Clinical trial NCT03838731
Conditions: Cat Allergy Mild Asthma
Sponsor: Regeneron Pharmaceuticals
Start date: 2019-02-12; Completion date: 2020-04-06
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to evaluate the prophylactic efficacy of REGN1908-1909 (anti-Fel d 1) administered as a single dose on day 1 in cat-allergic asthmatic patients not living with a cat in the prevention of a Controlled Cat Allergen Challenge-induced early asthmatic response (EAR) assessed by measures of lung function (FEV1) compared to placebo-treated patients.

Secondary Efficacy Objectives:

* To evaluate the prophylactic efficacy of REGN1908-1909 administered as a single dose on day 1 in cat-allergic asthmatic patients not living with a cat, in the prevention of a Controlled Cat Allergen Challenge-induced: Allergic rhinitis and Ocular symptoms
* To evaluate the prophylactic efficacy of REGN1908-1909 administered as a single dose on day 1 in cat-allergic asthmatic patients not living with a cat to increase the exposure to cat allergen, measured as a product of minute ventilation and time, required to induce EAR in a Controlled Cat Allergen Challenge as compared to placebo patients

Secondary Safety Objective:

* To evaluate the safety and tolerability of REGN1908-1909 vs. placebo in patients with cat allergen-triggered asthma

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: REGN1908-1909 intervention 2: Placebo
Intervention descriptions: intervention 1: Single subcutaneous (SC) dose of REGN1908 and REGN1909 intervention 2: Single subcutaneous (SC) dose of matching placebo

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
R1908-1909-ALG-1703 Amendment 2 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 88 
CONFIDENTIAL 
EudraCT Number: 2018-002477-22 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
STUDY TITLE 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study in Cat-
Allergic Patients with Asthma to Evaluate the Efficacy of a Single Dose of REGN1908-1909 to 
Reduce Bronchoconstriction Upon Cat Allergen Challenge 
Compound: 
REGN1908-1909 
Clinical Phase: 
2 
Protocol Number: 
R1908-1909-ALG-1703 
Protocol Version: 
R1908-1909-ALG-1703 Amendment 2 
Amendment 2 Date of Issue: 
See appended electronic signature page 
Amendment 1 Date of Issue: 
18 Dec 2018 
Original Date of Issue: 
16 Aug 2018 
Medical /Study Director: 
 
 
  
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
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NCT03838731


Clinical Study Protocol 
 
R1908-1909-ALG-1703 Amendment 2 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 88 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 2 
The following changes have been made based on operational considerations and input from investigators. 
The table outlines the changes made to the protocol and the affected sections: 
Change and Rationale for Change 
Section Changed 
Clarified that asthmatic and allergic symptoms that occur in 
response to the environmental exposure unit (EEU) are not to 
be reported as adverse events (AEs), as they will be recorded 
as outcome measures. However, AEs that occur in response to 
allergen exposure in the EEU that are outside of expected 
symptoms, including events which qualify as serious adverse 
events (SAEs), up to 24 hours after EEU should be reported as 
AEs and SAEs as applicable. 
Section 9.4.1 Adverse Events 
Clarified that if patients have a screening asthma control test 
(ACT) <20 at any screening visit, they may be rescheduled 
after asthma control improves (eg, if patient has transient 
upper respiratory tract infection or exposure to natural 
allergens).  Patients who are rescheduled must demonstrate 
stable asthma control by having an ACT ≥20 at 2 consecutive 
visits, separated by at least a week. 
Section 6.2.2 Exclusion Criteria, #30 
Clarified that forced expiratory volume (FEV1) will be 
monitored at home for approximately 18 hours after leaving 
the clinical unit and if there is a 30% (changed from 15%) 
drop in FEV1, the investigator(s) will receive an alarm by 
email to inform about the change in spirometry and the patient 
will be contacted and evaluated by the medical doctor. A 15% 
drop is expected with a late asthmatic response and therefore 
does not require an email message, whereas a 30% drop is 
considered a significant clinical change.  FEV1 will be 
monitored at home using a portable hand-held spirometer for 
approximately 18 hours after leaving the clinical unit (a total 
of 24 hours of monitoring from the end of the EEU exposure). 
Section 1 Introduction 
Section 7.4 Management of Acute 
Reactions 
Section 10.4.3.4 Timing of Analyses 
Added that patient reported history (for at least 2 years) of 
symptomatic cat allergen-triggered asthma will be collected. 
Section 6.2.1 Inclusion Criteria, #2 
Clarified that randomization/study drug administration must 
occur within 14 to 28 days from screening and that the cat 
allergen challenges in the EEU are separated by at least 21 
days. 
Added “This will be the final analysis of the primary 
endpoint” to the First Step Analysis section, where the first-
step analysis may be performed when the last patient 
completes day 8 of the treatment period and has undergone the 
Cat Allergen Challenge in the EEU at day 8.   
Section 8.1.1 Footnotes for the 
Schedule of Events Table, 
Footnote #2 
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Change and Rationale for Change 
Section Changed 
Added that additional spirometry may be performed when 
prompted by asthma symptoms and included further 
procedural details regarding how spirometry is conducted 
during the study. 
Section 8.2.2.4 Spirometry 
Section 8.1.1 Footnotes for the 
Schedule of Events Table, 
Footnote #5 
Clarified that postmenopausal women do not need FSH testing 
unless required to confirm their postmenopausal status. 
Pregnancy testing is not required for women with bilateral 
oophorectomy 
Clinical Study Synopsis: Procedures 
and Assessments 
Section 8.2.1 Procedures Performed 
Only at the Screening/Baseline Visit 
Section 8.2.3.6 Laboratory Testing 
Table 1 Schedule of Events 
Section 8.1.1 Footnotes for the 
Schedule of Events Table, 
Footnote #16, #26 e 
Added that in patients who receive EEU related medications 
(including medications given on-site and rescue medications 
taken at-home), the impact of the carryover of medications 
between challenges will be explored.  
Added that the time course of asthma response comprising 
early asthmatic response (EAR) and late asthmatic response 
(LAR) will be visualized and summarized 
Section 10.4.3.1 Primary Efficacy 
Analysis 
Section 10.4.3.2 Secondary Efficacy 
Analysis 
Procedural clarifications were added regarding the timing of 
the titrated skin prick test (SPT), vital signs measurements, 
physical 
examinations, 
spirometry, 
minute 
ventilation, 
fractional exhaled nitric oxide (FeNO) measurement, 
collection of nasal brushing samples, randomization, screening 
visits 1 and 2, as well as replacement of patients.   
Section 6.4 Replacements of Patients 
Table 1 Schedule of Events 
Section 8.2.2.4 Spirometry 
Section 8.1.1 Footnotes for the 
Schedule of Events Table, 
Footnotes #2, #5, #6, #8, #9, #20, 
#25 (new), #26 (new), #27 (new) 
Clarified that rescue treatment kit medications, taken at home 
within 24 hours from the EEU exposure will not be considered 
concomitant medications.  Rescue medications taken from the 
kit within 24 hours of EEU exposure will be collected 
separately. 
Section 7.8 Concomitant Medications 
Updated language per current protocol template. 
Section 2.3.3 Exploratory 
Immunogenicity Objective 
Section 4.5 Immunogenicity 
Variables 
Section 6.2.2 Exclusion Criteria #26.e  
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Change and Rationale for Change 
Section Changed 
Modifications for consistency and clarity, and administrative 
updates. 
Clinical Study Synopsis: Objectives, 
Study Design 
Section 1 Introduction 
Section 3.2.4 Rationale for Endpoints 
Section 4.6 Pharmacodynamic and 
Other Biomarker Variables 
Section 7.6 Method of Treatment 
Assignment 
Section 7.8.1 Prohibited Medications 
Table 1 Schedule of Events: Minute 
Ventilation row  
Section 8.2.6.1 Biomarkers 
Section 8.2.7.1 Genomics Study- 
(Mandatory) 
Section 9.4.4 Reporting Adverse 
Events Leading to Withdrawal from 
the Study 
Section 10.3.3 Pharmacokinetic 
Analysis Set 
Section 10.4.3.4 Timing of Analyses 
Section 10.4.5.1 Analysis of Drug 
Concentration Data 
Section 10.5 Interim Analysis 
Section 10.6 Additional Statistical 
Data Handling Conventions 
Correction of typographical, grammatical, and formatting 
errors 
Throughout the protocol 
 
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Amendment 1 
The following table outlines the changes made to the protocol and the affected sections: 
Change and Rationale for Change (listed in 
numerical order by Section) 
Section Changed  
The following exploratory objectives are added as 
they were inadvertently excluded from the 
previous version of the protocol: 
 To assess the prophylactic effect of 
REGN1908-1909 on TNSS, TOSS, and chest 
symptoms up to 24 hours after leaving the 
EEU 
 To assess the extent of REGN1908-1909 
interference with the measurement of 
endogenous anti-Fel d1 IgE in baseline 
samples and its relationship to clinical benefit 
Section 2.3.1 Exploratory Objectives 
The design rationale has been revised to clarify 
the length of serious adverse event follow-up as 
per a Health Authority request: 
The follow-up period of 16 weeks (12-week 
assessment period and then a 4-week safety 
follow-up) after the single dose of REGN1908-
1909, plus an additional 30 days of follow-up for 
any investigational drug-related SAE that occurs 
after study completion, represents a follow-up 
period of approximately 5 months, which is 
within the 4 to 5 half-life window for antibody 
levels to fall to undetectable levels. Serious 
adverse events considered by the investigator to 
be related to the investigational product are to be 
reported even if onset is greater than 30 days from 
the end of study 
Section 3.2.1 Rationale for Study Design  
Section 5.1 Study Description and Duration 
The study flow diagram schema 1 has been 
revised to clarify the duration of the exposure 
period as 12 weeks followed by 4 weeks of 
follow-up as per the Health Authority request. 
Figure 1 Study Flow Diagram Schema 1 
A subclass of serum antibodies IgA, IgG1, and 
IgG2 will not be measured due to unavailability of 
the assay methods. 
Gene Expression Analysis of Type 2 
Inflammation of Nasal Mucosa by RNAseq on 
day 85 biomarker sample will not be performed as 
the day 85 nasal brushing sample will not be 
collected. 
Section 4.6 Pharmacodynamic and Other 
Biomarker Variables 
Section 8.2.6.1 Biomarkers 
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Change and Rationale for Change (listed in 
numerical order by Section) 
Section Changed  
Screening period is revised as -85 to -14 days. 
Clarified that the cat EEU visit 3 during screening 
must be at least 3 weeks from the cat EEU visit 6 
(visits must be spaced apart by at least 3 weeks to 
avoid allergen priming). Previously the period of -
85 to -1 did not account for the required necessary 
3-week period between cat EEU visit 3 and cat 
EEU visit 6. 
Added the following clarification per the Ethics 
Committee request: The informed consent will be 
provided to the patient prior to visit 1 so that 
he/she has sufficient time to read the informed 
consent and to ask questions to the investigator.   
Study Synopsis 
Section 5 Study Design 
Section 5.1 Study Description and Duration 
An Independent data monitoring committee will 
be assembled for the study and a IDMC section 
has been added to the protocol per the Health 
Authority request. 
Section 5.2.2 Independent Data Monitoring 
Committee 
Protocol exit criteria updated as per the Health 
Authority feedback to provide explicit criteria for 
discontinuation as follows: 
 
The patient experiences a FEV1 
reduction ≥50% from the baseline 
measurement of FEV1 (before EEU 
exposure) at any time during the 
study 
 
The 
patient 
requires 
emergency 
treatment 
of 
asthma 
or 
of 
a 
hypersensitivity reaction in a hospital 
or emergency room 
 
The patient experiences a systemic 
allergic response and/or anaphylaxis 
requiring epinephrine 
Section 6.3 Premature Withdrawal from the Study 
Misplaced criterion inadvertently written as an 
inclusion criterion and moved to the exclusion 
criteria section which is what was intended: 
Revised inclusion criterion #2e to now be 
exclusion criterion #30:  
Screening asthma control test (ACT) <20 at any 
screening visits as higher scores are normal and 
lower scores suggest poorly controlled asthma 
Section 6.2.1 Inclusion criteria #2 
Section 6.2.2  Exclusion Criteria #30 
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Change and Rationale for Change (listed in 
numerical order by Section) 
Section Changed  
Exclusion criterion #17 revised to remove the 
following text: “causing TNSS >2” as this 
qualifier of significant rhinitis was confusing to 
the study site staff. 
Exclusion criteria #26 revised to clarify that the 
duration 
of 
the 
use 
of 
highly 
effective 
contraception methods is at least 6 months after 
the last dose of study drug in women of 
childbearing potential per the Health Authority 
request. 
Exclusion criterion #27 describing requirements 
for 
male 
contraception 
added 
to 
ensure 
consistency with the Investigator's Brochure 
language. 
Section 6.2.2 Exclusion Criteria, #17, #26, and 
#27 
Added the following text to clarify the study 
activities in the case that the patient has received 
the 1 dose of study drug but who then opts out of 
study-related EEU challenges: 
Patients who opt out of EEU challenges after 
receipt of study drug and who do not withdraw 
from the study will be asked to return to the clinic 
for all remaining study visits per the visit schedule 
except for EEU exposures and EEU related 
procedures (see Section 8 ) 
Section 7.3.2 Study Drug Discontinuation 
Following text added in reference to the criteria 
for discharge from the unit to home per the Health 
Authority request:  
Otherwise, in case of FEV1 is <90% of the 
baseline value, patients will continue to be 
monitored at the clinic until the patient meets 
criteria for discharge 
Section 7.4 Management of Acute Reactions 
Section 8.2.2.4 Spirometry 
The following text deleted; “Randomization will 
be stratified according to visit date”.   
In original study design, randomization was 
stratified such that the patients who are in the 
EEU together at the same time are equally 
allocated to drug and placebo; however, there 
were logistical difficulties in achieving this 
consistently throughout the study.  As there are 4 
Cat EEU visits after randomization, each with a 
visit window of ±3 days, it is not possible to 
ensure that the group of patients who complete the 
Cat EEU visits together will be the same for each 
of the visits.  Therefore, the randomization will 
not be stratified. 
Section 7.5 Method of Treatment Assignment 
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Change and Rationale for Change (listed in 
numerical order by Section) 
Section Changed  
Following clarifications added: 
Nasal brushing samples will be collected 6 hours 
from the start of the EEU challenge instead of 
after the EEU challenge. Phrase “from the start” 
was added. 
Nasal brushing sample collection frequency has 
been updated to eliminate sample collection at day 
85.   
Currently, the induction of type-2 response in the 
nasal epithelium after chamber exposure has not 
yet been fully established. This would be the first 
time that Sponsor will test the gene expression 
changes as exploratory biomarkers post chamber 
exposure for cat dander. In previous studies for 
cat 
allergy 
with 
neutralizing 
antibodies 
(REGN1908-1909-ALG-1325), 
maximal 
suppression of clinical symptoms after nasal 
allergen challenge was observed on day 29 after 
dosing.  Comparison of expression changes 
between baseline and day 29 provides the best 
opportunity to detect this inflammatory response 
and assess how these changes correlate with 
clinical response.  
Section 8.2.6.1 Biomarkers  
Section 2.3.1 Exploratory Efficacy Objectives 
Serum samples from patients obtained before drug 
exposure will be tested in an in-vitro competition 
assay to assess whether REGN1908-1909 can 
inhibit the binding of endogenous anti-fel-d1 IgE 
to the allergen 
Section 8.2.6.1 Biomarkers (Interference Assay 
with REGN1908-1909) 
Following clarification added: 
Serum allergen-specific IgE levels (cat hair, Fel d 
1) will be measured at screening visit 1 and as 
described in schedule of events Table 1. 
Section 8.2.6.1 Biomarkers 
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Change and Rationale for Change (listed in 
numerical order by Section) 
Section Changed  
Following edits/clarifications were done: 
Revised text: The challenge will not proceed if 
patients have a TNSS greater than 4, an asthma 
control test (ACT) score <20 at any of the 
screening visits, or FEV1 of less than 70% of 
predicted value.   
Following text added in reference to the criteria 
for discharge from the unit to home per the Health 
Authority request: 
At the end of the 6-hour monitoring period, 
patients are discharged home if FEV1 ≥90% of 
the baseline value. 
In schedule of events table, screening days was 
revised to "-85 to -14" instead of days "-85 to -1" 
to clarify that cat EEU visit 3 and visit 6 must be 
spaced at least 3 weeks apart to prevent a priming 
effect of visit 3 on visit 6. 
Skin prick test with serial allergen titration (CAT 
SPT) will be performed at Cat EEU visit 3 instead 
of Cat EEU visit 2. 
Footnote #1 revised to add “-85 to -14” 
Footnote #5 revised as follows: FEV1 will be 
performed at baseline prior to entry into the EEU, 
every 10 minutes during the EEU exposure, every 
30 minutes in the observation room for 6 hours 
after leaving the EEU, and then every hour for 18 
hours after EEU exposure, except during sleeping.   
Footnote # 6 revised as follows: TNSS, TOSS, 
and chest symptom questions are assessed prior to 
Cat Allergen Challenge, approximately every 20 
minutes during the challenge in the exposure unit, 
every 1 hour for 6 hours post-challenge while 
patients are being observed in the observation 
room, and then every 2 hours up to 18 hours after 
EEU exposure, while they are home, except for 
the time that they are sleeping.  Further details are 
provided in the study manual. 
“Fel d 1” deleted from footnote #4 as a skin prick 
test specific for Fel d 1 is currently not available. 
Footnote #7 clarified as follows: PNIF is assessed 
prior to Cat Allergen Challenge, approximately at 
the time of the EAR, and approximately 6 hours 
post-challenge while patients are being observed 
in the observation room.  Further details are 
provided in the study manual. 
Clinical Study Protocol - Synopsis: Study Design 
Section 8.1.1 Footnotes for the Schedule of 
Events Table  
Table 1: Schedule of Events  
Section 5.1 Study Description and Duration 
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Change and Rationale for Change (listed in 
numerical order by Section) 
Section Changed  
Footnote#8 revised to add the following text: 
Titrated skin prick test will be performed prior to 
EEU exposure at all visits. 
Footnote #20 Following clarification added:  Vital 
signs and spirometry will be collected once per 
hour. AEs will be collected during the observation 
period. 
Footnote #22 added to the Schedule of Events 
Table to clarify that blood draws should be 
performed before the EEU exposure 
Footnote #23 added to clarify that cat EEU visit 3 
and visit 6 must be spaced at least 3 weeks apart 
to prevent a priming effect of visit 3 on visit 6. 
A 
new 
footnote 
#24 
added 
as 
follows: 
Assessments and procedures at the unscheduled 
visit(s) are to be performed at the discretion of the 
principle investigator. 
Serum samples for specific IgE for Fel d 1 and cat 
hair will not be collected at early termination, end 
of study, and any unscheduled visits as there is no 
EEU exposure at these visits.  
Serum samples for sIgE (Fel-D 2, 4, 7) tests will 
not be collected at early termination, end of study, 
and any unscheduled visits as there is no EEU 
exposure at these visits.  
Following text deleted: “or within 30 days of last 
study drug administration”  
Section 9.4.2 Serious Adverse Events 
It is clarified that pregnancy reporting to the 
sponsor should be within 6 months (not 84 days) 
of the last dose of the study drug 
Section 9.4.3 Other Events that Require 
Accelerated Reporting to Sponsor 
Minor editorial changes 
Throughout the protocol 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-
Group Study in Cat-Allergic Patients with Asthma to Evaluate the 
Efficacy of a Single Dose of REGN1908-1909 to Reduce 
Bronchoconstriction Upon Cat Allergen Challenge 
Site Location(s) 
Principal Investigator 
France 
Professor Frédéric de Blay 
Objective(s) 
Primary Objective: To evaluate the prophylactic efficacy of 
REGN1908-1909 (anti- Felis catus [domestic cat] allergen 1 [Fel d 
1]) administered as a single dose on day 1 in cat-allergic asthmatic 
patients not living with a cat in the prevention of a Controlled Cat 
Allergen Challenge-induced early asthmatic response (EAR) assessed 
by measures of lung function (Forced expiratory volume in 1 second: 
FEV1) compared to placebo-treated patients on day 8. 
Secondary Objectives:  
Secondary Efficacy Objectives 
 
To evaluate the prophylactic efficacy of REGN1908-1909 
administered as a single dose on day 1 in cat-allergic 
asthmatic patients not living with a cat, in the prevention of a 
Controlled Cat Allergen Challenge-induced: 
o Early asthmatic response (EAR) assessed by 
measures of lung function (FEV1) compared to 
placebo-treated patients on days 29, 57, and 85 
o Allergic rhinitis symptoms assessed by total nasal 
symptom score (TNSS) compared to placebo patients 
on days 8, 29, 57, and 85 
o Ocular symptoms assessed by total ocular symptom 
score (TOSS) compared to placebo patients on days 
8, 29, 57, and 85 
 
To evaluate the prophylactic efficacy of REGN1908-1909 
administered as a single dose on day 1 in cat-allergic 
asthmatic patients not living with a cat to increase the 
exposure to cat allergen, measured as a product of minute 
ventilation and time, required to induce EAR in a Controlled 
Cat Allergen Challenge (40 ng/m3 Fel d 1 allergen x minute 
ventilation x time) as compared to placebo patients on 
days 8, 29, 57, and 85 
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Secondary Safety Objective 
To evaluate the safety and tolerability of REGN1908-1909 vs. 
placebo in patients with cat allergen-triggered asthma.  
Study Design 
This is a phase 2, randomized, double-blind, parallel-group, single-
dose study in approximately 60 cat-allergic patients with mild asthma 
(Global initiative for asthma stage 1 [GINA stage 1]), who are not 
living with a cat, to evaluate the efficacy of a single 600 mg SC 
prophylactic dose of REGN1908-1909 in the prevention of a 
Controlled Cat Allergen Challenge-induced EAR as assessed by 
FEV1 and compared to placebo-treated patients.   
This single-site study will incorporate specialized safety monitoring 
appropriate for a design that intends to induce reductions in FEV1 in 
a population with mild asthma. 
The study consists of up to a 12-week screening period followed by 
1:1 randomization on day 1 to receive 600 mg REGN1908-1909 or 
placebo administered SC in eligible patients followed by a 12-week 
assessment period and a 4-week safety follow-up period.  During 
screening, patients undergo a 2-hour placebo exposure in an 
environmental exposure unit (EEU), a state-of-the-art windowed 
ISO 8 cleanroom with 20 seats, located in Nouvel Hôpital Civil in 
Strasbourg, France.  While comfortably seated in the EEU, patients 
undergo spirometry every 10 minutes using portable spirometers 
which convey data in real time to the clinical monitoring room 
adjacent to the EEU.  Patients with nonspecific bronchial 
hyperreactivity in the placebo EEU exposure, defined as those who 
experience an FEV1 reduction >10% on 3 consecutive occasions 
while undergoing spirometry every 10 minutes, will be excluded from 
continuing in the study.  Patients who are not excluded after the 
placebo exposure will undergo a baseline 2-hour Controlled Cat 
Allergen Challenge.   
During the Cat Allergen Challenge, standardized cat allergen extract 
(40 ng/m3) is continuously nebulized into the EEU and patients 
perform spirometry every 10 minutes until they experience 
bronchoconstriction, when their FEV1 is reduced by ≥20%, defined 
as an EAR.  Patients leave the EEU once they achieve an EAR, and 
they are then monitored outside of the EEU in an observation room 
for 6 hours.  Patients who fail to achieve an EAR within 2 hours in 
the baseline Cat Allergen Challenge in the EEU will be excluded 
from the study.  During the time they are in the EEU, they record 
their TNSS, a validated, patient-reported, composite symptom 
assessment of congestion, itching, rhinorrhea, and sneezing, and 
TOSS, a validated, patient-reported, composite symptom assessment 
of ocular symptoms (itching, redness, tearing, and swelling) using 
handheld tablets every 20 minutes.  During the 6-hour observation 
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period after leaving the EEU, FEV1 is measured every 30 minutes to 
assess for a late asthmatic response (LAR), defined as a delayed drop 
of 15% after exiting the EEU.  During the 6-hour observation period, 
TNSS, TOSS, and chest symptom questions are recorded every hour.  
At the end of the 6-hour monitoring period, patients are discharged 
home if FEV1 ≥90% of the baseline value; if FEV1 is <90% of the 
baseline value, patients will continue to be monitored at the clinic 
until the patient meets criteria for discharge.  FEV1 is monitored 
during 6 hours after the EEU session using portable spirometers, and 
patients are followed up 18 hours after leaving the clinical unit.  
Patients meeting eligibility criteria are randomized to a single dose of 
REGN1908-1909 (600 mg SC) or placebo.  Patients then return to the 
study site to undergo a 4-hour Cat Allergen Challenge in the EEU on 
days 8, 29, 57, and 85 with a 6-hour observation period, at which time 
EAR, TNSS, and TOSS are assessed using the same time points that 
were used at baseline.  Exploratory measures are also assessed at 
baseline and throughout the study, as detailed in the exploratory 
objectives section.  
Study Duration 
The duration of the study for a patient is approximately 16 weeks, 
excluding the screening period. 
End of Study Definition 
The end of study for this study is defined as the last visit of the last 
patient. 
Population 
 
 
Sample Size: 
Approximately 60 patients with GINA 1 asthma sensitized to cat 
allergen.  
 
Target Population: 
Male and female adult patients 18 to 65 years inclusive not living 
with a cat, with cat allergy, as determined by history and positive skin 
prick test (SPT) to cat hair extract and positive anti-Fel d 1 and cat 
hair IgE, and whose asthma with allergic rhinitis (AR) with or 
without conjunctivitis symptoms are triggered by cat exposure. 
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
REGN1908-1909 
Single 600 mg subcutaneous (SC) dose (300 mg of each mAb 
[REGN1908 and REGN1909]) 
 
Placebo 
 
Route/Schedule: 
Matching placebo 
Subcutaneous 
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Endpoint(s) 
 
 
Primary: 
Time to EAR upon Controlled Cat Allergen Challenge in an EEU on 
day 8 
 
Secondary: 
 
Time to EAR upon Controlled Cat Allergen Challenge in 
an EEU on days 29, 57, and 85 
 
AUC of the percent change (%/h) in FEV1 induced by a 
Controlled Cat Allergen Challenge over the exposure 
interval (%/h) from baseline to the Controlled Cat 
Allergen Challenge on days 8, 29, 57, and 85 
 
AUC of the percent change (%/h) in patient-assessed 
nasal symptoms induced by a Controlled Cat Allergen 
Challenge over the exposure interval (%/h) from baseline 
to the Controlled Cat Allergen Challenge on days 8, 29, 
57, and 85  
 
AUC of the percent change (%/h) in patient-assessed 
ocular symptoms induced by a Controlled Cat Allergen 
Challenge over the exposure interval (%/h) from baseline 
to the Controlled Cat Allergen Challenge on days 8, 29, 
57, and 85 
 
Change and percent change in cat allergen quantity as 
experienced by patients during exposure (measured by 
40 ng/m3 x minute ventilation x time) on days 8, 29, 57, 
and 85 
 
Incidence rates of treatment-emergent adverse events 
(TEAEs) and serious TEAEs through end of study  
Procedures and Assessments 
The following procedures and assessments will be performed for the 
purpose of determining study eligibility, characterizing the baseline 
population, safety monitoring, or determining efficacy:   
 
Demographics, medical history 
 
Screening for human immunodeficiency virus (HIV), 
screening for hepatitis (HBsAg and hepatitis C antibody), 
follicle-stimulating hormone (FSH) determination (for 
postmenopausal women if postmenopausal status is in 
question), spirometry including FEV1, and electrocardiogram 
(ECG), screening skin prick test (SPT), placebo challenge in 
EEU, and Controlled Cat Allergen Challenge in EEU 
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Patients who meet all inclusion criteria and none of the exclusion 
criteria are dosed on Day 1. 
 
Safety Procedures will include vital signs, physical exams, 
spirometry, ECG, and laboratory testing 
 
Efficacy procedures will include spirometry (including 
FEV1), peak nasal inspiratory flow (PNIF), TNSS, TOSS, 
and chest symptom questions 
 
Pharmacokinetic (PK) procedures will include sample 
collection and assessment of serum concentration of 
REGN1908-1909 
 
Anti-drug antibody (ADA) procedures include sample 
collection for status (positive or negative) and titer 
 
A 
genomic 
DNA 
sample 
will 
be 
collected 
for 
pharmacogenetic analyses 
 
Biomarker procedures will include:  
o Serum total and allergen-specific IgE levels (cat hair, Fel 
d 1, Fel d 2, Fel d 4, Fel d 7) 
o Standard SPT with cat hair extract and other common 
allergens  
o Skin prick test with serial allergen titration with cat 
allergen 
o Fractional exhaled nitric oxide (FeNO) 
o Nasal brushing for exploratory transcriptome analysis 
Statistical Plan 
Patients will be randomized (1:1) to receive placebo or REGN1908-
1909.  The primary endpoint is the time to EAR during the day 8 
Controlled Cat Allergen Challenge.  If a patient remains in the EEU 
for the maximum time of 4 hours without experiencing an EAR, their 
time to EAR will be censored at 4 hours. Censoring implies that the 
time to EAR is at least 4 hours, but the exact time is unknown. The 
statistical model will be a Cox’s proportional hazards model to 
compare the hazard ratio of EAR on day 8 in REGN1908-1909-
treated patients compared to placebo-treated patients, which allows 
for the patients’ time to EAR during the baseline Cat Allergen 
Challenge to be adjusted for as a covariate.  Under this model, the 
hazard ratio is directly related to the ratio of median duration of 
tolerated exposure, where a hazard ratio of 1 implies that the median 
duration of tolerated exposure in the 2 treatment groups is the same.   
With 30 patients per treatment group, an increase in median time to 
EAR from 58 minutes in the placebo treated patients to 132 minutes 
in patients treated with REGN1908-1909 (ratio of median duration of 
tolerated exposure of 2.25 or, equivalently, hazard ratio of 0.44) can 
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be detected with 84% power assuming a one-sided type I error of 0.05 
and a 13% drop-out rate (8 patients).  The ratio of median duration of 
tolerated exposure of 2.25 is based on the estimated effect size in 
median duration of tolerated exposure observed in a previously 
reported Cat Allergen Challenge study.  The sample size calculation 
was performed based on the log-rank test comparing the duration of 
tolerated exposure of 2 groups with the above-mentioned 
assumptions.  The primary analysis will be conducted on the full 
analysis set (FAS) population, which consists of randomized patients.  
Efficacy analyses will also be performed on a secondary population, 
the per-protocol population, as will be discussed in the Statistical 
Analysis Plan (SAP). 
The time to EAR for each treatment will be examined using Kaplan 
Meier estimates, with patients being censored at 4 hours if they did 
not experience an EAR.  The median time to EAR for each treatment 
group and the corresponding 95% confidence intervals will be 
presented for Controlled Cat Allergen Challenges on days 8, 29, 57, 
and 85. A formal comparison of time to EAR in the treatment groups 
at day 8 will be performed using a Cox’s proportional hazards model, 
adjusting for allergen exposure and time to EAR in the baseline 
Controlled Cat Allergen Challenge. Similar comparisons will be 
made at days 29, 57, and 85 as secondary analyses. 
With 60 cat-allergic patients, the study has adequate power to detect 
differences in the key secondary endpoint:  AUC of percent change in 
FEV1 from baseline Controlled Cat Allergen Challenge in placebo 
and REGN1908-1909, based on estimated effect sizes from a 
previous Cat Allergen Challenge study.  Specifically, there is 88% 
power to detect a difference in the mean AUC of 27% in the placebo-
treated patients compared to 15% in REGN1908-1909-treated 
patients. 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AR 
Allergic rhinitis 
ARISg 
Pharmacovigilance and clinical safety software system 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CPK 
Creatinine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
EAR 
Early asthmatic response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EEU 
Environmental exposure unit 
EPR 
Early phase reaction 
FAS 
Full analysis set 
FEV1 
Forced expiratory volume in 1 second  
Fel d 1 
Felis catus (domestic cat) allergen 1  
FeNO 
Fractional exhaled nitric oxide 
FDA 
Food and Drug Administration 
FIH 
First in human 
GINA 
Global initiative for asthma 
GCP 
Good clinical practice 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgG 
Immunoglobulin G 
IgE 
Immunoglobulin E  
INS 
Intranasal corticosteroids 
IRB 
Institutional Review Board 
kAU/L 
Kilo allergy units per liter 
LAR 
Late asthmatic response 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model repeated measures 
NAC 
Nasal allergen challenge  
PBMC 
Peripheral blood mononuclear cell 
PCSV 
Potentially clinically significant value 
PNIF 
Peak nasal inspiratory flow 
PK 
Pharmacokinetics 
POM 
Proof of mechanism 
PPS 
Per protocol analysis set 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SC 
Subcutaneous 
SIT 
Systemic immunotherapy 
SMT 
Safety monitoring team 
SOC 
System organ class 
SPT 
Skin prick test 
SQU 
Square units 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TNSS 
Total nasal symptom score 
TOSS 
Total ocular symptom score 
WBC 
White blood cell 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................17 
1. 
INTRODUCTION ......................................................................................................25 
2. 
STUDY OBJECTIVES ..............................................................................................29 
2.1. 
Primary Objective .......................................................................................................29 
2.2. 
Secondary Objective(s) ...............................................................................................29 
2.3. 
Exploratory Objective(s) ............................................................................................30 
2.3.1. 
Exploratory Efficacy Objectives .................................................................................30 
2.3.2. 
Exploratory Pharmacokinetic Objective .....................................................................31 
2.3.3. 
Exploratory Immunogenicity Objective .....................................................................31 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................31 
3.1. 
Hypothesis ..................................................................................................................31 
3.2. 
Rationale .....................................................................................................................31 
3.2.1. 
Rationale for Study Design .........................................................................................31 
3.2.2. 
Environmental Exposure Unit ....................................................................................32 
3.2.3. 
Rationale for Dose Selection ......................................................................................32 
3.2.4. 
Rationale for Endpoints ..............................................................................................33 
4. 
STUDY VARIABLES................................................................................................35 
4.1. 
Demographic and Baseline Characteristics ................................................................35 
4.2. 
Primary and Secondary Endpoints..............................................................................35 
4.3. 
Exploratory Efficacy Variable ....................................................................................35 
4.4. 
Pharmacokinetic Variables .........................................................................................36 
4.5. 
Immunogenicity Variables ..........................................................................................36 
4.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................36 
5. 
STUDY DESIGN .......................................................................................................37 
5.1. 
Study Description and Duration .................................................................................37 
5.1.1. 
End of Study Definition ..............................................................................................40 
5.1.2. 
Planned Interim Analysis ............................................................................................40 
5.2. 
Study Committees .......................................................................................................40 
5.2.1. 
Safety Monitoring Team .............................................................................................40 
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5.2.2. 
Independent Data Monitoring Committee ..................................................................41 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............41 
6.1. 
Number of Patients Planned .......................................................................................41 
6.2. 
Study Population .........................................................................................................41 
6.2.1. 
Inclusion Criteria ........................................................................................................41 
6.2.2. 
Exclusion Criteria .......................................................................................................42 
6.3. 
Premature Withdrawal from the Study .......................................................................44 
6.4. 
Replacement of Patients .............................................................................................45 
7. 
STUDY TREATMENTS............................................................................................45 
7.1. 
Investigational and Reference Treatments ..................................................................45 
7.2. 
Rescue Treatment(s) ...................................................................................................45 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................45 
7.3.1. 
Dose Modification ......................................................................................................45 
7.3.2. 
Study Drug Discontinuation .......................................................................................46 
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................46 
7.4. 
Management of Acute Reactions ................................................................................46 
7.5. 
Blinding ......................................................................................................................47 
7.5.1. 
Emergency Unblinding ...............................................................................................47 
7.6. 
Method of Treatment Assignment ..............................................................................47 
7.7. 
Treatment Logistics and Accountability .....................................................................48 
7.7.1. 
Packaging, Labeling, and Storage ..............................................................................48 
7.7.2. 
Supply and Disposition of Treatments .......................................................................48 
7.7.3. 
Treatment Accountability ...........................................................................................48 
7.7.4. 
Treatment Compliance ................................................................................................48 
7.8. 
Concomitant Medications ...........................................................................................48 
7.8.1. 
Prohibited Medications ...............................................................................................49 
7.8.2. 
Permitted Medications ................................................................................................50 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................50 
8.1. 
Schedule of Events .....................................................................................................50 
8.1.1. 
Footnotes for the Schedule of Events Table ...............................................................55 
8.1.2. 
Early Termination Visit ..............................................................................................57 
8.1.3. 
Unscheduled Visits .....................................................................................................57 
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8.2. 
Study Procedures ........................................................................................................57 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................57 
8.2.2. 
Efficacy Procedures ....................................................................................................57 
8.2.2.1. 
Total Nasal Symptom Score .......................................................................................57 
8.2.2.2. 
Total Ocular Symptom Score .....................................................................................57 
8.2.2.3. 
Chest Symptoms Questions ........................................................................................57 
8.2.2.4. 
Spirometry ..................................................................................................................57 
8.2.2.5. 
Fractional Exhaled Nitric Oxide .................................................................................58 
8.2.2.6. 
Peak Nasal Inspiratory Flow .......................................................................................58 
8.2.2.7. 
Skin Prick Test with Serial Allergen Titration ...........................................................58 
8.2.3. 
Safety Procedures .......................................................................................................58 
8.2.3.1. 
Vital Signs ..................................................................................................................58 
8.2.3.2. 
Physical Examination .................................................................................................59 
8.2.3.3. 
Asthma Control Test ...................................................................................................59 
8.2.3.4. 
Telephone Call ............................................................................................................59 
8.2.3.5. 
Electrocardiogram .......................................................................................................59 
8.2.3.6. 
Laboratory Testing ......................................................................................................59 
8.2.4. 
Drug Concentration and Measurements .....................................................................60 
8.2.5. 
Anti-Drug Antibody Measurements and Samples ......................................................61 
8.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................61 
8.2.6.1. 
Biomarkers ..................................................................................................................61 
8.2.6.2. 
Environmental Cat Hair Density ................................................................................62 
 
 
8.2.7.1. 
Genomics Study (Mandatory) .....................................................................................62 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................63 
9.1. 
Obligations of Investigator .........................................................................................63 
9.2. 
Obligations of Sponsor ...............................................................................................63 
9.3. 
Definitions ..................................................................................................................63 
9.3.1. 
Adverse Event .............................................................................................................63 
9.3.2. 
Serious Adverse Event ................................................................................................64 
9.3.3. 
Adverse Events of Special Interest .............................................................................64 
9.4. 
Recording and Reporting Adverse Events ..................................................................64 
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9.4.1. 
Adverse Events ...........................................................................................................64 
9.4.2. 
Serious Adverse Events ..............................................................................................65 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................65 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................65 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................66 
9.4.6. 
Follow-up ....................................................................................................................66 
9.5. 
Evaluation of Severity and Causality .........................................................................66 
9.5.1. 
Evaluation of Severity ................................................................................................66 
9.5.2. 
Evaluation of Causality ...............................................................................................67 
9.6. 
Safety Monitoring .......................................................................................................69 
9.7. 
Investigator Alert Notification ....................................................................................69 
10. 
STATISTICAL PLAN................................................................................................69 
10.1. 
Statistical Hypothesis ..................................................................................................70 
10.2. 
Justification of Sample Size........................................................................................70 
10.3. 
Analysis Sets ...............................................................................................................71 
10.3.1. 
Efficacy Analysis Sets ................................................................................................71 
10.3.2. 
Safety Analysis Set .....................................................................................................71 
10.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................71 
10.3.4. 
Anti-Drug Antibody Analysis Sets .............................................................................71 
10.4. 
Statistical Methods ......................................................................................................71 
10.4.1. 
Patient Disposition ......................................................................................................72 
10.4.2. 
Demography and Baseline Characteristics .................................................................72 
10.4.3. 
Efficacy Analyses .......................................................................................................72 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................72 
10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................73 
10.4.3.3. 
Multiplicity Considerations ........................................................................................73 
10.4.3.4. 
Timing of Analyses .....................................................................................................73 
10.4.4. 
Safety Analysis ...........................................................................................................73 
10.4.4.1. 
Adverse Events ...........................................................................................................74 
10.4.4.2. 
Other Safety ................................................................................................................74 
10.4.4.3. 
Treatment Exposure ....................................................................................................75 
10.4.4.4. 
Treatment Compliance ................................................................................................75 
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10.4.5. 
Pharmacokinetics ........................................................................................................75 
10.4.5.1. 
Analysis of Drug Concentration Data .........................................................................75 
10.4.5.2. 
Analysis of Pharmacokinetic Parameters ...................................................................75 
10.4.6. 
Analysis of Immunogenicity Data ..............................................................................75 
10.4.7. 
Exposure-Response Analysis......................................................................................75 
10.5. 
Interim Analysis ..........................................................................................................75 
10.6. 
Additional Statistical Data Handling Conventions .....................................................76 
10.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........76 
10.8. 
Data Management and Electronic Systems ................................................................76 
10.8.1. 
Data Management .......................................................................................................76 
10.8.2. 
Electronic Systems ......................................................................................................77 
11. 
STUDY MONITORING ............................................................................................77 
11.1. 
Monitoring of Study Sites ...........................................................................................77 
11.2. 
Source Document Requirements ................................................................................77 
11.3. 
Case Report Form Requirements ................................................................................77 
12. 
AUDITS AND INSPECTIONS .................................................................................78 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................78 
13.1. 
Good Clinical Practice Statement ...............................................................................78 
13.2. 
Patients Confidentiality and Data Protection ..............................................................79 
13.3. 
Ethics Committee ........................................................................................................79 
14. 
PROTOCOL AMENDMENTS ..................................................................................80 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................80 
15.1. 
Premature Termination of the Study ...........................................................................80 
15.2. 
Close-Out of a Site ......................................................................................................80 
16. 
STUDY DOCUMENTATION ...................................................................................81 
16.1. 
Certification of Accuracy of Data ...............................................................................81 
16.2. 
Retention of Records ..................................................................................................81 
17. 
DATA QUALITY ASSURANCE ..............................................................................81 
18. 
CONFIDENTIALITY ................................................................................................82 
19. 
FINANCING AND INSURANCE .............................................................................82 
20. 
PUBLICATION POLICY ..........................................................................................82 
21. 
REFERENCES ...........................................................................................................83 
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22. 
INVESTIGATOR’S AGREEMENT ..........................................................................87 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................88 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................51 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram Schema 1 ..................................................................................38 
Figure 2: 
Study Flow Diagram Schema 2 ..................................................................................39 
 
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1. 
INTRODUCTION  
Cat allergens are among the most important indoor allergens and a common cause of Type 1 
(IgE-mediated) allergic disease worldwide, affecting 10 to 15% of patients with allergic 
rhinoconjunctivitis and/or asthma.  Felis catus (domestic cat) allergen 1 (Fel d 1) in cat hair is 
produced by the skin and by salivary and lacrimal glands of the cat (Kleine-Tebbe, 1993) 
(Gronlund, 2010).  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.  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) (Neisler, 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).  Therefore, it is difficult to avoid exposure to cat hair allergen in the 
environment. 
Nasal and eye symptoms are the most frequently reported and most bothersome of all cat allergy 
symptoms.  Rhinoconjunctivitis is treated with antihistamines and intranasal corticosteroids 
(INS), which are only moderately effective for nasal symptoms (Ciprandi, 2011).  The best 
reported treatment effects for antihistamines and INS are 5 to 11% relative reduction of total 
nasal symptoms compared to placebo (Durham, 2016).  Intranasal corticosteroids are considered 
ineffective for allergic eye symptoms. 
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 (Perzanowski, 2016) 
(Olivieri, 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 (Zuberbier, 2010) (Walker, 2011).  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 on mast cell and basophil surfaces, thereby 
effectively preventing early phase allergic symptoms (Kundig, 2010) (James, 2011).  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 (Leung, 2010) (Durham, 2012) (Scadding 2017). 
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REGN1908 and REGN1909 are monoclonal antibodies (mAbs), which bind independently and 
non-competitively to the Fel d 1 allergen and are being developed as a 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 60–90% of the total allergenic activity in cat dander (Kleine-Tebbe, 1993). 
These fully human, high-affinity IgG4 monoclonal antibodies 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 42% improvement in TNSS (total nasal symptom score) nasal challenge response 
8 days after REGN1908-1909 administration, compared with placebo. 
This magnitude of effect is approximately 2-fold above what was observed in a natural-exposure, 
perennial allergic rhinoconjunctivitis study with intranasal corticosteroids (Wu, 2013). The effect 
of REGN1908-1909 on a local response to a nasal allergen challenge could also be observed 
4 weeks post-dose, with some patients continuing to show improvement 12 weeks post-dose. In 
addition, REGN1908-1909 was well tolerated, with no anaphylaxis or evidence of systemic 
hypersensitivity. 
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 native 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. 
This phase 2 study (R1908-1909-ALG-1703) aims to investigate the prophylactic effect of 
REGN1908-1909 to reduce bronchoconstriction in cat-allergic patients with mild asthma when 
exposed to cat allergen in a controlled environmental exposure unit (EEU).  Environmental 
exposure units are enclosed spaces that control temperature, air flow, and humidity, and provide 
diffuse allergen exposure to simulate natural circumstances. Because EEUs provide allergen 
exposures which are standardized and reproducible, they have been developed for the 
investigation of mechanisms and treatment of allergies (Pfaar, 2017).  Globally to date, one EEU 
clinical trial site has been developed and validated to study asthmatic responses to cat allergen 
exposures, namely Alyatec in Strasbourg, France.  Alyatec is an independent, clinical trial unit 
situated in the Nouvel Hôpital Civil, directed by pulmonologist and allergist Dr. Frédéric De 
Blay.  The EEU is optimally designed to study patients with asthma upon allergen exposure with 
real-time electronic monitoring of FEV1 using hand-held spirometers (Medical International 
Research Spirobank II) and continuous, direct visualization of patients by clinic staff.  
Additionally, medications to treat asthma, allergy, and anaphylaxis are readily available, and the 
hospital emergency room is within the same hospital building as Alyatec in case of emergency.   
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Alyatec has performed a validation study in the EEU, evaluating 20 patients with cat allergy (by 
history, positive skin prick test, and positive IgE) and mild asthma, defined by the Global 
Initiative for Asthma stage 1 (GINA 1:  asthma symptoms are controlled with short-acting beta 
agonists as needed, asthma symptoms are rare, there is no night awakening due to asthma, no 
exacerbations in the last year, and normal FEV1) (Bateman , 2008), as well as 10 patients with 
GINA 1 asthma and other allergies, but not cat allergy (by history, negative skin prick test to cat, 
and negative IgE to cat hair, and positive skin prick test and IgE to other allergens, eg, mite, 
grass, birch, or ash).  All 30 patients were exposed continuously to nebulized cat allergen 
(40 ng/m3 Fel d 1) in the EEU for a maximum of 2 hours.  Patients underwent spirometry with 
FEV1 testing every 10 minutes during the EEU exposure and were removed from the EEU when 
they experienced bronchoconstriction, when their FEV1 was reduced by ≥20%, defined as an 
EAR.  Patients were then monitored outside of the EEU for 6 hours to assess if/when a late 
asthmatic response (LAR) occurred, defined as a delayed drop of 15% after exiting the allergen 
exposure in the EEU.  Fifty percent (50%) of patients achieved an EAR within 2 hours of EEU 
exposure and of those who achieved an EAR, approximately 50% of those achieved a LAR.  The 
mean reduction in FEV1 during EAR and LAR was -28.1% range (-20.2 to -44.6) and -19.5% 
range (-14.9 to -23.5) respectively.  Patients experienced EARs as early as within 30 minutes of 
exposure in the EEU to as late as 121 minutes; the mean time to an EAR was 60 minutes and the 
mean time to a LAR was 180 minutes (Radu, 2018) (Gherasim, 2018).  None of the non-cat-
allergic asthmatic patients reached EAR and only experienced minimal changes in FEV1 during 
cat allergen exposure, with a mean change of FEV1 of 2%, suggesting that the cat-allergen 
exposure unit is highly specific.  All patients tolerated the allergen exposure well.  Cat-allergic 
asthmatic patients who experienced an EAR were offered treatment with a short-acting 2 
agonist upon exiting the EEU chamber, and those who experienced a LAR were also treated with 
a short-acting 2 agonist, with all patients experiencing a return of FEV1 ≥90% baseline after 
EAR and LAR.  None of the 20 cat-allergic patients with asthma required escalation of asthma 
therapy beyond a short-acting 2 agonist, demonstrating that the FEV1 changes induced by the 
allergen exposure in the EEU are reversible and highly responsive to therapy.  
The current 2-arm, placebo-controlled, double-blind, single-dose, randomized, parallel-group 
proof-of-concept (POC) study will enroll approximately 60 cat-allergic patients with allergic 
rhinitis (AR) with or without conjunctivitis not currently living with a cat who have a history of 
GINA 1 asthma (1:1 ratio) (Figure 1).  The study will explore over a 12-week assessment period 
whether a single 600 mg SC prophylactic treatment with REGN1908-1909 can prevent an EAR 
during exposure to cat allergen as measured by spirometry.  During the screening period, patients 
will be exposed to 2 baseline EEU challenges.  To exclude asthmatic patients with reductions in 
FEV1 not attributable to allergen, the first baseline EEU challenge will be a 2-hour placebo 
challenge where normal saline will be nebulized into the chamber.  Patients will perform 
spirometry every 10 minutes, and those who experience a reduction in FEV1 >10% at 
3 consecutive spirometry measurements will be excluded from the study. A second screening 
challenge to cat allergen will then be performed to exclude patients who do not experience an 
EAR with cat allergen exposure.  Cat allergen (40 ng/m3 Fel d 1) will be nebulized into the EEU 
for a maximum of 2 hours, with the patient performing spirometry every 10 minutes until the 
patient reaches EAR (FEV1 reduction ≥20%) or when the patient voluntarily departs the EEU 
due to clinically significant allergic and/or asthma symptoms.  Upon exiting the EEU, patients 
will receive a short-acting 2 agonist, have vitals performed, and then be monitored outside of 
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the EEU for 6 hours for safety follow-up, during which time the LAR is measured if it occurs.  
During this 6-hour observation period, spirometry will be performed every 30 minutes, and 
TNSS, TOSS, and chest symptom questions are recorded every hour. At the end of 6-hour 
monitoring period, patients will be discharged home if their FEV1 is ≥90% of the baseline value; 
additional monitoring will be performed if the FEV1 is below 90%.  A physical examination and 
vital signs measurement will also be performed prior to leaving the clinical trial unit.  FEV1 will 
be monitored at home using a portable hand-held spirometer for approximately 18 hours after 
leaving the clinical unit (a total of 24 hours of monitoring from the end of the EEU exposure).  
Alyatec’s investigator(s) will be connected to spirometry data performed by the patients at home.  
If there is a 30% drop in FEV1, the investigator(s) will receive an alarm by email to inform 
him/her about the change in spirometry and the patient will be contacted and evaluated by a 
medical doctor.  Patients will also receive contact information that they will be able to contact 
Investigator(s) 24 hours a day in case of symptoms.   
Cat-allergic patients who fail to reach EAR within 2 hours during baseline exposure will be 
excluded from the study.  At time point days 8, 29, 57, and 85 after randomization, patients will 
be exposed to the EEU for a maximum of 4 hours or until they reach EAR (FEV1 reduction 
≥20%) and then will be monitored outside of the EEU for 6 hours for safety follow-up, during 
which time the LAR is measured if it occurs.  Although the amount of Fel d 1 that is nebulized 
into the EEU is continuously 40 ng/m3, the individual exposure increases over time in 
association with minute ventilation (the volume of air that can be inhaled or exhaled for 
1 minute).  Therefore, minute ventilation will be measured in each patient at baseline using 
spirometry, so that the Fel d 1 airborne exposure, as a product of the individual’s minute 
ventilation and time, can be assessed at each Cat Allergen Challenge on days 8, 29, 57, and 85.  
Minute ventilation will be measured 1 time at baseline while the patient is at rest rather than in 
real time in the EEU during cat allergen exposure to minimize variability in the measurement.   
The primary objective of this study is to assess the time to EAR at day 8 in a Controlled Cat 
Allergen Challenge in patients receiving a single dose of REGN1908-1909 (600 mg) on day 1 
compared to placebo-treated patients.  We hypothesize that patients will be able to tolerate cat 
allergen for a significantly longer amount of time before they experience bronchoconstriction in 
an EEU, 8 days after receiving a single dose of REGN1908-1909 as compared to placebo.  With 
30 patients per treatment arm, an increase in median time to EAR from 58 minutes in the 
placebo-treated patients to 132 minutes in patients treated with REGN1908-1909 is estimated.  A 
median time to EAR of 58 minutes was observed in cat-allergic patients with asthma upon 
Controlled Cat Allergen Challenge in the Alyatec validation study (Gherasim, 2018), and the 
ratio of median duration of tolerated exposure of 2.25 is based on the estimated effect size 
observed in a previous Cat Allergen Challenge study (Corren, 2011).  The secondary objectives 
will assess the safety and tolerability of a single dose of REGN1908-1909 (600 mg) in GINA 1 
cat-allergic patients and whether GINA 1 cat-allergic asthmatic patients 1) tolerate longer cat 
allergen exposure times before experiencing bronchoconstriction in an EEU at days 29, 57, and 
85 after a single dose of REGN1908-1909 as compared to placebo, 2) experience reduced nasal 
(TNSS) and ocular (TOSS) symptom scores in an EEU at days 8, 29, 57, and 85 after a single 
dose of REGN1908-1909 as compared to placebo, and 3) tolerate a higher Fel d 1 exposure over 
time in the EEU as measured by 40 ng/m3 Fel d 1 x minute ventilation x time.  Exploratory 
objectives will be performed to elucidate inflammatory and immunological pathways that are 
affected by REGN1908-1909 and will be included in a separate Exploratory Biomarker Report.  
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Exploratory objectives will assess total and allergen-specific IgE levels (cat hair, Fel d 1, Fel d 2, 
Fel d 4, Fel d 7) at baseline and on study drug; standard skin prick test with common allergens at 
baseline to assess poly-allergy; early-phase allergic skin responses as measured by skin prick test 
with serial allergen titration with cat hair extract at baseline, day 29, and day 85; nasal 
congestion in an EEU as measured by peak nasal inspiratory flow (PNIF) at the time of EAR and 
6 hours after exposure; biochemical measures of asthma control as measured by fractional 
exhaled nitric oxide (FeNO) at baseline and 24 hours after EEU exposure; patient-reported chest 
symptoms in an EEU as measured by chest symptom questions every 20 minutes in the EEU and 
hourly for 6 hours after EAR; and changes in type 2 inflammation in the nasal mucosa as 
measured by RNA sequencing, measured at baseline and 6 hours after EEU exposure.   
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
To evaluate the prophylactic efficacy of REGN1908-1909 (anti-Fel d 1) administered as a single 
dose on day 1 in cat-allergic asthmatic patients not living with a cat in the prevention of a 
Controlled Cat Allergen Challenge-induced early asthmatic response (EAR) assessed by 
measures of lung function (FEV1) compared to placebo-treated patients on day 8. 
2.2. 
Secondary Objective(s) 
Secondary Efficacy Objectives 
 To evaluate the prophylactic efficacy of REGN1908-1909 administered as a single 
dose on day 1 in cat-allergic asthmatic patients not living with a cat, in the prevention 
of a Controlled Cat Allergen Challenge-induced: 
 Early asthmatic response (EAR) assessed by measures of lung function (FEV1) 
compared to placebo-treated patients on days 29, 57, and 85 
 Allergic rhinitis symptoms assessed by TNSS compared to placebo patients on 
days 8, 29, 57, and 85 
 Ocular symptoms assessed by total ocular symptom score (TOSS) compared to 
placebo patients on days 8, 29, 57, and 85 
 To evaluate the prophylactic efficacy of REGN1908-1909 administered as a single 
dose on day 1 in cat-allergic asthmatic patients not living with a cat to increase the 
exposure to cat allergen, measured as a product of minute ventilation and time, 
required to induce EAR in a Controlled Cat Allergen Challenge (40 ng/m3 Feld 1 
allergen x minute ventilation x time) as compared to placebo patients on days 8, 29, 
57, and 85 
Secondary Safety Objective: To evaluate the safety and tolerability of REGN1908-1909 vs. 
placebo in patients with cat allergen-triggered asthma.  
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2.3. 
Exploratory Objective(s) 
2.3.1. 
Exploratory Efficacy Objectives 
 To evaluate LAR on days 8, 29, 57, and 85 
 To evaluate whether a single prophylactic SC administration of REGN1908-1909 
inhibits a wheal-and-flare response to a skin prick test with serial allergen titration 
with cat allergen in patients with cat allergen-triggered asthma and AR with or 
without conjunctivitis on days 29 and 85 
 To evaluate the prophylactic efficacy of REGN1908-1909 in cat-allergic patients not 
living with a cat to reduce respiratory symptoms induced by a Controlled Cat 
Allergen Challenge on days 8, 29, 57, and 85 as measured by chest symptom 
questions 
 To assess the prophylactic effect of REGN1908-1909 on biochemical measures of 
asthma control (FeNO) in patients with cat allergen-triggered asthma induced by a 
Controlled Cat Allergen Challenge on days 30 and 86 and measured 24 hours after 
challenge 
 To assess the prophylactic effect of REGN1908-1909 on TNSS, TOSS, and chest 
symptoms up to 24 hours after leaving the EEU 
 To assess the prophylactic effect of REGN1908-1909 on objective measures of nasal 
congestion (PNIF) in patients with cat allergen-triggered asthma induced by a Cat 
Allergen Challenge on 8, 29, 57, and 85 
 To assess the relationship between baseline cat allergen-specific IgE levels (cat hair 
sIgE, Fel d 1 sIgE), total IgE, and the ratio of cat allergen-specific IgE/total IgE (cat 
hair sIgE/total IgE and Fel d 1-specific IgE/total IgE levels) and efficacy of 
REGN1908-1909  
 To assess the relationship between cat allergen-specific IgE levels (Fel d 2, Fel d 4, 
Fel d 7, and other common allergens) at screening and baseline to evaluate the 
relationship between response to REGN1908-1909 and poly/mono-sensitization 
 To assess the extent of REGN1908-1909 interference with the measurement of 
endogenous anti-Fel d1 IgE in baseline samples and its relationship to clinical benefit  
 To assess the degree to which REGN1908-1909 prevents induction of type 2 
inflammation in the nasal mucosa as assessed by RNA sequencing of nasal brushing 
on day 29. 
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2.3.2. 
Exploratory Pharmacokinetic Objective  
To characterize the concentration-time profile of REGN1908 and REGN1909 after a single SC 
dose. 
2.3.3. 
Exploratory Immunogenicity Objective 
To assess the incidence of treatment-emergent anti-drug antibodies (ADA) to REGN1908-1909 
in patients with cat allergen-triggered asthma and AR with or without conjunctivitis over time. 
3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
A single SC dose of REGN1908-1909 600 mg (anti-Fel d 1) will reduce cat allergen-induced 
bronchoconstriction, as measured by an increase in time to EAR upon Cat Allergen Challenge in 
an EEU, in cat-allergic asthmatic patients not living with a cat compared to placebo-treated 
patients. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
An EEU that simulates natural exposure and provides standardized and reproducible cat allergen 
levels will be used to demonstrate the effectiveness of REGN1908-1909.  Environmental 
exposure units have been used for modeling environmental exposure and response to a variety of 
anti-allergic agents, including antihistamines, anti-leukotrienes, intranasal and inhaled 
corticosteroids, and immunologics (Wood, 1995) (Perry, 2004) (Corren, 2011) (Patel, 2013).  
The EEU provides a means of simultaneously exposing upper and lower airways to uniform 
concentrations and particle sizes of allergen under uniform conditions, including CO2 levels, 
humidity, and temperature.  The nebulized cat hair extract concentration that will be used in this 
study is 40 ng/m3 Fel d 1.  Forty (40) ng/m3 Fel d 1 is the equivalent concentration that patients 
experience upon live cat exposure in homes where cats live (Blay, 1990) (Custovic, 1998) 
(Bollinger 1996) (Bollinger 1998).  When tested in an EEU, 40 ng/m3 (but not 20 ng/m3) Fel d 1 
produced a reduction in FEV1 ≥20% in over 50% of cat-allergic GINA 1 asthmatic patients 
(Gherasim, 2018).  In the current study, patients will be exposed to a placebo exposure of saline 
only in the EEU during screening to exclude patients who have a non-specific reduction in FEV1 
upon EEU exposure. Patients who experience a non-specific reduction in FEV1 >10% in 3 
consecutive spirometry measurements will be excluded from the study (Diamant, 2014).  Patients 
will next undergo a screening EEU exposure to nebulized cat hair extract (40 ng/m3 Fel d 1).  
Patients who fail to experience a reduction in FEV1 ≥20% within 2 hours in the Cat Allergen 
Challenge in the EEU will be excluded from the study.  FEV1 ≥20% is considered to be a 
clinically significant reduction and this threshold has been used for previous inhaled allergen 
bronchoprovocation tests (Diamant, 2014) (O’Byrne, 2009).   
Patients who live with a cat will not be allowed to enter the study because these persons have a 
modified immune system with high levels of specific “blocking antibodies” IgG/IgG4 which 
may ameliorate the IgE-mediated allergic response (Erwin, 2014).  Since this type of immune 
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response might induce clinical tolerance, diminishing the severity of symptoms upon allergen 
exposure, this study will exclude patients living with cats.  Patients with moderate and severe 
asthma (GINA 2-5) will be excluded from the study, as moderate asthmatic patients are unable to 
tolerate challenges with cat allergen for longer than 30 minutes (Corren, 2011).   
The follow-up period of 16 weeks (12 weeks of assessment plus 4-week safety follow-up) after 
the single dose of REGN1908-1909, plus an additional 30 days of follow-up for any SAE that 
occurs after study completion, represents a follow-up period of approximately 5 months, within 
the 4 to 5 half-life window for antibody levels to fall to largely undetectable levels. Serious 
adverse events considered by the investigator to be related to the investigational product are to be 
reported even if onset is greater than 30 days from the end of study. 
3.2.2. 
Environmental Exposure Unit 
Alyatec’s EEU is a 65 m2 International Standards Organization 8 cleanroom (Standard 14644-1) 
with continuous air circulation, containing 20 seats to accommodate up to 20 patients at 1 time, 
and with an anteroom and exit room.  The EEU contains 10 particle counters spread equally 
throughout the room, and glass fiber filters adjacent to seats to be used for Fel d 1 allergen 
testing by ELISA.  Standardized, commercially available cat hair extract prepared by a 
pharmacist is nebulized into the EEU through a specialized system that maintains consistent 
particle counts and Fel d 1 counts approximating 40 ng/m3 across the 20 seat positions of the 
EEU.  Particle counts and Fel d 1 counts fall below the limit of detection within minutes of 
stopping the nebulization and Fel d 1 measurements are below the limit of quantification outside 
of the EEU (eg, in the observation area and in the rest rooms).  Other allergens have been tested 
in the EEU, observation room, and the rest rooms and are below the limit of quantification 
(eg, house dust mite, birch), suggesting that there is no cross-contamination of allergens.  During 
each exposure, the patients wear protective suits (TS Plus Microgard 2000) to ensure that no 
contaminant enters or exits the EEU.  The cleaning procedure after each EEU exposure session 
includes the following: rinsing of the nebulization system, disinfectant of the floor, walls, the 
armchairs, and of all the small material stored in the EEU (Ecowipes, THX medical).  
Additionally, air qualification is performed by an independent company (Air Qualif) 4 times a 
year to test for the absence of bacteria and molds in the EEU. 
3.2.3. 
Rationale for Dose Selection  
Dose and Regimen of REGN1908-1909 
A single SC dose of 600 mg REGN1908-1909 is the highest dose previously tested in the first-
in-human (FIH) study with cat-sensitized and allergic but otherwise healthy patients.  This dose 
of REGN1908-1909 also appeared to be efficacious, reducing the TNSS in a nasal allergen 
challenge (NAC) study, a proof-of-mechanism (POM) study in cat-induced AR patients, 
R1908-1909-ALG-1325.  This dose has been well tolerated and may provide effect for up to 
12 weeks. The pharmacokinetic (PK) profiles of both REGN1908 and REGN1909 were 
characterized by linear and dose-proportional kinetics.  The terminal half-lives of total 
REGN1908 and REGN1909 were determined to be approximately 30 (±7) and 21 (±3) days 
(Standard Deviation), respectively. 
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3.2.4. 
Rationale for Endpoints 
Inhaled allergen bronchoprovocation tests have been used to study the pathophysiology of 
asthmatic responses to allergens (Popa, 2001) as well as to study the efficacy of anti-allergy 
therapeutic interventions.  For example, Corren et al. reported that omalizumab, which inhibits 
the binding of IgE to the high-affinity IgE receptors on the surface of mast cells and basophils, 
reduced bronchoconstriction, as measured by a reduction in FEV1, in cat-allergic asthmatics in a 
live Cat Allergen Challenge (Corren, 2011).  
To determine the efficacy of REGN1908-1909 to reduce bronchoconstriction in cat-allergic 
patients with asthma, an inhaled allergen bronchoprovocation test using a cat allergen EEU will 
be used.  FEV1 will be measured by spirometry using portable hand-held devices at baseline and 
during the Cat Allergen Challenge in the EEU until the patient experiences an FEV1 
reduction ≥20% of the baseline measurement or when the patient voluntarily departs the EEU 
due to clinically significant allergic and/or asthma symptoms.  A reduction in FEV1 ≥20% is 
considered to be clinically significant (Popa, 2001) and is achievable in patients with mild 
asthma (GINA 1).  In the Alyatec validation study using the cat allergen EEU model to evaluate 
bronchoconstriction in GINA 1 mild asthmatics allergic to cat, the mean reduction in FEV1 
during early and LAR was -28.1% range (-20.2 to -44.6) and -19.5% range (-14.9 to -23.5) 
respectively.  Patients experienced EARs as early as within 30 minutes of exposure in the EEU 
to as late at 121 minutes, but the mean time to an EAR was 60 minutes (median of 58 minutes) 
and the mean time to a LAR was 180 minutes (Gherasim, 2018). 
In the current study which will use the cat allergen EEU model, the primary endpoint is to assess 
the time to EAR during 4 hours of continuous exposure to 40 ng/m3 of cat allergen in patients 
receiving 1 dose of REGN1908-1909 compared to placebo at day 8.  Secondary endpoints are to 
assess the time to EAR in the cat allergen EEU at day 29 (week 4), day 57 (week 8), and day 85 
(week 12) in patients receiving REGN1908-1909 compared to placebo.  
Allergic rhinitis and conjunctivitis symptom scores and chest symptom questions will be 
measured at baseline, during the Cat Allergen Challenge, and for 24 hours following the 
challenge.  Total nasal symptom score is based on regulatory (FDA and EMA) guidance for 
assessment of AR.  Individual nasal symptoms, including rhinorrhea, nasal congestion, nasal 
itching, and sneezing are evaluated on a 4-point Likert scale (0, none; 1, mild; 2, moderate; and 
3, severe) and combined to give the TNSS with a maximum score of 12.  Individual ocular 
symptoms for itching/burning, redness, swelling/puffiness, and tearing/watery eyes are evaluated 
on a 4-point Likert scale (0, none; 1, mild; 2, moderate; and 3, severe) and combined to give the 
TOSS, with a maximum score of 12.  Individual chest symptoms for chest tightness/shortness of 
breath/trouble breathing, wheezing, and coughing are evaluated on a 4-point Likert scale (0, 
none; 1, mild; 2, moderate; and 3, severe).  In the omalizumab Cat Allergen Challenge study, 
there was a significantly lower decrease in the AUC of the change from pre-challenge values in 
the chest symptom questions (2.1 per hour vs. 5.6 per hour, p <.0001) and a combined nasal-
ocular symptom score (NOSS) (2.5 per hour vs. 5.2 per hour, p <.0002 in patients treated with 
omalizumab as compared to placebo (Corren, 2011).  In an allergen challenge in an EEU, 
allergic rhinoconjunctivitis symptoms typically peak at 3 hours (Ellis, 2017) (Horak, 2009), 
therefore patients who experience a reduction in FEV1 ≥20% in less than 3 hours may not reach 
their peak allergy symptom scores.  However, symptom scores (TNSS, TOSS, chest symptom 
questions) will be measured every 20 minutes during the cat allergen exposure in the EEU, every 
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hour for 6 hours following EAR, and thereafter every 2 hours, except when the patient is 
sleeping, for up to 18 hours after leaving the clinical unit, to compare patients receiving 
REGN1908-1909 to placebo.   
The skin prick test with serial cat allergen titration assesses the early phase reaction (EPR) at 
0-60 min.  The early phase reaction is characterized by histamine release and is thought to reflect 
cutaneous mast cell degranulation upon allergen exposure.  In the proof-of-mechanism (POM) 
study in cat-induced AR patients, R1908-1909-ALG-1325, the percent change from baseline in 
normalized average wheal diameter AUC of titrated (100-33,000 SQU/mL) cat hair extract skin 
prick test, read 15 min after administration on study days 29 and 85, was significantly reduced in 
REGN1908-1909-treated patients as compared to placebo-treated patients (Orengo, 2018).  
These data suggest that the skin prick test with serial cat allergen titration can be used to test 
pharmacodynamics of 1 dose of REGN1908-1909 in this study. 
Serum antibodies against total cat hair and Fel d 1 will be measured to assess the levels of 
clinical sensitization against cat in patients prior to the beginning of treatment.  As has been 
widely shown in SIT studies, clinical sensitization to a specific allergen is associated with 
decreased allergen-specific IgE over time.  Concentrations of allergen-specific Ig subclasses, 
including IgA, IgG1, and IgG4, also increase concomitantly during clinical desensitization 
therapy.  These protective antibodies are considered to be serum “IgE-blocking factors” 
(Shamji, 2012) and contribute to the induction of desensitization.   
The sponsor hypothesizes that REGN1908-1909 may reduce the induction of genes and 
inflammatory pathways associated with type 2 inflammation post-EEU exposure.  Existing data 
in the literature suggest that type 2 inflammation in asthmatic or AR patients could be detected 
by gene expression analysis of nasal tissue samples, collected either by nasal brushing or nasal 
curettes.  For instance, RNA expression analysis of type 2-associated genes in nasal brushings 
from 50 asthmatic patients and 50 healthy controls have identified “Th2-high” and “Th2-low” 
patients differentiated by the expression of 70 genes associated with type 2 pathways, including 
IL-13, IL-5, and periostin.  The analysis also revealed that Th2-high patients were more likely to 
have atopy, atopic asthma, higher blood eosinophil counts, and rhinitis, compared with Th2-low 
patients.  Nasal IL-13 expression was 3.9-fold higher in asthmatic participants who experienced 
an asthma exacerbation in the past year (Poole, 2014).  In a study of AR patients treated with 
prednisone or placebo, nasal challenge with Timothy grass was performed.  Eight hours post-
NAC, significant increases in eosinophil-related gene-expression were detected in the nasal 
sampling of placebo-treated patients compared to baseline, but not in prednisone-treated patients 
(Leaker, 2017).  These data suggest that transcriptome analysis of nasal brushings could be used 
to assess underlying type 2-driven inflammation. 
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4. 
STUDY VARIABLES  
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, weight, height, etc), disease 
characteristics including medical history, and medication history for each patient. 
4.2. 
Primary and Secondary Endpoints 
The primary endpoint in the study is the time to EAR upon Controlled Cat Allergen Challenge in 
an EEU on day 8. 
The secondary endpoints are: 
 Time to EAR upon Controlled Cat Allergen Challenge in an EEU on days 29, 57, and 
85 
 AUC of the percent change (%/h) in FEV1 induced by a Controlled Cat Allergen 
Challenge over the exposure interval (%/h) from baseline to the Controlled Cat 
Allergen Challenge on days 8, 29, 57, and 85 
 AUC of the percent change (%/h) in patient-assessed nasal symptoms induced by a 
Controlled Cat Allergen Challenge over the exposure interval (%/h) from baseline to 
the Controlled Cat Allergen Challenge on days 8, 29, 57, and 85  
 AUC of the percent change (%/h) in patient-assessed ocular symptoms induced by a 
Controlled Cat Allergen Challenge over the exposure interval (%/h) from baseline to 
the Controlled Cat Allergen Challenge on days 8, 29, 57, and 85 
 Change and percent change in cat allergen quantity as experienced by patients during 
exposure (measured by 40 ng/m3 x minute ventilation x time) on days 8, 29, 57, and 
85   
 Incidence rates of treatment-emergent adverse events (TEAEs) and serious TEAEs 
through end of study 
4.3. 
Exploratory Efficacy Variable 
 Time to LAR upon Controlled Cat Allergen Challenge after an EEU exposure on 
days 8, 29, 57, and 85 
 AUC of the percent change (%/h) in patient-assessed chest symptom question 
responses 
 Levels of FeNO (measured in parts per billion, which is equivalent to nanoliters per 
liter) 24 hours after Controlled Cat Allergen Challenge (days 30 and 86) 
 Peak nasal inspiratory flow (measured in nasal patency, L/min) measured during the 
EEU exposure according to Table 1 
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4.4. 
Pharmacokinetic Variables 
Pharmacokinetic variables are total concentration of REGN1908 and total concentration of 
REGN1909 in serum, at the sampling times specified in the visit schedule (Table 1). 
4.5. 
Immunogenicity Variables  
Immunogenicity variables include status, titer, and time-point/visit. 
Samples in this study will be collected at the visits specified in Table 1 (Schedule of Events).  
 
4.6. 
Pharmacodynamic and Other Biomarker Variables 
Serum Antibodies 
 Allergen-specific IgE levels (cat hair, Fel d 1) at screening visit 1 (V1) and baseline.   
 Allergen-specific IgE levels (Fel d 2, Fel d 4, Fel d 7, and other common allergens) at 
screening and baseline to assess sensitization status and to evaluate the relationship 
between response to REGN1908-1909 and poly/mono-sensitization (van Ree 1999).  
 Allergen-specific IgE levels (cat hair, Fel d 1, Fel d 2, Fel d 4, Fel d 7, and other common 
allergens on days 8, 29, 57, and 85 using blood samples collected prior to the Controlled 
Cat Allergen Challenge in the EEU 
 Additional subclass of serum antibodies (eg, IgG4 against Fel d 1, 2, 4, 7) may be 
measured at screening, baseline, and on days 8, 29, 57, and 85 using blood samples 
collected prior to the allergen challenge 
 
 
Skin Prick Test 
Standard SPT with cat hair extract and other common allergens will only be performed at 
screening visit 1 to assess sensitization status.  
Skin Prick Test with Serial Allergen Titration   
Titrated SPT with Serial Allergen Titration with cat allergen will be performed at screening 
visit 3, days 29, 85, and 113 to confirm pharmacodynamic effects of REGN1908-1909 on wheal 
size response (mediated by mast cell degranulation).  On days when an allergen challenge is 
performed, the test will be performed prior to allergen challenge.   
Gene Expression Analysis of Type 2 Inflammation of Nasal Mucosa by RNAseq 
Nasal brushing samples will be collected from the patients before and after the allergen challenge 
at screening, as well as day 29.  RNA will be extracted from these samples for RNA sequencing 
to evaluate temporal changes in the mucosal transcriptome by comparing pre- and post-exposure 
to cat allergen.  The impact on genes associated with type 2 inflammation will also be assessed.  
The exploratory nasal brushing analyses will not be reported in the clinical study report.  
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Interference Assay with REGN1908-1909 
Serum samples collected from patients prior to drug exposure will be tested in an in-vitro 
competition assay to assess whether REGN1908-1909 effectively inhibits the binding of 
endogenous anti-fel-d1 IgE to Fel-d1 allergen.  Individual blocking efficiencies will be compared 
to the patient's observed clinical efficacy to determine if efficiency of blocking influences the 
magnitude of clinical benefit.  The analysis will be not reported in the clinical study report. 
5. 
Study Design  
5.1. 
Study Description and Duration 
This is a phase 2, randomized, double-blind, parallel-group, single-dose study in approximately 
60 cat-allergic patients with mild asthma (GINA stage 1) with rhinitis, with or without 
conjunctivitis to cat hair, who are not living with cats, to evaluate the efficacy of a prophylactic, 
single 600 mg SC dose of REGN1908-1909 to prevent acute, allergic, lower respiratory 
symptoms during exposure to cat allergen as measured by spirometry.  This single-site study will 
incorporate clinical monitoring appropriate for conducting a study measuring a mild-to-moderate 
reduction in FEV1 in the asthmatic population.  
The study consists of up to a 12-week screening period followed by 1:1 randomization and 
treatment of eligible patients with double-blind, single SC dose of study drug at day 1 followed 
by a 12-week assessment period and then a 4-week safety follow-up period.  Patients undergo a 
saline challenge (placebo challenge) during screening day -85 to -14 where they are exposed to 
nebulized normal saline for 2 hours in the EEU while FEV1 is monitored every 10 minutes.  
Patients then undergo an allergen challenge (which involves exposure to cat allergen in the EEU) 
during screening (baseline challenge) for up to 2 hours, and then allergen challenges on study 
drug (challenge) at days 8 (week 1), 29 (week 4), 57 (week 8), and 85 (week 12) for up to 4 
hours (Figure 1, Schema 1).  A final safety follow-up visit at week 16, 4 weeks after the last Cat 
Allergen Challenge, will be performed to assess for asthma symptoms after undergoing repeated 
Cat Allergen Challenges.   
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Figure 1: 
Study Flow Diagram Schema 1 
 
R: randomization; d: day; wk: week 
The informed consent will be provided to the patient prior to visit 1 so that he/she has sufficient 
time to read the informed consent and to ask questions to the investigator.   
After obtaining informed consent, patients will be assessed for eligibility during a 3-part 
screening period (Table 1). 
1. During screening visit 1, patients will undergo eligibility criteria evaluation, collection of 
medical history, physical examination, vital signs, cat hair extract SPT, standard regional 
SPT (Dermatophagoides pteronyssinus, Dermatophagoides farinae, dog, aspergillus, 
Alternaria, birch pollen, 3 grasses pollen, ash pollen), electrocardiogram (ECG), and 
spirometry.  Blood samples will be collected for anti-cat hair and Fel d 1-specific anti-
IgE along with other common allergen determination and serum laboratory testing. 
2. Eligible patients will undergo a screening placebo challenge in the EEU for up to 2 hours.  
Patients who experience a ≥10% fall in FEV1 at 3 consecutive spirometry measurements 
during this placebo challenge will be excluded (eg, over 3 separate consecutive 
spirometry readings during the 2 hours EEU patients must demonstrate ≥10% fall in 
FEV1).  Baseline skin prick testing with serial allergen titration with cat allergen will be 
performed at this visit in patients who successfully complete the placebo challenge 
without experiencing a ≥10% fall in FEV1 at 3 consecutive spirometry measurements. 
3. If patients are eligible after the placebo challenge in the EEU, they will undergo a 
Controlled Cat Allergen Challenge for a maximum of 2 hours.  Patients must demonstrate 
≥20% fall in FEV1 during exposure and ability to withstand exposure for at least 
10 minutes, or they will be excluded.  Patients will be removed from the EEU once they 
have demonstrated ≥20% fall in FEV1, and the time to this reduction in minutes will be 
recorded.  The cat EEU visit 3 during screening must be at least 3 weeks from the cat 
EEU visit 6 (visits must be spaced apart by at least 3 weeks to avoid allergen priming).  
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After randomization, patients will undergo serial Controlled Cat Allergen Challenges for a 
maximum of 4 hours at days 8, 29, 57, and 85 for evaluation of study drug efficacy (Figure 2, 
Schema 2) 
Figure 2: 
Study Flow Diagram Schema 2 
 
Before entry into the cat allergen exposure unit, prohibited medications are withheld (See 
Prohibited Medications Section 7.8.1), and patients receive a physical examination; chest, nasal, 
and ocular symptoms, as well as pulmonary function, will be evaluated and recorded.  The 
challenge will not proceed if patients have a TNSS greater than 4, an asthma control test (ACT) 
score <20 at any of the screening visits, or FEV1 of less than 70% of predicted value.  Patients 
may leave the exposure unit at any time.  Patients wear a disposable suit to protect them from 
allergen inside the EEU and to avoid contaminating the EEU with other allergens brought in 
from their clothing, which could interfere with the cat allergen studied.   
Assessments 
Study staff-supervised spirometry will be performed in all patients at visits shown in Table 1 
with a standard measurement of FEV1 (Section 8.2.2.4).   
 
Schema 2. At baseline, patients will be exposed in the EEU for up to 2 hours, until they demonstrate an early 
phase response (≥20% fall in FEV1) and then patients will be observed outside of the EEU for 6 hours to 
observe if/when a late phase response occurs (≥15% fall in FEV1). At subsequent challenge visits (days 8, 29, 
57, and 85) patients will be exposed in the EEU for up to 4 hours, until they demonstrate an early phase response 
(≥20% fall in FEV1) or until they depart due to clinically significant allergic and/or asthma symptoms, and then 
patients will be observed outside of the EEU for 6 hours to observe a late phase response (≥15% fall in FEV1). 
Although the amount of Fel d 1 that is aerosolized into the EEU is maintained at 40 ng/m3, the individual 
exposure actually increases over time in association with minute ventilation (the volume of air that can be 
inhaled or exhaled during 1 minute).  
Cat allergen exposure = 40 ng/m3 aerosolized cat allergen extract 
X minute ventilation (L/minute) X exposure time (minutes)
Q10 minutes: FEV1
1st hour                 2nd hour             3rd hour             4th hour 
I    I    I    I    I    I    I    I    I    I    I    I    I    I    I    I    I    I    I    I    I    I    I    I    I
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The asthma control test (ACT), which uses a 5-point Likert scale, will be used prior to the 
screening cat allergen EEU to determine whether the patient’s asthma is well controlled, and 
again at the final safety follow-up study visit (Section 8.2.2.3). 
Patient-reported allergic symptoms (nasal, ocular, and chest symptoms) will be recorded by 
patients using a 4-point Likert scale (Section 8.2.2.1, Section 8.2.2.2, and Section 8.2.2.3). 
Measurement of FeNO, a marker of airway inflammation, will be analyzed from exhaled breath 
condensates obtained at baseline and 24 hours after the Controlled Cat Allergen Challenges 
during screening, on day 30 and day 86 (Section 8.2.2.5). 
Randomized Single-Dose Treatment/ Follow-up Period (16 weeks): 
Approximately 60 adult patients who meet eligibility criteria will be randomized in a 1:1 ratio 
into 1 of 2 treatment regimens (n=30 in each group): 
 REGN1908-1909 600 mg SC dose at day 1  
 Matching placebo SC dose at day 1 
All patients will be assessed at scheduled visits for safety, laboratory, and clinical assessments 
for 16 weeks after the single SC dose of study drug treatment. 
The duration of the 16-week follow-up period (12-week assessment period and then a 4-week 
safety follow up) is based on the time expected for drug levels to be insignificant after the single 
600 mg SC dose of REGN1908-1909. 
5.1.1. 
End of Study Definition 
The end of study for this study is defined as the last visit of the last patient.   
5.1.2. 
Planned Interim Analysis 
No interim analysis is planned. 
5.2. 
Study Committees  
5.2.1. 
Safety Monitoring Team 
A safety monitoring team (SMT) at Regeneron Pharmaceuticals, Inc. will meet periodically to 
review blinded safety data as needed.  The team may be comprised of the medical director, a 
safety/pharmacovigilance representative, and representatives from biostatistics and data 
management (BDM), as well as representatives from clinical operations and regulatory affairs. 
The data to be reviewed includes but is not limited to:  
1. Treatment-emergent adverse events that result in an early study withdrawal 
2. Serious adverse events (SAEs) 
3. Selected laboratory tests, as deemed appropriate by the SMT 
4. Additional AEs of interest to the SMT 
Appropriate action, if needed, will be taken based upon this review and in consultation with the 
medical monitor.   
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5.2.2. 
Independent Data Monitoring Committee 
An IDMC, composed of members who are independent from the sponsor and the study 
investigators, will monitor patient safety by conducting formal reviews of cumulative unblinded 
safety data.  If requested, the IDMC may have access to any other data for the purposes of a risk-
benefit assessment. 
The IDMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the patients enrolled in the study.  The IDMC 
will also institute any measures that may be required for ensuring the integrity of the study 
results during the study execution.  
All activities and responsibilities of the IDMC are described in the IDMC charter. 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Approximately 60 patients are planned for enrollment. 
6.2. 
Study Population  
The population will be adults 18-65 years inclusive of males and females with cat-induced 
asthma (GINA 1) and AR with or without conjunctivitis symptoms with cat sensitization 
confirmed at screening. 
6.2.1. 
Inclusion Criteria  
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Generally healthy men and women between the ages of 18 and 65 inclusive at the time of 
screening. 
2. Documented or patient reported history (for at least 2 years) of symptomatic cat allergen-
triggered asthma with rhinitis with or without conjunctivitis 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 hair and Fel d 1 (>0.35 kAU/l at 
screening) 
c. History of asthma GINA 1 
d. Screening FEV1 ≥70% predicted after withholding long-acting β2-agonists for 
> 36 hours and short-acting β2-agonists for > 6 hours 
e. Demonstrated ≥20% fall in FEV1 within 2 hours during Cat Allergen Challenge in 
EEU and ability to withstand exposure for at least 10 minutes during screening 
3. Willing and able to comply with clinic visits and study-related procedures 
4. Provide informed consent signed by study patient or legally acceptable representative 
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5. Patients covered by health social identification number  
6. Able to understand and complete study-related questionnaires 
7. No cat exposure at home for the past year and must continue having no exposure at home 
during the study; cat exposure outside of the home shall be avoided for at least 1 week 
prior to any Cat Allergen Challenge and during the defined follow-up period. 
8. Less than 10 pack-years of smoking history 
6.2.2. 
Exclusion Criteria  
A patient who meets any of the following criteria will be excluded from the study: 
1. Patients who experience a ≥10% fall in FEV1 at 3 consecutive spirometry measurements 
during the placebo challenge  
2. Positive human immunodeficiency virus (HIV) test 
3. Positive hepatitis test (HBsAg and hepatitis C antibody) 
4. History of significant multiple and/or severe allergies (including latex gloves) or has had 
an anaphylactic reaction or significant intolerability to prescription or nonprescription 
drugs or food 
5. Participation in a prior REGN1908-1909 clinical trial 
6. History of severe anaphylactic or severe asthmatic reactions to cat exposure 
7. Active lung disease other than asthma 
8. Treatment with an investigational drug within 2 months or within 5 half-lives (if known), 
whichever is longer, prior to screening 
9. Persistent chronic or recurring acute infection requiring treatment with antibiotics, 
antivirals, or antifungals, or any untreated respiratory infections within 4 weeks prior to 
screening 
10. Serum creatinine, creatinine phosphokinase (CPK), alkaline phosphatase, hepatic 
enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), total 
bilirubin (unless the Investigator has evidence that increased indirect bilirubin 
corresponds to a Gilbert’s-type syndrome) that exceed 1.5 x the upper limit of normal 
(1.5 x ULN), or 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 
11. 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 cardiovascular 
disease, hypertension, diabetes, etc.) 
12. Patients taking any prohibited treatment (Section 7.8.1 Prohibited Medications) 
13. Use of systemic corticosteroids within 8 weeks prior to screening visit 1 
14. Use of anti-IgE or other biological therapy within 6 months prior to screening visit 1 
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15. History of SIT with cat allergen or vaccines against cat allergy within 5 years of 
screening visit 1 
16. SIT with any allergen within 6 months prior to screening visit 1 
17. Significant rhinitis, or sinusitis, due to daily contact with other allergens causing 
symptoms that are expected to coincide with the baseline or the final cat allergen 
exposure unit assessments as assessed by the investigator, before each exposure 
18. Patients who anticipate major changes in allergen exposure in their home or work 
environments that are expected to coincide with the baseline or the final cat allergen 
exposure assessments as assessed by the investigator 
19. Hospitalization for any reason within 30 days prior to screening visit 1  
20. 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 
21. Treatment of asthma requiring systemic (oral or parenteral) corticosteroid treatment more 
than twice within 12 months or once within 3 months prior to screening or has been 
hospitalized or has attended the ER/Urgent Care facility for asthma more than twice in 
prior 12 months before screening. 
22. History of hypersensitivity to corticosteroids or antihistamines, or drug treatment 
excipient 
23. Known sensitivity to doxycycline, tetracyclines, or to any of the components of the 
investigational product formulation 
24. Positive serum human chorionic gonadotropin pregnancy test at the screening visit or 
urine pregnancy test at the baseline visit 
25. Pregnant or breastfeeding women 
26. Women of childbearing potential* who are unwilling to practice highly effective 
contraception prior to the initial dose/start of the first treatment, during the study, and for 
at least 6 months after the last dose of study drug.  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 
e. and/or sexual abstinence†, ‡. 
 
*Postmenopausal women must be amenorrheic for at least 12 months in order not to 
be considered of childbearing potential; if in question, a follicle stimulating hormone 
(FSH) of ≥25 mU/mL must be documented. 
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f. Pregnancy testing and contraception are not required for women with documented 
hysterectomy, bilateral oophorectomy, 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 treatments.  
 
‡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. Sexually active men who are unwilling to use the following forms of medically 
acceptable birth control during the study drug treatment period and for 6 months after the 
last dose of study drug: vasectomy with medical assessment of surgical success OR 
consistent use of a condom.  Sperm donation is prohibited during the study and for 
6 months after the last dose of study drug. 
28. Inability to understand and act upon the information provided (what to do in an 
emergency situation, patient has difficulty understanding/communicating, etc) 
29. Patient under legal custody, guardianship, or curatorship 
30.  Screening asthma control test (ACT) <20 at any screening visits 
NOTE:  Patients may be rescreened after asthma control improves. Patients who are 
rescheduled must demonstrate stable asthma control by having an ACT ≥20 at 2 
consecutive visits, separated by at least a week. 
6.3. 
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.  Criteria for withdrawal include but 
are not limited to the following:  
 The patient experiences a FEV1 reduction ≥50% from the baseline measurement of 
FEV1 (before EEU exposure) at any time during the study  
 The patient requires emergency treatment of asthma or of a hypersensitivity reaction in a 
hospital or emergency room  
 The patient experiences a systemic allergic response and/or anaphylaxis requiring 
epinephrine 
The investigator and/or sponsor have the right to withdraw a patient from the study 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. 
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Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 8.1.2.   
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.3.2. 
6.4. 
Replacement of Patients  
Patients prematurely discontinued from study after randomization will not be replaced.   
7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
Pre-lyophilized 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.   
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.   
Placebo will be supplied in vials that match, but do not contain the protein. Colored, transparent 
“blinding labels” will be placed on drug product syringes to blind staff that will administer drug 
products. 
This is a single-dose study.  Study drug will be administered SC on day 1, by the investigator, or 
other qualified study personnel.  Patients will be randomized in a 1:1 ratio to receive 600 mg 
REGN1908-1909 or placebo.   
Three 2.0 mL SC injections will be administered in the abdomen in different quadrants. 
Instructions on dose preparation are provided in the pharmacy manual. 
7.2. 
Rescue Treatment(s) 
After each allergen challenge, all patients will leave the site with a rescue treatment kit 
containing: short-acting β2 agonist, oral corticosteroids, and oral antihistamines.  The patients 
will also receive oral and written information about the procedure to be followed in case of the 
occurrence of AEs which may be related to the study, as well as the telephone number of the 
physicians of the study. 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules 
7.3.1. 
Dose Modification 
This is a single-dose study.  Dose modification for an individual patient is not allowed. 
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7.3.2. 
Study Drug Discontinuation 
Study drug discontinuation is not applicable in this single-dose study.  Patients who opt out of 
EEU challenges after receipt of study drug and who do not withdraw from the study will be 
asked to return to the clinic for all remaining study visits per the visit schedule except for EEU 
exposures and EEU related procedures (see Section 8 ) .Patients who opt to withdraw from the 
study will be asked to complete study assessments, per Section 8.1.2.  
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Permanent study drug discontinuation is not applicable in this single-dose study.   
7.4. 
Management of Acute Reactions  
Allergen exposure can induce immediate or late allergic reactions in sensitized patients which 
will be managed as follow: 
Allergic Conjunctivitis: 
If there is a conjunctivitis response, topical treatment will be administrated, and oral 
antihistamines provided as needed at the discretion of the investigator. 
Allergic Rhinitis: 
If there is a rhinitis response, topical treatment will be administrated, and oral antihistamines 
provided as needed at the discretion of the investigator. 
Early Asthmatic Response (EAR) and Late Asthmatic Response (LAR) 
During a session in the EEU, an EAR is expected to be mild or moderate.  As soon as the patient 
has a drop in FEV1 of 20% and/or asthma symptoms, the patient will be removed from the EEU 
and will be treated with short-acting 2 agonist every 20 minutes for 1 hour if necessary.  
Patients will stay under supervision in the observation room during 6 hours after leaving the 
EEU and FEV1 will be monitored every 30 minutes.  During this 6-hour monitoring period, a 
LAR can appear with a drop in FEV1 of 15% and will be treated with short-acting 2 agonist 
and corticosteroids if necessary.  Approximately at the end of the 6-hour monitoring period, 
patients will undergo a physical exam and vital signs, including spirometry, and will be 
discharged home if there are no abnormal findings and if FEV1 ≥90% of baseline.  If FEV1 is 
<90% of the baseline value, patients will continue to be monitored at the clinic until the patient 
meets criteria for discharge.  FEV1 will be monitored at home for approximately 18 hours after 
leaving the clinical unit (a total of 24 hours of monitoring from the end of the EEU exposure).  If 
there is a 30% drop in FEV1 during home monitoring, the investigator(s) will receive an alarm 
by email to inform about the change in spirometry and the patient will be contacted and 
evaluated by a medical doctor. 
Severe bronchoconstriction will be treated with oxygen, short-acting 2 agonist by nebulization, 
and oral systemic corticosteroids. 
Under the extremely rare circumstance that patients experience a severe systemic reaction to the 
EEU (anaphylaxis), with arterial hypotension, angioedema, or urticaria, patients will be treated 
with adrenaline 0.3 mg IM and will be transferred to the hospital emergency room, which is 
located within a 5-minute walk of the clinical trial unit.  
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7.5. 
Blinding 
Study patients, the principal investigators, and study site personnel (with the exception of the 
study pharmacist) will be blinded to all randomization assignments throughout the study.  The 
Regeneron Study Director, Medical Monitor, Study Monitor, and all other Regeneron personnel 
who will be in regular contact with the study site will be blinded to all patient randomization 
assignments.  Study drug kits coded with a medication numbering system will be used.  In order 
to maintain the blind, lists linking these codes with product lot numbers will not be accessible to 
blinded individuals involved in study conduct.  Although the designated study 
pharmacist(s)/designee at the study site are unblinded, the treatment assignment will not be 
provided to site personnel, including the investigator, at any time during the conduct of the study, 
except in the case of a true emergency.  
Selected individuals who are not responsible for the treatment or clinical evaluation of patients 
may have access to unblinded data as needed for safety review or other data review. 
7.5.1. 
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). 
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 
 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.  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. 
7.6. 
Method of Treatment Assignment 
Approximately 60 patients will be randomized in a 1:1 ratio to receive either 600 mg 
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).  
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7.7. 
Treatment Logistics and Accountability 
7.7.1. 
Packaging, Labeling, and Storage  
A medication numbering system will be used in labeling investigational study drug.  Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging.   
Study drug will be stored at the site at a temperature of 2°C to 8°C; storage instructions will be 
provided in the pharmacy manual. 
7.7.2. 
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. 
7.7.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication:  
 dispensed to each patient,  
 returned from each patient (if applicable), and  
 disposed of at the site or returned to the sponsor or designee 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.7.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the 
sponsor and regulatory agency inspectors. 
7.8. 
Concomitant Medications  
Any treatment administered from the time of informed consent to the end of the treatment final 
study visit will be considered concomitant medication.  This includes medications that were 
started before the study and are ongoing during the study. This excludes all rescue treatment kit 
medications, taken at home within 24 hours from the EEU exposure.  Rescue medications taken 
from the kit within 24 hours of EEU exposure will be collected separately. 
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7.8.1. 
Prohibited Medications  
1. Use of these concomitant medications within the following time period is preceding any 
screening visit or any EEU visit: 
(NOTE: Patients may be rescheduled 1 time for the screening visit or EEU visit after the 
time period for taking these concomitant medications has passed.) 
a. Topical or systemic first generation H1 antihistamines (5 days) 
b. Topical or systemic second generation H1 blockers (7 days)  
c. Systemic anti-H2 (8 days) 
d. Astemizole (6 weeks) 
e. Cromoglycates, leukotriene modifiers (7 days) 
f. Systemic steroid treatment (8 weeks prior to screening and during the study) 
(NOTE: systemic steroid treatment is allowed if clinically indicated for a LAR treatment after 
exposure to cat allergen in the EEU.) 
g. Topical steroids (48 hours) 
h. Short-acting β2 agonists (8 hours) 
i. Long-acting β2 agonists (eg, salmeterol) (36 hours) 
j. Ultra-long-acting β2 agonists (eg, indacaterol, vilanterol, olodaterol) (48 hours) 
k. Anticholinergics eg, Ipratropium (Atrovent 40 μg) (12 hours)  
l. Long-acting anti-muscarinic agents (7 days) 
m. Methylxanthynes (eg, oral theophylline) (24 hours) 
n. Intramuscular corticosteroids (3 months prior to screening and during the study) 
o. Systemic or topical calcineurin inhibitors (14 days prior to screening and during 
the study) 
p. Tricyclic antidepressants/antipsychotics (14 days) 
q. Topical decongestants (72 hours) 
r. Caffeine-containing drinks or products (8 hours of EEU visits only)  
2. History of SIT with cat allergen or vaccines against cat allergy within 5 years of 
screening 
3. SIT with any allergen within 6 months of screening 
4. Beta-blockers during the study period  
5. Immunomodulatory therapy, anti-IgE, or other biological, agent-based antagonist therapy 
is not allowed in the 6 months prior to baseline (eg, cyclosporine) or during the study 
6. Change in prescription medications within 4 weeks before screening 
7. Aspirin and any nonsteroidal anti-inflammatory drug  
NOTE: paracetamol is allowed to be used for occasional pain relief. 
8. Active treatment for respiratory infections (antiviral, antifungals, or antibiotics) within 4 
weeks prior to screening or EEU 
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7.8.2. 
Permitted Medications  
Use of standard-of-care medications not listed as prohibited will be allowed.  Treatment for acute 
reactions is allowed during the study (See Section 7.4). 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
 
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Table 1: 
Schedule of Events 
Study 
Procedure 
Screening1 
Randomization and Treatment Period 
End of 
Study/Early 
Termination 
Visit 
Unsche
duled 
Visit24 
Visit 
V125 
Placebo 
EEU 
V225 
Cat 
EEU3
,22 
V3 
V4 
R2 
V5 
Cat 
EEU22, 
23 
V6 
Tel
. 
Cat 
EEU22 
V7 
V8 
Cat 
EEU22 
V9 
Tel
. 
Cat 
EEU22 
V10 
V11 
V12 
 
Days 
-85 to -14 
1 
8 
9 
29 
30 
57 
58 
85 
86 
113 
 
Window (day) 
+7 
±3 
±2 
 
±2 
 
±3 
 
±3 
 
±3 
 
Weeks 
-12 
1 
1 
2 
4 
4 
8 
8 
12 
12 
16 
 
Screening/Baseline 
 
Inclusion/ 
Exclusion 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Skin 
prick test for cat 
hair 4  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skin prick test for 
other common 
allergens4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo challenge 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Cat 
Allergen 
Challenge3 
 
 
X 
 
 
 
 
 
 
 
 
 
 
  
 
Spirometry5 
(includes FEV1) 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
  
 
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Study 
Procedure 
Screening1 
Randomization and Treatment Period 
End of 
Study/Early 
Termination 
Visit 
Unsche
duled 
Visit24 
Visit 
V125 
Placebo 
EEU 
V225 
Cat 
EEU3
,22 
V3 
V4 
R2 
V5 
Cat 
EEU22, 
23 
V6 
Tel
. 
Cat 
EEU22 
V7 
V8 
Cat 
EEU22 
V9 
Tel
. 
Cat 
EEU22 
V10 
V11 
V12 
 
Days 
-85 to -14 
1 
8 
9 
29 
30 
57 
58 
85 
86 
113 
 
Window (day) 
+7 
±3 
±2 
 
±2 
 
±3 
 
±3 
 
±3 
 
Weeks 
-12 
1 
1 
2 
4 
4 
8 
8 
12 
12 
16 
 
Minute ventilation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Randomization2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Administer Study 
Drug2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Cat Allergen 
Challenge 3 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy 
TNSS nasal 
symptoms score6 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
TOSS ocular 
symptoms score6 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Chest symptoms 
questions6 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Spirometry 
(includes FEV1)5 
 
 
 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
PNIF7 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Skin Prick Test 
with Serial 
Allergen Titration 
(Cat-SPT)8 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
FeNO9 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
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Study 
Procedure 
Screening1 
Randomization and Treatment Period 
End of 
Study/Early 
Termination 
Visit 
Unsche
duled 
Visit24 
Visit 
V125 
Placebo 
EEU 
V225 
Cat 
EEU3
,22 
V3 
V4 
R2 
V5 
Cat 
EEU22, 
23 
V6 
Tel
. 
Cat 
EEU22 
V7 
V8 
Cat 
EEU22 
V9 
Tel
. 
Cat 
EEU22 
V10 
V11 
V12 
 
Days 
-85 to -14 
1 
8 
9 
29 
30 
57 
58 
85 
86 
113 
 
Window (day) 
+7 
±3 
±2 
 
±2 
 
±3 
 
±3 
 
±3 
 
Weeks 
-12 
1 
1 
2 
4 
4 
8 
8 
12 
12 
16 
 
Safety10 
Vital Signs 
X 
X12 
X12 
X 
X11 
X12 
 
X12 
X 
X12 
 
X 
X 
X 
X 
Physical 
Examination 
X 
 
X27 
 
X 
X27 
 
X27 
 
X27 
 
X27 
 
X 
X 
Electrocardiogra
m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACT 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Observation 
 
 
X20 
 
X21 
X20 
 
X20 
 
X20 
 
X20 
 
 
 
Distribution of 
rescue treatment 
kit 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Telephone Call13 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Laboratory Testing14 
Hematology 
X 
 
 
 
X15 
 
 
X 
 
X 
 
X 
 
X 
X 
Blood Chemistry 
X 
 
 
 
X15 
 
 
X 
 
X 
 
X 
 
X 
X 
Urinalysis 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
βHCG serum 
pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy 
test (for female 
patients only)16 
 
X 
X 
 
X16 
X 
 
X 
 
X 
 
X 
 
X 
X 
FSH test (in 
postmenopausal 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study 
Procedure 
Screening1 
Randomization and Treatment Period 
End of 
Study/Early 
Termination 
Visit 
Unsche
duled 
Visit24 
Visit 
V125 
Placebo 
EEU 
V225 
Cat 
EEU3
,22 
V3 
V4 
R2 
V5 
Cat 
EEU22, 
23 
V6 
Tel
. 
Cat 
EEU22 
V7 
V8 
Cat 
EEU22 
V9 
Tel
. 
Cat 
EEU22 
V10 
V11 
V12 
 
Days 
-85 to -14 
1 
8 
9 
29 
30 
57 
58 
85 
86 
113 
 
Window (day) 
+7 
±3 
±2 
 
±2 
 
±3 
 
±3 
 
±3 
 
Weeks 
-12 
1 
1 
2 
4 
4 
8 
8 
12 
12 
16 
 
women only)28 
Serum for specific 
IgE for Fel d 1 
and cat hair 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
Serum for sIgE 
(Fel-D 2, 4, 7) 
tests17 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
Research samples 
(serum and 
plasma) 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Research 
Samples: whole 
blood for PBMCs 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Nasal brushing 
samples for RNA 
analysis26 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Genomic DNA 
sample18 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
PK19 and ADA 
Drug conc. 
sample 
 
 
 
 
X15 
X19 
 
X 
 
X 
 
X 
 
X 
X 
ADA sample 
 
 
 
 
X15 
 
 
 
 
 
 
X 
 
X 
X 
 
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8.1.1. 
Footnotes for the Schedule of Events Table 
1. 
All screening-related procedure should be performed between day -85 to -14 
2. 
Randomization/study drug administration (visit 5) must occur within 14 to 28 days of 
visit 3.   
3. 
Controlled Cat Allergen Challenge is performed as described in the study manual. 
4. 
Screening Skin prick test for cat hair and skin prick testing for other common 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 allergen skin prick testing, blood draw, spirometry, etc). 
5. 
At screening visit 1, a spirometry session will be completed to check for FEV1 inclusion 
criteria.  At visit 2, spirometry will be performed at baseline prior to the placebo EEU 
challenge, and then every 10 minutes during the placebo challenge, then every 30 minutes 
in the supervision room for 6 hours.  On the Cat Allergen Challenge visits (3, 6, 7, 9, and 
10) spirometry will be performed at baseline prior to entry into the EEU, every 10 minutes 
during the EEU exposure, every 30 minutes in the observation room for 6 hours after 
leaving the EEU, and then every hour for up to 18 hours after leaving the clinical unit 
except during sleeping.  At visit 5, on the day of randomization, a spirometry session will 
be performed twice: once prior to receiving the study drug and once prior to leaving the 
clinical trial unit.  Additional spirometry may be performed when prompted by asthma 
symptoms.   
6. 
TNSS, TOSS, and chest symptom questions are assessed prior to Cat Allergen Challenge, 
approximately every 20 minutes during the challenge in the exposure unit, every 1 hour 
for 6 hours post-challenge while patients are being observed in the observation room, and 
then every 2 hours up to 18 hours after leaving the clinical unit, while they are home, 
except for the time that they are sleeping.  Further details are provided in the study 
manual. 
7. 
PNIF is assessed prior to Cat Allergen Challenge, approximately at the time of the EAR, 
and approximately 6 hours post-challenge while patients are being observed in the 
observation room.  Further details are provided in the study manual. 
8. 
Titrated SPT with Serial Allergen Titration with cat allergen will be performed at 
screening visit 3, days 29, 85, and 113.  On days when an allergen challenge is performed, 
the test will be performed prior to allergen challenge.   
9. 
FeNO is assessed during screening, Visit 4 and then 24 hours after EEU exposure at day 
30 and day 86. 
10. All safety assessments performed at screening have to be normal and checked against the 
inclusion/exclusion criteria prior to REGN1908-1909 administration on day 1 (baseline). 
11. On day 1, vital signs are taken prior to PK draw, prior to REGN1908-1909 administration, 
and at 2 hours (±10 min) after completion of the injection. 
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12. Vital signs are taken prior to entry into the EEU, at exit from the EEU, and prior to 
leaving the clinical trial unit, and any additional times as needed.  
13. Telephone call to collect AEs and concomitant medications, including any medications 
used from the rescue treatment kit, up to 24 hours after the EEU exposure.  
14. Total blood draw at any visit will never exceed 60 mL.  Blood volumes are never to 
exceed 350 mL in 12 weeks. 
15. Samples are collected prior to administration of REGN1908-1909. 
16. On day 1, urine pregnancy test is completed prior to administration of REGN1908-1909 in 
women of childbearing potential.  Postmenopausal women do not need urine pregnancy 
testing. 
17. Total IgE and allergen-specific serum IgE levels (Fel d 2, Fel d 4, Fel d 7).  
18. Genomic analysis is mandatory 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.  
 
 
19. PK samples are drawn at any time in the outpatient visit day from day 8 through day 113 
(end of study) visit. 
20. After exiting the EEU, patients are monitored outside the EEU in an observation room for 
approximately 6 hours.    
21. Patients will be observed for 6 hours in the observation room after receiving a single dose 
of REGN1908-1909 or placebo. 
22. Blood draws should be performed before the EEU exposure 
23. Cat EEU visit 3 and visit 6 must be spaced at least 3 weeks apart  
24. Assessments and procedures at the unscheduled visit(s) are to be performed at the 
discretion of the principle investigator. 
25. Screening visits 1 and 2 may be combined into 1 visit if the patient has a historical, 
positive cat SPT or cat IgE that was completed in the last 12 months. 
26. Nasal brushing samples will be collected from the patients before and after Cat Allergen 
Challenge in the EEU on the day of the screening challenge (visit 3) and day 29 (visit 7). 
Before the challenge in the EEU, a baseline nasal brushing will be performed in 1 nare and 
the samples will be processed. Six hours from the start of the EEU challenge, a nasal 
brushing will be performed in the contralateral nare. 
27. Physical examination will be performed prior to entering the EEU and approximately 
6 hours after the exit or before leaving the observation room, whichever is later. 
28. FSH test to be performed in postmenopausal women only, if postmenopausal status in a 
woman is in question. 
ACT: asthma control test; EEU: environmental exposure unit; PBMC: peripheral blood 
mononuclear cell; R: randomization; V: visit 
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8.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study after randomization or at any visit before the end of 
study day 113 will be asked to return to the study site once for an early termination visit 
consisting of the end of treatment assessments described in Table 1.  
8.1.3. 
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. 
8.2. 
Study Procedures 
The following procedures are performed as described in the Study Operations Manual, at time 
points according to Table 1: 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed to determine study eligibility or to characterize the 
baseline population:  demographics, screening for HIV, screening for hepatitis (HBsAg and 
hepatitis C antibody), FSH determination (in postmenopausal women if postmenopausal status is 
in question), medical history, and ECG. 
8.2.2. 
Efficacy Procedures  
8.2.2.1. 
Total Nasal Symptom Score  
Total nasal symptom score is 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 congestion, itching, and 
rhinorrhea, and from 0 (none) to 3 (5 or more sneezes) for sneezing. 
8.2.2.2. 
Total Ocular Symptom Score  
Total ocular symptom score is from 0 to 12 and is based on a 4-point Likert scale ranging from 0 
(none) to 3 (severe) for itching/burning, redness, swelling/puffiness, and tearing/watery eyes.   
8.2.2.3. 
Chest Symptoms Questions 
Individual respiratory symptoms of chest tightness/shortness of breath/trouble breathing, 
wheezing, and coughing are evaluated on a 4-point Likert scale ranging from 0 (none) to 3 
(severe). 
8.2.2.4. 
Spirometry 
Study staff-supervised spirometry will be performed in all patients at visits shown in Table 1 
with a standard measurement of FEV1.  FEV1 will be measured by means of spirometry at 
10-minute intervals during placebo and cat allergen exposures in the EEU, every 30 minutes 
during the 6-hour observation period after leaving the EEU. Additional spirometry may be 
performed when prompted by asthma symptoms and/or at the discretion of the investigator.  
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At home spirometry will be performed hourly for approximately 18 hours after leaving the 
clinical unit, excluding hours when the patient is sleeping.  Additional spirometry may be 
performed when prompted by asthma symptoms  
Spirometry will be measured on the day of randomization prior to receiving the study drug and 
will be measured after 6 hours prior to leaving the clinic.  At the end of the 6-hour monitoring 
period, patients will undergo a physical exam and vital signs, including spirometry, and will be 
discharged home if there are no abnormal findings and if FEV1 ≥90% of baseline.  Otherwise, in 
case of FEV1 is <90% of the baseline value, patients will continue to be monitored at the clinic 
until the patient meets criteria for discharge.  
Spirometry measurements include FVC (L), FEV1 (L), FEV1/FVC (%), PEF (L/s), FEF 25-75 
(L/s).  Minute ventilation (L/min) will also be measured using spirometry at screening 1 time 
while the patient is at rest, and this value will be used to calculate allergen exposure throughout 
the study (minute ventilation x Fel d 1 40 ng/m3 x time). 
8.2.2.5. 
Fractional Exhaled Nitric Oxide  
Fractional exhaled nitric oxide (measured in parts per billion, which is equivalent to nanoliters 
per liter) will be assessed as described in the study manual at each time point according to 
Table 1.  FeNO is sampled by the nitric oxide analyzer, and the resultant nitric oxide profile 
versus time or exhaled volume, together with other exhalation variables (eg, airway flow rate 
and/or pressure), is captured and displayed.  
8.2.2.6. 
Peak Nasal Inspiratory Flow 
Peak nasal inspiratory flow (PNIF) (measured in nasal patency, L/min) will be assessed as 
described in the Study Operations Manual at each time point according to Table 1.  PNIF will be 
measured and recorded approximately at the time of the EAR during the Cat Allergen Challenge 
in the EEU and then approximately 6 hours after the EAR during the observational period.   
8.2.2.7. 
Skin Prick Test with Serial Allergen Titration 
The skin prick test (SPT) with serial allergen titration assesses the early phase reaction.  Serial 
dilutions of cat hair extract are placed in duplicate, using skin prick tests on the patient’s 
forearm, and mean wheal diameters are measured 15 minutes after placement.  
8.2.3. 
Safety Procedures  
8.2.3.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, pulse, respiratory rate, and oximetry, 
will be collected at time points according to Table 1.  During EEU visits, vital signs will be 
collected before each EEU exposure, at the end of the EEU exposure, and 6 hours after the 
exposure.  
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8.2.3.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1.  Care should be taken to examine and assess any abnormalities that may be present, as 
indicated by the patient’s medical history. 
8.2.3.3. 
Asthma Control Test 
The asthma control test (ACT) is comprised of patient-reported asthma symptoms using a 
5-point Likert scale comprised of 5 elements rated 1-5, with higher scores representing better 
asthma control.  ACT will be performed at screening and at the end of the study at time points 
according to Table 1. 
8.2.3.4. 
Telephone Call 
Patients will be called approximately 24 hours after EEU exposure after the EEU visits on days 8 
and 57.  Phone calls will collect information on AEs and concomitant medications, including any 
asthma symptoms and medications used from the rescue treatment kit that the patient was sent 
home with after the EEU visit.  During the call, study staff will recommend any further treatment 
and visit follow-up if needed based on investigator discretion. 
NOTE: patients will return to the Alyatec site approximately 24 hours after the EEU exposure on 
days 29 and 85 for FeNO measurements, therefore they will not receive a telephone call after 
these visits per SOE (Table 1).   
8.2.3.5. 
Electrocardiogram 
A standard 12-lead ECG will be performed at screening. 
8.2.3.6. 
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.  No 
greater than the allowed maximum of 350 mL of blood collection will be collected during a 
12-week period.  Samples for laboratory testing will be collected at visits according to Table 1.  
Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Uric acid 
Chloride 
Blood urea nitrogen (BUN)/Urea 
Creatine phosphokinase (CPK) 
Carbon dioxide 
Aspartate aminotransferase (AST) 
 
Calcium 
Alanine aminotransferase (ALT) 
 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
 
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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 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
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 menopausal. Samples will be collected for quantitative 
assessment of total and allergen-specific IgE. 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality.  When necessary, appropriate ancillary investigations 
should be initiated.  If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director 
must be consulted.   
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5. 
8.2.4. 
Drug Concentration and Measurements 
Samples for drug concentration will be collected at visits listed in Table 1.  
 
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8.2.5. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 1. 
Detailed instructions for blood sample collection are included in the laboratory manual provided. 
 
8.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
8.2.6.1. 
Biomarkers 
Serum Antibodies 
Serum allergen-specific IgE levels (cat hair, Fel d 1) will be measured at screening visit 1 and as 
described in Table 1.  Serum allergen-specific IgE levels (Fel d 2, Fel d 4, Fel d 7 and other 
common allergens) will be measured at baseline and days of EEU challenge to assess 
sensitization status and to evaluate the relationship between response to REGN1908-1909 and 
poly/mon-sensitization.  
 
 
Screening Skin Prick Test 
Standard SPT with cat hair extract and other common allergens will only be performed at 
screening visit 1 to assess sensitization status. 
SPT with Serial Allergen Titration with Cat Hair Extract  
Skin Prick Test with Serial Allergen Titration with cat hair extract (Cat-SPT) will be performed 
at screening visit 3 and days 29, 85, and end of study to confirm pharmacodynamic effects of 
REGN1908-1909 on wheal size response (mediated by mast cell degranulation). 
Nasal Brushing Samples 
Nasal brushing samples will be collected from the patients before and after Cat Allergen 
Challenge in the EEU on the day of the screening challenge (Visit 3) and day 29 (Visit 7). Before 
the challenge in the EEU, a baseline nasal brushing will be performed in 1 nare and the samples 
will be processed.  Six hours from the start of the EEU challenge, a nasal brushing will be 
performed in the contralateral nare and the sample will be processed.  Nasal brushing is 
performed by a clinician experienced in nasal procedures under direct visualization, by inserting 
a soft, sterile cytobrush into the nare alongside the inferior nasal turbinate of 1 nostril 
approximately 0.5 cm above the floor of the nose and 1.5 cm into the nasal cavity and rotating 
the brush 180 degrees once to the lateral aspect of the nostril.  RNA will be extracted from nasal 
brushing samples and will be used to perform RNA sequencing to determine changes in type 2 
inflammation in the nasal mucosa.  
Interference Assay with REGN1908-1909 
Serum samples from patients before drug exposure will be tested an in-vitro competition assay to 
assess whether REGN1908-1909 could inhibit the binding of endogenous anti-fel-d1 IgE to the 
allergen.  
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8.2.6.2. 
Environmental Cat Hair Density 
The EEU is operated under conditions to maintain stringent control of temperature, relative 
humidity, ventilation rate, particle number, particle size, and concentration of aorne cat hair 
extract. Standardized allergen extracts are administered through a nebulizer (SinapTec®) to 
ensure uniform particle count and size in the EEU.  Ten particle counters (APEX R05) 
positioned in the EEU provide continuous monitoring to confirm uniformity of patient allergen 
exposure during the allergen challenge.  Airborne Fel d 1 concentrations will be sampled at 
5 locations in the EEU using 25 mm round fiber filters (Millipore Corp, Bedford, MA) and a 
multiplex proteomics platform that will be used to measure airborne concentrations of cat 
allergens.  Fel d 1 levels will be measured with a Fel d 1–specific ELISA (King, 2013).   
Fel d 1 levels will be measured with a Fel d 1–specific ELISA performed by Indoor 
Biotechnologies.  
 
 
 
 
 
  
 
 
 
 
 
8.2.7.1. 
Genomics Study (Mandatory) 
DNA samples for the genomics study will be single-coded as defined by the International 
Council for Harmonisation (ICH) guideline E15.  Samples for DNA extraction should be 
collected on day 1/baseline (predose) according to Table 1.  
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
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9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patients, according to local regulations.  This 
may include death from any cause and all SAEs related to the use of the study drug. It is 
recommended that all SAEs be reported to the EC, according to local regulations.  
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, ECs/s as appropriate, and to the 
investigators (in a blinded manner).  
Any AE not listed as an expected event in the Reference Safety Information section of the 
Investigator’s Brochure will be considered as unexpected. Any worsening of or new onset of 
symptoms related to cat-allergen-induced allergy which occur during the screening/washout 
period prior to study drug administration will be considered expected. 
In addition, the sponsor will report all other SAEs to the health authorities, according to local 
regulations. 
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 ECs/s as appropriate. 
9.3. 
Definitions 
9.3.1. 
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. 
An AE also includes any 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. 
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9.3.2. 
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 inpatient hospitalization or prolongation of existing hospitalization.  
Inpatient hospitalization is defined as admission to a hospital or an emergency room 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.  See Section 9.4 for more 
information on recording and reporting SAEs. 
9.3.3. 
Adverse Events of Special Interest 
No AEs of special interest are defined for this study. 
9.4. 
Recording and Reporting Adverse Events  
9.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of study with the exception of symptoms that occur in response to the 
EEU within 24 hours following the EEU.  Asthmatic and allergic symptoms that occur in 
response to the EEU are not to be reported as AEs, as they will be recorded as outcome 
measures.  However, AEs that occur in response to allergen exposure in the EEU that are outside 
of expected symptoms, including events which qualify as SAEs, up to 24 hours after EEU should 
be reported as AEs and SAEs as applicable.   
Information on follow-up for AEs is provided in Section 9.4.6.  Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
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9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours.   
Information not available at the time of the initial report must be documented in a follow-up 
report.  Substantiating data such as relevant hospital or medical records and diagnostic test 
reports may also be requested. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
 SAE with an onset within 30 days of the end of study/early termination if the patient 
early terminated from the study - the SAE will be reported to the sponsor.  The 
investigator should make every effort to obtain follow-up information on the outcome 
until the event is considered chronic and/or stable. 
 SAE with an onset day greater than 30 days from the end of study/early termination 
visit - only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of 
learning of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 
2 times the intended dose of study drug within the intended therapeutic window, if 
associated with an AE, 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of 
identification, any pregnancy occurring in a female or female partner of a male, 
during the study or within 6 months of the last dose of study drug.  Any 
complication of pregnancy affecting a female study patient or female partner of a 
male 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. 
Adverse Events of Special Interest: 
No Adverse Events of Special Interest (AESIs) have been defined for this study. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
Medical/Study Director within 30 days. 
 
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9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 the test result is associated with accompanying symptoms,  
 the test result requires additional diagnostic testing or medical/surgical intervention,  
Contact the Medical/Study Director in the event the investigator feels that an abnormal test 
finding should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale 
outlined in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of 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. 
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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 
ER visit or hospitalization; necrosis or exfoliative dermatitis 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the blinded investigator and will be a 
clinical decision based on all available information.  The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related: 
There is no reasonable possibility that the event may have been caused by 
the study drug 
Related: There is a reasonable possibility that the event may have been caused by the study 
drug 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided 
below.  Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable, temporal sequence following the time of administration of 
the dose of study drug 
 do not reappear or worsen when dosing with study drug is resumed 
 are not a suspected response to the study drug based upon preclinical data or prior 
clinical data 
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Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable, temporal sequence following the time of administration of the 
dose of study drug  
 resolve or improve after discontinuation of study drug  
 reappear or worsen when dosing with study drug  
 are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
Relationship of Adverse Events to Study Procedure 
The relationship of AEs to the EEU exposure will be assessed by the blinded investigator and 
will be a clinical decision based on all available information.  The following question will be 
addressed: 
Is there a reasonable possibility that the AE may have been caused by the EEU exposure? 
The possible answers are: 
Not Related: 
There is no reasonable possibility that the event may have been caused by 
the EEU exposure 
Related: There is a reasonable possibility that the event may have been caused by the EEU 
exposure 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
A list of factors to consider in assessing the relationship of AEs to EEU exposure is provided 
below.  Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by EEU exposure? 
No: 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the EEU exposure  
 do not reappear or worsen when the EEU exposure is resumed 
 are not a suspected response to the EEU exposure based upon preclinical data or prior 
clinical data 
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Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the patient’s disease state or clinical condition 
 follow a reasonable, temporal sequence following the EEU exposure  
 resolve or improve after discontinuation of study drug EEU exposure  
 reappear or worsen when the EEU exposure is resumed 
 are known or suspected to be a response to EEU exposure. based upon preclinical 
data or prior clinical data 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The Medical/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but will be supported by other 
departments (eg, Pharmacovigilance and Risk Management; Biostatistics and Data 
Management).  Safety monitoring will be performed on an ongoing basis (eg, individual review 
of SAEs) and on a periodic, cumulative aggregate basis. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the reference 
safety information in the Investigator’s Brochure and has a reasonable suspected causal 
relationship to the study drug). 
10. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP 
may be revised during 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 database is locked. 
Analysis variables are listed in Section 4. 
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10.1. 
Statistical Hypothesis  
The primary endpoint is the time to EAR upon day 8 Controlled Cat Allergen Challenge in an 
EEU.  During the allergen challenge, the patient may remain in the EEU for a maximum of 4 
hours.  If a patient does not experience an EAR and remains in the EEU for the maximum time, 
their time to EAR will be censored at 4 hours.  Censoring implies that the time to EAR is at least 
4 hours, but the exact time is unknown.  The statistical model will be a Cox’s proportional 
hazards model to compare the hazard ratio of EAR on day 8 in REGN1908-1909-treated patients 
to placebo-treated patients.  This model allows for covariate adjustment for allergen exposure 
and the patient’s time to EAR during the baseline Cat Allergen Challenge.  Under this model, the 
hazard ratio is directly related to the ratio of median duration of tolerated exposure, where a 
hazard ratio of 1 implies that the median duration of tolerated exposure in the 2 treatment groups 
is the same.  The following null and alternative hypotheses of the primary endpoint will be 
tested: 
H0: 
The hazard rate of EAR during the day 8 Controlled Cat Allergen Challenge is the same 
in patients receiving REGN1908-1909 and placebo (hazard ratio, HR = 1) 
H1: 
The hazard rate of EAR during the day 8 Controlled Cat Allergen Challenge is lower (ie, 
the median duration of tolerated exposure is longer) in the REGN1908-1909-treated patients as 
compared to placebo-treated patients (HR <1) 
10.2. 
Justification of Sample Size 
The primary objective of this study is to assess the time to EAR in a Controlled Cat Allergen 
Challenge in patients receiving REGN1908-1909 compared to placebo-treated patients.  Patients 
will be randomized (1:1) to receive placebo or REGN1908-1909.  With 30 patients per treatment 
arm, an increase in median time to EAR from 58 minutes in the placebo-treated patients to 
132 minutes in patients treated with REGN1908-1909 (ratio of median duration of tolerated 
exposure of 2.25 or, equivalently, hazard ratio of 0.44) can be detected with 84% power 
assuming a one-sided type I error of 0.05 and a 13% dropout rate (8 patients).  A median time to 
EAR of 58 minutes was observed in untreated patients in the Alyatec validation study 
(Gherasim, 2018) and the ratio of median duration of tolerated exposure of 2.25 is based on the 
estimated effect size observed in a previous Cat Allergen Challenge study (Corren, 2011).  The 
sample size calculation was performed based on the log-rank test comparing the duration of 
tolerated exposure of 2 groups with the above-mentioned assumptions.   
With 60 cat-allergic patients, this study also has 88% power to detect differences in the key 
secondary endpoint, AUC of the percent change (%/h) in FEV1 induced by a Controlled Cat 
Allergen Challenge over the exposure interval (%/h) from baseline to the Controlled Cat 
Allergen Challenge in patients treated with placebo as compared to REGN1908-1909.  This 
power calculation assumes a mean AUC of 27% in the placebo-treated patients compared to 15% 
in patients treated with drug, based on a previous Cat Allergen Challenge study and a one-sided 
type I error of 0.05 (Corren, 2011).  The primary analysis will be conducted on the full analysis 
set (FAS) population. 
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10.3. 
Analysis Sets  
10.3.1. 
Efficacy Analysis Sets 
The FAS includes all randomized patients who received any study drug; it is based on the 
treatment allocated (as randomized).  Efficacy endpoints will be analyzed using the FAS. 
The per protocol analysis set (PPS) includes all patients in the FAS except for those who are 
excluded because of efficacy-related major protocol violations.  Final determination of the PPS 
will be made prior to the database lock and will be outlined in the SAP. 
10.3.2. 
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.  No missing data will be imputed for 
safety analyses. 
10.3.3. 
Pharmacokinetic Analysis Sets 
The PK population includes all treated patients who received any study drug (safety population) 
and had at least 1 non-missing blood sample for drug concentration following a single dose of 
REGN1908-1909. Patients will be analyzed according to the treatment actually received. 
10.3.4. 
Anti-Drug Antibody Analysis Sets 
The ADA analysis set will consist of all patients who received any study drug and who had at 
least 1 non-missing ADA result after a single dose of the study drug.  Patients will be analyzed 
according to the treatment actually received. 
10.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information:  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. 
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10.4.1. 
Patient Disposition 
The following will be provided: 
 The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the informed consent form (ICF) 
 The total number of randomized patients:  received a randomization number 
 The total number of patients in each analysis set (eg, FAS, provided in Section 10.3.2) 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 A listing of patients treated but not randomized, patients randomized but not treated, and 
patients randomized but not treated as randomized 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.   
10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The time to EAR will be defined as the time to a ≥20% reduction in FEV1 or when the patient 
voluntarily departs the EEU due to clinically significant allergic and/or asthma symptoms.  The 
time to EAR for each treatment will be examined using Kaplan Meier estimates with patients 
being censored at 4 hours if they did not experience an EAR and remained in the EEU for 4 
hours.  If a patient leaves the EEU before experiencing an EAR and for reasons unrelated to their 
clinical symptoms, they will be censored at the time of EEU departure.  The median time to EAR 
for each treatment group and the corresponding 95% confidence intervals will be presented for 
each Controlled Cat Allergen Challenge. A formal comparison of time to EAR in the treatment 
groups at day 8 will be performed using a Cox proportional hazards model, adjusting for allergen 
exposure and time to EAR in the baseline Cat Allergen Challenge.  The ratio of Fel d 1 IgE to 
Cat Hair IgE at baseline will also be explored as potential covariate in the model.  In patients 
who receive EEU related medications (including medications given on-site and rescue 
medications taken at-home), the impact of the carryover of medications between challenges will 
be explored.  A one-sided statistical test of the hazard ratio for placebo compared to drug will be 
performed.  
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10.4.3.2. Secondary Efficacy Analysis 
The time to EAR for Cat Allergen Challenges on days 29, 57, and 85 will be evaluated in a 
similar way to the primary analysis.  The time course of asthma response comprising EAR and 
LAR will be visualized and summarized.  Methods for handling missing data in the case that a 
patient does not complete 1 or more of the Cat Allergen Challenges will be addressed in the 
SAP. 
The AUC of percentage change from baseline FEV1 during the Controlled Cat Allergen 
Challenge will be analyzed by mixed-effect model repeated measures (MMRM) with the 
treatment, time, treatment-by-time interaction, and day of challenge as factors and baseline 
FEV1 as a continuous covariate.  An unstructured covariance structure will be utilized; if the 
model does not converge, an autoregressive structure will be employed.  Between-group 
estimates and nominal p values will be reported for Controlled Cat Allergen Challenges on days 
8, 29, 57, and 85.  The AUC will be a time-adjusted-based duration of exposure to account for 
patients exiting the EEU at different times.  Missing data from Controlled Cat Allergen 
Challenges on days 8, 29, 57, or 85 will be accounted for via MMRM.  The AUC of percent 
change in TNSS and TOSS and change and percent change in cat allergen exposure from the 
baseline Cat Allergen Challenge, will be analyzed in a similar manner. 
10.4.3.3. Multiplicity Considerations 
There is no control for multiplicity on the secondary or exploratory endpoints. 
10.4.3.4. Timing of Analyses 
10.4.3.4.1. First-Step Analysis 
A first-step analysis may be performed when the last patient completes day 8 of the treatment 
period and has undergone the Cat Allergen Challenge in the EEU at day 8.  No changes in the 
conduct of the study will be made based on this first-step analysis.  The purpose of the first-step 
analysis is to accelerate the planning of future studies.  This will be the final analysis of the 
primary endpoint of the study.  If a decision is made to perform the first-step analysis, in order to 
maintain study integrity with respect to the treatment follow-up visits, safety visits, and analyses, 
a dissemination plan will be written.  This plan will clearly identify the team (including the 
statistician) that will perform the first-step analysis and all related activities, restrict other clinical 
team members and other Sponsor personnel from access to individual patient treatment 
allocation, and ensure that the dedicated team will not participate in the data review or data 
decisions for the following treatment analyses.  However, the dedicated team can participate in 
the analysis following the final database lock.   
10.4.4. 
Safety Analysis 
Safety analysis will be based on the SAF.  This includes reported TEAEs and other safety data 
(ie, clinical laboratory evaluations and vital sign results).  A descriptive summary of safety 
results will be presented by treatment group. 
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10.4.4.1. Adverse Events 
Definitions 
For safety variables, 2 observation periods are defined: 
 The pretreatment period is defined as the time from signing the ICF to before the 
single dose of study drug. 
 The treatment period is defined as the time after the single dose of study drug until 
the end of study (week 16). 
Treatment-emergent adverse events are defined as those that are not present at baseline or 
represent the exacerbation of a pre-existing condition during the treatment period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest-level terms.  The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs by treatment group will include: 
 The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
 TEAEs by severity (according to the grading scale outlined in Section 9.5.1), 
presented by SOC and PT 
 TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
10.4.4.2. 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.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out-of-laboratory range values. 
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10.4.4.3. Treatment Exposure 
This is single-dose study. 
10.4.4.4. Treatment Compliance 
As a single-dose trial where patients are dosed in clinic, the patients who are randomized but do 
not receive study treatment drug will be listed. 
10.4.5. 
Pharmacokinetics 
10.4.5.1. Analysis of Drug Concentration Data 
Descriptive statistics of total REGN1908 and total REGN1909 at each sampling time will be 
provided.  Plots of mean concentrations (linear and log scales) versus time will be presented.   
10.4.5.2. Analysis of Pharmacokinetic Parameters 
Descriptive statistics of the calculated PK parameter specified in Section 4.4 will be provided. 
10.4.6. 
Analysis of Immunogenicity Data 
Formation of ADA will be assessed in individual patients and per treatment group as follows:  
 Possible association between changes in PK profile and the presence of R1908-1909 
antibodies will be evaluated to assess the potential impact of anti-R1908-1909 antibodies 
on drug exposure   
 Possible association between AEs and the presence of anti-R1908-1909 antibodies may 
be evaluated to identify a potential impact of anti-R1908-1909 antibodies on safety. 
Patients with ADA response categories will be listed and summarized as appropriate 
10.4.7. 
Exposure-Response Analysis 
If appropriate, exploratory analyses investigating the relationship between measures of drug 
exposure and response (including biomarkers) may be performed. 
10.5. 
Interim Analysis  
No formal interim analysis is planned.10.4.3.4   
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10.6. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline:  
The last assessment before the administration of study drug on day 1 will be considered as the 
baseline evaluation. 
General rules for handling missing data:  
 Rules for handling missing data for assessment (other than efficacy) 
 If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment.  If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be 
imputed; otherwise, the missing day or month by the first day or the first month will 
be imputed.  
 No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be made for the purposes of safety analyses. 
Visit windows: 
 Assessments taken outside of protocol allowable windows will be displayed 
according to the case report form (CRF) assessment recorded by the investigator. 
Unscheduled assessments: 
 Extra assessments (laboratory data or vital signs associated with nonprotocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings and PCSV tabulations, but not summaries.  If more than 1 laboratory value is 
available for a given visit, the first observation will be used in summaries and all 
observations will be presented in listings. 
10.7. 
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. 
10.8. 
Data Management and Electronic Systems 
10.8.1. 
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). 
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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 Medidata Rave. 
10.8.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IWRS system – randomization, study drug supply 
 Medidata Rave electronic data capture (EDC) System – clinical data capture 
 Statistical Analysis System (SAS) – statistical review and analysis 
 Pharmacovigilance safety database 
 Connected Spirometry 
11. 
STUDY MONITORING 
11.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient, and periodically during the study. 
The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current, approved protocol version and any other study agreements, ICH 
GCP, and all applicable regulatory requirements. 
11.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
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. 
11.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (eCRFs) within the EDC system by trained site personnel.  All required CRFs must be 
completed for each and every patient enrolled in the study.  After review of the clinical data for 
each patient, the investigator must provide an electronic signature.  A copy of each patient CRF 
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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. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
 Informing the sponsor of a planned inspection by the authorities as soon as notification is 
received, and authorizing the sponsor’s participation in the inspection 
 Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
 Communicating any information arising from inspection by the regulatory authorities to 
the sponsor immediately 
 Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
 Documents subject to audit or inspection which include but are not limited to all source 
documents, CRFs, medical records, correspondence, ICFs, ECs 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. 
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. 
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 EC.  A copy of the EC-approved ICF and documentation of 
approval must be provided to the sponsor before study drug will be shipped to the study site. 
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It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient 
in language that he/she can understand.  The ICF should be signed and dated by the patient and 
by the investigator or authorized designee who reviewed the ICF with the patient.   
 Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
 Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF 
must be reviewed and updated appropriately.  All study patients must be informed of the new 
information and provide their written consent if they wish to continue in the study.  The original, 
signed, revised ICF must be maintained in the patient’s study record and a copy must be given to 
the patient. 
13.2. 
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. 
13.3. 
Ethics Committee 
An appropriately constituted 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 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 EC should be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical study. 
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A copy of the EC approval letter with a current list of the 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 EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
EC-approved amendment. All substantial protocol amendments will be approved by the 
competent authorities before changes are implemented according to national regulations. 
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 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. 
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16. 
STUDY DOCUMENTATION 
16.1. 
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 
eCRF that will be provided to the sponsor. 
16.2. 
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.  
17. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted, and the data are 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 summarized.  
Data Management 
The sponsor is responsible for the data management of this study including quality checking of 
the data (Section 10.8.1). 
Study Monitoring 
The investigator must allow study-related monitoring, EC review, audits, and inspections from 
relevant health regulatory authorities, and provide direct access to source data documents 
(Section 11.1, Section 11.2, and Section 12) 
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 (Section 11.1). 
All patient data collected during the study will be recorded on paper or electronic CRF unless the 
data are transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for affirming that data entries in the CRF are accurate and correct by 
electronically signing a declaration that accompanies each set of patient final CRF (Section 11.3 
and Section 16.1).  
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Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF (Section 11.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 16.2).  
18. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
19. 
FINANCING AND INSURANCE  
Financing and insurance information is provided as a separate agreement. 
20. 
PUBLICATION POLICY  
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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26. O'Byrne PM, van der Linde J, Cockcroft DW, Gauvreau GM, Brannan JD, Fitzgerald M, 
et al. Prolonged bronchoprotection against inhaled methacholine by inhaled BI 1744, a 
long-acting beta(2)-agonist, in patients with mild asthma. J Allergy Clin Immunol. 2009 
Dec;124(6):1217-21. 
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27. Olivieri M, The risk of respiratory symptoms on allergen exposure increases with 
increasing specific IgE levels. Allergy 2016; 71: 859–868  
28. Orengo J, Radin A, Kamat V, Badithe A, Ben L, Bennett B, Sharon Zhong S,  Birchard D, 
Limnander A, Rafique A,Bautista J, Kostic A, Newell D,  Duan X, Franklin M, Olson W, 
Huang T, Gandhi N, Lipsich L, Stahl N,  Papadopoulos N,  Murphy A, and Yancopoulos 
G.  Treating cat allergy with monoclonal IgG antibodies that bind allergen and prevent IgE 
engagement. Nature Communications (In Press, 2018) 
29. Patel D, Couroux P, Hickey P, Salapatek AM, Laidler P, Larché M, Hafner RP. Fel d 1-
derived peptide antigen desensitization shows a persistent treatment effect 1 year after the 
start of dosing: a randomized, placebo-controlled study. Allergy Clin Immunol 2013 
131(1): 103-9. e1-7 
30. Perry T, Corren J, Philip G, Kim E, Conover-Walker M K, Malice M P, Massaad R, Dass 
S, Reiss T, and Wood R, Protective effect of montelukast on lower and upper respiratory 
tract responses to short-term cat allergen exposure. Ann Allergy Asthma Immunol. 2004; 
93:431–438 
31. Poole A, et al. Dissecting childhood asthma with nasal transcriptomics distinguishes 
subphenotypes of disease. J Allergy Clin Immunol. 2014. 133:670-678 e612. 
32. Perzanowski M, Relevance of specific IgE antibody titer to the prevalence, severity, and 
persistence of asthma among 19-year-olds in northern Sweden. J Allergy Clin Immunol 
2016; 138(6):1582-1590 
33. Pfaar O, Calderon MA, Andrews CP, Angieli E, Bergmann KC, et al.  Allergen exposure 
chambers: harmonizing current concepts and projecting the needs for the future- an 
EAACI position paper. Allergy 2017; Jul; 72(7): 1035-1042. 
34. Popa V. ATS guidelines for methacholine and exercise challenge testing. Am J Respir Crit 
Care Med 2001; Jan; 163(1):292-3. 
35. Radu C, Choual I, Khayath N, Schoettel F, et al.  Clinical validation of environmental 
exposure chamber in Strasbourg (ALYATEC) with cat in asthmatic patients.  J Allergy 
Clin Immunol 2018; 141(2), suppl: AB213. 
36. Scadding GW, Calderon MA, Shamji MH, Eifan AO, Penagos M, Dumitru F, Sever ML, 
Bahnson HT, Lawson K, Harris KM, Plough AG, Panza JL, Qin T, Lim N, Tchao NK, 
Togias A, Durham SR, 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; Feb 14;317(6):615-625 
37. van Ree R, van Leeuwen WA, Bulder I, Bond JF, Aalberse RC. Purified natural and 
recombinant Fel d 1 and cat albumin in in vitro diagnostics for cat allergy. J Allergy Clin 
Immunol 1999;104(6):1223-30 
38. Walker SM, Durham SR, Till SJ, Roberts G, Corrigan CJ, Leech SC, et al. 
Immunotherapy for allergic rhinitis. Clin Exp Allergy 2011;41(9):1177-2000 
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39. Wood RA, Eggleston PA. The effects of intranasal steroids on nasal and pulmonary 
responses to cat exposure. Am J Respir Crit Care Med 1995; 151:315–320.  
40. Wu W, Walters RD, Nadeau GA, Botnick W, Broughton N. An integrated analysis of the 
efficacy of fluticasone furoate nasal spray versus placebo on the nasal symptoms of 
perennial allergic rhinitis.  Allergy Asthma Proc 2013; 34:283-291   
41. Zuberbier T, Bachert C, Bousquet P, Passalacqua G, Walter Canonica G, Merk H, et al.  
GA2 LEN/EAACI pocket guide for allergen-specific immunotherapy for allergic rhinitis 
and asthma.  Allergy 2010;65(12):1525-30. 
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22. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study in Cat-Allergic Patients with Asthma to Evaluate the Efficacy of a Single 
Dose of REGN1908-1909 to Reduce Bronchoconstriction Upon Cat Allergen Challenge 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 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 Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
 A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study in Cat-Allergic Patients with Asthma to Evaluate the Efficacy of a Single Dose of 
REGN1908-1909 to Reduce Bronchoconstriction Upon Cat Allergen Challenge 
 
Patient 
Protocol Number: 
R1908-1909-ALG-1703 
Protocol Version 
R1908-1909-ALG-1703 Amendment 2 
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 Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
 
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Signature Page for VV-RIM-00076626 v1.0
Signature Page for VV-RIM-00076626 v1.0 Approved
ESig Approval
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ESig Approval
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ESig Approval
19 12:54:42 GMT+0000
ESig Approval
000
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 50 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
Clinical Study Protocol Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study in Cat-Allergic Patients with Asthma to Evaluate the Efficacy of a Single 
Dose of REGN1908-1909 to Reduce Bronchoconstriction Upon Cat Allergen Challenge 
Compound: 
REGN1908-1909 
Protocol Number: 
R1908-1909-ALG-1703 
Clinical Phase:  
Phase 2a 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date:  
Statistical Analysis Plan Version 2 / 30 January 2020 
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CONFIDENTIAL
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale ..................................................................................................9 
1.2. 
Study Objectives .........................................................................................................11 
1.2.1. 
Primary Objectives .....................................................................................................11 
1.2.2. 
Secondary Objectives .................................................................................................11 
1.2.3. 
Modifications from SAP Version 1 ............................................................................12 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design and Randomization ..............................................................................13 
2.2. 
Sample Size and Power Considerations .....................................................................13 
2.3. 
Study Plan ...................................................................................................................13 
3. 
ANALYSIS POPULATIONS ....................................................................................15 
3.1. 
The Full Analysis Set (FAS) .......................................................................................15 
3.2. 
The Per Protocol Set (PPS) .........................................................................................15 
3.3. 
The Safety Analysis Set (SAF) ...................................................................................15 
3.4. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................15 
3.5. 
The Anti-Drug Antibody (ADA) Analysis Set ...........................................................15 
4. 
ANALYSIS VARIABLES .........................................................................................17 
4.1. 
Demographic and Baseline Characteristics ................................................................17 
4.2. 
Medical History ..........................................................................................................17 
4.3. 
Pre-Treatment / Concomitant Medication ..................................................................18 
4.4. 
Rescue Medication/or Prohibited Medication During Study ......................................18 
4.4.1. 
Rescue Medications ....................................................................................................19 
4.5. 
Efficacy Variables ......................................................................................................19 
4.5.1. 
Primary Efficacy Variables .........................................................................................19 
4.5.2. 
Secondary Efficacy Variable(s) ..................................................................................19 
4.5.3. 
Exploratory Efficacy Variables ..................................................................................21 
4.6. 
Safety Variables ..........................................................................................................21 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................21 
4.6.2. 
Adverse Events of Special Interest .............................................................................22 
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4.6.3. 
Laboratory Safety Variables .......................................................................................22 
4.6.4. 
Vital Signs ..................................................................................................................23 
4.6.5. 
12-Lead Electrocardiography (ECG) ..........................................................................23 
4.6.6. 
Physical Examination Variables .................................................................................23 
4.7. 
Pharmacokinetic Variables .........................................................................................23 
4.8. 
Immunogenicity Variables ..........................................................................................23 
4.9. 
Biomarker Variables ...................................................................................................23 
5. 
STATISTICAL METHODS .......................................................................................24 
5.1. 
Demographics and Baseline Characteristics ...............................................................24 
5.2. 
Medical History ..........................................................................................................24 
5.3. 
Prior/Concomitant Illnesses and Medications ............................................................24 
5.4. 
Rescue/ Prohibited Medications .................................................................................24 
5.5. 
Subject Disposition .....................................................................................................24 
5.6. 
Analyses of Efficacy Variables ..................................................................................25 
5.6.1. 
Analysis of Primary Efficacy Variable(s) ...................................................................25 
5.6.2. 
Analysis of Secondary Efficacy Variables .................................................................26 
5.6.3. 
Analysis of Other Efficacy Variables .........................................................................26 
5.6.4. 
Adjustment for Multiple Comparison .........................................................................28 
5.7. 
Analysis of Safety Data ..............................................................................................28 
5.7.1. 
Adverse Events ...........................................................................................................28 
5.7.2. 
Clinical Laboratory Measurements.............................................................................30 
5.7.3. 
Analysis of Vital Signs ...............................................................................................30 
5.7.4. 
Analysis of 12-Lead ECG ...........................................................................................30 
5.7.5. 
Physical Exams ...........................................................................................................30 
5.8. 
Analysis of Pharmacokinetic Data ..............................................................................30 
5.9. 
Analysis of Immunogenicity Data ..............................................................................31 
5.9.1. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................31 
5.10. 
Analysis of Biomarker Data .......................................................................................32 
6. 
DATA CONVENTIONS ............................................................................................33 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................33 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................33 
6.3. 
Data Handling Convention for Missing Data .............................................................33 
6.4. 
Data Handling Conventions for Biomarker Data .......................................................34 
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6.5. 
Visit Windows ............................................................................................................34 
6.6. 
Unscheduled Assessments ..........................................................................................34 
7. 
INTERIM ANALYSIS ...............................................................................................35 
8. 
SOFTWARE ...............................................................................................................36 
9. 
REFERENCES ...........................................................................................................37 
10. 
APPENDIX.................................................................................................................38 
10.1. 
Summary of Statistical Analyses ................................................................................38 
10.2. 
Schedule of Time and Events .....................................................................................40 
10.2.1. 
Footnotes for the Schedule of Events Table ...............................................................44 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................46 
 
LIST OF TABLES 
Table 1: 
Schedule of Time and Events .....................................................................................40 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram Schema 1 ..................................................................................11 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AR 
Allergic rhinitis 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
BUN 
Blood urea nitrogen 
CPK 
Creatinine phosphokinase 
EAR 
Early asthmatic response 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EEU 
Environmental exposure unit 
EPR 
Early phase reaction 
FAS 
Full analysis set 
FEV1 
Forced expiratory volume in 1 second  
Fel d 1 
Felis catus (domestic cat) allergen 1  
FeNO 
Fractional exhaled nitric oxide 
GINA 
Global initiative for asthma 
GCP 
Good clinical practice 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgE 
Immunoglobulin E  
INS 
Intranasal corticosteroids 
kAU/L 
Kilo allergy units per liter 
LAR 
Late asthmatic response 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model repeated measures 
PCSV 
Potentially clinically significant value 
PNIF 
Peak nasal inspiratory flow 
PK 
Pharmacokinetics 
PPS 
Per protocol analysis set 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
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Date: 30 January 2020 
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SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SC 
Subcutaneous 
SIT 
Systemic immunotherapy 
SOC 
System organ class 
SPT 
Skin prick test 
TEAE 
Treatment-emergent adverse event 
TNSS 
Total nasal symptom score 
TOSS 
Total ocular symptom score 
WBC 
White blood cell 
 
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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 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 for the R1908-1909-ALG-1703 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/Rationale 
REGN1908 and REGN1909 are monoclonal antibodies (mAbs), which bind independently and 
non-competitively to the Fel d 1 allergen and are being developed as a 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 60–90% of the total allergenic activity in cat dander (Kleine-Tebbe, 1993). 
This phase 2 study (R1908-1909-ALG-1703) aims to investigate the prophylactic effect of 
REGN1908-1909 (anti-Fel d 1) to reduce bronchoconstriction in cat-allergic patients with mild 
asthma when exposed to cat allergen in a controlled environmental exposure unit (EEU).  
Environmental exposure units are enclosed spaces that control temperature, air flow, and humidity, 
and provide diffuse allergen exposure to simulate natural circumstances. Because EEUs provide 
allergen exposures which are standardized and reproducible, they have been developed for the 
investigation of mechanisms and treatment of allergies (Pfaar, 2017).  Globally to date, one EEU 
clinical trial site has been developed and validated to study asthmatic responses to cat allergen 
exposures, namely Alyatec in Strasbourg, France.  Alyatec is an independent, clinical trial unit 
situated in the Nouvel Hôpital Civil, directed by pulmonologist and allergist Dr. Frédéric De Blay.  
The EEU is optimally designed to study patients with asthma upon allergen exposure with real-
time electronic monitoring of FEV1 using hand-held spirometers (Medical International Research 
Spirobank II) and continuous, direct visualization of patients by clinic staff.  Additionally, 
medications to treat asthma, allergy, and anaphylaxis are readily available, and the hospital 
emergency room is within the same hospital building as Alyatec in case of emergency.   
The current 2-arm, placebo-controlled, double-blind, single-dose, randomized, parallel-group 
proof-of-concept (POC) study will enroll approximately 60 cat-allergic patients with allergic 
rhinitis (AR) with or without conjunctivitis not currently living with a cat who have a history of 
GINA 1 asthma.  Patients will be randomized (1:1 ratio) to receive REGN1908-1909 or placebo.  
The study will explore whether a single dose of 600 mg REGN1908-1909 SC can prevent an Early 
Asthmatic Response (EAR) during exposure to cat allergen as measured by spirometry over a 12-
week assessment period. During the screening period, patients will be exposed to 2 EEU 
challenges.  The first EEU challenge will be a 2-hour placebo challenge where normal saline will 
be nebulized into the chamber to exclude asthmatic patients with reductions in FEV1 not 
attributable to allergen. Patients will perform spirometry every 10 minutes, and those who 
experience a reduction in FEV1 >10% at 3 consecutive spirometry measurements will be excluded 
from the study. A second screening challenge to cat allergen, the baseline challenge, will then be 
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performed to exclude patients who do not experience an EAR with cat allergen exposure.  Cat 
allergen (approximately 40 ng/m3 Fel d 1) will be nebulized into the EEU for a maximum of 2 
hours, with the patient performing spirometry every 10 minutes until the patient reaches EAR 
(FEV1 reduction ≥20%) or when the patient voluntarily departs the EEU due to clinically 
significant allergic and/or asthma symptoms.  Upon exiting the EEU, patients will receive a short-
acting 2 agonist, have vitals evaluated, and monitored outside of the EEU for 6 hours for safety 
follow-up and surveillance for a Late Asthmatic Response (LAR).  During this 6-hour observation 
period, spirometry will be performed every 30 minutes, and TNSS, TOSS, and chest symptom 
questions are recorded every hour. At the end of 6-hour monitoring period, patients will be 
discharged home if their FEV1 is ≥90% of the baseline value; additional monitoring will be 
performed if the FEV1 is below 90%.  A physical examination will also be performed and vital 
signs evaluated prior to leaving the clinical trial unit.  After leaving the clinical trial unit, 
spirometry will be performed every hour at home during waking hours using a portable hand-held 
spirometer for approximately 18 hours (a total of 24 hours of monitoring from the end of the EEU 
exposure).  Alyatec’s investigator(s) will be connected to spirometry data performed by the 
patients at home.  If there is a 30% drop in FEV1, the investigator(s) will receive an alarm by email 
to inform him/her about the change in spirometry and the patient will be contacted and evaluated 
by a medical doctor.  Patients will also receive contact information that they will be able to contact 
Investigator(s) 24 hours a day in case of symptoms.   
At time point days 8, 29, 57, and 85 after randomization, patients will be exposed to the EEU for 
a maximum of 4 hours or until they reach EAR (FEV1 reduction ≥20%) and then monitored outside 
of the EEU for 6 hours for safety follow-up, and surveillance of a LAR.  Although the amount of 
cat allergen that is nebulized into the EEU is continuously 40 ng/m3 Fel d 1 (approximately), the 
individual exposure increases over time in association with minute ventilation (the volume of air 
that can be inhaled or exhaled for 1 minute).  Therefore, minute ventilation will be measured in 
each patient at baseline using spirometry, so that the cat allergen airborne exposure, as a product 
of the individual’s minute ventilation and time, can be assessed at each Cat Allergen Challenge on 
days 8, 29, 57, and 85.  Minute ventilation will be measured 1 time at baseline while the patient is 
at rest rather than in real time in the EEU during cat allergen exposure to minimize variability in 
the measurement.   
 
 
 
 
 
 
 
 
 
 
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Figure 1: 
Study Flow Diagram Schema 1 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objective of this study is to evaluate the prophylactic efficacy of REGN1908-1909 
(anti-Fel d 1) administered as a single dose on day 1 in cat-allergic asthmatic patients (not living 
with a cat) in the prevention of a Controlled Cat Allergen Challenge-induced early asthmatic 
response (EAR) assessed by measures of lung function (FEV1) compared to placebo-treated 
patients on day 8. 
1.2.2. 
Secondary Objectives 
Secondary Efficacy Objectives 
 To evaluate the prophylactic efficacy of REGN1908-1909 administered as a single 
dose on day 1 in cat-allergic asthmatic patients not living with a cat, in the prevention 
of a Controlled Cat Allergen Challenge-induced: 
 Early asthmatic response (EAR) assessed by measures of lung function (FEV1) 
compared to placebo-treated patients on days 29, 57, and 85 
 Allergic rhinitis symptoms assessed by TNSS compared to placebo patients on 
days 8, 29, 57, and 85 
 Ocular symptoms assessed by total ocular symptom score (TOSS) compared to 
placebo patients on days 8, 29, 57, and 85 
 To evaluate the prophylactic efficacy of REGN1908-1909 to increase the exposure to 
cat allergen, measured as a product of minute ventilation and time, required to induce 
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EAR in a Controlled Cat Allergen Challenge (Feld 1 allergen concentration (ng/ m3)x 
minute ventilation x time) as compared to placebo patients on days 8, 29, 57, and 85 
Secondary Safety Objective: To evaluate the safety and tolerability of REGN1908-1909 vs. 
placebo in patients with cat allergen-triggered asthma. 
1.2.3. 
Modifications from SAP Version 1 
The following modifications have been made from Version 1 of the SAP as a result of blinded 
review of the data prior to the first-step analysis: 
 Limited biomarker variables and analysis methods have been incorporated. 
 The wording in the secondary endpoints for the AUC of TNSS and TOSS have been 
updated; however, the corresponding objectives will remain the same.  In blinded review 
of baseline data, it was noted that some patients were asymptomatic at baseline.  
Therefore, the percent change as originally proposed in the SAP cannot be utilized and 
these endpoints will use a change from baseline metric. 
 Analysis methods for exploratory efficacy endpoints have been added. 
 The calculation of the cat allergen quantity as experienced by the patient will use the 
recorded levels of Fel d 1 in the EEU, rather than the target level of 40 ng/m3.  
 The PK and ADA sections have been updated. 
 Additional clarifications and details added throughout. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a phase 2, randomized, double-blind, parallel-group, single-dose study in approximately 
60 cat-allergic patients (not living with a cat) with mild asthma (GINA stage 1) with rhinitis, 
with or without conjunctivitis to cat allergen, to evaluate the efficacy of a single 600 mg SC 
prophylactic dose of REGN1908-1909 to prevent acute, allergic, lower respiratory symptoms 
during exposure to cat allergen as measured by spirometry.  This single-site study will 
incorporate clinical monitoring appropriate for conducting a study measuring a mild-to-moderate 
reduction in FEV1 in the asthmatic population. 
2.2. 
Sample Size and Power Considerations 
The primary objective of this study is to assess the time to EAR in a Controlled Cat Allergen 
Challenge in patients receiving REGN1908-1909 compared to placebo-treated patients.  Patients 
will be randomized (1:1) to receive placebo or REGN1908-1909.  With 30 patients per treatment 
arm, an increase in median time to EAR from 58 minutes in the placebo-treated patients to 
132 minutes in patients treated with REGN1908-1909 (ratio of median duration of tolerated 
exposure of 2.25 or, equivalently, hazard ratio of 0.44) can be detected with 84% power assuming 
a one-sided type I error of 0.05 and a 13% dropout rate (8 patients).  A median time to EAR of 
58 minutes was observed in untreated patients in the Alyatec validation study (Gherasim, 2018) 
and the ratio of median duration of tolerated exposure of 2.25 is based on the estimated effect size 
of Omalizumab observed in a previous Cat Allergen Challenge study performed in a live cat room 
(Corren, 2011).  These estimates of drug effect from this live cat room challenge provide the closest 
data available for powering this study, as an interventional study has not previously been 
performed in an EEU with cat allergen.  The sample size calculation was performed based on the 
log-rank test comparing the duration of tolerated exposure of 2 groups with the above-mentioned 
assumptions.   
With 60 cat-allergic patients, this study also has 88% power to detect differences in the key 
secondary endpoint, percent change in the AUC of FEV1 induced by a Controlled Cat Allergen 
Challenge over the exposure interval from baseline to the Controlled Cat Allergen Challenge in 
patients treated with placebo as compared to REGN1908-1909.  This power calculation assumes 
a mean AUC of 27 in the placebo-treated patients compared to 15 in patients treated with drug, 
based on a previous Cat Allergen Challenge study and a one-sided type I error of 0.05 (Corren, 
2011).  The primary analysis will be conducted on the full analysis set (FAS) population 
(Section 3.1). 
2.3. 
Study Plan 
Study patients, the principal investigators, and study site personnel (with the exception of the study 
pharmacist) will be blinded to all randomization assignments throughout the study.  The 
Regeneron Study Director, Medical Monitor, Study Monitor, and all other Regeneron personnel 
who will be in regular contact with the study site will be blinded to all patient randomization 
assignments.  Study drug kits coded with a medication numbering system will be used.  In order 
to maintain the blind, lists linking these codes with product lot numbers will not be accessible to 
blinded individuals involved in study conduct.  Although the designated study 
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pharmacist(s)/designee at the study site are unblinded, the treatment assignment will not be 
provided to site personnel, including the investigator, at any time during the conduct of the study, 
except in the case of a true emergency.  
Selected individuals who are not responsible for the treatment or clinical evaluation of patients 
may have access to unblinded data as needed for safety review or other data review. 
The Study event table is presented in Section 10.2. 
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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) 
FAS includes all randomized subjects who receive any investigational product and have 
completed the Day 8 Cat Allergen Challenge. Efficacy analyses will be based on the treatment 
allocated by the IVRS at randomization (as randomized).  
FAS is the primary analysis set for efficacy endpoints.    
3.2. 
The Per Protocol Set (PPS) 
PPS includes all subjects in the FAS except for those who may relate to efficacy analysis and 
who are excluded because of major protocol violations . A major protocol violation is one that 
may affect the interpretation of study efficacy results.  Final determinations of the PPS will be 
made before data base lock. 
 
Major protocol violation: 
The criteria of major protocol deviation are defined as following: 
 Had not received study treatment 
 Had any major violations of entry criteria 
 Had not received treatment as randomized  
 Had taken any prohibited medication during the double-blind phase 
3.3. 
The Safety Analysis Set (SAF) 
SAF includes all subjects who receive any investigational product and be analyzed as treated. 
Treatment compliance/administration and all clinical safety variables will be analyzed using the 
SAF.  No missing data will be imputed for safety analyses. 
3.4. 
The Pharmacokinetic Analysis Set (PKAS) 
The PKAS includes all treated patients who received any study drug and had at least 1 non-
missing blood sample for drug concentration following a single dose of REGN1908-1909. 
Patients will be analyzed according to the treatment actually received. 
3.5. 
The Anti-Drug Antibody (ADA) Analysis Set 
The anti-drug antibody (ADA) analysis set will consist of all patients who received any study 
drug and who had at least 1 non-missing ADA result in the anti-REGN1908 or anti-REGN1909 
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assay after a single dose of the study drug. Patients will be analyzed according to the treatment 
actually received. 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic variables will be summarized:  
 Age at screening (year) 
 Age range if needed  
 Sex (Male, Female) 
 Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White and Other) 
 Ethnicity (Hispanic/Latino) 
 Baseline Weight (kg) 
 Baseline Height (cm) 
 Baseline Body mass index (BMI) calculated from weight and height (kg/m2) 
The following baseline characteristics will be summarized: 
 Minute ventilation (L/min) 
 FEV1 (L) 
 Baseline challenge FEV1 AUC 
 Baseline challenge TNSS AUC 
 Baseline challenge TOSS AUC 
 Screening skin prick test for cat allergen (mm) 
 Skin prick test for other common allergens (mm) 
 Skin Prick Test with Serial Allergen Titration, measured by AUC of the wheal sizes 
(diameter) over log-transformed allergen concentrations 
 Baseline serum total IgE 
 Baseline serum cat hair sIgE 
 Baseline serum Fel d 1 sIgE 
 Baseline serum Fel d 2 sIgE 
 Baseline serum Fel d 4 sIgE 
 Baseline serum Fel d 7 sIgE 
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
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4.3. 
Pre-Treatment / Concomitant Medication 
Medications/Procedures will be recorded from the day of informed consent until the end-of-study 
(EOS) visit. This includes medications that were started before the study and are ongoing during 
the study. 
Medications will be coded to the ATC level 2 (therapeutic main group) and ATC level 4 
(chemical/therapeutic subgroup), according to the latest available version of WHO Drug 
Dictionary (WHODD). Patients will be counted once in all ATC categories linked to the 
medication. 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the study drug. 
Concomitant medications/procedures: medications taken or procedures performed following the 
dose of study drug through the EOS visit, with the exception of rescue treatment kit medications 
taken at home within 24 hours from the EEU exposure. 
4.4. 
Rescue Medication/or Prohibited Medication During Study 
The use of the following concomitant medications is not permitted during the study: 
1. Use of these concomitant medications within the following time period preceding any 
screening visit or any EEU visit: 
(NOTE: Patients may be rescheduled 1 time for the screening visit or EEU visit after the 
time period for taking these concomitant medications has passed.) 
a. Topical or systemic first generation H1 antihistamines (5 days) 
b. Topical or systemic second generation H1 blockers (7 days)  
c. Systemic anti-H2 (8 days) 
d. Astemizole (6 weeks) 
e. Cromoglycates, leukotriene modifiers (7 days) 
f. Systemic steroid treatment (8 weeks prior to screening and during the study) 
(NOTE: systemic steroid treatment is allowed if clinically indicated for a LAR 
treatment after exposure to cat allergen in the EEU.) 
g. Topical steroids (48 hours) 
h. Short-acting β2 agonists (8 hours) 
i. Long-acting β2 agonists (eg, salmeterol) (36 hours) 
j. Ultra-long-acting β2 agonists (eg, indacaterol, vilanterol, olodaterol) (48 hours) 
k. Anticholinergics eg, Ipratropium (Atrovent 40 μg) (12 hours)  
l. Long-acting anti-muscarinic agents (7 days) 
m. Methylxanthynes (eg, oral theophylline) (24 hours) 
n. Intramuscular corticosteroids (3 months prior to screening and during the study) 
o. Systemic or topical calcineurin inhibitors (14 days prior to screening and during 
the study) 
p. Tricyclic antidepressants/antipsychotics (14 days) 
q. Topical decongestants (72 hours) 
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r. Caffeine-containing drinks or products (8 hours of EEU visits only)  
2. History of systemic immunotherapy (SIT) with cat allergen or vaccines against cat 
allergy within 5 years of screening 
3. SIT with any allergen within 6 months of screening 
4. Beta-blockers during the study period  
5. Immunomodulatory therapy, anti-IgE, or other biological, agent-based antagonist therapy 
(eg, cyclosporine) is not allowed in the 6 months prior to baseline or during the study 
6. Change in prescription medications within 4 weeks before screening 
7. Aspirin and any nonsteroidal anti-inflammatory drug  
NOTE: paracetamol is allowed to be used for occasional pain relief. 
8. Active treatment for respiratory infections (antiviral, antifungals, or antibiotics) within 4 
weeks prior to screening or EEU 
4.4.1. 
Rescue Medications 
As soon as the patient has a drop in FEV1 of 20% and/or asthma symptoms, the patient will be 
removed from the EEU and will be treated with short-acting 2 agonist every 20 minutes for 1 
hour if necessary.  Patients will stay under supervision in the observation room during 6 hours 
after leaving the EEU and FEV1 will be monitored every 30 minutes.  During this 6-hour 
monitoring period, a LAR can appear with a drop in FEV1 of 15% and will be treated with short-
acting 2 agonist and corticosteroids if necessary. 
 After each allergen challenge, all patients will leave the site with a rescue treatment kit 
containing: short-acting β2 agonist, oral corticosteroids, and oral antihistamines.  The patients 
will also receive oral and written information about the procedure to be followed in case of the 
occurrence of AEs which may be related to the study, as well as the telephone number of the 
physicians of the study. 
4.5. 
Efficacy Variables 
4.5.1. 
Primary Efficacy Variables 
The primary endpoint in the study is the time to EAR upon Controlled Cat Allergen Challenge in 
an EEU on day 8. The time to EAR will be defined as the time to a ≥20% reduction in FEV1 or 
when the patient voluntarily departs the EEU due to clinically significant allergic and/or asthma 
symptoms. During the allergen challenges (post-randomization), the patient may remain in the 
EEU for a maximum of 4 hours. If a patient does not experience an EAR and remains in the EEU 
for the maximum time, their time to EAR will be censored at 4 hours. Censoring implies that the 
time to EAR is at least 4 hours, but the exact time is unknown. 
4.5.2. 
Secondary Efficacy Variable(s) 
The secondary endpoints are: 
 Time to EAR upon Controlled Cat Allergen Challenge in an EEU on days 29, 57, and 
85 
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 Change and percent change in AUC of the FEV1 during a Controlled Cat Allergen 
Challenge over the exposure interval (maximum of 4 hours) from the baseline 
Controlled Cat Allergen Challenge to challenges on days 8, 29, 57, and 85 
 Change in AUC of patient-assessed nasal symptoms induced by a Controlled Cat 
Allergen Challenge over the exposure interval (maximum of 4 hours) from the baseline 
Controlled Cat Allergen Challenge to challenges on days 8, 29, 57, and 85  
 Change in AUC of patient-assessed ocular symptoms induced by a Controlled Cat 
Allergen Challenge over the exposure interval (maximum of 4 hours) from the baseline 
Controlled Cat Allergen Challenge to challenges on days 8, 29, 57, and 85 
 Change and percent change in cat allergen quantity as experienced by patients during 
exposure (measured by Fel d 1 allergen concentration (ng/m3) x minute ventilation x 
time in hours) from the baseline Controlled Cat Allergen Challenge to challenges on 
days 8, 29, 57, and 85   
 Incidence rates of treatment-emergent adverse events (TEAEs) and serious TEAEs 
through end of study 
Total Nasal Symptom Score 
Total nasal symptom score is 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 congestion, itching, and rhinorrhea, and 
from 0 (none) to 3 (5 or more sneezes) for sneezing. 
Total Ocular Symptom Score 
Total ocular symptom score is from 0 to 12 and is based on a 4-point Likert scale ranging from 0 
(none) to 3 (severe) for itching/burning, redness, swelling/puffiness, and tearing/watery eyes.   
Spirometry 
Study staff-supervised spirometry will be performed in all patients at visits shown in Table 1   with 
a standard measurement of FEV1. FEV1 will be measured by means of spirometry at 10-minute 
intervals during placebo and cat allergen exposures in the EEU, every 30 minutes during the 6-hour 
observation period after leaving the EEU. Additional spirometry may be performed when 
prompted by asthma symptoms and/or at the discretion of the investigator. In the case where a 
patient has multiple spirometry efforts from the same time point, the study staff will select an effort 
for use in analysis based on the quality of the efforts as assessed by a flow volume loop. 
At home spirometry will be performed hourly for approximately 18 hours after leaving the clinical 
unit, excluding hours when the patient is sleeping.  Additional spirometry may be performed when 
prompted by asthma symptoms  
Spirometry will be measured on the day of randomization prior to receiving the study drug and 
will be measured after 6 hours prior to leaving the clinic.  At the end of the 6-hour monitoring 
period, patients will undergo a physical exam and vital signs, including spirometry, and will be 
discharged home if there are no abnormal findings and if FEV1 ≥90% of baseline.  Otherwise, in 
case of FEV1 is <90% of the baseline value, patients will continue to be monitored at the clinic 
until the patient meets criteria for discharge.  
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Spirometry measurements include FVC (L), FEV1 (L), FEV1/FVC (%), PEF (L/s), FEF 25-75 
(L/s).  Minute ventilation (L/min) will also be measured using spirometry at screening 1 time while 
the patient is at rest, and this value will be used to calculate allergen exposure throughout the study 
(minute ventilation x Fel d 1 allergen concentration (ng/m3) x time (in hours)). 
4.5.3. 
Exploratory Efficacy Variables 
The exploratory efficacy variables are: 
 Time to Late Asthmatic Response (LAR) on days 8, 29, 57, and 85 
 Time to Any Asthmatic Response on days 8, 29, 57, and 85 
 Change and percent change from FeNO (parts per billion) (adjusted for the pre-
challenge baseline) from baseline to days 30 and 86 
 Change and percent change in the skin prick test with serial allergen titration, 
measured by AUC of the wheal sizes (diameter) over log-transformed allergen 
concentrations with cat allergen from baseline to day 29, 85, and 113 
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 with the exception of symptoms that 
occur in response to the EEU within 24 hours following the EEU. Asthmatic and allergic 
symptoms that occur in response to the EEU are not to be reported as AEs, as they will be 
recorded as outcome measures.  However, AEs that occur in response to allergen exposure in the 
EEU that are outside of expected symptoms, including events which qualify as SAEs, up to 24 
hours after EEU should be reported as AEs and SAEs as applicable.  
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, 
the Version 10 or the latest current available version). 
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
A Serious Adverse Event is an adverse event (AE) that is classified as serious according to the 
criteria specified in the protocol. 
Acute administration reactions are defined as any AE that occurs during the study drug 
administration or within 2 hours after the administration is completed. Infusion reactions must be 
reported as AEs and graded according to the NCI-CTCAE version 4.03 grading scale. Injection 
site reactions must be reported as AEs and graded according to the Food and Drug 
Administration (FDA) September 2007 Guidance for Industry, Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. 
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The severity of AEs that are not infusion reactions, or are not covered in the Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials, will be graded according to the following scale:  
 Mild: Does not interfere in a significant manner with the subject’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 subject.  
 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 subject’s health. Treatment for symptom may be given and/or 
subject hospitalized.  
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. 
The relationship of AEs to the EEU exposure will be assessed by the blinded investigator. 
4.6.2. 
Adverse Events of Special Interest 
No AEs of special interest are defined for this study. 
4.6.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of serum chemistry, hematology, and other. 
Clinical laboratory values will be converted to standard international (SI) units and grouped by 
function in summary tables. Conventional unit may be provided. Functions are defined as 
follows: 
 Liver function including ALT, AST, alkaline phosphatase, gamma GT, total bilirubin 
(and, in case of values above the normal range, differentiation in conjugated and non-
conjugated bilirubin), 
 Renal function including creatinine, uric acid, 
 Electrolytes including sodium, potassium, 
 Metabolic parameters including total proteins, albumin, 
 White blood cells (WBCs) including WBCs count and differential count (neutrophils, 
lymphocytes, eosinophils, basophils, monocytes),F 
 Red blood cells and platelets including red blood cells count, hemoglobin, hematocrit 
and platelets count, 
 Other 
 
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4.6.4. 
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. 
4.6.5. 
12-Lead Electrocardiography (ECG) 
12-Lead ECG parameters include 
 P-R interval ,QT interval, QTc interval, QRS interval, Ventricular rate and Heart rate and etc.. 
QTcF and QTcB:  
QTcF (ms) =QT/RR1/3  and  QTcB (ms) =QT/RR1/2 , 
Where QT is the uncorrected QT interval measured in ms, and RR is 60/HR with HR being the 
heart rate in beats per minutes. 
4.6.6. 
Physical Examination Variables 
A full or brief physical examination will be performed according to the site’s procedures at the 
time points in Table 1. The limited physical examination will include assessment of HEENT, 
respiratory, cardiovascular, dermatologic, and allergic/immunologic. The physical examination 
variable values will be indicated to be either normal or abnormal, clinically significant.  
4.7. 
Pharmacokinetic Variables 
Pharmacokinetic variables are total concentration of REGN1908, total concentration of 
REGN1909 and total antibody (REGN1908+REGN1909) in serum, at the sampling times 
specified in Section 10.2  (Appendix).  
4.8. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer and time-point/visit. Serum samples for 
ADA will be collected at the clinic visits specified in Section 10.2  (Appendix).  
   
4.9. 
Biomarker Variables 
 Allergen-specific IgE levels (cat hair, Fel d 1) at screening visit 1 (V1) and baseline. 
 Allergen-specific IgE levels (Fel d 2, Fel d 4, Fel d 7) at screening and baseline to assess 
sensitization status and to evaluate the relationship between response to REGN1908-1909 
and poly/mono-sensitization (van Ree, 1999). 
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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. 
5.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group for the FAS. 
A listing of demographics and baseline characteristics will also be presented. 
5.2. 
Medical History 
Medical history will be based on the safety population.   
Medical history will be summarized by primary SOC and PT for each treatment group. The table 
will be sorted by decreasing frequency of SOC followed by PT based on the overall incidence 
across treatment groups. Medical history will also be presented in a listing. 
5.3. 
Prior/Concomitant Illnesses and Medications  
Prior/concomitant illnesses and medications will be based on the safety population. 
The number and proportion of patients taking prior/concomitant medications, and prohibited 
medications will be summarized, sorted by decreasing frequency of ATC Level 2 and ATC level 
4, based on the overall incidence for the combined treatment groups. Patients will be counted 
only once for each medication class (ATC level 2 and 4) linked to the medication. 
Concomitant treatments for asthma and allergic symptoms, including allowed and rescue 
treatments, will be analyzed similarly. 
Concomitant medications used to treat EEU related events will be tabulated separately. 
Listings of prior and concomitant medications will be provided. 
5.4. 
Rescue/ Prohibited Medications 
Rescue and prohibited medications will be based on both the efficacy and safety population. 
The number and proportion of patients taking rescue medications at EEU exit, during the 6-hour 
observation period on-site and during the at-home monitoring period will be summarized for 
each treatment group and by type of rescue medication.  The total dose of each rescue 
medication taken per patient will be calculated at each visit at EEU exit, during the 6-hour 
observation period on-site and during the at-home monitoring period, and will be summarized for 
each treatment group. 
5.5. 
Subject Disposition 
The following summaries will be provided: 
Summary of total screened subjects, numbers of FAS, PPS and SAF by treatment and total. 
Summaries of discontinuations and/or dropouts by reasons and treatments will be presented.  
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If necessary, the discontinuations and/or dropouts will be compared among the treatment groups.  
If necessary, the mechanisms, (missing completely at random, missing at random, and non-
ignorable) of the missing and/or dropouts will be explored. 
5.6. 
Analyses of Efficacy Variables 
The primary endpoint is the time to EAR upon day 8 Controlled Cat Allergen Challenge in an 
EEU.  The time to EAR will be defined as the time to a ≥ 20% reduction in FEV1 (adjudicated 
by the blinded investigators) or when the patient voluntarily departs the EEU due to clinically 
significant allergic and/or asthma symptoms.  During the post-randomization allergen challenges, 
the patient may remain in the EEU for a maximum of 4 hours. If a patient does not experience an 
EAR and remains in the EEU for the maximum time, their time to EAR will be censored at 4 
hours. Censoring implies that the time to EAR is at least 4 hours, but the exact time is unknown.  
The statistical model will be a cause-specific Cox’s proportional hazards model to compare the 
hazard ratio of EAR on day 8 in REGN1908-1909-treated patients to placebo-treated patients. 
This model allows for covariate adjustment for allergen concentration in the EEU on day 8 and 
the patient’s time to EAR during the baseline Cat Allergen Challenge. Under this model, the 
hazard ratio is directly related to the ratio of median duration of tolerated exposure in the current 
challenge test on day 8, where a hazard ratio of 1 implies that the median duration of tolerated 
exposure in the 2 treatment groups is the same. The following null and alternative hypotheses of 
the primary endpoint will be tested: 
H0: 
The hazard rate of EAR during the day 8 Controlled Cat Allergen Challenge is the same in 
patients receiving REGN1908-1909 and placebo (hazard ratio, HR = 1) 
H1: 
The hazard rate of EAR during the day 8 Controlled Cat Allergen Challenge is lower (ie, 
the median duration of tolerated exposure is longer) in the REGN1908-1909-treated patients as 
compared to placebo-treated patients (HR <1) 
5.6.1. 
Analysis of Primary Efficacy Variable(s) 
The time to EAR for each treatment will be examined using Kaplan Meier estimates with patients 
being censored at 4 hours if they did not experience an EAR and remained in the EEU for 4 hours. 
If a patient leaves the EEU before experiencing an EAR and for reasons unrelated to their clinical 
symptoms, they will be censored at the time of EEU departure. The median time to EAR for each 
treatment group and the corresponding 95% confidence intervals will be presented for each 
Controlled Cat Allergen Challenge. A formal comparison of time to EAR in the treatment groups 
at day 8 will be performed using a Cox proportional hazards model, adjusting for allergen 
concentration in the EEU and time to EAR in the baseline Cat Allergen Challenge. In patients who 
receive EEU related medications (including medications given on-site and rescue medications 
taken at-home), the impact of the carryover of medications between challenges will be explored 
by including taking medication or not as baseline variable for the model of each subsequent visit. 
A one-sided 5% statistical test of the hazard ratio for placebo compared to drug will be performed. 
If the Cox proportional hazards model does not converge, an extension of the Wilcoxon Rank Sum 
test comparing the ranks of time to EAR under censoring, adjusted by the covariates specified 
above, will be used (LaVange and Koch, 2006).  As an additional sensitivity analysis, the presence 
or absence of an EAR within the 4-hour period in the REGN1908-1909 treatment group as 
compared to placebo will be tested using a Fisher’s Exact Test. 
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Subgroup analyses may be performed by gender, age, baseline IgE and the ratio of Fel d 1 IgE to 
Cat Allergen IgE at baseline.  The ratio of Fel d 1 IgE to Cat Allergen IgE at baseline (log 
transformed if the distribution is skewed) will also be explored as potential covariate in the Cox 
proportional hazards model. 
5.6.2. 
Analysis of Secondary Efficacy Variables 
The time to EAR for Cat Allergen Challenges on days 29, 57, and 85 will be evaluated in a similar 
way to the primary analysis.   
The change and percent change from the Baseline Controlled Cat Allergen Challenge in AUC of 
FEV1 (L) during the Controlled Cat Allergen exposure will be calculated and analyzed by mixed-
effect model repeated measures (MMRM) with the treatment, visit, and treatment-by-visit 
interaction as factors and the AUC of FEV1 during the baseline Controlled Cat Allergen 
Challenge, time to EAR during the baseline controlled cat allergen challenge, and allergen 
concentration in the EEU for each visit as continuous covariates.  The primary method for the 
calculation of the AUC is described in Section 6.2, where last observation carried forward (LOCF) 
is used to calculate the AUC from 0 to 2 hours. An unstructured covariance structure will be 
utilized; if the model does not converge, an autoregressive structure will be employed.  Between-
group estimates and nominal p values will be reported for Controlled Cat Allergen Challenges on 
days 8, 29, 57, and 85. Missing data from Controlled Cat Allergen Challenges on days 8, 29, 57, 
or 85 will be accounted for via MMRM.  The change from the Baseline Challenge in AUC of 
TNSS and TOSS will be analyzed in a similar manner.   
The change and percent change in cat allergen quantity (tolerated exposure) from the baseline Cat 
Allergen Challenge, will also be analyzed using a similar MMRM model with the treatment, visit, 
and treatment by-visit interaction as factors and the cat allergen quantity tolerated in the baseline 
Controlled Cat Allergen Challenge as a covariate. 
As a sensitivity analysis the AUC for each endpoint will also be calculated during the period of 
time where the patient was in the EEU (adjusted for the exposure interval) to give the average 
value of FEV1, TNSS, and TOSS during the EEU exposure.  An MMRM model will be used to 
model the change (and percent change for FEV1) from the Baseline Challenge in the average 
value during the EEU exposure.  An additional sensitivity analysis will be performed, where the 
AUC will also be calculated from 0 to 4 hours with LOCF at post-randomization Cat Allergen 
Challenges following the method outlined in Section 6.2.    An MMRM model will be used to 
model the AUC at each visit (rather than the change in AUC), adjusting for the Baseline 
Challenge AUC in addition to the time to EAR in the baseline challenge test and the allergen 
concentration in the EEU.  A similar analysis looking at the AUC from 0 to 2 hours with LOCF 
will also be performed, modeling the raw AUC values at each visit rather than the percent 
change from baseline.    
Subgroup analyses will be performed for the change in AUC of TNSS and TOSS for patients 
who had a non-zero baseline AUC value and in patients who attained a TNSS of at least 3 during 
the EEU challenge at baseline.  
5.6.3. 
Analysis of Other Efficacy Variables 
The time to LAR at each of the Controlled Cat Allergen Challenges in an EEU will also be 
explored.  After the allergen challenge (when the patient exits the EEU), the patient is observed 
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onsite for 6 hours and then for an additional 18 hours at home.  If a patient does not experience 
an LAR within the 24-hour period, their time to LAR will be censored at 24 hours.  
The time to LAR will be defined as the time to a ≥15% reduction in FEV1 during the 6-hour onsite 
observation period (adjudicated by the blinded investigators).  During the at-home monitoring 
period up to 24 hours after the patient exits the EEU, the time to LAR will be defined as the time 
to a ≥15% reduction in FEV1 (confirmed by two spirometry efforts within 5 minutes) along with 
either rescue medication use (any medication at any dose) within 1 hour or the presence of chest 
symptoms within 1 hour of the drop in FEV1 (adjudicated by the blinded investigators).  Chest 
symptoms are identified by a response of Mild, Moderate or Severe to the chest symptom questions 
involving chest tightness, wheezing, cough, throat tightness, and difficulty breathing.    Multiple 
asthma exacerbations during the observation period or at-home monitoring period within the same 
patient may be adjudicated by the site to be an extended LAR (no more than one LAR within 24 
hours of leaving the EEU may be adjudicated, e.g. a subject cannot have more than one LAR 
within 24 hours of leaving the EEU).   
The time to LAR for each treatment will be examined using Kaplan Meier estimates with patients 
being censored at 24 hours if they did not experience an LAR.  The median time to LAR for each 
treatment group and the corresponding 95% confidence intervals will be presented for each 
Controlled Cat Allergen Challenge. A formal comparison of time to LAR in the treatment groups 
at each EEU challenge visit will be performed using a Cox proportional hazards model, adjusting 
for allergen concentration in the EEU. The Kaplan Meier and Cox Proportional Hazards models 
will be fit separately on the subgroup of patients who receive rescue medications upon EEU exit 
and for patients who do not.  In patients who receive EEU related medications (including 
medications given on-site and rescue medications taken at-home), the impact of the carryover of 
medications between challenges will be explored by including taking medication or not as baseline 
variable for the model of each subsequent visits. A one-sided statistical test of the hazard ratio for 
placebo compared to drug will be performed. 
The ratio of Fel d 1 IgE to Cat Allergen IgE at baseline will also be explored as potential covariate 
in the Cox Proportional Hazards model and will be log transformed if necessary.   
If the Cox proportional hazards model does not converge, an extended Wilcoxon Rank Sum test 
comparing the ranks of time to LAR, adjusted by the covariates specified above, will be used 
(LaVange and Koch, 2006). 
A time-to-event analysis with competing risks may also be used to examine the incidence of LAR, 
where the use of rescue medications upon EEU exit is treated as a competing risk with allergen 
concentration as a covariate in the model.  The comparison of LAR-specific and rescue 
medication-specific cumulative incidences within 24 hours of an EEU challenge across treatment 
groups will be performed using Gray’s method.  The model will be fit for each EEU Challenge 
visit. 
As an additional sensitivity analysis, the presence or absence of an LAR within the 24-hour period 
in the REGN1908-1909 treatment group as compared to placebo will be tested using a Fisher’s 
Exact Test. 
The time course of asthma response comprising both EAR and LAR will also be visualized and 
summarized.  A similar analysis will be repeated for the time to any Asthma Reaction.  The first 
asthma reaction that occurs, whether it occurs while the patient is in the EEU, in the on-site 6-
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hour observation period, or in the at-home monitoring period, will be treated as the event time.  
If the subject experiences no asthmatic reaction at a given Allergen Challenge visit, the patient’s 
time will be censored at 24 hours.  Kaplan-Meier estimates and curves will be produced for each 
visit. 
The presence or absence of any asthma exacerbation (EAR or LAR) in the REGN1908-1909 
treatment group as compared to placebo will be tested using a Fisher’s Exact Test. 
Individual spaghetti plots and mean plots of the percent change in FEV1 over time will also be 
examined.  LOCF will be used in the calculation for any graphical displays of the mean change 
in FEV1 over the Cat Allergen Challenge. 
The peak TNSS and TOSS and change from pre-challenge baseline to peak TNSS and TOSS 
across EEU challenge visits may also be examined using MMRM models. 
The change and percent change from the Baseline Cat Allergen Challenge in the Fractional 
exhaled Nitric Oxide (FeNO) (adjusted for the pre-challenge baseline) will be explored using an 
MMRM model, with the treatment, visit, and treatment by visit interaction, and use of steroid 
rescue medications within 24 hours of the EEU challenge as factors.  The time in EEU will be 
included as a covariate in the model. 
The skin prick test with serial allergen titration with cat allergen will also be compared between 
treatment groups using an MMRM model, with the treatment, visit and treatment by visit 
interaction as factors. 
5.6.4. 
Adjustment for Multiple Comparison 
There is no adjustment for multiplicity for the primary or secondary efficacy variables. 
5.7. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the SAF, as defined in Section 3.3. 
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations, vital signs and 12-lead ECG).  
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables, vital signs 
and ECG are defined in Section 10.3. 
The summary of safety results will be presented for each treatment group. 
5.7.1. 
Adverse Events  
The verbatim text, the PT, and the primary SOC will be listed in subject listings. Summaries that 
include frequencies and proportions of patients reporting AEs will include the PTs and the SOCs. 
AEs will also be summarized by relationship to EEU procedure. Also, asthma related AEs, 
specifically, reported throughout the study will be presented for each treatment group and will be 
summarized by relationship to EEU procedure.  Medications used to treat any asthma related 
AEs will also be listed and summarized by treatment group. 
Period of observation: The observation period will be divided into two segments: pre-treatment 
and treatment periods. The pre-treatment period is defined as the time between when the subjects 
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give informed consent to before the single dose of study drug. The on-treatment period is defined 
as the time after the single dose of study drug until the end of study (week 16). 
Day 1 is the first day of investigational product, Day –1 is the day before, and there is no Day 0. 
Pre-treatment AEs are defined as AEs that developed or worsened during the pre-treatment 
period. 
Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened during the 
treatment period. 
The focus of adverse event reporting in the clinical study report will be on TEAEs. 
For details on handling missing data and partial dates, see Section 6. 
Summaries of all TEAEs in each treatment group will include: 
 All TEAEs by system organ class 
 Possibly related TEAEs by system organ class  
 Possibly related TEAEs by intensity and SOC (recommended) 
 Time to first occurrence of any (or selected) TEAE (optional) 
 Alert terms: all and possibly related TEAEs (optional) 
 Serious adverse events: All and possibly related TEAEs by seriousness criterion 
 Serious adverse events: All and possibly related TEAEs by SOC 
 Death: All and possibly related TEAEs by SOC 
 Other significant adverse events: All and possibly related TEAEs by “other 
significant” adverse event criterion 
 Discontinuation: All and possibly related TEAEs by system organ class 
 Non-serious possibly related TEAEs by SOC (mandatory if study includes a German 
center) 
Counts will be provided according to treatment group for each PT within each SOC. Percentages 
will be calculated using the number of patients from the safety population in each treatment 
group. 
Primary SOCs will be sorted according to the order described in the Guideline on summary of 
product characteristics (December 1999, European commission), with the total overall classes 
coming first and labeled “Any class”. Within each primary SOC, PTs will be sorted by 
decreasing frequency of investigational product. 
A second type of table with counts of each primary SOC in decreasing order of frequency will be 
provided.  A third type of table with counts of each PT in decreasing order of frequency will also 
be provided. 
Common TEAEs (preferred terms ≥1% in any treatment group) and very common TEAEs 
(preferred terms ≥5% in any treatment group) will be summarized in the report.  
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The description of very common TEAEs will also be performed for demographic factors 
including: gender, age (<65, >=65), and race. 
5.7.2. 
Clinical Laboratory Measurements  
A treatment-emergent Potential Clinically Significant abnormal value (PCSV) is a laboratory 
value that was normal at Screening and Baseline but clinically significantly abnormal after 
treatment with investigational product, or a laboratory value that was abnormal at Baseline and 
exacerbates after treatment with investigational product.  “Exacerbations” will be identified by 
the Medical Monitor using clinical judgment. 
Baseline clinical laboratory analytes and change from Baseline in clinical laboratory analytes to 
each scheduled assessment time will be summarized with descriptive statistics. Summary 
statistics will include the number of patients, mean, median, standard deviation, quartiles, 
minimum, and maximum.  The graphs of mean (or median) value of some lab parameter vs. visit 
will also be plotted. 
5.7.3. 
Analysis of Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate, and oximetry) will be 
summarized by Baseline and change from Baseline to each scheduled assessment time with 
descriptive statistics. The graphs of mean (or median) value of some vital sign parameter vs. visit 
will also be plotted. 
A summary of PCSVs will be constructed. Shift tables based on baseline normal/abnormal and 
other tabular and graphical methods may be used to present the results for laboratory test of 
interest. 
5.7.4. 
Analysis of 12-Lead ECG 
ECG parameters (P-R interval ,QT interval, QTc interval, QRS interval, Ventricular rate and 
Heart rate) will be summarized at Baseline by treatment group.      
5.7.5. 
Physical Exams 
The number (n) and percentage (%) of subjects with abnormal, clinically significant physical 
exams will be summarized at each scheduled assessment time by treatment. Listings of physical 
examinations will be provided, including comments if examination was not performed. Listings 
of clinically significant abnormal physical examinations for each patient will be provided, along 
with comments from the investigator describing these abnormalities. These abnormalities will be 
organized into physical system classifications. 
5.8. 
Analysis of Pharmacokinetic Data 
Descriptive statistics of total REGN1908, total REGN1909 and total antibody 
(REGN1908+REGN1909) at each sampling time will be provided. Plots of mean concentrations 
versus time will be presented.  
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5.9. 
Analysis of Immunogenicity Data 
The immunogenicity variables described in Section 4.8  will be summarized using descriptive 
statistics. Analysis described in this section will be performed separately for ADA against 
REGN1908 and ADA against REGN1909 in all treatment groups unless otherwise specified. 
Immunogenicity will be characterized by ADA responses and titers observed in patients in the 
ADA analysis set. ADA response categories and titer categories are defined as follows: 
 
ADA response categories: 
 Pre-existing immunoreactivity, defined as either an ADA positive response in the ADA 
assay at baseline with all post first dose ADA results negative, OR a positive response at 
baseline with all post first dose ADA responses less than 9-fold over baseline titer levels. 
 Treatment-emergent response, defined as a positive response in the ADA assay post dose 
when baseline results are negative or missing.  
 Treatment-boosted response, defined as a positive response in the ADA assay post first 
dose that is greater than or equal to 9-fold over baseline titer levels, when baseline results 
are positive 
 
Titer categories (Maximum titer values) 
 Low (titer <1,000) 
 Moderate (1,000 ≤ titer ≤ 10,000) 
 High (titer >10,000) 
 
The following analysis will be provided: 
 Number (n) and percent (%) of ADA-negative patients (pre-existing immunoreactivity or 
negative in the ADA assay at all time points) by treatment groups  
 Number (n) and percent (%) of treatment-emergent ADA positive patients by treatment 
groups and ADA titer categories 
 Number (n) and percent (%) of treatment-boosted ADA positive patients by treatment 
groups and ADA titer categories  
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-
emergent, and treatment-boosted ADA response. 
5.9.1. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
Immunogenicity and Exposure 
Potential association between ADA variables and systemic exposure to REGN1908 or 
REGN1909 will be explored separately by treatment groups. Plots of drug concentration may be 
provided for analyzing the potential impact of ADA response status and titer on PK.  
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Immunogenicity and Safety and Efficacy 
Potential association between ADA 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 and lasting 24 hours or longer) 
 
Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
 
Anaphylaxis (SMQ: Anaphylaxis [Narrow])   
Potential association between ADA 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 patients, that is patients with treatment-emergent or treatment-
boosted response. 
 
ADA negative patients, that is patients with pre-existing immunoreactivity or 
negative in the ADA assay at all time points. 
Maximum post-baseline titer in treatment-emergent or treatment-boosted ADA positive patients:  
 
Low (titer <1,000) 
 
Moderate (1,000 ≤ titer ≤ 10,000) 
 
High (titer >10,000) 
5.10. 
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 IgE 
(or percent of detectable IgE compared to baseline) by treatment and visit will be provided for 
the biomarker variables.   
The percent of detectable IgE at each visit compared to baseline, and the ratio of Fel d 1 IgE to 
Cat Dander IgE at baseline will 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.   
 
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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 administration of investigational product.  
If the scheduled Baseline Day 1 measurements are not available, screening assessments may be 
used. 
6.2. 
Data Handling Convention for Efficacy Variables  
Algorithm for Calculation of Area Under the Curve (AUC) 
The AUC for the FEV1, TNSS, and TOSS for each Cat Allergen Challenge will be calculated 
using the trapezoidal rule.  For each patient at each EEU visit, the AUC will be calculated over 
the time period of 0 to 2 hours.  For example, the AUC will be calculated using the formula: 
𝐴𝑈𝐶[0−2 ℎ𝑟] = [∑(𝑡𝑖
12
𝑖=1
−𝑡𝑖−1) ∗(𝐷𝑖+ 𝐷𝑖−1)/2] /(𝑡12 −𝑡0) 
 
Where  
 Di is the FEV1, TNSS or TOSS value obtained at time ti 
 ti is the time (in hours) for which Di is measured, such as t0 = 0, t1 = 1/6 hour, t2 = 2/6 
hour, t3 = 3/6 hour, t4 = 4/6 hour, …, t12 = 2 hours. 
If the patient remains in the EEU for less than 2 hours, LOCF will be used to impute values out 
to 2 hours. In the case of missing FEV1 measurements at one or more time points at a visit while 
the patient is in the EEU, linear interpolation will be used to impute missing values.  
Additional analyses will be performed where the LOCF will be used to impute values out to 4 
hours, where 𝑖 ranges from 0 to 24.  Also, the AUC will be calculated over the time while the 
patient is in the EEU, where the maximum value of 𝑖 corresponds to the timepoint of the last 
spirometry effort performed in the EEU to provide the average FEV1 value during EEU 
exposure. 
6.3. 
Data Handling Convention for Missing Data 
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 4.5.1  and Section 4.5.2. 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented. 
To determine whether a medication is prior or concomitant, the missing medication start date is 
estimated as early as possible up to randomization date, and the missing medication end date is 
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estimated as late as possible. If the medication start date is missing, the onset day will not be 
imputed in medication listings. 
If a baseline value is missing for an efficacy endpoint, the patient will be excluded from analyses 
involving a change or percent change from baseline. 
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. 
6.4. 
Data Handling Conventions for Biomarker Data 
The following analysis conventions will be used in the statistical analysis: 
a) The baseline measurement will be the last measurement prior to dosing.  If patients 
are missing baseline data, the values obtained at screening will be used. 
b) For data points above ULQ (e.g. for results reported as >XX), the ULQ plus one 
significant digit will be used. 
c) For data points below LLQ (e.g. for results reported as <XX), 0.5X the LLQ will be 
used. 
6.5. 
Visit Windows 
Data analyzed by visit (including efficacy, laboratory data, vital signs, and ECG) 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, early termination (ET) visit and end of treatment (EOT)/end of study (EOS) 
have the potential to be summarized. 
6.6. 
Unscheduled Assessments 
The determination of baselines and values at the end of treatment for both efficacy and safety 
variables will be based on scheduled available assessments and unscheduled available 
assessments.  
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing adverse events) will be included in listings, 
but not summaries except for the endpoint determination.  If more than one laboratory value is 
available for a given visit, the first observation will be used in summaries and all observations 
will be presented in listings. 
 
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7. 
INTERIM ANALYSIS 
No formal interim analysis is planned. 
A first-step analysis may be performed when the last patient completes day 8 of the treatment 
period and has undergone the Cat Allergen Challenge in the EEU at day 8.  No changes in the 
conduct of the study will be made based on this first-step analysis.  The purpose of the first-step 
analysis is to accelerate the planning of future studies.  This will be the final analysis of the primary 
endpoint of the study.  If a decision is made to perform the first-step analysis, in order to maintain 
study integrity with respect to the treatment follow-up visits, safety visits, and analyses, a 
dissemination plan will be written.  This plan will clearly identify the team (including the 
statistician) that will perform the first-step analysis and all related activities, restrict other clinical 
team members and other Sponsor personnel from access to individual patient treatment allocation, 
and ensure that the dedicated team will not participate in the data review or data decisions for the 
following treatment analyses.  However, the dedicated team can participate in the analysis 
following the final database lock.   
 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or above. 
 
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9. 
REFERENCES 
1. Corren J, Patel D, Zhu J, Yegin A, Dhillon G, Fish JE. Effects of Omalizumab on 
Changes in Pulmonary Function Induced by Controlled Cat Room Challenge.  J Allergy 
Clin Immunol 2011;127 (2) 398-405. 
2. Gherasim A. Clinical Validation of Environmental Exposure Chamber in Strasbourg 
(Alyatec) in Asthmatic Patients Allergic to Cat Allerens.  EAACI 2018 Poster Abstract 
0994.  
3. ICH. (1996, July 30). Harmonized tripartite guideline: Structure and content of clinical 
study reports (E3). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
4. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for 
clinical trials (E8). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
5. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use. 
6. Kleine-Tebbe J, Kleine-Tebbe A, Jeep S, Schou C, Lowenstein H, Kunkel G. Role of the 
major allergen (Fel d 1) in patients sensitized to cat allergens. Int Arch Allergy Immunol 
1993;100 (3):256-62.  
7. LaVange, L. M., & Koch, G. G. (2006). Rank score tests. Circulation, 114(23), 2528-
2533. 
8. Pfaar O, Calderon MA, Andrews CP, Angieli E, Bergmann KC, et al.  Allergen exposure 
chambers: harmonizing current concepts and projecting the needs for the future- an 
EAACI position paper. Allergy 2017; Jul; 72(7): 1035-1042. 
9. van Ree R, van Leeuwen WA, Bulder I, Bond JF, Aalberse RC. Purified natural and 
recombinant Fel d 1 and cat albumin in in vitro diagnostics for cat allergy. J Allergy Clin 
Immunol 1999;104(6):1223-30. 
 
 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Efficacy Analysis: 
Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
Time to EAR 
FAS, PPS 
Time to EAR (a 20 
% drop in FEV1 
or when the 
subject exits the 
EEU on day 8 due 
to clinically 
significant 
symptoms), 
censored at 4 
hours if the patient 
does not 
experience an 
EAR 
Cox 
proportional 
hazards model 
Yes 
Kaplan  
Meier 
estimates 
and plots 
No 
Sensitivity 
Analysis:  
Fisher’s 
exact test 
comparing 
the 
proportion 
of subjects 
with EAR 
Secondary Endpoints 
Time to EAR 
FAS, PPS 
Time to EAR (a 20 
% drop in FEV1 
or when the 
subject exits the 
EEU on days 29, 
57, and 85 due to 
clinically 
significant 
symptoms), 
censored at 4 
hours if the patient 
does not 
experience an 
EAR 
Cox 
proportional 
hazards model 
Yes 
Kaplan  
Meier 
estimates 
and plots 
No 
Sensitivity 
Analysis:  
Fisher’s 
exact test 
comparing 
the 
proportion 
of subjects 
with EAR 
AUC of FEV1 
FAS 
Percent change in 
the AUC of FEV1 
from baseline to 
days 8, 29, 57, and 
85 
MMRM 
No 
No 
No 
AUC of TNSS 
FAS 
Change in the 
AUC of TNSS 
from baseline to 
days 8, 29, 57, and 
85 
MMRM 
No 
Yes 
No 
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Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
AUC of TOSS 
FAS 
Change in the 
AUC of TOSS 
from baseline to 
days 8, 29, 57, and 
85 
MMRM 
No 
Yes 
No 
Cat allergen 
quantity 
FAS 
Change and 
percent change in 
cat allergen 
quantity as 
experienced by 
patients from 
baseline to days 8, 
29, 57 and 85 
MMRM 
No 
No 
No 
Safety Analyses: 
Endpoint 
Analysis 
Populations 
Primary 
Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Adverse Events 
FAS 
Percent of 
patients by 
system organ 
class 
Descriptive 
Statistics 
No 
No 
No 
                                        VV-RIM-00099260-1.0 Approved - 03 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1908-1909-ALG-1703 
Statistical Analysis Plan 
Date: 30 January 2020 
CONFIDENTIAL 
Page 40 of 50 
 
10.2. 
Schedule of Time and Events 
Table 1: 
Schedule of Time and Events 
Study 
Procedure 
Screening1 
Randomization and Treatment Period 
End of 
Study/Early 
Termination 
Visit 
Unsche
duled 
Visit24 
Visit 
V125 
Placebo 
EEU 
V225 
Cat 
EEU
3,22 
V3 
V4 
R2 
V5 
Cat 
EEU22, 
23 
V6 
Tel
. 
Cat 
EEU22 
V7 
V8 
Cat 
EEU22 
V9 
Tel
. 
Cat 
EEU22 
V10 
V11 
V12 
 
Days 
-85 to -14 
1 
8 
9 
29 
30 
57 
58 
85 
86 
113 
 
Window (day) 
+7 
±3 
±2 
 
±2 
 
±3 
 
±3 
 
±3 
 
Weeks 
-12 
1 
1 
2 
4 
4 
8 
8 
12 
12 
16 
 
Screening/Baseline 
 
Inclusion/ 
Exclusion 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Skin 
prick test for cat 
allergen 4  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skin prick test for 
other common 
allergens4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo challenge 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00099260-1.0 Approved - 03 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1908-1909-ALG-1703 
Statistical Analysis Plan 
Date: 30 January 2020 
CONFIDENTIAL 
Page 41 of 50 
Study 
Procedure 
Screening1 
Randomization and Treatment Period 
End of 
Study/Early 
Termination 
Visit 
Unsche
duled 
Visit24 
Visit 
V125 
Placebo 
EEU 
V225 
Cat 
EEU
3,22 
V3 
V4 
R2 
V5 
Cat 
EEU22, 
23 
V6 
Tel
. 
Cat 
EEU22 
V7 
V8 
Cat 
EEU22 
V9 
Tel
. 
Cat 
EEU22 
V10 
V11 
V12 
 
Days 
-85 to -14 
1 
8 
9 
29 
30 
57 
58 
85 
86 
113 
 
Window (day) 
+7 
±3 
±2 
 
±2 
 
±3 
 
±3 
 
±3 
 
Weeks 
-12 
1 
1 
2 
4 
4 
8 
8 
12 
12 
16 
 
Screening Cat 
Allergen 
Challenge3 
 
 
X 
 
 
 
 
 
 
 
 
 
 
  
 
Spirometry5 
(includes FEV1) 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
  
 
Minute 
ventilation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Randomization2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Administer Study 
Drug2 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Cat Allergen 
Challenge 3 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy 
TNSS nasal 
symptoms score6 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
TOSS ocular 
symptoms score6 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Chest symptoms 
questions6 
 
 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Spirometry 
(includes FEV1)5 
 
 
 
 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
PNIF7 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
                                        VV-RIM-00099260-1.0 Approved - 03 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1908-1909-ALG-1703 
Statistical Analysis Plan 
Date: 30 January 2020 
CONFIDENTIAL 
Page 42 of 50 
Study 
Procedure 
Screening1 
Randomization and Treatment Period 
End of 
Study/Early 
Termination 
Visit 
Unsche
duled 
Visit24 
Visit 
V125 
Placebo 
EEU 
V225 
Cat 
EEU
3,22 
V3 
V4 
R2 
V5 
Cat 
EEU22, 
23 
V6 
Tel
. 
Cat 
EEU22 
V7 
V8 
Cat 
EEU22 
V9 
Tel
. 
Cat 
EEU22 
V10 
V11 
V12 
 
Days 
-85 to -14 
1 
8 
9 
29 
30 
57 
58 
85 
86 
113 
 
Window (day) 
+7 
±3 
±2 
 
±2 
 
±3 
 
±3 
 
±3 
 
Weeks 
-12 
1 
1 
2 
4 
4 
8 
8 
12 
12 
16 
 
Skin Prick Test 
with Serial 
Allergen Titration 
(Cat-SPT)8 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
FeNO9 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Safety10 
Vital Signs 
X 
X12 
X12 
X 
X1
1 
X12 
 
X12 
X 
X12 
 
X 
X 
X 
X 
Physical 
Examination 
X 
 
X27 
 
X 
X27 
 
X27 
 
X27 
 
X27 
 
X 
X 
Electrocardiogra
m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACT 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Observation 
 
 
X20 
 
X21 
X20 
 
X20 
 
X20 
 
X20 
 
 
 
Distribution of 
rescue treatment 
kit 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
Telephone Call13 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Laboratory Testing14 
Hematology 
X 
 
 
 
X15 
 
 
X 
 
X 
 
X 
 
X 
X 
Blood Chemistry 
X 
 
 
 
X15 
 
 
X 
 
X 
 
X 
 
X 
X 
Urinalysis 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
βHCG serum 
pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
                                        VV-RIM-00099260-1.0 Approved - 03 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1908-1909-ALG-1703 
Statistical Analysis Plan 
Date: 30 January 2020 
CONFIDENTIAL 
Page 43 of 50 
Study 
Procedure 
Screening1 
Randomization and Treatment Period 
End of 
Study/Early 
Termination 
Visit 
Unsche
duled 
Visit24 
Visit 
V125 
Placebo 
EEU 
V225 
Cat 
EEU
3,22 
V3 
V4 
R2 
V5 
Cat 
EEU22, 
23 
V6 
Tel
. 
Cat 
EEU22 
V7 
V8 
Cat 
EEU22 
V9 
Tel
. 
Cat 
EEU22 
V10 
V11 
V12 
 
Days 
-85 to -14 
1 
8 
9 
29 
30 
57 
58 
85 
86 
113 
 
Window (day) 
+7 
±3 
±2 
 
±2 
 
±3 
 
±3 
 
±3 
 
Weeks 
-12 
1 
1 
2 
4 
4 
8 
8 
12 
12 
16 
 
Urine pregnancy 
test (for female 
patients only)16 
 
X 
X 
 
X16 
X 
 
X 
 
X 
 
X 
 
X 
X 
FSH test (in 
postmenopausal 
women only)28 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for 
specific IgE for 
Fel d 1 and cat 
allergen 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
Serum for sIgE 
(Fel-D 2, 4, 7) 
tests17 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
Research samples 
(serum and 
plasma) 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Research 
Samples: whole 
blood for PBMCs 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Nasal brushing 
samples for RNA 
analysis26 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Genomic DNA 
sample18 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
PK19 and ADA 
                                        VV-RIM-00099260-1.0 Approved - 03 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1908-1909-ALG-1703 
Statistical Analysis Plan 
Date: 30 January 2020 
CONFIDENTIAL 
Page 44 of 50 
Study 
Procedure 
Screening1 
Randomization and Treatment Period 
End of 
Study/Early 
Termination 
Visit 
Unsche
duled 
Visit24 
Visit 
V125 
Placebo 
EEU 
V225 
Cat 
EEU
3,22 
V3 
V4 
R2 
V5 
Cat 
EEU22, 
23 
V6 
Tel
. 
Cat 
EEU22 
V7 
V8 
Cat 
EEU22 
V9 
Tel
. 
Cat 
EEU22 
V10 
V11 
V12 
 
Days 
-85 to -14 
1 
8 
9 
29 
30 
57 
58 
85 
86 
113 
 
Window (day) 
+7 
±3 
±2 
 
±2 
 
±3 
 
±3 
 
±3 
 
Weeks 
-12 
1 
1 
2 
4 
4 
8 
8 
12 
12 
16 
 
Drug conc. 
sample 
 
 
 
 
X15 
X19 
 
X 
 
X 
 
X 
 
X 
X 
ADA sample 
 
 
 
 
X15 
 
 
 
 
 
 
X 
 
X 
X 
10.2.1. 
Footnotes for the Schedule of Events Table 
1. 
All screening-related procedure should be performed between day -85 to -14 
2. 
Randomization/study drug administration (visit 5) must occur within 14 to 28 days of visit 3.   
3. 
Controlled Cat Allergen Challenge is performed as described in the study manual. 
4. 
Screening Skin prick test for cat allergen and skin prick testing for other common allergens is performed as described in the study 
manual.  If screening skin prick test for cat allergen 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 allergen skin prick testing (eg, perform skin prick testing prior to other allergen skin prick testing, blood 
draw, spirometry, etc). 
5. 
At screening visit 1, a spirometry session will be completed to check for FEV1 inclusion criteria.  At visit 2, spirometry will be 
performed at baseline prior to the placebo EEU challenge, and then every 10 minutes during the placebo challenge, then every 30 
minutes in the supervision room for 6 hours.  On the Cat Allergen Challenge visits (3, 6, 7, 9, and 10) spirometry will be performed 
at baseline prior to entry into the EEU, every 10 minutes during the EEU exposure, every 30 minutes in the observation room for 
6 hours after leaving the EEU, and then every hour for up to 18 hours after leaving the clinical unit except during sleeping.  At 
visit 5, on the day of randomization, a spirometry session will be performed twice: once prior to receiving the study drug and 
once prior to leaving the clinical trial unit.  Additional spirometry may be performed when prompted by asthma symptoms.   
                                        VV-RIM-00099260-1.0 Approved - 03 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1908-1909-ALG-1703 
Statistical Analysis Plan 
Date: 30 January 2020 
CONFIDENTIAL 
Page 45 of 50 
6. 
TNSS, TOSS, and chest symptom questions are assessed prior to Cat Allergen Challenge, approximately every 20 minutes during 
the challenge in the exposure unit, every 1 hour for 6 hours post-challenge while patients are being observed in the observation 
room, and then every 2 hours up to 18 hours after leaving the clinical unit, while they are home, except for the time that they are 
sleeping.  Further details are provided in the study manual. 
7. 
PNIF is assessed prior to Cat Allergen Challenge, approximately at the time of the EAR, and approximately 6 hours post-challenge 
while patients are being observed in the observation room.  Further details are provided in the study manual. 
8. 
Titrated SPT with Serial Allergen Titration with cat allergen will be performed at screening visit 3, days 29, 85, and 113.  On 
days when an allergen challenge is performed, the test will be performed prior to allergen challenge.   
9. 
FeNO is assessed during screening, Visit 4 and then 24 hours after EEU exposure at day 30 and day 86. 
10. All safety assessments performed at screening have to be normal and checked against the inclusion/exclusion criteria prior to 
REGN1908-1909 administration on day 1 (baseline). 
11. On day 1, vital signs are taken prior to PK draw, prior to REGN1908-1909 administration, and at 2 hours (±10 min) after 
completion of the injection. 
12. Vital signs are taken prior to entry into the EEU, at exit from the EEU, and prior to leaving the clinical trial unit, and any 
additional times as needed.  
13. Telephone call to collect AEs and concomitant medications, including any medications used from the rescue treatment kit, up to 
24 hours after the EEU exposure.  
14. Total blood draw at any visit will never exceed 60 mL.  Blood volumes are never to exceed 350 mL in 12 weeks. 
15. Samples are collected prior to administration of REGN1908-1909. 
16. On day 1, urine pregnancy test is completed prior to administration of REGN1908-1909 in women of childbearing potential.  
Postmenopausal women do not need urine pregnancy testing. 
17. Total IgE and allergen-specific serum IgE levels (Fel d 2, Fel d 4, Fel d 7).  
18. Genomic analysis is mandatory 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.  
 
 
19. PK samples are drawn at any time in the outpatient visit day from day 8 through day 113 (end of study) visit. 
20. After exiting the EEU, patients are monitored outside the EEU in an observation room for approximately 6 hours.    
                                        VV-RIM-00099260-1.0 Approved - 03 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1908-1909-ALG-1703 
Statistical Analysis Plan 
Date: 30 January 2020 
CONFIDENTIAL 
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21. Patients will be observed for 6 hours in the observation room after receiving a single dose of REGN1908-1909 or placebo. 
22. Blood draws should be performed before the EEU exposure 
23. Cat EEU visit 3 and visit 6 must be spaced at least 3 weeks apart  
24. Assessments and procedures at the unscheduled visit(s) are to be performed at the discretion of the principle investigator. 
25. Screening visits 1 and 2 may be combined into 1 visit if the patient has a historical, positive cat SPT or cat IgE that was 
completed in the last 12 months. 
26. Nasal brushing samples will be collected from the patients before and after Cat Allergen Challenge in the EEU on the day of the 
screening challenge (visit 3) and day 29 (visit 7). Before the challenge in the EEU, a baseline nasal brushing will be performed 
in 1 nare and the samples will be processed. Six hours from the start of the EEU challenge, a nasal brushing will be performed in 
the contralateral nare. 
27. Physical examination will be performed prior to entering the EEU and approximately 6 hours after the exit or before leaving the 
observation room, whichever is later. 
28. FSH test to be performed in postmenopausal women only, if postmenopausal status in a woman is in question. 
ACT: asthma control test; EEU: environmental exposure unit; PBMC: peripheral blood mononuclear cell; R: randomization; V: visit 
 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
 
Parameter 
PCSV 
For Studies in healthy subjects only 
Comments 
Clinical chemistry 
ALT 
By distribution analysis: 
> 3 ULN 
> 5 ULN 
> 10 ULN 
> 20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007 
Internal DILI WG Oct 2008 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be deleted. 
                                        VV-RIM-00099260-1.0 Approved - 03 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1908-1909-ALG-1703 
Statistical Analysis Plan 
Date: 30 January 2020 
CONFIDENTIAL 
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Parameter 
PCSV 
For Studies in healthy subjects only 
Comments 
AST 
By distribution analysis: 
> 3 ULN 
> 5 ULN 
> 10 ULN 
> 20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007 
Internal DILI WG Oct 2008 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be deleted. 
Alkaline Phosphatase 
> 1.5 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008 
Total Bilirubin 
> 1.5 ULN 
> 2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L.  
Concept paper on DILI – FDA draft Guidance Oct 2008 
Internal DILI WG Oct 2008 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be deleted. 
Conjugated bilirubin 
> 35% total bilirubin (when total bilirubin 
>1.5 ULN) 
Conjugated bilirubin dosed on a case-by-case basis 
ALT and Total Bilirubin 
ALT > 3 ULN and Total Bilirubin > 2 
ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007 
Internal DILI WG Oct 2008 
To be counted within the same treatment phase, whatever the interval between 
measurement 
CPK 
> 3 ULN 
>10 ULN 
FDA Feb 2005 
Am J Cardiol April 2006 
Categories are cumulative 
First row is mandatory. Rows following one mentioning zero can be deleted. 
Creatinine 
 150 mol/L (adults) 
   90 mol/L (6-12 year-old) 
 30%  from baseline 
 100%  from baseline 
Benichou C., 1994 
 
                                        VV-RIM-00099260-1.0 Approved - 03 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1908-1909-ALG-1703 
Statistical Analysis Plan 
Date: 30 January 2020 
CONFIDENTIAL 
Page 48 of 50 
Parameter 
PCSV 
For Studies in healthy subjects only 
Comments 
Creatinine Clearance 
(Cockcroft's formula) 
< 30 ml/min (severe renal impairment) 
30 - < 50 ml/min (moderate renal 
impairment) 
50 -  80  ml/min (mild renal 
impairment) 
Use is optional. 
FDA criteria May 1998 
Uric Acid 
Hyperuricemia: 
Hypouricemia: 
 
>408 µmol/L 
<120 µmol/L 
Harrison- Principles of internal Medicine 17th Ed. 2008 
Sodium 
129 mmol/L 
 160 mmol/L 
 
Potassium 
< 3  mmol/L 
 5.5 mmol/L 
FDA Feb 2005 
Total Cholesterol 
 7.74 mmol/L (3 g/L) 
Threshold for therapeutic intervention 
Triglycerides 
 4.6 mmol/L (4 g/L) 
Threshold for therapeutic intervention 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
 3.9 mmol/L and < LLN 
  7 mmol/L (fasted);  11.1 mmol/L 
(unfasted) 
 
ADA May 2005 
ADA Jan 2008 
 
CRP 
> 2 ULN or 
 >10 mg/L, if ULN not provided 
 FDA Sept 2005 
 
Hematology 
WBC 
< 3.0 Giga/L (3000/mm3) 
< 2.0 Giga/L (2000/mm3) (Black) 
Increase in WBC: not relevant 
To be interpreted only if no differential count available. 
Neutrophils 
< 1.5 Giga/L (1500/mm3) 
< 1.0 Giga/L (1000/mm3) Black 
International Consensus meeting on drug-induced blood cytopenias, 1991. 
FDA criteria 
                                        VV-RIM-00099260-1.0 Approved - 03 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1908-1909-ALG-1703 
Statistical Analysis Plan 
Date: 30 January 2020 
CONFIDENTIAL 
Page 49 of 50 
Parameter 
PCSV 
For Studies in healthy subjects only 
Comments 
Eosinophils 
> 0.5 Giga/L (500/mm3) 
or > ULN if ULN  0.5 Giga/L 
Gallin 1989, Harrisson 13th Ed, 1994. 
Hemoglobin 
At least 20 g/L (1.24 mmol/L) decrease 
versus baseline 
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) 
Platelets 
< 100 Giga/L (100 000/mm3) 
International Consensus meeting on drug-induced blood cytopenias, 1991. 
Vital signs 
HR 
 40 bpm and decrease from baseline  20 
bpm 
 100 bpm and increase from baseline  
20 bpm 
Proposed change: To be are applied for all position (including missing) except 
STANDING 
SBP 
 95 mmHg and decrease from baseline  
20 mmHg 
 140 mmHg and increase from baseline  
20 mmHg 
Proposed change: To be are applied for all position (including missing) except 
STANDING 
DBP 
Young and elderly subjects 
 45 mmHg and decrease from baseline  
10 mmHg 
 90 mmHg and increase from baseline  
10 mmHg 
 
Proposed change: To be are applied for all position (including missing) except 
STANDING 
Orthostatic Hypotension 
SBP St – Su  - 20 mmHg 
DBP St – Su  - 10 mmHg 
 
Weight 
 5 % increase versus baseline 
5% decrease versus baseline 
FDA Feb 2007  
ECG parameters 
CPMP 1997 guideline 
                                        VV-RIM-00099260-1.0 Approved - 03 Feb 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R1908-1909-ALG-1703 
Statistical Analysis Plan 
Date: 30 January 2020 
CONFIDENTIAL 
Page 50 of 50 
Parameter 
PCSV 
For Studies in healthy subjects only 
Comments 
HR 
 40 bpm and decrease from baseline  20 
bpm 
 100 bpm and increase from baseline  
20 bpm 
 
PR 
 220 ms 
 
QRS 
 120 ms 
 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms) 
                Males           Females 
Borderline  
           431-450 ms     451-470 ms 
Prolonged* 
           > 450 ms         > 470 ms 
QTc   ≥500 ms           ≥ 500 ms 
 
Increase versus baseline (Males and 
Females) 
Borderline 
 30-60 ms 
Prolonged * 
 > 60 ms 
To be applied to any kind of QT correction formula  
 
*QTc prolonged and QTc > 60 ms are the PCSA to be identified in individual 
subjects/patients listings. 
 
 
                                        VV-RIM-00099260-1.0 Approved - 03 Feb 2020 GMT-5:00