SMQ: Hypersensitivity [Narrow]) followed by manual adjudication 
(same as AESI ‘Hypersensitivity’)) 
a) Anaphylaxis (SMQ: Anaphylactic Reaction [Narrow] and identified by an algorithmic 
approach) followed by manual adjudication if needed.  Details for the algorithmic 
approach are provided in Section 10.4. 
Potential association between immunogenicity variables and efficacy endpoints may be explored 
(e.g., scatter plot or spaghetti plot).  
The safety and efficacy analyses mentioned above will be conducted using the following 
categories: 
− ADA Positive 
• Treatment-emergent 
• Treatment-boosted 
− Maximum post-baseline titer category in ADA positive patients/subjects 
− NAb positive 
5.11. 
Analysis of Biomarker Data 
All biomarker analyses will be performed on the FAS using all observed data.   
Descriptive statistics for the observed values and change and percent change from baseline in 
detectable allergen specific IgE by treatment and visit will be provided for the biomarker variables.   
Baseline serum total IgE, serum cat dander sIgE, serum Fel d 1 sIgE, serum Fel d 2 sIgE, serum 
Fel d 4 sIgE, serum Fel d 7 sIgE, and the ratio of serum Fel d 1 sIgE/ serum cat dander sIgE will 
be correlated to the primary and secondary clinical efficacy endpoints using spearman’s rho test.   
The percent of detectable IgE at each visit (V5 and V7) compared to baseline may also be 
correlated to the primary and secondary clinical efficacy endpoints using spearman’s rho test. Both 
the spearman correlation coefficients and p-values will be reported. Multiple linear regression 
models may also be used to explore these relationships, with the efficacy endpoints as dependent 
variables and the IgE values at baseline (log transformed if appropriate) as dependent variables. 
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The poly-allergen sensitization status for each study subject will be determined by the number of 
allergen-specific IgE values that are equal to or above 0.35kUa/L.  The number of allergens that 
each subject was sensitized to will be correlated with the primary and secondary clinical outcomes.  
5.12. 
Sample Size Adjustment 
Once at least 50% of patients are enrolled, if the observed blinded standard deviation (SD) for 
CSMS during the initial 12 weeks is greater than a 5% increase over the assumed SD (6.2), sample 
size may be increased accordingly, see Appendix Section 10.6.  If the SD is lower than the current 
assumption (6.2), then no adjustment will be made.  Similar methods may be considered if the SD 
of TNSS is larger than a 5% increase over the assumed SD (2.3).  
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the first administration of study drug. If any randomized 
patients are not treated, the baseline will be the last value on or prior to the randomization. The 
following rules specify the determination of baseline by both date/time information: 
• For the AE, lab, PK and ADA data, both date and time of the measurement will be used 
to determine baseline by comparing with the first injection date and time. 
• For other data except AE, lab, PK or ADA, only date of the measurement will be used 
to determine baseline by comparing with the first injection date. 
For the rescreened patients, all data from the same patient will be used to derive baseline 
regardless if the data is from the screen-failure subject ID or enrolled subject ID. 
6.2. 
Data Handling Conventions  
For the laboratory safety variables and biomarker data, if the data are below the lower limit of 
quantification (LLOQ)/limit of linearity, half the lower limit value (i.e., LLOQ/2) will be used for 
quantitative analyses. For data above the upper limit of quantification (ULOQ)/ limit of linearity, 
the upper limit value (i.e., ULOQ) will be used for quantitative analyses. 
For efficacy endpoints defined as percent change from baseline, if both baseline and post-baseline 
values are 0s, the percent change from baseline will be 0; if baseline value is 0 and post-baseline 
value is a positive number, the percent change from baseline will be assigned by 100%.  Missing 
baseline values for efficacy endpoints will be imputed using the average baseline value across all 
patients. 
6.3. 
Data Handling Convention for Spirometry Data 
This applies to the selection of the FEV1 and FVC values to be used in analysis. As part of a central 
OverRead review, the best FEV1value and best FVC value will be identified from multiple 
spirometry efforts performed at the same time. Additionally, spirometry measures will be 
classified during the OverRead as Acceptable, Borderline Acceptable or Unacceptable.  
In the event that the best value at the baseline visit is graded as Unacceptable, the best spirometry 
effort from a prior screening visit that is graded as Acceptable or Borderline Acceptable should be 
considered the baseline value. If all available values prior to first administration of study drug are 
graded as Unacceptable, the baseline value should be set to missing. 
Similarly, for post-baseline visits, if all available values are graded as Unacceptable, the data from 
that visit should be set to missing. Otherwise, the best value should be used in the case of multiple 
efforts performed at the same time. 
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6.4. 
Data Handling Convention for Missing Data 
Missing data will not be imputed in listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 5.6.1 and Section 5.6.2. 
Adverse event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAEs. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as related to the investigational product. 
Adverse event start date 
AE start date will be used for AE classification and analysis of AESIs. If AE start date is not 
complete, then the character variable will keep the original incomplete date, the numerical date 
variable will be imputed, and an imputation flag will be used to indicate which date component is 
missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and AE start month is the same as first dose month, then AE start day will 
be imputed using the day of first dose. If this leads to a date after the AE end date, AE end date 
will be used instead. If AE start year is the same as first dose year and AE start month different 
from first dose month, AE start day will be imputed using the first day of the month. If this leads 
to a date before informed consent date, the informed consent date will be used. Imputation flag is 
‘D’. 
If AE start month is missing, and AE start year is not missing: If AE start year is before the first 
dose year, the informed consent day and month will be used. If AE start year is the same as first 
dose year, the first dose day and month will be used. If this leads to a date after AE end date, AE 
end date will be used instead. If AE start year is after the first dose year, January 1st will be used. 
Imputation flag is ‘M’. 
If AE start year is missing: The date of first dose will be used. If this leads to a date after the AE 
end date, AE end date will be used instead. Imputation flag is ‘Y’. 
Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for AE start date imputation, to carry through the logic for programming, the following 
intermediate step will be used. Afterwards, only the original character/numeric date recorded in 
CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: AE end date will be imputed 
using the last day of the month. If this leads to a date after end of study follow up date, the end of 
follow up date will be used instead. 
If AE end month is missing, and AE end year is not missing: AE end date will be imputed using 
December 31st as the day and month. If this leads to a date after end of study follow up date, the 
end of follow up date will be used instead.  
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If AE end year is missing: AE end date will be imputed using end of follow up date. 
Medication start and end date missing 
To determine whether a medication is prior medication or concomitant medication or both, the 
missing medication start date is estimated as early as possible, and the missing medication end 
date is estimated as late as possible. If the medication start date is missing, the onset day will not 
be calculated in medication listing.  
Prior medication start date 
If start day is missing, and start month and year are not missing: the start day will be imputed using 
the first day of the month. Imputation flag is ‘D’. 
If start month is missing, and start year is not missing: the day and month will be imputed using 
January 1st. Imputation flag is ‘M’. 
If start year is missing: the start date will be imputed using 2 years before informed consent date. 
Imputation flag is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However, to 
simplify the programming flow, the imputation is proposed to align with protocol which specifies 
to collect up to 2 years prior medication. Since the start date of prior medication will not be used 
in any analysis, the rule will not impact the analysis result.  
Prior medication end date 
If end day is missing, and end month and year are not missing: the end date will be imputed using 
the last day of the month. If this leads to a date on or after first dose intake date, the first dose 
intake date – 1 will be used. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: the end date will be imputed using December 
31st as the day and month. If this leads to a date on or after first dose intake date, the first dose 
intake date – 1 will be used instead. Imputation flag is ‘M’. 
If end year is missing: the end date will be imputed using the first dose intake date – 1. Imputation 
flag is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: the end date will be imputed using 
the last day of the month. If this leads to a date after end of study follow up date, the end of follow 
up date will be used. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: the end date will be imputed using December 
31st as the day and month. If this leads to a date after end of study follow up date, the end of follow 
up date will be used instead. Imputation flag is ‘M’. 
If end year is missing: the end date will be imputed using the end of follow up date. Imputation 
flag is ‘Y’. 
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Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study data manager and study medical director. 
PCSV 
Subjects who had post-baseline PCSV but missing baseline value will be regarded as having 
treatment-emergent PCSV. 
6.5. 
Visit Windows 
Data collected by daily diary will be summarized by the study treatment period (the initial 12 
weeks, or the last 12 weeks). The last (initial) 12 weeks will be defined as below: 
Treatment 
period 
Collected days >= 84* 
Collected days < 84 
Initial 12 weeks 
[date of Visit 3, date of Visit 3 + 84) 
[date of Visit 3, date of Visit 6) 
Last 12 weeks 
[date of Visit 12, date of Visit 12 + 84) 
[date of Visit 12, date of Visit 14] 
* Collected days = (date of visit 6– date of visit 3 + 1) for the initial 12 weeks ; Collected days = (date of visit 14– 
date of visit 12 + 1) for the last 12 weeks.  
Data analyzed by-visit-analysis (efficacy [excluding daily diary data], laboratory data, vital sign) 
will be summarized by the study scheduled visits described in the study protocol and SAP 
“Schedule of Events”. The analysis visit windows will be exhaustive so that all available values 
obtained from unscheduled visits and early termination (ET) visit have the potential to be 
summarized. No analysis visit windows will be applied for the study scheduled visits. 
The analysis visit windows are created per study Schedule of Events (SOE) table for each 
parameter and will be applied if the data from study scheduled visits are unavailable. The following 
general rules will be applied to unscheduled visit and/or ET visit mapping for each parameter. 
1. If ET due to an AE or lack of efficacy, the ET data for efficacy will not be mapped and 
the next scheduled visit data will be imputed using the worst score of all the observations 
in corresponding treatment group; if ET due to random reason, the ET data for efficacy 
will be mapped using rule 2 below.  (Safety data will be mapped in either scenario.) 
2. If ET visit falls in an analysis window which already has non-missing observed value of 
this parameter from the scheduled visit, ET will be mapped to the next scheduled visit. 
3. If both ET visit and unscheduled visit of the same parameter are available in the same 
analysis visit window, only ET visit will be mapped. 
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4. If multiple unscheduled visits of the same parameter are available in the same analysis 
visit window, the unscheduled visits will be mapped using the following rules: 
a. The closest unscheduled visit from the target day will be selected. 
b. If multiple unscheduled visits exist on the same day, the first unscheduled visit will 
be used. 
c. If the distance is a tie, the unscheduled visit after the target day of the scheduled visit 
will be used. 
5. If mapping distance is greater than 6 weeks, the unscheduled visit will not be mapped. 
Unscheduled visits and ET visit will be mapped per the following analysis visit windows based on 
the study day/visit of each parameter. 
Analysis Visit Window for Efficacy Endpoints 
Visit from SOE 
Target Study 
Day* 
PGIS, SPT for Cat and 
HDM 
RQLQ, Spirometry, ACQ-5 for Asthma 
patients 
Baseline 
1 
≤1 
≤1 
Visit 6 
85 
[2, 253] 
[2, 211] 
Visit 12 
337 
 
[212,379] 
Visit 14 (EOT) 
421 
>253 
>379 
*Study days are calculated from the day of 1st injection. Study day = (date of assessment – 1st injection date + 1) 
when date of assessment ≥1st injection date; otherwise, study day = (date of assessment – 1st injection date). If 
subject never received any dose of study drug, randomization date will be used in the place of 1st injection date. 
Analysis Visit Window for Safety and Biomarkers 
Visit from 
SOE 
Target Study 
Day* 
Vital Sign, 
Drug conc. 
Hematology, 
Blood 
chemistry 
ADA 
Serum for 
sIgE for Fel d 
2, 4, and 7 
Biomarkers 
Baseline 
1 
≤1 
≤1 
≤1 
≤1 
≤1 
Visit 6 
85 
[2, 127] 
[2, 127] 
[2, 169] 
[2, 253] 
[2,211] 
Visit 8 
169 
[128, 211] 
[128, 211] 
 
 
 
Visit 10 
253 
[212, 295] 
[212, 295] 
[170, 295] 
 
 
Visit 12 
337 
[296, 379] 
[296, 379] 
[296, 379] 
 
[212,379] 
Visit 14 
(EOT) 
421 
[380,463] 
[380,463] 
[380,463] 
>253 
[380,463] 
Visit 15 
(EOS) 
505 
> 463 
> 463 
> 463 
 
> 463 
* Study days are calculated from the day of 1st injection. Study day = (date of assessment – 1st injection date + 1) 
when date of assessment ≥1st injection date; otherwise, study day = (date of assessment – 1st injection date). If 
subject never received any dose of study drug, randomization date will be used in the place of 1st injection date. 
# Post-baseline urinalysis will not be mapping since no scheduled measurements will be collected per protocol.  
6.6. 
Statistical Technical Issues 
None. 
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7. 
INTERIM ANALYSIS 
7.1. 
Futility Interim Analysis 
A non-binding futility interim analysis (IA) in the study is planned to be performed when at least 
40% of randomized patients have completed the week 12 visit or discontinued before week 12. 
There is no plan to change the conduct of this trial except a possibility to stop the trial due to 
unfavorable benefit-risk. The IA will be performed by independent statisticians that support the 
IDMC and who are separate from personnel involved in the trial conduct. The IDMC will review 
the unblinded IA results and recommend action based on the non-binding futility criteria based on 
CSMS and TNSS that will be specified in Section 7.2.  
If the non-binding futility criteria are met, the unblinded results will be viewed by a small group 
of senior sponsor individuals, who are separate from sponsor personnel involved in the conduct of 
the study.  Individuals involved in the conduct of the study (i.e., patients, Investigators, Study 
Team, and Project Team, etc.) will have no access to the IA results.  
The analysis population for the interim futility analysis will include at least the first 40% of the 
randomized patients. An administrative penalty of 0.001 will be taken from the significance level 
used at final analysis (i.e., 2-sided 0.049 will be used for the final analysis). 
7.2. 
Interim Futility Criteria 
Futility will be assessed using criteria based on the following two efficacy endpoints: 
• Daily CSMS, averaged over the initial 12 weeks of the treatment period (weeks 0 to 
12), in patients who receive REGN1908-1909 versus placebo 
• Daily TNSS, averaged over the initial 12 weeks of treatment period (weeks 0 to 12), 
in patients who receive REGN1908-1909 versus placebo 
For the IA, the efficacy will be analyzed using the same methods described in the efficacy analyses 
section (Section 5.6).  The least squares means estimates for these two endpoints for each treatment 
group, as well as the difference between the REGN1908-1909 and placebo will be provided based 
on an ANCOVA model, with the treatment group, randomization stratification factors (as 
stratified), and cat sIgE (<17.5 kUa/L versus ≥17.5 kUa/L) as fixed effects and the baseline 
CSMS/TNSS as a covariate.  This ANCOVA model as the primary analysis in the study will be 
conducted for the IA.  
Based on these estimates, the standardized effect size and percent reduction in average CSMS and 
average TNSS for REGN1908-1909 relative to placebo will be calculated.  The two steps below 
will be followed to assess futility: 
Step 1:  Assess CSMS endpoint.  Futility criteria for CSMS will be met if: 
a. Mean difference between REGN1908-1909 and placebo is <5% 
or 
b. Effect size (mean diff./SD) < 0.073* 
(* Note:  The effect size of 0.073 corresponds to an assumed mean difference in CSMS 
of 0.455 and a standard deviation of 6.2.)  
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If neither a. nor b. is met for CSMS, then futility criterion is not met and the study will 
proceed as planned.  If either criteria a. or b. are met, the TNSS endpoint will be 
evaluated in step 2. 
Step 2:  Assess TNSS endpoint.  Futility criteria for TNSS will be met if: 
a. Mean difference between REGN1908-1909 and placebo is <5% 
or 
b. Effect size (mean diff./SD) < 0.072** 
(** Note:  The effect size of 0.072 corresponds to an assumed mean difference in TNSS 
of 0.165 and a standard deviation of 2.3.) 
If neither a. nor b. is met for TNSS, then the study will proceed as planned.  If either 
criteria a. or b. are met, the non-binding futility criteria have been met and unblinded 
results will be reviewed by a small group of senior sponsor individuals. 
7.3. 
Timing of Unblinded Primary Analysis 
The unblinded primary analysis may be performed when the last patient completes 60 weeks of 
treatment duration (or discontinues prior to week 60) in order to expedite the submission to 
regulatory agencies. No changes in the conduct of the study will be made based on this primary 
analysis. The assessment of primary and secondary endpoints performed during the analysis will 
be the final analysis of the primary endpoint and secondary endpoints and 2-sided alpha of 0.049 
will be used. 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or above or using R Version 3.5 or above. 
 
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9. 
REFERENCES 
1. 
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Bielory L, Katelaris CH, Lightman S,Naclerio RM. Treating the ocular component of 
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Bollinger M, Eggleston P, Flanagan E,Wood R. Cat antigen in homes with and without cats 
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Bollinger ME, Wood RA, Chen P,Eggleston PA. Measurement of cat allergen levels in the 
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Bousquet J, Van Cauwenberge P, Khaltaev N, Aria Workshop G,World Health O. Allergic 
rhinitis and its impact on asthma. J Allergy Clin Immunol 2001; 108(5 Suppl):S147-334. 
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Chapman MD,Wood RA. The role and remediation of animal allergens in allergic diseases. 
J Allergy Clin Immunol 2001; 107(3 Suppl):S414-421. 
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Ciprandi G, Incorvaia C, Scurati S, Puccinelli P, Soffia S, Frati F, et al. Patient-related 
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Coren S. Allergic patients do not comply with doctors' advice to stop owning pets. Bmj 
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10. Demoly P, Emminger W, Rehm D, Backer V, Tommerup L,Kleine-Tebbe J. Effective 
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Allergy Clin Immunol 2016; 137(2):444-451.e448. 
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standardized sublingual grass immunotherapy: confirmation of disease modification 2 
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12. Durham SR,Penagos M. Sublingual or subcutaneous immunotherapy for allergic rhinitis? J 
Allergy Clin Immunol 2016; 137(2):339-349.e310. 
13. Giavina-Bianchi P, Aun M, Takejima P, Kalil J,Agondi R. United airway disease: current 
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14. Gomes PJ. Trends in prevalence and treatment of ocular allergy. Curr Opin Allergy Clin 
Immunol 2014; 14(5):451-456. 
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15. Grönlund H, Saarne T, Gafvelin G,van Hage M. The Major Cat Allergen, Fel d 1, in 
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19. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
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term tolerance after allergen immunotherapy is accompanied by selective persistence of 
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22. Karlsson AS, Renstrom A, Hedren M,Larsson K. Allergen avoidance does not alter 
airborne cat allergen levels in classrooms. Allergy 2004; 59(6):661-667. 
23. Kleine-Tebbe J, Kleine-Tebbe A, Jeep S, Schou C, Løwenstein H,Kunkel G. Role of the 
Major Allergen Fel d I in Patients Sensitized to Cat Allergens. International Archives of 
Allergy and Immunology 1993; 100(3):256-262. 
24. Kündig TM,Bachmann MF. Allergen-specific immunotherapy: Regulatory T cells or 
allergen-specific IgG? Human Vaccines 2010; 6(8):673-675. 
25. Leung DYM, Sampson HA, Geha R,Szefler SJ. Preface.  Pediatric Allergy: Principles and 
Practice. Elsevier; 2010: ix. 
26. Mounsey AL,Gray RE. Topical Antihistamines and Mast Cell Stabilizers for Treating 
Allergic Conjunctivitis. Am Fam Physician 2016; 93(11):915-916. 
27. Niesler A, Ścigała G,Łudzeń-Izbińska B. Cat (Fel d 1) and dog (Can f 1) allergen levels in 
cars, dwellings and schools. Aerobiologia 2016; 32(3):571-580. 
28. Olivieri M, Heinrich J, Schlünssen V, Antó JM, Forsberg B, Janson C, et al. The risk of 
respiratory symptoms on allergen exposure increases with increasing specific IgE levels. 
Allergy 2016; 71(6):859-868. 
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REGENERON CONFIDENTIAL 
29. Orengo JM, Radin AR, Kamat V, Badithe A, Ben LH, Bennett BL, et al. Treating cat 
allergy with monoclonal IgG antibodies that bind allergen and prevent IgE engagement. 
Nature Communications 2018; 9(1). 
30. Perzanowski MS, Ronmark E, James HR, Hedman L, Schuyler AJ, Bjerg A, et al. 
Relevance of specific IgE antibody titer to the prevalence, severity, and persistence of 
asthma among 19-year-olds in northern Sweden. Journal of Allergy and Clinical 
Immunology 2016; 138(6):1582-1590. 
31. Riedi CA,Rosario NA. Prevalence of allergic conjunctivitis: a missed opportunity? Allergy 
2010; 65(1):131-132. 
32. Salo PM, Calatroni A, Gergen PJ, Hoppin JA, Sever ML, Jaramillo R, et al. Allergy-related 
outcomes in relation to serum IgE: results from the National Health and Nutrition 
Examination Survey 2005-2006. J Allergy Clin Immunol 2011; 127(5):1226-1235.e1227. 
33. Scadding GW, Calderon MA, Shamji MH, Eifan AO, Penagos M, Dumitru F, et al. Effect 
of 2 Years of Treatment With Sublingual Grass Pollen Immunotherapy on Nasal Response 
to Allergen Challenge at 3 Years Among Patients With Moderate to Severe Seasonal 
Allergic Rhinitis: The GRASS Randomized Clinical Trial. Jama 2017; 317(6):615-625. 
34. van Ree R, van Leeuwen WA, Bulder I, Bond J,Aalberse RC. Purified natural and 
recombinant Fel d 1 and cat albumin in in vitro diagnostics for cat allergy. Journal of 
Allergy and Clinical Immunology 1999; 104(6):1223-1230. 
35. Walker SM, Durham SR, Till SJ, Roberts G, Corrigan CJ, Leech SC, et al. Immunotherapy 
for allergic rhinitis. Clinical & Experimental Allergy 2011; 41(9):1177-1200. 
36. Wood RA, Chapman MD, Adkinson NF, Jr.,Eggleston PA. The effect of cat removal on 
allergen content in household-dust samples. J Allergy Clin Immunol 1989; 83(4):730-734. 
37. Zuberbier T, Bachert C, Bousquet PJ, Passalacqua G, Walter Canonica G, Merk H, et al. 
GA2LEN/EAACI pocket guide for allergen-specific immunotherapy for allergic rhinitis 
and asthma. Allergy 2010; 65(12):1525-1530. 
 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
10.1.1. 
Summary of Efficacy Analyses 
Endpoint 
Analysis 
Populations 
Primary Analysis 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
Daily CSMS, averaged over 
the last 12 weeks of the 
treatment period (weeks 48 to 
60) 
FAS 
ANCOVA model with 
treatment group, stratification 
factors, and cat sIgE (<17.5 
kUa/L versus ≥17.5 kUa/L) 
as fixed factors and baseline 
CSMS as a covariate 
Yes - All 
intercurrent 
events 
handled via 
a treatment 
policy  
Yes 
Plot 
Secondary Endpoints 
Daily TNSS, TSS, CSMS, 
TOSS, and DMS over the last 
12 and the initial 12 weeks of 
the efficacy assessment period 
(weeks 48 to 60, and weeks 0 to 
12) and the percent change from 
baseline in these endpoints 
(except for daily CSMS over 
the last 12 weeks) 
FAS 
ANCOVA model with 
treatment group, stratification 
factors, and cat sIgE (<17.5 
kUa/L versus ≥17.5 kUa/L) 
as fixed factors and relevant 
baseline measurement as a 
covariate 
N/A 
Yes 
Plot 
Percent change from baseline to 
week 12 cat SPT mean wheal 
diameter 
Percent change from baseline to 
end of treatment (week 60) cat 
SPT mean wheal diameter 
Change from baseline to week 
60 in RQLQ(S)+12 
FAS 
ANCOVA model with 
treatment group, stratification 
factors, and cat sIgE (<17.5 
kUa/L versus ≥17.5 kUa/L) 
as fixed factors and baseline 
SPT mean wheal diameter as 
a covariate 
N/A 
Yes 
Plot 
Percent change from baseline to 
week 12 FEV1  
Percent change from baseline to 
week 60 FEV1 
Asthma daily symptom score 
(ADSS), averaged over the last 
12 weeks and the initial 12 
weeks of the treatment period 
(weeks 48-60, weeks 0 to 12) 
Change from baseline to week 
60 in ACQ-5 
FAS with 
asthma 
ANCOVA model with 
treatment group, stratification 
factors, and cat sIgE (<17.5 
kUa/L versus ≥17.5 kUa/L) 
as fixed factors and relevant 
baseline measurement as a 
covariate 
N/A 
Yes 
Plot 
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10.1.2. 
Summary of Safety Analyses 
Endpoint 
Analysis 
Populations 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Adverse Events 
SAF 
Descriptive statistics 
and model-based 
analyses 
No 
Yes, for selected 
AE summary 
No 
Laboratory Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
ECG 
SAF 
Descriptive Statistics 
No 
No 
No 
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10.2. 
Schedule of Time and Events 
Table 6: 
Schedule of Events  
 
Screening Period1 
Randomization 
Double-Blind Treatment Period 
Follow Up Period 
 
Initial 
Efficacy 
Assessment 
 
Final 
(Primary) 
Efficacy 
Assessment 
End of 
Treatment 
(EOT)/ 
Early 
Term. 
End 
of 
Study 
(EOS) 
 
Visit 
Screening 
Visit 11 
Baseline 
V22 
R  
V34 
Tel 
V4 
Tel 
V5 
V6 
Tel 
V7 
V8 
Tel  
V9 
V10 
Tel 
V11 
V12 
Tel 
V13 
EOT  
V14 
EOS  
V15 
Un-
scheduled 
Visit13 
Day 
-85 to -1 
1 
8 
43 
85 
127 
169 
211 
253 
302 
337 
365 
421 
505 
 
Window (day) 
 
 
±3 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±7 
±7 
 
Week 
- 12  
0 
1 
6 
12 
18 
24 
30 
36 
43 
48 
52 
60 
72 
 
Screening/Baseline: 
Inclusion/exclusion 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics (age, 
race, height, weight) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skin prick test for 
cat and HDM3 
X3 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Skin prick test for 
other allergens3 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense e-diary 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Collect e-diary 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Dispense rescue 
meds 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Randomization4 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
Administer study 
drug5 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Concomitant meds 
and treatment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Screening Period1 
Randomization 
Double-Blind Treatment Period 
Follow Up Period 
 
Initial 
Efficacy 
Assessment 
 
Final 
(Primary) 
Efficacy 
Assessment 
End of 
Treatment 
(EOT)/ 
Early 
Term. 
End 
of 
Study 
(EOS) 
 
Visit 
Screening 
Visit 11 
Baseline 
V22 
R  
V34 
Tel 
V4 
Tel 
V5 
V6 
Tel 
V7 
V8 
Tel  
V9 
V10 
Tel 
V11 
V12 
Tel 
V13 
EOT  
V14 
EOS  
V15 
Un-
scheduled 
Visit13 
Day 
-85 to -1 
1 
8 
43 
85 
127 
169 
211 
253 
302 
337 
365 
421 
505 
 
Window (day) 
 
 
±3 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±7 
±7 
 
Week 
- 12  
0 
1 
6 
12 
18 
24 
30 
36 
43 
48 
52 
60 
72 
 
Efficacy: 
TNSS, TOSS, DMS 
 
X 
Nightly in e-diary 
 
 
 
 
 
Nightly in e-diary 
 
 
PGIS  
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
PGIC 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
RQLQ(S) 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
Evaluation of cat 
exposure 
 
 
 
 
 
X 
 
X 
 
X 
 
Daily in e-diary 
 
X 
Patient Experience 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Spirometry6,7 
X6 
 
X6 
 
 
X7 
 
 
 
 
 
X7 
 
X7 
 
 
ACQ-5 for asthma 
patients7 
 
 
X6 
 
 
X7 
 
 
 
 
 
X7 
 
X7 
 
 
ANSD and 
nighttime 
awakening for 
asthma patients7 
 
X7 
Daily in e-diary7 
 
 
 
 
 
Daily in e-diary7 
 
 
ADSD and asthma 
rescue med use for 
asthma patients7 
 
X7 
Nightly in e-diary7 
 
 
 
 
 
Nightly in e-diary7 
 
 
Safety: 
Vital signs8 
X 
X 
X8 
 
 
X8 
 
X8 
 
X8 
 
X8 
 
X 
X 
X 
Physical 
examination 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Adverse events 
X 
 
X 
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Screening Period1 
Randomization 
Double-Blind Treatment Period 
Follow Up Period 
 
Initial 
Efficacy 
Assessment 
 
Final 
(Primary) 
Efficacy 
Assessment 
End of 
Treatment 
(EOT)/ 
Early 
Term. 
End 
of 
Study 
(EOS) 
 
Visit 
Screening 
Visit 11 
Baseline 
V22 
R  
V34 
Tel 
V4 
Tel 
V5 
V6 
Tel 
V7 
V8 
Tel  
V9 
V10 
Tel 
V11 
V12 
Tel 
V13 
EOT  
V14 
EOS  
V15 
Un-
scheduled 
Visit13 
Day 
-85 to -1 
1 
8 
43 
85 
127 
169 
211 
253 
302 
337 
365 
421 
505 
 
Window (day) 
 
 
±3 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±7 
±7 
 
Week 
- 12  
0 
1 
6 
12 
18 
24 
30 
36 
43 
48 
52 
60 
72 
 
Laboratory Testing: 
Hematology 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Blood chemistry 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum pregnancy 
test for WOCBP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy for 
WOCBP9 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
FSH test for 
postmenopausal 
women only10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum for specific 
IgE for Fel d 1 and 
cat 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for sIgE for 
Fel d 2, 4, and 7  
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Serum for sIgE for 
other allergens (eg, 
HDM, etc) 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK and ADA: 
Drug conc. sample11 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
ADA sample11 
 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
Biomarkers: 
Research sample for 
serum  
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Research sample for 
plasma 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
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Screening Period1 
Randomization 
Double-Blind Treatment Period 
Follow Up Period 
 
Initial 
Efficacy 
Assessment 
 
Final 
(Primary) 
Efficacy 
Assessment 
End of 
Treatment 
(EOT)/ 
Early 
Term. 
End 
of 
Study 
(EOS) 
 
Visit 
Screening 
Visit 11 
Baseline 
V22 
R  
V34 
Tel 
V4 
Tel 
V5 
V6 
Tel 
V7 
V8 
Tel  
V9 
V10 
Tel 
V11 
V12 
Tel 
V13 
EOT  
V14 
EOS  
V15 
Un-
scheduled 
Visit13 
Day 
-85 to -1 
1 
8 
43 
85 
127 
169 
211 
253 
302 
337 
365 
421 
505 
 
Window (day) 
 
 
±3 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±14 
±7 
±7 
±7 
 
Week 
- 12  
0 
1 
6 
12 
18 
24 
30 
36 
43 
48 
52 
60 
72 
 
Pharmacogenomics: 
Optional DNA 
sample (whole 
blood)12 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional Research 
Samples: whole 
blood for RNAseq  
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
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Footnotes for the Schedule of Events Table 
1. 
Screening SPT for birch, birch homologous trees, and other common allergens will be 
performed as described in the study manual. Skin prick test for birch should be performed 
prior to other screening assessments. If screening SPT for birch is negative (ie, mean wheal 
diameter <5 mm greater than a negative control), then other screening visit procedures do not 
need to be performed as the subject will have failed screening (refer to Protocol Section 7.2.1 
Inclusion Criteria, #3).  
2. 
Randomization may occur within 1 day prior to study drug administration. All safety 
assessments performed at screening must be normal and checked against the 
inclusion/exclusion criteria prior to study drug administration.  
3. 
The timing of in-clinic visits may vary for each study site, depending on the start, peak, and 
end dates of the local birch pollen season (as determined by local pollen counts; refer to 
Protocol Section 9.2.2). The randomization visit will be scheduled approximately 2 weeks 
before the start of birch pollen season, and the end of study (EOS) visit approximately 16 
weeks after the randomization visit (depending on the duration of the local birch pollen 
season). In addition, visit 5 will be scheduled to occur within 2 weeks of the anticipated local 
peak of the birch pollen season.  
4. 
If randomization occurs >60 days after the screening visit, medical history, blood chemistry, 
hematology, and spirometry must be repeated prior to randomization. 
5. 
E-diary and rescue medications will be dispensed at the randomization visit. E-diary and any 
unused rescue medications will be returned at the EOS visit. Refer to Protocol Section 8.2 for 
more information on rescue treatments. 
6. 
TNSS, TOSS, and DMS will be recorded daily via e-diary, starting at the randomization visit 
until EOS. Refer to Protocol Section 9.2.4.1, 9.4.2.2 and 9.4.2.4 for procedural details. 
7. 
In asthmatic subjects, ACQ-5 scores will be recorded weekly via e-diary, starting from the 
randomization visit until EOS. Refer to Protocol Section 9.2.4.6 for procedural details.  
8. 
In all subjects, RQLQ (S) scores will be recorded weekly via e-diary starting from the 
randomization visit until EOS. Refer to Protocol Section 9.2.4.7 for procedural details. In 
asthmatic subjects, the weekly RQLQ (S) and ACQ-5 assessments may be performed on the 
same day.  
9. 
Refer to for Protocol Section 9.2.4.8 procedural details. 
10. Refer to for Protocol Section 9.2.4.9 procedural details. 
11. Vital signs include systolic and diastolic blood pressure, respiratory rate, and heart rate. Vital 
signs will be collected in a seated position. At the randomization visit, vital signs are taken 
prior to PK blood draw, prior to study drug administration, and at 2 hours (±10 min) after 
completion of the injection.  
12. A full physical exam must be performed at screening, at baseline, and at EOS. A limited 
physical exam will be done at remaining visits depending on presentation of the subject. 
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13. If the urine pregnancy test is positive, the site must perform a serum pregnancy test for 
confirmation. At the randomization visit, if a serum pregnancy test must be performed, study 
drug cannot be administered unless the serum pregnancy test is negative. Urine pregnancy 
test can be performed on day -1 of the visit at the investigator’s discretion.  
14. At-home pregnancy testing: WOCBP will be provided with urine pregnancy tests for 
at-home testing prior to visits 4 and 6. Study sites will collect the results by telephone at these 
visits. If the urine pregnancy test is positive, the site must perform a serum pregnancy test for 
confirmation.  
15. PK and ADA samples are to be collected prior to study drug administration. In the event of 
suspected SAEs, such as anaphylaxis or hypersensitivity, additional samples for PK and ADA 
analyses may be collected as close to the event as practically possible. 
16. Refer to Protocol Section 9.2.11. 
17. Genomic analysis is optional for all subjects enrolling in the study. One DNA sample is to be 
collected at the randomization visit, but if this sample collection was omitted at baseline, it 
can be collected at any subsequent visit. Refer to Protocol Section 9.2.12. 
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10.3. 
Criteria for Potentially Clinically Significant Values (PCSV)  
Parameter 
Adults 
Comments for adults 
Adolescents  
(≥12 to <18) 
Comments  
for adolescents 
Combined 
Clinical Chemistry 
ALT 
>3 and ≤ 5 ULN and 
baseline ≤ 3 ULN 
>5 and ≤ 10 ULN and 
baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and 
baseline ≤ 10 ULN 
>20 ULN and baseline 
≤ 20 ULN 
Enzymes activities must 
be expressed in ULN, not 
in IU/L.  
Concept paper on DILI – 
FDA draft Guidance 
Oct 2007. 
Each category is 
calculated independently. 
 
>3 and ≤ 5 ULN and 
baseline ≤ 3 ULN 
>5 and ≤ 10 ULN and 
baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and 
baseline ≤ 10 ULN 
>20 ULN and baseline 
≤ 20 ULN 
Enzyme activity must be 
expressed in ULN, not in 
IU/L.  
Concept paper on DILI – 
FDA draft Guidance Oct 
2007. 
Each category is 
calculated independently. 
>3 and ≤ 5 ULN and 
baseline ≤ 3 ULN 
>5 and ≤ 10 ULN and 
baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and 
baseline ≤ 10 ULN 
>20 ULN and baseline 
≤ 20 ULN 
AST 
>3 and ≤ 5 ULN and 
baseline ≤ 3 ULN 
>5 and ≤ 10 ULN and 
baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and 
baseline ≤ 10 ULN 
>20 ULN and baseline 
≤ 20 ULN 
Enzymes activities must 
be expressed in ULN, not 
in IU/L.  
Concept paper on DILI – 
FDA draft Guidance 
Oct 2007. 
Each category is 
calculated independently. 
 
>3 and ≤ 5 ULN and 
baseline ≤ 3 ULN 
>5 and ≤ 10 ULN and 
baseline ≤ 5 ULN 
>10 and ≤ 20 ULN and 
baseline ≤ 10 ULN 
>20 ULN and baseline 
≤ 20 ULN 
Enzyme activity must be 
expressed in ULN, not in 
IU/L.  
Concept paper on DILI – 
FDA draft Guidance Oct 
2007. 
Each category is 
calculated independently. 
>3 and ≤ 5 ULN and 
baseline ≤ 3 ULN>5 and 
≤ 10 ULN and baseline 
≤ 5 ULN 
>10 and ≤ 20 ULN and 
baseline ≤ 10 ULN 
>20 ULN and baseline 
≤ 20 ULN 
Alkaline 
Phosphatase 
>1.5 ULN and baseline 
≤ 1.5 ULN 
Enzyme activity must be 
expressed in ULN, not in 
IU/L. 
Concept paper on DILI – 
FDA draft Guidance 
Oct 2007. 
≥1.5 ULN and baseline < 
1.5 ULN 
 
 
Enzyme activity must be 
expressed in ULN, not in 
IU/L. 
Concept paper on DILI – 
FDA draft Guidance Oct 
2007. 
>1.5 ULN [≥1.5 ULN] 
and baseline ≤ 1.5 ULN 
[<1.5 ULN] 
 
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Parameter 
Adults 
Comments for adults 
Adolescents  
(≥12 to <18) 
Comments  
for adolescents 
Combined 
Total Bilirubin 
>1.5 and ≤ 2 ULN and 
baseline ≤ 1.5 ULN 
>2 ULN and baseline 
≤ 2.0 ULN 
Must be expressed in 
ULN, not in µmol/L or 
mg/L.  
Concept paper on DILI – 
FDA draft Guidance 
Oct 2007. 
 
≥1.3 ULN and baseline <  
1.3 ULN 
 
 
Must be expressed in 
ULN, not in µmol/L or 
mg/L. 
Based on normal range: 
<1 mg/dL, CF = mg x 1.7 
= μmol 
Concept paper on DILI – 
FDA draft Guidance Oct 
2007. 
Based on normal ranges: 
<6 mg/dL (Term 0-1 
day), <8 mg/dL (Term 1-
2 days), <12 mg/dL 
(Term 3-5 days), 
<1 mg/dL (Term >5 days) 
>1.5 and ≤ 2 ULN and 
baseline ≤ 1.5 ULN (adults 
only) 
>2 ULN [≥1.3 ULN] and 
baseline ≤ 2.0 ULN [<1.3 
ULN] 
(ALT or AST) and 
Total Bilirubin 
((ALT >3 ULN or AST>3 
ULN) and TBILI>2 
ULN) and baseline ((ALT 
≤3 ULN and AST ≤3 
ULN) or TBILI ≤2 
ULN)) 
Concept paper on DILI – 
FDA draft Guidance 
Oct 2007. 
((ALT >3 ULN or AST>3 
ULN) and TBILI>2 
ULN) and baseline ((ALT 
≤3 ULN and AST ≤3 
ULN) or TBILI ≤2 
ULN)) 
Concept paper on DILI – 
FDA draft Guidance Oct 
2007. 
((ALT >3 ULN or AST>3 
ULN) and TBILI>2 
ULN) and baseline ((ALT 
≤3 ULN and AST ≤3 
ULN) or TBILI ≤2 ULN)) 
Creatinine 
≥150 μmol/L (Adults) 
and baseline < 150 
μmol/L 
≥30%  change from 
baseline and <100% 
change from baseline 
≥100% change from 
baseline 
Benichou C., 1994. 
3 independent criteria  
≥132µmol/L and baseline 
< 132µmol/L 
 (or ≥1.5 mg/dL and 
baseline <1.5 mg/dL) 
≥30%  change from 
baseline  
 
Benichou C., 1994. 
3 independent criteria 
>150 [≥132] μmol/L and 
baseline < 150 [<132] 
μmol/L 
≥30% change from 
baseline and <100% 
change from baseline 
≥100% change from 
baseline 
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Protocol: R1908-1909-ALG-2102 
Statistical Analysis Plan 
 
Date: 18 August, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 68 
 
REGENERON CONFIDENTIAL 
Parameter 
Adults 
Comments for adults 
Adolescents  
(≥12 to <18) 
Comments  
for adolescents 
Combined 
Uric Acid  
<120 μmol/L and 
≥ 120 μmol/L at baseline 
>408 μmol/Land 
≤ 408 μmol/L at baseline 
Harrison- Principles of 
Internal Medicine 17th 
Ed., 2008. 
Two independent criteria 
≤2 mg/dL and >2 mg/dL 
at baseline (or ≤119 
µmol/L and baseline 
>119 µmol/L) 
>8.0 mg/dL and 
≤8.0 mg/dL at baseline ( 
or >476 µmol/L and 
≤476 µmol/L at baseline) 
Harrison- Principles of 
internal Medicine 17th 
Ed., 2008. 
Two independent criteria 
>408 [>476] μmol/L and 
≤408 [≤476] μmol/L at 
baseline 
<120 μmol/L and 
≥120 μmol/L at baseline 
Blood Urea 
Nitrogen (BUN) 
≥17 mmol/L and 
<17 mmol/L at baseline 
Two independent criteria 
≥20  mg/dL and 
<20 mg/dL at baseline (or 
≥7.14 mmol/L and <7.14 
mmol/L at baseline) 
 
≥17 [≥7.14] mmol/L and 
<17 [<7.14] mmol/L at 
baseline 
Calcium 
 
 
<2 mmol/L and baseline 
≥2 mmol/L  
(or ≤ 8 mg/dL and 
baseline >8 mg/dL) 
≥2.9 mmol/L and baseline 
<2.9 mmol/L  
(or ≥11.6 mg/dL and 
baseline <11.6 mg/dL) 
 
<2 mmol/L and baseline 
≥2 mmol/L   
(or ≤ 8 mg/dL and 
baseline >8 mg/dL) 
≥2.9 mmol/L and baseline 
<2.9 mmol/L  
(or ≥11.6 mg/dL and 
baseline <11.6 mg/dL) 
(adolescents only) 
Chloride 
<80 mmol/L and baseline 
≥ 80 mmol/L  
>115 mmol/L and 
baseline  ≤115 mmol/L  
Two independent criteria  
<80 mmol/L and baseline 
≥80 mmol/L  
≥115 mmol/L and 
baseline < 115 mmol/L  
 
 
<80 mmol/L and baseline 
≥80 mmol/L  
>115 [≥115] mmol/Land 
baseline ≤ 115 [< 115] 
mmol/L  
 
                                        VV-RIM-00201802-2.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1908-1909-ALG-2102 
Statistical Analysis Plan 
 
Date: 18 August, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 69 
 
REGENERON CONFIDENTIAL 
Parameter 
Adults 
Comments for adults 
Adolescents  
(≥12 to <18) 
Comments  
for adolescents 
Combined 
Sodium 
≤129 mmol/L  and 
baseline > 129 mmol/L  
≥160 mmol/L  and 
baseline < 160 mmol/L  
Two independent criteria 
<129 mmol/L  and 
baseline ≥ 129 mmol/L  
≥150 mmol/L  and 
baseline <150 mmol/L 
 
Two independent criteria  
Reference ranges are 
same in adolescents (12-
17 yrs. old) and adults 
≤129 [<129] mmol/L and 
baseline 
> 129 [≥129] mmol/L  
≥160 [≥150] mmol/L  and 
baseline 
<160 [<150] mmol/L 
Potassium 
<3 mmol/L and baseline 
≥ 3 mmol/L  
≥5.5 mmol/L and baseline 
< 5.5 mmol/L  
FDA Feb 2005. 
Two independent criteria 
≤3.5 mmol/L and baseline 
>3.5 mmol/L  
≥5.5 mmol/L and baseline 
<5.5 mmol/L 
FDA Feb 2005. 
Two independent criteria 
<3 [≤3.5] mmol/L and 
baseline 
≥ 3 [>3.5] mmol/L  
≥5.5 mmol/L and baseline 
<5.5 mmol/L 
Glucose 
 
Hypoglycaemia: (≤3.9 
mmol/L and <LLN) and 
(>3.9 mmol/L or ≥LLN) 
at baseline 
Hyperglycaemia: >=7 
mmol/L (fasted) and <7 
mmol/L at baseline  
(fasted); >=11.1 mmol/L 
(unfasted) and <11.1 
mmol/L at baseline 
(unfasted)  
 
ADA Jan 2008. 
<2.7 mmol/L and 
≥2.7 mmol/L at baseline 
(or < 50 mg/dL and 
≥ 50 mg/dL at baseline)  
≥10 mmol/L (unfasted) 
and < 10 mmol/L 
(unfasted) at baseline (or 
≥180 mg/dl and 
<180 mg/dl at baseline); 
≥7 mmol/L (fasted) and 
<7 mmol/L (fasted) at 
baseline (or ≥120 mg/dL 
and <120 mg/dL at 
baseline) 
 
(≤3.9 [<2.7] mmol/L and 
<LLN) and 
(>3.9 [≥2.7] mmol/L or 
>=LLN) at baseline 
≥11.1 [≥10] mmol/L 
(unfasted) and <11.1 
[<10] mmol/L (unfasted) 
at baseline; ≥7 mmol/L 
(fasted) and <7 mmol/L 
(fasted) at baseline 
Albumin 
≤25 g/L and >25 g/L at 
baseline 
 
≤25 g/L and >25 g/L at 
baseline 
 
Reference ranges are 
same in children (6-17 
yrs. old) and adults 
≤25 g/L and >25 g/L at 
baseline 
 
                                        VV-RIM-00201802-2.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1908-1909-ALG-2102 
Statistical Analysis Plan 
 
Date: 18 August, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 70 
 
REGENERON CONFIDENTIAL 
Parameter 
Adults 
Comments for adults 
Adolescents  
(≥12 to <18) 
Comments  
for adolescents 
Combined 
Hematology 
WBC 
<3.0 Giga/L and 
≥3.0 Giga/L at baseline 
(Non-Black);  
<2.0 Giga/L and 
≥2.0 Giga/L at baseline 
(Black) 
≥16.0 Giga/L and 
< 16 Giga/L at baseline 
Increase in WBC: not 
relevant. 
*The default criteria. 
Summary by race (black 
and Non-black) are 
optional. 
 
To be interpreted only if 
no differential count 
available. 
<4.0 Giga/L and 
≥4.0 Giga/L at baseline  
>13.5 Giga/L and 
≤13.5 Giga/L at baseline 
 
<3.0 Giga/L and 
≥3.0 Giga/L at baseline 
(Non-Black); <2.0 Giga/L 
and ≥2.0 Giga/L at 
baseline (Black) 
[<4.0 Giga/L and ≥4.0 
Giga/L at baseline]  
 
≥16.0 [>13.5] Giga/L and 
< 16 [≤13.5] Giga/L at 
baseline 
Lymphocytes 
(ALC) 
>4.0 Giga/L and 
≤4.0 Giga/L at baseline  
 
<0.6 Giga/L and 
≥0.6 Giga/L at baseline  
>6.0 Giga/L and 
≤6.0 Giga/L at baseline   
 
<0.6 Giga/L and ≥0.6 
Giga/L at baseline 
(adolescents only) 
 
>4.0 [>6.0] Giga/L and 
≤4.0 [≤6.0] Giga/L at 
baseline   
Neutrophils 
<1.5 Giga/L and 
≥1.5 Giga/L at baseline 
(Non-Black);  
<1.0 Giga/L and 
≥1.0 Giga/L at baseline 
(Black) 
International Consensus 
meeting on drug-induced 
blood cytopenias, 1991. 
*The default criteria. By 
race (black and Non-
black) are optional. 
<1.2 Giga/L and 
≥1.2 Giga/L at baseline  
>ULN and baseline 
≤ ULN 
 
<1.5 Giga/L and ≥1.5 
Giga/L at baseline (Non-
Black); <1.0 Giga/L and 
≥1.0 Giga/L at baseline 
(Black) [<1.2 Giga/L and 
≥1.2 Giga/L at baseline] 
 
 >ULN and baseline 
≤ ULN (adolescents only) 
Monocytes  
>0.7 Giga/L and 
≤ 0.7 Giga/L at baseline 
 
>1.2 Giga/L and <= 
1.2 Giga/L at baseline 
 
>0.7 [>1.2] Giga/L 
<= 0.7 [≤1.2] Giga/L at 
baseline 
                                        VV-RIM-00201802-2.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1908-1909-ALG-2102 
Statistical Analysis Plan 
 
Date: 18 August, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 71 
 
REGENERON CONFIDENTIAL 
Parameter 
Adults 
Comments for adults 
Adolescents  
(≥12 to <18) 
Comments  
for adolescents 
Combined 
Basophils 
>0.1 Giga/L and 
≤ 0.1 Giga/L at baseline 
 
>0.2 Giga/L 
 
>0.1 Giga/L and 
≤ 0.1 Giga/L at baseline 
[>0.2 Giga/L] 
Eosinophils 
(>0.5 Giga/L and >ULN) 
and (≤0.5 Giga/L or 
≤ ULN at baseline) 
Harrison- Principles of 
Internal Medicine 17th 
Ed., 2008. 
(>0.5 Giga/L and >ULN) 
and (≤ 0.5 Giga/L or ≤ 
ULN at baseline) 
Harrison- Principles of 
internal Medicine 17th 
Ed., 2008. 
(>0.5 Giga/L and >ULN) 
and (≤0.5 Giga/L or 
≤ULN at baseline) 
Hemoglobin 
≤115 g/L and > 115 g/L 
at baseline for male; 
≤95 g/L and> 95 g/L at 
baseline for Female. 
≥185 g/L and <185 g/L at 
baseline for Male; 
≥165 g/L and < 165 g/L 
at baseline for Female 
Decrease from Baseline 
≥20 g/L 
Three criteria are 
independent. 
 
*The default criteria. By 
gender (male and female) 
are optional. 
 
Criteria based upon 
decrease from baseline 
are more relevant than 
based on absolute value. 
Other categories for 
decrease from baseline 
can be used (≥30 g/L, 
≥40 g/L, ≥50 g/L). 
<100 g/L and ≥100 g/L at 
baseline (or <10 g/dL and 
>10 g/dL at baseline)  
≥200 g/L and <200 g/L at 
baseline (or ≥20 g/dL and 
<20 g/dL at baseline) 
Decrease from Baseline 
≥20 g/L 
Two criteria are 
independent 
≤115 g/L and > 115 g/L 
at baseline for male; 
≤95 g/L and> 95 g/L at 
baseline for Female. 
[<100 g/L and ≥100 g/L 
at baseline] 
≥185 g/L and <185 g/L at 
baseline for Male;  
≥165 g/L and < 165 g/L 
at baseline for Female 
[≥200 g/L and <200 g/L 
at baseline] 
Decrease from Baseline 
≥20 g/L 
Hematocrit 
≤0.37 v/v and > 0.37 v/v 
at baseline for Male ; 
≤0.32 v/v and > 0.32 v/v 
at baseline for Female 
≥0.55 v/v and < 0.55 v/v 
at baseline for Male ; 
≥0.5 v/v and < 0.5 v/v at 
baseline for Female 
Two Criteria are 
independent 
 
*The default criteria. By 
gender (male and female) 
are optional. 
<0.37 v/v and ≥ 0.37 v/v 
at baseline for Male ; 
<0.33 v/v and ≥0.33 v/v 
at baseline for Female 
>0.52 v/v and ≤0.52 v/v 
at baseline for Male ; 
>0.47 v/v and ≤0.47 v/v 
at baseline for Female 
Two criteria are 
independent 
≤0.37 [<0.37] v/v and 
> 0.37 [≥ 0.37] v/v at 
baseline for Male ; 
≤0.32 [<0.33] v/v and 
> 0.32 [≥0.33] v/v at 
baseline for Female 
≥0.55 [>0.52] v/v and 
< 0.55 [≤0.52] v/v at 
baseline for Male ; 
≥0.5 [>0.47] v/v and 
< 0.5 [≤0.47] v/v at 
baseline for Female 
                                        VV-RIM-00201802-2.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1908-1909-ALG-2102 
Statistical Analysis Plan 
 
Date: 18 August, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 72 
 
REGENERON CONFIDENTIAL 
Parameter 
Adults 
Comments for adults 
Adolescents  
(≥12 to <18) 
Comments  
for adolescents 
Combined 
RBC 
<4 Tera/L and  ≥ 4 Tera/L 
at baseline for Male ; 
<3 Tera/L and  ≥ 3 Tera/L 
at baseline for Female 
≥7 Tera/L and   <7 Tera/L 
at baseline for Male ; 
≥6 Tera/L and   <6 Tera/L 
at baseline for Female 
Unless specifically 
required for particular 
drug development, the 
analysis is redundant with 
that of Hb. 
NONE 
 
<4 Tera/L and  ≥ 4 Tera/L 
at baseline for Male ; 
<3 Tera/L and  ≥ 3 Tera/L 
at baseline for Female 
≥7 Tera/L and   <7 Tera/L 
at baseline for Male ; 
≥6 Tera/L and   <6 Tera/L 
at baseline for Female 
(adults only) 
Platelets 
<100 Giga/L and 
≥100 Giga/L at baseline 
≥700 Giga/L and < 
700 Giga/L at baseline 
International Consensus 
meeting on drug-induced 
blood cytopenias, 1991. 
Two independent criteria 
<100 Giga/L and 
≥100 Giga/L at baseline 
>700 Giga/L and 
≤ 700 Giga/L at baseline 
International Consensus 
meeting on drug-induced 
blood cytopenias, 1991. 
Two independent criteria 
<100 Giga/L and ≥ 
100 Giga/L at baseline 
≥700 Giga/L and 
< 700 Giga/L at baseline 
Vital signs 
HR 
≤50 bpm and decrease 
from baseline ≥20 bpm 
≥120 bpm and increase 
from baseline≥20 bpm 
 
≤50 bpm and decrease 
from baseline ≥20 bpm 
≥120 bpm and increase 
from baseline≥20 bpm 
 
≤50 bpm and decrease 
from baseline ≥20 bpm 
≥120 bpm and increase 
from baseline≥20 bpm 
SBP  
≤95 mmHg and decrease 
from baseline ≥20mmHg 
≥160 mmHg and increase 
from baseline ≥20 mmHg 
 
Hypotension: SBP 
≤90 mmHg; and decrease 
from baseline ≥20 mmHg 
Hypertension: 
≥119 mmHg; and 
increase from baseline 
≥20 mmHg 
 
Based on definition of 
hypotension as SBP<5th 
percentile for gender, age 
and height 
 
Based on definition of  
Hypertension as average 
SBP ≥ 95th percentile for 
gender, age, and height 
on ≥ 3 occasions 
≤95 [≤90] mmHg and 
decrease from baseline 
≥20 mmHg   
 
≥160 [≥119] mmHg and 
increase from baseline 
≥20 mmHg  
                                        VV-RIM-00201802-2.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1908-1909-ALG-2102 
Statistical Analysis Plan 
 
Date: 18 August, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 73 
 
REGENERON CONFIDENTIAL 
Parameter 
Adults 
Comments for adults 
Adolescents  
(≥12 to <18) 
Comments  
for adolescents 
Combined 
DBP 
≤45 mmHg and decrease 
from baseline ≥10 mmHg 
≥110 mmHg and increase 
from baseline ≥10 mmHg 
 
Hypotension: DBP 
≤54 mmHg and 
decrease from baseline 
≥10 mmHg 
Hypertension: ≥78 mmHg  
and increase from 
baseline ≥10 mmHg 
 
Based on definition of 
Hypertension as 
average DBP ≥ 95th 
percentile for 
gender, age, and height 
on ≥ 3 occasions 
≤45 [≤54] mmHg and 
decrease from baseline 
≥10 mmHg  
≥110 [≥78] mmHg and 
increase from baseline 
≥10 mmHg  
Respiratory rate 
< 12 per minutes and 
≥12 per minute at 
baseline 
>20 per minute and 
≤20 per minute at 
baseline 
 
<12 per minute and 
≥12 per minute at 
baseline 
>20 per minute and 
≤20 per minute at 
baseline 
 
<12 per minute and 
≥12 per minute at 
baseline 
>20 per minute and 
≤20 per minute at 
baseline 
                                        VV-RIM-00201802-2.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1908-1909-ALG-2102 
Statistical Analysis Plan 
 
Date: 18 August, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 74 
 
REGENERON CONFIDENTIAL 
10.4. 
Search Criteria for TEAE of Special Interest 
AESI 
Search Criteria 
Systemic or severe hypersensitivity 
reactions  
Narrow SMQ for hypersensitivity  
Anaphylaxis will be prospectively analysised as follows: 
For SMQ “anaphylactic reaction”, an algorithmic approach will be used.  A case must include either: 
1. A narrow term (a term from Category A); 
2. Patient with both a term from Category B AND a term from Category C; 
3. Patient with a term from Category D AND { a term from Category B OR a term from Category C } 
For bullets 2 and 3, the search terms that are included under the SMQ for a particular event need to have 
the same start date (for e.g. if search shows cough (category B term) occurring at day 3 and urticaria 
(category C term) occurring at day 7, this event is not adjudicated as anaphylactic reaction as this is 
inconsistent with the clinical presentation of anaphylaxis as an acute event with simultaneous involvement 
of 2 or more body systems. 
Note:  manual adjudication of relevant PTs will be required by the study medical monitor, before database 
lock 
Asthma exacerbations  
Asthma symptoms (based on narrow SMQ for asthma) requiring treatment with systemic corticosteroids or 
resulting in an emergency room visit or hospitalization. 
 
                                        VV-RIM-00201802-2.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1908-1909-ALG-2102 
Statistical Analysis Plan 
 
Date: 18 August, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 75 
 
REGENERON CONFIDENTIAL 
10.5. 
Prohibited Medications Relevant for Analysis 
Prohibited medications as defined in Section 4.4 have been further categorized into groups based 
on their expected impact on the efficacy variables and planned data handling method: 
• Category 1 – Medications that are not expected to impact efficacy variables 
(treatment policy) 
• Category 2 – Medications that require blinded adjudication (considering factors such 
as the type of medication, indication, timing, and frequency) to determine if data 
should be handled by treatment policy, composite strategy (in the case of medications 
that are expected to impact efficacy variables and may be indiciative of treatment 
failure), or hypothetical strategy (in the case of medications that are expected to 
impact efficacy variables but are not indicative of treatment failure) 
• Category 3 – Medications that are expected to impact efficacy variables, but are not 
indicative of treatment failure (hypothethical strategy) 
These categories have been defined separately for the following groups of endpoints: 
• CSMS, TNSS, TOSS, DMS and RQLQ(S)+12 endpoints (Table 7)  
• Asthma-related endpoints (Table 8)  
• SPT endpoints (Table 9) 
 
                                        VV-RIM-00201802-2.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1908-1909-ALG-2102 
Statistical Analysis Plan 
 
Date: 18 August, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 76 
 
REGENERON CONFIDENTIAL 
Table 7: 
Prohibited medication categories for CSMS, TNSS, TOSS, DMS and 
RQLQ(S)+12 endpoints 
Category 1  
Category 2  
Treatment policy 
Adjudication to determine treatment policy, 
composite strategy, or hypothethical strategy 
1st gen, 2nd gen oral antihistamines/ intranasal 
antihistamines/ ocular antihistamines 
Corticosteroids (intra-muscular/ intra-articular/ 
extended duration implants such as intravitreal etc) 
Longer acting antihistamines (eg, Hydroxyzine/ 
Cyproheptadine) 
Oral/ IV corticosteroids 
Topical/ oral decongestants 
Systemic calcineurin inhibitors 
Intranasal anticholinergics 
SIT with any allergen other than cat 
Immune directed biologics and/or therapies that 
would interfere with Type 2 allergic disease or 
suppress the immune system, including but not 
limited to anti-IgE, anti IL-5, anti Il-4 
Specific immunotherapy (SIT) with cat allergen or 
vaccines against cat allergy 
Intranasal corticosteroids 
 
Ocular corticosteroids 
Ocular/intranasal cromoglycates 
Methylxanthines 
Leukotreine modifiers 
                                        VV-RIM-00201802-2.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1908-1909-ALG-2102 
Statistical Analysis Plan 
 
Date: 18 August, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 77 
 
REGENERON CONFIDENTIAL 
Table 8: 
Prohibited medication categories for asthma-related endpoints 
Category 1  
Treatment policy 
Category 2  
Adjudication to determine 
Treatment Policy, Composite 
Strategy, or Hypothethical 
Strategy 
Category 3  
Hypothethical Strategy 
(Multiple Imputation) 
1st gen, 2nd gen oral 
antihistamines/ intranasal 
antihistamines/ ocular 
antihistamines 
Corticosteroids (intra-muscular/ 
intra-articular/ extended duration 
implants such as intravitreal etc) 
Inhalational Corticosteroids, 
SABA/LABA/LAMA if not 
washed out within timeframes 
specified in the study protocol 
Longer acting antihistamines 
(eg, Hydroxyzine/ 
Cyproheptadine) 
Oral/ IV corticosteroids 
 
Topical/ oral decongestants 
Immune directed biologics and/or 
therapies that would interfere 
with Type 2 allergic disease or 
suppress the immune system, 
including but not limited to anti-
IgE, anti IL-5, anti Il-4 
Intranasal anticholinergics 
Specific immunotherapy (SIT) 
with cat allergen or vaccines 
against cat allergy 
Intranasal corticosteroids 
Ocular corticosteroids 
Ocular/intranasal 
cromoglycates 
Methylxanthines 
Leukotreine modifiers 
 
                                        VV-RIM-00201802-2.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1908-1909-ALG-2102 
Statistical Analysis Plan 
 
Date: 18 August, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 78 
 
REGENERON CONFIDENTIAL 
Table 9: 
Prohibited medication categories for SPT endpoints 
Category 1 
Treatment policy 
Category 2 
Adjudication to determine Treatment Policy, 
Composite Strategy or Hypothethical Strategy 
Category 3 
Hypothethical Strategy (Multiple 
Imputation) 
1st gen, 2nd gen intranasal antihistamines/ 
ocular antihistamines 
Immune directed biologics and/or therapies that 
would interfere with Type 2 
allergic disease or suppress the immune system, 
including but not limited to 
anti-IgE, anti IL-5, anti Il-4 
1st gen, 2nd gen oral antihistamines (5 day 
window) 
Topical/ oral decongestants 
Specific immunotherapy (SIT) with cat allergen or 
vaccines against cat allergy 
Longer acting antihistamines (eg, 
Hydroxyzine/ Cyproheptadine) (10 day 
window) 
Intranasal anticholinergics 
 
 
Intranasal corticosteroids 
Ocular corticosteroids 
Ocular/intranasal cromoglycates 
Methylxanthines 
Leukotreine modifiers 
Corticosteroids (intra-muscular/ intra-
articular/ extended duration implants 
such as intravitreal etc) 
Oral/ IV corticosteroids 
Systemic calcineurin inhibitors 
SIT with any allergen other than cat 
                                        VV-RIM-00201802-2.0 Approved - 19 Aug 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R1908-1909-ALG-2102 
Statistical Analysis Plan 
 
Date: 18 August, 2022 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 79 
 
REGENERON CONFIDENTIAL 
10.6. 
Additional Details on Sample Size Adjustment 
 The table below provides power and sample size calculations based on various observed values 
of standard deviation of CSMS and TNSS.  These calculations may be used as a guide if a 
sample size adjustment is deemed necessary. 
Endpoint 
(mean in 
protocol) 
Observed SD (% of 
the SD in protocol) 
Effect size 
Power with 
current planned 
sample size*± 
Sample size [% 
increase from protocol] 
required for 90% 
power*¥  
CSMS 
(9.1) 
6.2 (as assumed in 
protocol) 
0.293 
90% 
315 [as assumed in 
protocol] 
6.5 (4.8% increase) 
0.280 
87% 
346 [10%] 
6.8 (10% increase) 
0.267 
83% 
379 [20.3%] 
7.1 (15% increase) 
0.256 
80% 
413 [31.1%] 
7.4 (20% increase) 
0.246 
77% 
449 [42.5%] 
TNSS 
(3.3) 
2.3 (as assumed in 
protocol) 
0.29 
89% 
323 [2.5%] 
2.4 (4.3% increase) 
0.28 
86% 
346 [10%] 
2.5 (10% increase) 
0.26 
83% 
382 [21.3%] 
2.65 (15% increase) 
0.25 
79% 
428 [35.9%] 
2.8 (20% increase) 
0.24 
74% 
478 [51.7%] 
*: Two-sided t-test with alpha = 0.049, assuming 20% reduction from PBO (mean difference = 
1.8 for CSMS and 0.66 for TNSS)  
±:  Power assuming sample size = 251/arm (assuming 315/arm are enrolled and a 20% dropout 
rate) 
¥:  Sample size is inflated to account for a 20% drop-out rate 
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