Clinical trial NCT05692154
Conditions: Seasonal Allergic Rhinitis
Sponsor: Opella Healthcare Group SAS, a Sanofi Company
Start date: 2023-01-23; Completion date: 2023-03-14
Enrollment: 95 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a proof-of-concept study to demonstrate if a daily dose of a 2-days pre-treatment of Fexofenadine 180mg is effective in alleviating the AR symptoms and to assess the additional benefit to the patient in terms of preventing Allergic Rhinitis (AR) symptoms.

The total study duration per participant is expected at least 4 months, depending on the timing of the screening visit. 5 visits are planned, screening, confirmation inclusion challenge, randomization visit, challenge and end of study visit.

Detailed description:
The end of the study is defined as the date of the last visit of the last participant in the study.

A participant is considered to have completed the study if he/she has completed all visits of the study including Visit 5 (Day 5).

Arms: arm 1: Two days of pre-treatment with Fexofenadine 180 mg each day in the morning on Day 2 and Day 3, then Fexofenadine180 mg after the pollen challenge on Day 4. arm 2: Two days of pre-treatment with tablet of matching placebo each day in the morning on Day 2 and Day 3, then Fexofenadine180 mg after the pollen challenge on Day 4.
Interventions: intervention 1: Fexofenadine intervention 2: Placebo
Intervention descriptions: intervention 1: Fexofenadine oral tablet intervention 2: Fexofenadine matching placebo oral tablet

Protocol documents:
Prot_000.pdf: 
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Protocol LPS17180 (FEXPRESAR), Original Protocol
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TITLE PAGE 
Protocol Title: A Phase IIIb, single-center, double-blind, two-arms, placebo-controlled, 
randomized, parallel-group clinical trial to evaluate the efficacy and safety of 
2-day pre-treatment with fexofenadine in patients suffering from Seasonal
Allergic Rhinitis
Protocol Number: LPS17180 (FEXPRESAR) 
Amendment Number: Not applicable  
Compound: Allegra® (Fexofenadine HCl) 
Brief Title: A placebo-controlled study for 2-day pre-treatment with fexofenadine in seasonal 
allergic rhinitis 
Study Phase: IIIb 
Sponsor Name: Opella Healthcare Group SAS 
Legal Registered Address: 82, Avenue Raspail, 94250 Gentilly, France. 
Regulatory Agency Identifier Number(s): 
Registry 
ID 
Universal Trial 
Number (UTN) 
U1111-1278-3949 
Approval Date: 21 September 2022 
Sponsor Signatory 
 
 
Date 
Medical Monitor name and contact information will be provided separately.  
21 September 2022
NCT05692154


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TABLE OF CONTENTS 
1.0 
PROTOCOL SUMMARY .......................................................................................... 7 
1.1 
Synopsis ............................................................................................................ 7 
1.2 
Schema ............................................................................................................ 10 
1.3 
Schedule of Activities .................................................................................... 11 
2.0 
INTRODUCTION ..................................................................................................... 13 
2.1 
Study Rationale .............................................................................................. 13 
2.2 
Background .................................................................................................... 13 
2.3 
Benefit/Risk Assessment ............................................................................... 17 
2.3.1 
Risk Assessment ................................................................................ 17 
2.3.2 
Benefit Assessment ........................................................................... 18 
2.3.3 
Overall Benefit Risk Conclusion ...................................................... 18 
3.0 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ............................................... 19 
4.0 
STUDY DESIGN ....................................................................................................... 20 
4.1 
Overall Design ................................................................................................ 20 
4.1.1 
Visit 1 (Screening): Within 3 Months Prior Visit 2 .......................... 21 
4.1.2 
Visit 2 (Confirmation Ragweed Pollen Challenge) .......................... 21 
4.1.3 
Washout Period (≥15 Days) .............................................................. 22 
4.1.4 
Visit 3 (Randomization) Day 1 ......................................................... 22 
4.1.5 
At Home: Day 2 and Day 3 (Study Drug Intake and Diary 
Card Completion) .............................................................................. 23 
4.1.6 
Visit 4 (Test Ragweed Pollen Challenge) Day 4 .............................. 23 
4.1.7 
End-of-Study Telephone Call or On-site Visit on Day 5 .................. 24 
4.2 
Scientific Rationale for Study Design .......................................................... 25 
4.3 
Justification for Dose ..................................................................................... 25 
4.4 
End-of-Study Definition ................................................................................ 26 
5.0 
STUDY POPULATION ............................................................................................ 27 
5.1 
Inclusion Criteria ........................................................................................... 27 
5.2 
Exclusion Criteria .......................................................................................... 27 
5.3 
Lifestyle Considerations ................................................................................ 29 
5.4 
Screen Failures ............................................................................................... 29 
5.5 
Criteria for Temporarily Delaying Enrollment, Randomization, 
or Study Drug Administration ..................................................................... 29 
6.0 
STUDY DRUG(S) AND CONCOMITANT THERAPY ....................................... 31 
6.1 
Study Drug(s) Administered ......................................................................... 31 
6.2 
Preparation, Handling, Storage, and Accountability ................................. 32 
6.3 
Measures to Minimize Bias: Randomization and Blinding ....................... 33 
6.3.1 
Randomization .................................................................................. 33 


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6.3.2 
Blinding ............................................................................................. 33 
6.4 
Study Drug Compliance ................................................................................ 34 
6.5 
Dose Modification .......................................................................................... 35 
6.6 
Continued Access to Study Drug after the End of the Study .................... 35 
6.7 
Management of Overdose ............................................................................. 35 
6.8 
Concomitant Therapy ................................................................................... 36 
6.8.1 
Prohibited Medications ..................................................................... 36 
6.8.2 
Rescue Medicine ............................................................................... 37 
7.0 
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................ 38 
7.1 
Discontinuation of Study Drug ..................................................................... 38 
7.1.1 
Temporary Discontinuation .............................................................. 38 
7.1.2 
Rechallenge ....................................................................................... 38 
7.2 
Participant Discontinuation/Withdrawal from the Study ......................... 39 
7.3 
Lost to Follow-up ........................................................................................... 39 
8.0 
STUDY ASSESSMENTS AND PROCEDURES .................................................... 41 
8.1 
Efficacy Assessments ..................................................................................... 41 
8.2 
Safety Assessments ........................................................................................ 42 
8.2.1 
Physical Examinations ...................................................................... 42 
8.2.2 
Nasal Examination ............................................................................ 42 
8.2.3 
Vital Signs ......................................................................................... 42 
8.2.4 
Electrocardiograms ........................................................................... 43 
8.2.5 
Clinical Safety Laboratory Tests ....................................................... 43 
8.2.6 
Pregnancy Testing ............................................................................. 43 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting ........................................................................................................ 43 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information ........................................... 43 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events ................................................................................................ 44 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events .............. 44 
8.3.4 
Regulatory Reporting Requirements for SAEs ................................. 44 
8.3.5 
Pregnancy .......................................................................................... 45 
8.3.6 
Adverse Events of Special Interest ................................................... 46 
8.3.7 
Treatment Satisfaction and Recommendation .................................. 46 
8.4 
Pharmacokinetics .......................................................................................... 46 
8.5 
Pharmacodynamics ....................................................................................... 46 
8.6 
Genetics .......................................................................................................... 46 
8.7 
Biomarkers ..................................................................................................... 46 
8.8 
Immunogenicity Assessments ....................................................................... 47 
8.9 
Health Economics .......................................................................................... 47 


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9.0 
STATISTICAL CONSIDERATIONS ..................................................................... 48 
9.1 
Statistical Hypotheses .................................................................................... 48 
9.1.1 
Multiplicity Adjustment .................................................................... 48 
9.2 
Analysis Sets ................................................................................................... 48 
9.3 
Statistical Analyses ........................................................................................ 49 
9.3.1 
General Considerations ..................................................................... 49 
9.3.2 
Primary Endpoint Analysis ............................................................... 49 
9.3.3 
Secondary Endpoints Analysis .......................................................... 50 
9.3.4 
Exploratory Endpoint(s) Analysis ..................................................... 51 
9.3.5 
Safety Analyses ................................................................................. 51 
9.3.6 
Study Drug Compliance .................................................................... 51 
9.4 
Interim Analysis ............................................................................................. 52 
9.5 
Sample Size Determination ........................................................................... 52 
10.0 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ................................................................................................. 54 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................... 54 
10.1.1 
Regulatory and Ethical Considerations ............................................. 54 
10.1.2 
Adequate Resources .......................................................................... 55 
10.1.3 
Financial Disclosure .......................................................................... 55 
10.1.4 
Insurance ........................................................................................... 55 
10.1.5 
Informed Consent Process ................................................................. 55 
10.1.6 
Data Protection .................................................................................. 56 
10.1.7 
Committees Structure ........................................................................ 56 
10.1.8 
Dissemination of Clinical Study Data ............................................... 56 
10.1.9 
Data Quality Assurance ..................................................................... 56 
10.1.10 Source Documents ............................................................................ 57 
10.1.11 Start and Closure of Study and Study Site ........................................ 58 
10.1.12 Publication Policy ............................................................................. 59 
10.2 
Appendix 2: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting for Study Drug ............................................................... 60 
10.2.1 
Definition of Adverse Event ............................................................. 60 
10.2.2 
Definition of Serious Adverse Event ................................................ 61 
10.2.3 
Recording and Follow-up of AE and/or SAE ................................... 62 
10.2.4 
Reporting of Serious Adverse Events ............................................... 64 
10.2.5 
Reporting of Suspected Unexpected Serious Adverse 
Reactions ........................................................................................... 64 
10.3 
Appendix 3: Contraceptive and Barrier Guidance and 
Collection of Pregnancy Information .......................................................... 66 
10.3.1 
Definitions ......................................................................................... 66 
10.3.2 
Contraception Guidance .................................................................... 66 
10.4 
Appendix 4: Evolution of Seasonal Allergic Rhinitis Symptoms, 
Following United States Food and Drug Administration 
Guidelines 2018 .............................................................................................. 69 


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10.5 
Appendix 5: Abbreviations ........................................................................... 70 
11.0 
REFERENCES .......................................................................................................... 72 
 


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LIST OF TABLES 
Table 1 
Schedule of Activities ....................................................................................... 11 
Table 2 
Study Drugs Administered ............................................................................... 31 
Table 3 
Study Arms ....................................................................................................... 32 
Table 4 
Efficacy Analyses ............................................................................................. 50 
 
LIST OF FIGURES 
Figure 1 
Study Schema ................................................................................................... 10 
Figure 2 
Environmental Exposure Unit .......................................................................... 15 
 


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1.0 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title:  
A Phase IIIb, single-center, double-blind, two-arms, placebo-controlled, randomized, 
parallel-group clinical trial to evaluate the efficacy and safety of 2-day pre-treatment with 
fexofenadine in patients suffering from Seasonal Allergic Rhinitis 
Registry 
ID 
Universal Trial Number (UTN) 
U1111-1278-3949 
Rationale: 
Previous and pilot studies have suggested that administration of antihistamines a few days or 
weeks before the pollen season show a greater inhibitory effect on nasal allergy symptoms in 
patients with allergic rhinitis (AR) than when taken when symptoms appear.7, 8 Fexofenadine 
HCl is a second-generation, non-sedating, histamine H1 receptor antagonist (antihistamine) 
formulated for oral administration and is approved under different strengths and oral 
pharmaceutical forms for the relief of symptoms associated with AR in adults, adolescents, 
and children. This proof-of-concept study will assess fexofenadine as a pre-treatment option. 
The study will be performed under well-controlled conditions of exposure to Ragweed pollen 
in participants who experienced pollen allergy confirmed by skin prick tests and challenges 
tests, with the highest dosage of fexofenadine 180 mg. This study will assess the effect of a 
2-day pre-treatment regimen of fexofenadine 180 mg once daily in alleviating AR symptoms 
and possibly even preventing symptoms. 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the efficacy of fexofenadine 
180 mg when started 2 days before the exposure 
to the allergen in patients suffering from SAR  
• 
The AUC of the TNSS-3 from H0 to H6 at V4 
Secondary 
 
• 
To evaluate the efficacy of fexofenadine when 
started 2 days before the exposure to the 
allergen in patients suffering from SAR in terms 
of preventing nasal and ocular symptoms of 
rhinorrhea, sneezing, and nasal itching, 
red/burning eyes, tearing, and itchy/watery eyes 
• 
AUC of TOSS from H0 to H6 at V4  
• 
AUC of TNSS-3 from H0 to H12 at V4  
• 
AUC of TOSS from H0 to H12 at V4  
• 
AUC of TNSS-3 from randomization (D1) to V4 
(D4) 
• 
AUC of TOSS from randomization (D1) to V4 
(D4) 


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Objectives 
Endpoints 
Secondary (Contd.) 
• 
To evaluate the safety of fexofenadine when 
started 2 days before the exposure to the 
allergen in patients suffering from SAR 
 
• 
Frequency of AEs 
Exploratory 
 
• 
 
 
 
 
 
 
 
• 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
• 
 
 
• 
  
• 
 
 
• 
 
 
 
Abbreviations: AE = adverse event, AUC = area under the plasma concentration time curve, D = day, H = hour, 
SAR = Seasonal Allergic Rhinitis, TNSS-3 = Total Nasal Symptom Score of 3 symptoms, TOSS = Total 
Ocular Symptoms Score, TSS = Total Symptom Score, V = visit. 
Overall Design: 
This is a Phase IIIb, randomized, double-blind, single-center, two-arm, parallel-group, 
placebo-controlled, proof-of-concept study, outside of Ragweed pollen season. A total of 5 
visits to the study site or the Environmental Exposure Unit (EEU) is planned per participant. 
At Visit 3, participants will be randomized and be in the study for a total of 5 days. No review 
committee has been appointed for this study. 
Two Arms are planned: 
• Arm A (active-active): two days of pre-treatment with fexofenadine, then fexofenadine 
180 mg during the test pollen challenge  
• Arm B (placebo-active): two days of pre-treatment with placebo, then fexofenadine 
180 mg during the test pollen challenge 
Each participant will be screened, including skin prick tests at Visit 1 (V1). Eligible 
participants will return to the study site for a 3-hour pollen exposure (standard Ragweed 
pollen concentration of 3500 ± 500 grains/m3) at V2 and discharged thereafter. Only those 
participants with qualifying symptom scores (Total Nasal Symptom Score of 3 symptoms 
[TNSS-3] ≥4) in the last 90 minutes of the challenge will be eligible to be randomized into the 


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study. After a washout period of at least 15 days, randomization will occur at V3 (Day 1) in a 
1:1 proportion to either Arm A (active-active) or Arm B (placebo-active) group. 
Randomization may occur within a week after completion of the washout period, where the 
participants will be instructed not to take the study drug until 2 days before their planned V4. 
The participants will consume study drug at home, on Day 2 and Day 3. This will be followed 
by a Ragweed pollen challenge lasting 3 hours (standard Ragweed pollen concentration of 
3500 ± 500 grains/m3) at V4 (Day 4). During this challenge, participants in both Arms will 
receive a single dose of fexofenadine 180 mg after pollen exposure, at Hour 3. The 
participants will be discharged after the challenge at V4 (Day 4). Participants will record their 
symptoms using a diary card (or an e-diary, if applicable) while in the EEU and at home 
thereafter. On Day 5, all participants will participate in a telephonic visit, which will be 
recorded as End-of-Study (EOS) Visit. For return of the e-diary, the participants will come to 
the study site for an in-person EOS Visit. 
Number of Participants: 
An adequate number of participants will be screened to achieve 96 participants randomized 
(86 evaluable participants). 
Adult patients (18 to 80 years old) suffering from seasonal allergic rhinitis (SAR) provoked by 
Ragweed pollen, with a 2-year history of SAR with positive skin prick test to Ragweed 
allergen at screening (≥3 mm) and having a TNSS-3 of ≥4 (with 3 nasal symptoms) at first 
pollen challenge at Visit 2 will be enrolled. Any participant with history of anaphylaxis to 
Ragweed pollen, history of asthma or exacerbations in the past 12 months requiring regular 
inhaled corticosteroids for >4 weeks per year, any oral corticosteroid usage, any emergency 
department visit for asthma or any asthma-related hospitalization, or history of chronic 
sinusitis will be excluded. 
Intervention Groups and Duration: 
Participants in Arm A (active 2 days) will consume at home, 1 tablet of fexofenadine 180 mg 
each day in the morning on Day 2 and Day 3, followed by 1 tablet of fexofenadine 180 mg 
after the pollen challenge on Day 4. 
Participants in Arm B (placebo 2 days) will consume at home, 1 tablet of matching placebo 
each day in the morning on Day 2 and Day 3, followed by 1 tablet of fexofenadine 180 mg 
after the pollen challenge on Day 4. 
Data Monitoring/Other Committee: No  


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1.2 
Schema 
Figure 1 
Study Schema 
 
Abbreviations: Fex = fexofenadine, FU = follow up, H = hour, Inc/exc = inclusion and exclusion criteria, 
Inf.Cons. = informed consent, Plo = placebo, TNSS = Total Nasal Symptoms Score, V = visit. 


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1.3 
Schedule of Activities 
Table 1 
Schedule of Activities 
 
Screening 
Confirmation 
Washout 
Randomization 
Treatment 
Pollen Challenge  
End-of-study  
(telephone 
call or visit)  
Day 
 
Within 3 months 
after V1 
≥15 days 
D1 
D2 and 
D3 
D4 
D5 
Visits 
V1 
V2 
 
V3 
 
V4 
 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xa 
 
Xa 
 
Xa 
 
Medical history 
X 
 
 
 
 
 
 
Skin prick testing 
X 
 
 
 
 
 
 
Urine pregnancy test 
Xb 
Xb 
 
Xb 
 
Before challengeb 
 
COVID-19 testingc 
 
Before challenge 
 
 
 
Before challenge 
 
Physical examination 
X 
 
 
 
 
At H6 
 
Vital signs 
X 
 
 
 
 
At H6 
 
Nasal examination 
X 
 
 
 
 
At H6 
 
Symptoms scoring 
 
X 
 
X 
X 
Xd 
X 
Randomization 
 
 
 
X 
 
 
 
Study drug administration 
 
 
 
 
X 
Xe 
At H3 after challenge 
 
Diary card (e-diary) completionf 
 
Xf 
 
Xf 
Xf 
Xf 
Xf 
Pollen challenge (EEU)g  
 
3-hour pollen 
exposureh 
 
 
 
3-hours pollen 
exposurei 
 
AE recordingj  
X 
X 
X 
X 
X 
X 
X 
Concomitant medicationsk 
X 
X 
X 
X 
X 
X 
X 
Participant satisfaction and 
recommendation 
 
 
 
 
 
Xl 
 


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Abbreviations: AE = adverse event; D = day; COVID-19 = coronavirus disease 2019; eCRF = electronic case report form; EEU = Environmental Exposure Unit; 
H = hour; Random = randomization; SARS-CoV-2 = severe acute respiratory syndrome coronavirus-2; Treat = treatment period; V = visit; WO = washout 
period; WOCBP = women of childbearing potential. 
Note: If a participant is not able to visit the study site for any reason (including COVID-19) they should contact the study site by telephone. Adverse event and 
concomitant medication details may be collected during a telephone call. It may not be possible to collect all clinical laboratory samples or conduct clinical 
assessments during this time, but any details should be recorded in the eCRF. If alternative arrangements can be agreed for the sample collection or clinical 
assessments, the details should be documented in the eCRF. 
a 
Exclusion criteria will be re-verified 
b 
For WOCBP only. Urine pregnancy test on V2 and V4 must be performed before challenge. 
c 
COVID-19 rapid antigen test for SARS-CoV-2 infection must be performed before pollen exposure at V2 and V4. 
d 
See Section 4.1.6 for specific time points for symptom scoring at V2 and V4. Scores may be recorded in the e-diary (See Footnote f). 
e 
Participants will have to return their study drug wallet (which was dispensed at V3) before challenge at V4.  
f 
Diary card (or e-diary, if applicable) will be provided at screening and should be completed every day, in the morning. See Section 4.1.6 for specific time 
points for e-diary completion after discharge on V4. The e-diary will be provided on the participant’s own phone or provided device. 
g 
Participants will be exposed to a standard Ragweed pollen concentration of 3500 ± 500 grains/m3. If in the judgment of the Investigator, symptoms become 
intolerable the subjects will be removed from the EEU. 
h 
For 3-hour pollen exposure on V2: Pollen exposure begins at H0 and ends at H3.  
• 
H0: Start pollen exposure 
• 
H0 to H3: Allergic symptoms will be recorded every 15 minutes 
• 
H3: Stop pollen exposure and discharge from EEU. 
i 
For 3-hour pollen exposure on V4: Pollen exposure begins at H0 and ends at H3.  
• 
H0: Start pollen exposure 
• 
H0 to H3: Allergic symptoms will be recorded every 15 minutes,  
• 
H3: Stop pollen exposure  
• 
At H3: single dose of fexofenadine180 mg,  
• 
H3 to H6: Allergic symptoms will be recorded every 30 minutes,  
• 
After H6: Participant will be discharged, 
• 
H6 to H12: Allergic symptoms will be recorded every hour at home. 
j 
Adverse events will be collected at every visit. 
k 
Concomitant medications will include rescue medication. 
l 
Participant satisfaction and recommendation will be collected via e-diary. See Section 4.1.6 for time points for this assessment on V4. 
 


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2.0 INTRODUCTION 
2.1 
Study Rationale 
If patients have a prior history of seasonal allergic rhinitis (SAR), allergists in the US 
recommend starting medications to alleviate symptoms before they are expected to begin.1 
Pre-treatment may prevent or reduce allergic rhinitis (AR) symptoms if taken before exposure 
to a known allergen, or before the allergy season. Taking an H1 histamine receptor antagonist 
(antihistamine) prior to exposure, might reduce the allergic reaction by stopping the 
inflammatory cascade and easing AR symptoms.2 
The Practical Guideline for the Management of Allergic Rhinitis in Japan 2017 recommends 
that clinicians treat patients with SAR from the beginning of early symptoms, immediately 
after the start of pollen season. The Chinese clinical guidelines on Allergic Rhinitis published 
in 2018 states that the use of second-generation antihistamines prior to pollen exposure can 
improve nasal symptoms and activity by impairment in pollinosis.  
Fexofenadine HCl is a second-generation, non-sedating, histamine H1-receptor (H1R) 
antagonist (antihistamine) formulated for oral administration. It is approved in more than 
100 countries worldwide, covering Europe, North America, Central and South America, 
Australia, Japan, the Middle East, Asia, and Africa. This is a proof-of-concept study assessing 
the efficacy of fexofenadine as pre-treatment. The study will be performed under 
well-controlled exposure to Ragweed pollen in an Environmental Exposure Unit (EEU) in 
participants who experienced pollen allergy confirmed by skin prick tests and challenges tests, 
with the highest dosage of fexofenadine 180 mg marketed in multiple countries (eg, US and 
Brazil).  
2.2 
Background 
Allergic Rhinitis is one of the most common types of rhinitis and the most underestimated 
respiratory condition reported by physicians and patients in terms of prevalence. Its 
management is often suboptimal and frequently complicated by delayed diagnosis and 
appropriate treatment. Antihistamines (oral, intranasal) are the most commonly used 
medications for the relief of AR symptoms, both over-the-counter and by-prescription. 
Symptom severity and symptom onset were the primary signals to take allergy medications for 
47% of adults and 46% of children. Some respondents (12% of adults and 26% of children) 
started their allergy medications before seasonal symptom onset.3 
Since SAR due to different allergens is a predictable phenomenon, pre-treatment may benefit 
these patients as mentioned in the different guidelines.1, 4  


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Currently, applications and websites are available in the public domain, to inform the public 
about the presence of outdoor allergens such as pollen in the air. More importantly, these can 
be used to provide data that allows for an accurate prediction of AR symptom development 
over a period of 48 hours in susceptible individuals and to develop models based on forecasted 
temperature and concentration of pollen/m3 to predict hay fever symptoms up to 5 days in 
advance.5, 6 
If one has a prior history of indoor or outdoor allergies, allergists recommend starting 
medications to alleviate symptoms a few days to 2 weeks before they are expected to begin, 
before the allergy season.  
Fexofenadine HCl is a second-generation, non-sedating, antihistamine formulated for oral 
administration. 
 
 
 
 
 
 
 
 
 
 
  
The interest of starting the antihistamine treatment before the exposure to the allergen has 
already been observed, and administration of antihistamines few days or weeks before the 
pollen season started suggested a greater inhibitory effect on nasal allergy symptoms in 
patients with AR, than when taken after the symptoms appeared.7, 8 Accordingly, their 
administration 2 to 4 weeks before the onset of the pollen season is recommended in patients 
with pollinosis in Japan. Recently, several lines of evidence have suggested that in addition to 
their histamine-blocking effect at H1R, antihistamines possess anti-inflammatory activity 
through a histamine-cytokine network and decrease H1R gene upregulation with suppression 
of nasal symptoms.9, 10 A pre-seasonal prophylactic (1 to 4 weeks) treatment with 
antihistamines suppresses interleukin (IL)−5 but not IL-33 mRNA expression in the nasal 
mucosa of patients with SAR caused by Japanese cedar pollen, noted in 8 patients versus 
17 control patients.9 These findings suggest that the down-regulation of IL-5 gene expression 
in collaboration with the suppression of H1R gene expression in the nasal mucosa provides 
the basis for better therapeutic effects of pre-seasonal prophylactic treatment with 
antihistamines (Ebastine, Fexofenadine) in patients with pollinosis.  


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Histamine is a major chemical mediator causing symptoms of pollinosis.4 Its action occurs 
mainly through the activation of H1R. Activation of H1R results in the symptoms of AR. The 
level of H1R gene expression is strongly correlated with the severity of allergy symptoms in 
patients with pollinosis.11 Fexofenadine is a well-known, non-sedating antihistamine molecule 
that binds H1R and prevents histamine binding and subsequent H1R activation. Interestingly, 
fexofenadine when acting as an inverse agonist, binds the inactive form of H1R and down-
regulates constitutive receptor activity, could prevent histamine-induced H1R activation in a 
more effective manner by shifting the H1R equilibrium toward the inactive state.12, 13   
In a new in vitro model based on fully reconstituted human nasal epithelium tissue the effect 
of histamine and relevant biomarkers have been assessed and effect of fexofenadine has been 
evaluated on inflammatory cytokine, IL-8 and IL-6, as well as the benefits of inverse agonist 
activity of fexofenadine in prophylactic conditions versus that of concomitant with histamine 
has been explored. These data suggest that IL-8 and H1R gene expression levels are promising 
biomarkers of histamine-induced inflammation in human nasal epithelium model. Higher 
anti-inflammatory activity of fexofenadine (inhibition of IL-8 inflammatory cytokine and 
down-regulation of H1R gene expression) in prophylactic scenario has been demonstrated; 
these new findings correlate with inverse agonist fexofenadine mode of action. These data 
suggest that starting fexofenadine administration prior to allergen exposure before the 
symptoms appear or while the first symptoms occur could have a protective effect and better 
control of the intensity of nasal symptoms during allergic episodes.14  
The study is proposed to be conducted in an EEU. The EEU is a specifically engineered room 
(Figure 2). The EEU setup includes chairs, feeder, fans, and sampling equipment. A 
custom-engineered computer and laser-aided system disperses pollen at a single point of 
delivery. Evaluation of the efficacy of anti-allergic drugs in patients with pollinosis under 
natural exposure to pollen presents challenges due to unpredictability of various parameters 
such as pollen concentration, pollen antigenicity, and weather conditions. To overcome these 
complications, the EEU was developed to meet the criteria of stable environmental conditions 
including temperature, humidity and pollen concentration, and reproducibility of pollen-
induced nasal symptoms. The pollen will be distributed by selectively placed groups of 
directional fans, over the participant seating area. Ragweed pollen will be sourced from the 
USA and will be independently tested for fungal and bacterial contamination by a Canadian 
Center before use in the EEU.15  
This proof-of-concept study is proposed to assess the effect of a 2-day pre-treatment regimen 
of fexofenadine 180 mg once daily in alleviating AR symptoms and possibly even preventing 
symptoms. 
 
Figure 2 
Environmental Exposure Unit 


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Abbreviations: EEU = Environmental Exposure Unit; HDM-EEU = house dust mite unit-Environmental 
Exposure Unit; R = rotorod. 


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2.3 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of fexofenadine may be found in the Summary of Product 
Characteristics (SmPC). 
The Sponsor will immediately notify the Principal Investigator if any additional safety or 
toxicology information becomes available during the study. 
This study will be performed in compliance with the protocol, ICH-Good Clinical Practice 
(GCP), European Union-Clinical Trials Regulations, and applicable regulatory requirements.  
2.3.1 
Risk Assessment 


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2.3.2 
Benefit Assessment 
Potential benefits include contributing to the process of developing a new method of therapy 
as this study will contribute to the knowledge of AR management for patients and provide 
evidence of the benefit from pre-treatment for allergy sufferers.  
All participants can expect a treatment benefit as they all will have confirmed AR diagnosis, 
will have demonstrated the occurrence of AR symptoms during the pollen challenge which 
takes place after screening, and all participants will receive at least 1 dose of fexofenadine 
during the study, even those in the placebo arm, which they can continue at home after the 
pollen challenge is over if they wish to. This study may bring a better knowledge about the 
benefit of pre-treatment for SAR.  
 
 
 
 
 
 
 
 
 
 
 
 


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3.0 OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the efficacy of fexofenadine 
180 mg when started 2 days before the 
exposure to the allergen in patients suffering 
from SAR  
• 
The AUC of the TNSS-3 from H0 to H6 at V4 
Secondary 
 
• 
To evaluate the efficacy of fexofenadine 
when started 2 days before the exposure to 
the allergen in patients suffering from SAR in 
terms of preventing nasal and ocular 
symptoms of rhinorrhea, sneezing, and nasal 
itching, red/burning eyes, tearing, and 
itchy/watery eyes 
• 
AUC of TOSS from H0 to H6 at V4  
• 
AUC of TNSS-3 from H0 to H12 at V4  
• 
AUC of TOSS from H0 to H12 at V4  
• 
AUC of TNSS-3 from randomization (D1) to V4 
(D4) 
• 
AUC of TOSS from randomization (D1) to V4 (D4) 
• 
To evaluate the safety of fexofenadine when 
started 2 days before the exposure to the 
allergen in patients suffering from SAR 
• 
Frequency of AEs 
Exploratory 
 
• 
 
 
 
 
 
 
 
• 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
• 
 
 
• 
  
• 
 
 
• 
 
 
Abbreviations: AE = adverse event, AUC = area under the plasma concentration-time curve, D = day, H = hour, 
SAR = seasonal allergic rhinitis, TNSS-3 = Total Nasal Symptom Score of 3 symptoms, TOSS = Total Ocular 
Symptoms Score, TSS = Total Symptom Score, V=visit. 
Estimands: Not applicable. 


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4.0 STUDY DESIGN 
4.1 
Overall Design 
This is a Phase IIIb, randomized, double-blind, single-center, two-arm, parallel-group, 
placebo-controlled, proof-of-concept study, outside of Ragweed pollen season. Two Arms are 
planned: 
• Arm A (active 2 days): two days of pre-treatment with fexofenadine, then 
fexofenadine 180 mg during the test pollen challenge  
• Arm B (placebo 2 days): two days of pre-treatment with placebo, then 
fexofenadine 180 mg during the test pollen challenge 
A total of 5 visits to the study site or the EEU are planned per participant. 
An adequate number of participants will be screened to achieve 96 participants randomized 
(86 evaluable participants). Each participant will be screened, including skin prick tests at 
Visit 1 (V1). Eligible participants will return to the study site for a 3-hour pollen exposure 
(standard Ragweed pollen concentration of 3500 ± 500 grains/m3) at V2 and discharged 
thereafter. Only those participants with qualifying symptom scores (Total Nasal Symptom 
Score of 3 symptoms [TNSS-3] ≥4) in the last 90 minutes of the challenge will be eligible to 
be randomized into the study. After a washout period of at least 15 days, randomization will 
occur within a week, at V3 (Day 1) in a 1:1 proportion to either Arm A (active-active) or 
Arm B (placebo-active) group. Randomization may occur within a week after completion of 
the washout period, where the participants will be instructed not to take the study drug until 
2 days before their planned V4. The participants will consume study drug at home, on Day 2 
and Day 3. This will be followed by a Ragweed pollen challenge lasting 3 hours (standard 
Ragweed pollen concentration of 3500 ± 500 grains/m3) at V4 (Day 4). During this challenge, 
participants in both Arms will receive a single dose of fexofenadine 180 mg after pollen 
exposure, at Hour 3 (H3). The participants will be discharged after the challenge at V4 
(Day 4). Participants will record their symptoms using a diary card (e-diary) while in the EEU 
and at home thereafter. On Day 5, all participants will participate in a telephonic visit, which 
will be recorded as End-of-Study (EOS) Visit. For return of the e-diary, the participants will 
come to the study site for an in-person EOS Visit. Any emergency/pandemic concerns in the 
future will be minimized via use of an e-diary, which is a virtual interface, to document AEs, 
concomitant medications, symptoms, and the treatment satisfaction questionnaire. 
Considering an estimated 10% dropout rate, the number of evaluable subjects for the modified 
intent-to-treat (mITT) population will need to be 86 participants across both Arms. 


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4.1.1 
Visit 1 (Screening): Within 3 Months Prior Visit 2 
The following procedures will be performed: 
• Signature of the written Informed Consent 
• Inclusion/exclusion criteria verification  
• Medical history 
• Skin Prick testing to a panel of allergens (Ragweed, dog, cat, D. pteronyssinus, 
D. farinae, grass pollens, birch tree pollen)  
• Physical examination 
• Vital signs 
• Nasal examination 
• Urine pregnancy testing (for women of childbearing potential [WOCBP] only) 
• Prior and concomitant medication recording 
• Collection of screening day AEs 
• Provision of diary card, ie, electronic Patient-Reported Outcome (e-PRO) diary  
4.1.2 
Visit 2 (Confirmation Ragweed Pollen Challenge) 
Eligible participants will return to the EEU for a 3-hour pollen exposure. The following 
procedures will be performed: 
• Inclusion/exclusion criteria verification  
• Coronavirus disease 2019 (COVID-19) testing via a rapid antigen test for severe acute 
respiratory syndrome coronavirus-2 (SARS-CoV-2) infection before challenge 
• Urine pregnancy testing (for WOCBP only) 
• The participants will be exposed to a standard Ragweed pollen concentration of 
3500 ± 500 grains/m3 for a period of 3 hours (H0 to H3).  
• During pollen exposure in the EEU, participants will rate their allergic symptoms 
every 15 minutes, starting at zero minutes after start of challenge, until 3 hours after 
start of challenge. Only those participants with qualifying symptom scores 
(TNSS-3 ≥4) will be eligible to be randomized into the study. In case a TNSS-3 ≥4 is 
not achieved by H3, the participant can be challenged again if deemed appropriate by 


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the Investigator. If TNSS-3 ≥4 is still not achieved with the second session the 
participant is not eligible for study continuation. 
• If in the judgment of the Investigator, symptoms become intolerable the participants 
will be removed from the EEU. 
• After 3 hours of challenge: discharge from the EEU 
• e-Diary completion 
• Concomitant medication recording 
• Participants will be questioned with regards to AEs. 
Only those participants with qualifying symptom scores (TNSS-3 ≥4) in the last 90 minutes of 
the challenge will be confirmed for continuing in the study. 
4.1.3 
Washout Period (≥15 Days) 
The following information will be recorded every day preferably in the morning, via e-diary: 
• Any AEs  
• Concomitant medications  
During the washout period of at least 15 days, any antiallergic therapy is forbidden. Please see 
Section 6.8 for prohibited medications during the study, including the washout period. 
4.1.4 
Visit 3 (Randomization) Day 1 
Randomization may occur within a week after completion of washout period. The following 
procedures will be performed on Day 1: 
• Inclusion/exclusion criteria verification  
• Urine pregnancy testing (for WOCBP only) 
• E-diary completion 
• Concomitant medication recording 
• Collection of AEs 
• Baseline allergic symptoms scoring  
• Randomization will be performed as follows: 
o Arm A: Fexofenadine, one tablet of 180 mg in the morning for 2 days 
o Arm B: Placebo, one tablet in the morning for 2 days 


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4.1.5 
At Home: Day 2 and Day 3 (Study Drug Intake and Diary Card Completion) 
The following activities are to be completed at home in the morning on Day 2 and Day 3: 
• Diary card (e-diary) completion for: 
o Allergic symptom scores, before drug intake: instantaneous assessments 
o Any AEs 
o Concomitant medications 
• Study drug intake 
4.1.6 
Visit 4 (Test Ragweed Pollen Challenge) Day 4 
The following activities are to be completed in the morning: 
• Inclusion/exclusion criteria verification 
• Urine pregnancy testing (for WOCBP only) before challenge 
• COVID-19 testing via a rapid antigen test for SARS-CoV-2 infection before challenge 
• Return study drug wallet before challenge 
• Symptoms scoring before challenge 
• Starting pollen challenge (hour zero [H0]): all participants will be exposed to a 
standard Ragweed pollen concentration of 3500 ± 500 grains/m3 
If in the judgment of the Investigator, symptoms become intolerable the participants will 
be removed from the EEU. 
• Pollen exposure will last 3 hours (H0 to H3).  
o H0 to H3: symptoms evaluation every 15 minutes 
o At H3: stop pollen exposure 
o At H3 all participants will receive one packet of fexofenadine 180 mg and will 
be instructed to take one tablet from the pack: 
 Arm A: single dose of fexofenadine 180 mg 
 Arm B: single dose of fexofenadine 180 mg 
• H3 to H6: symptoms evaluation every 30 minutes 


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• At H6: 
o Physical examination 
o Vital signs 
o Nasal examination as per Investigator judgment 
• Concomitant medication recording  
• Participants will be questioned with regards to AEs 
• Participant satisfaction and recommendation  
• Discharge from the EEU 
Once the participants are discharged, the following procedures will be performed at home on 
Day 4 (post-test Ragweed pollen challenge): 
• Diary card (e-diary) completion: 
o H6 to H12: symptoms evaluation every hour  
o Any AEs 
o Concomitant medications 
o Need of rescue medication  
o Participant satisfaction and recommendation  
• The participant can contact the Investigator at any time if necessary 
4.1.7 
End-of-Study Telephone Call or On-site Visit on Day 5  
On Day 5, all participants will participate in a telephonic visit, which will be recorded as EOS 
Visit. For return of the e-diary, the participants will come to the study site for an in-person 
EOS Visit. The following will be recorded: 
• Allergic symptom scores: instantaneous assessments 
• e-Diary card completion  
• Return of e-diary in person (if applicable)  
• Any AEs 
• Concomitant medications, including need of rescue medication 


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4.2 
Scientific Rationale for Study Design 
This is a Phase IIIb, randomized, double-blind, single-center, two-arm, parallel-group, 
placebo-controlled, proof-of-concept study. 
A double-blind, randomized, placebo-controlled design is chosen to minimize bias in data 
collection and interpretation. A washout period of ≥15 days is included between the skin prick 
test to identify eligible participants and randomization (D1), to prevent carry over of 
symptoms as well as possible drug effects from previous antihistamine therapy. The patient 
population to be included in this study is directly relevant to the target population for the 
intended therapeutic use of the study drug prior to exposure to allergen. 
The results of the study will be reported in terms of the statistical significance. It will be 
important to bridge the gap between statistical and clinical significance to make an informed 
decision in recommending any intervention.16 In addition to global ratings, changes in related 
measures that have established consensus-based thresholds can be used to define the 
responder threshold for the main criteria measure. In the literature, some different thresholds 
for the minimum clinically important difference (MCID) have been proposed from 
0.5 standard deviation (SD)17 to 1 SD18 for the improvement of the Rhinoconjunctivitis Total 
Symptom Score in grass-pollen-induced AR. 
The study will attempt to demonstrate clinical relevance of pre-treatment in the current 
indication. This requires showing a robust statistical difference when comparing groups with 
and without pre-treatment. Therefore, the use of placebo in this study is justified and ethical. 
 
 
 
 
 
 
 
 
 
 
 
 


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4.4 
End-of-Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study.  
A participant is considered to have completed the study if he/she has completed all visits of 
the study including the telephone call/visit on D5. 


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5.0 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Participant is willing to provide written informed consent. 
2. Adult patients (18 to 80 years old) suffering from SAR provoked by Ragweed pollen. 
3. Patients having a TNSS-3 ≥4 (with 3 nasal symptoms) at first pollen challenge at 
Visit 2. 
4. Having a 2-year history of SAR with positive skin prick test to Ragweed allergen at 
screening (with a wheal diameter at least 3 mm larger than that produced by the 
negative control). 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. History of anaphylaxis to Ragweed pollen. 
2. History of asthma or exacerbations in the past 12 months requiring regular inhaled 
corticosteroids for >4 weeks per year, any oral corticosteroid usage, any emergency 
department visit for asthma or any asthma-related hospitalization. Mild asthmatics 
treated only with pro re nata short-acting β2-agonists, less than 2 doses per week can 
be enrolled. 
3. History of chronic sinusitis, defined as a sinus symptoms lasting greater than 12 weeks 
that includes 2 or more major factors or 1 major factor and 2 minor factors. Major 
factors are defined as facial pain or pressure, nasal obstruction or blockage, nasal 
discharge or purulence or discolored postnasal discharge, purulence in nasal cavity, or 
impaired or loss of smell. Minor factors are defined as headache, fever, halitosis, 
fatigue, dental pain, cough, and ear pain, pressure, or fullness. 
4. History of systemic disease affecting the immune system such as autoimmune 
diseases, immune complex disease, or immunodeficiency, where, in the opinion of the 
study physician, participation in the study would pose a risk or significant effect on the 
immune system.  
5. Presence or history of drug hypersensitivity to fexofenadine and/or its excipients. 
6. The use of any investigational drug within 30 days of the EEU procedures. 
7. Treatment with any antihistamine within 5 days of screening and within the defined 
washout period. Subjects receiving build-up injections of pollen allergen 
immunotherapy are to be excluded, whereas those on stable maintenance dosing can be 
included. 


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8. Subjects receiving systemic immunosuppressive treatment should be excluded. 
9. Subjects unable to stop the following forbidden treatments/nutriments prior to pollen 
challenge: 
a. Antihistamines: within 3 days for first-generation antihistamines, within 2 days 
for second-generation antihistamines. 
b. Intranasal or inhaled corticosteroids: 7 days. 
c. Ocular, intranasal, or inhaled sodium cromoglycate: 14 days. 
d. High doses of systemic corticosteroids: 30 days. 
e. Leukotriene antagonists: 30 days. 
f. Intranasal or systemic decongestants: 3 days. 
g. Tricyclic antidepressants: 7 days. 
h. Any citrus fruits (grapefruit, orange, etc.) or their juices, as well as all fruit 
juices: 5 days. 
i. Aluminum-and-magnesium containing antacids: 7 days. 
j. Omalizumab/dupilumab: within 6 months 
10. Not willing to sit the required time in the EEU during the planned 2 challenge tests. 
Participants should not be enrolled in any other clinical study.  
11. Women of childbearing potential not protected by highly effective method of birth 
control and/or who are unwilling or unable to be tested for pregnancy (See 
Section 10.3 for details.) 
12. Subjects who, at the discretion of the Investigator, have significant allergy to perennial 
allergens that cannot be avoided during the study. 
13. Subjects with clinically relevant symptoms or a clinically significant illness (in the 
judgment of the Investigator) in the last 7 days prior to screening through prior to first 
dosing post pollen challenge at V2. This includes the presence of an active infection 
requiring systemic antiviral or antimicrobial therapy. 
14. History of serious chronic medical conditions which might interfere with treatment or 
assessments or may pose additional risks from participation in the study. 
15. At time of allergen challenge, current symptoms of, or treatment for, an upper 
respiratory tract infection, acute sinusitis, acute otitis media, or other relevant 
infectious process; serous otitis media is not an exclusion criterion. Subjects may be 
re-evaluated for eligibility after symptoms resolve. 
16. The presence of any medical condition that the Investigator deems incompatible with 
participation in the study. 
17. Any clinically significant abnormal finding on physical examination or vital signs at 
screening as deemed so by the Investigator. 


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18. Any clinically significant physical findings of nasal anatomical deformities (including 
the presence of nasal mucosal ulceration, nasal polyps, purulent secretions, septal 
perforation or any other major abnormalities in the nose) which, at the discretion of the 
Investigator, would interfere with the study procedures. 
19. Any history of Grade 4 anaphylaxis due to any cause as defined by the Common 
Terminology Criteria for Adverse Events (CTCAE) grading criteria (“Life threatening 
consequences: urgent intervention indicated”). 
20. History or presence of drug or alcohol abuse at the judgment of the Investigator. 
21. Any contraindications to fexofenadine, according to the labeling. 
 
5.3 
Lifestyle Considerations 
No lifestyle restrictions are required. Participants will be asked to refrain from consumption of 
any form of alcohol, Seville oranges, Seville orange marmalade, grapefruit, or grapefruit juice, 
pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 5 days before the start of 
study drug until after the final dose. Participants will abstain from alcohol for 24 hours prior to 
V2 and each visit thereafter. 
5.4 
Screen Failures 
A screen failure occurs when a participant who consents to participate in the clinical study is 
not subsequently randomly assigned to study drug. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious AE (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a new participant number for every 
screening/rescreening event. 
5.5 
Criteria for Temporarily Delaying Enrollment, Randomization, or 
Study Drug Administration 
The study schedule includes a visit window up to 3 months post screening, to allow for any 
emergency situation before randomization into the study.  
Once randomized, the participant will be involved in the study for a maximum of 5 days. An 
e-PRO diary (e-diary) will be available to the participants via a web application on their own 
device or on a provided device.  


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The following assessments can be documented remotely, in the event of an 
emergency/pandemic situation during participation in the study: 
• Any AEs 
• Concomitant medications  
• Allergic symptoms  
• Treatment Satisfaction Questionnaire 
Frequent and ongoing detailed risk assessments of the impact of the coronavirus infectious 
disease due to SARS-CoV-2 pandemic on the study will be performed. A risk mitigation plan 
is in place, which takes into account current knowledge and also potential uncertainties. For a 
regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. For details of the contingency plan for 
maintaining study activities, including site initiation, monitoring, and close-out activities, refer 
to the study Clinical Monitoring Plan. 
The participant should be verbally informed prior to initiating any changes that are to be 
implemented for the duration of the emergency (eg, study visit delays, remote collection of 
data). 


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6.0 STUDY DRUG(S) AND CONCOMITANT THERAPY 
Study drug is defined as any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
Study Drug(s) Administered 
Table 2 
Study Drugs Administered 
Study Drug Label 
Active drug 
Placebo 
Study Drug Name 
marketed 180 mg fexofenadine HCl 
placebo 
Study Drug Description 
peach, oblong, film-coated oral tablet, 
with “018” on one side, scripted “e” 
on the other side. 
indistinguishable from active drug 
Type  
drug 
drug 
Dose Formulation 
tablet 
tablet 
Unit Dose Strength(s) 
180 mg fexofenadine HCl per tablet 
0 mg fexofenadine HCl per tablet 
Dosage Level(s) 
1 tablet once daily 
1 tablet once daily 
Route of Administration 
oral 
oral 
Use 
active drug 
placebo 
IMP and NIMP/AMP 
IMP 
IMP 
Sourcing 
Provided centrally by Sanofi 
Consumer Health Care 
Provided centrally by Sanofi Consumer 
Health Care 
Packaging and Labeling 
 
Randomized, double-blind, placebo-control study part: 
Fexofenadine HCl 180 mg and matching placebo will be provided as identical 
film-coated tablets and packaged in child-resistant wallets (containing a blister 
of 3 tablets of fexofenadine 180 mg or matching placebo – 2 doses and 
1 additional tablet in case of loss). 
Post pollen challenge, open-label study part: 
Fexofenadine HCl 180 mg will be provided as film-coated tablets and packaged 
in US commercial Allegra® 5-ct blister packs with open labeling (one pack per 
participant). The content of the labeling will be in accordance with local 
regulatory specifications and requirements. 
Current Name 
Allegra® (fexofenadine) 
Matching placebo 
Abbreviations: AMP = auxiliary medicinal product, IMP = investigational medicinal product, 
NIMP = non-investigational medicinal product. 


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Table 3 
Study Arms 
Arm Title 
Arm A 
Arm B 
Arm Type 
Active 2 days 
Placebo 2 days 
Arm Description 
During the randomized, double-
blind, placebo-control study part, 
participants will take 1 tablet of 
fexofenadine 180 mg each day in the 
morning on Day 2 and Day 3.  
During the open-label study part, 
participants will take 1 tablet of 
fexofenadine 180 mg after the pollen 
challenge on Day 4 
During the randomized, double-
blind, placebo-control study part, 
participants will take 1 tablet of 
matching placebo each day in the 
morning on Day 2 and Day 3.  
During the open-label study part, 
participants will take 1 tablet of 
fexofenadine 180 mg after the pollen 
challenge on Day 4 
Associated Study Drug Labels 
Active drug 
Placebo 
 
6.2 
Preparation, Handling, Storage, and Accountability 
Allegra® (fexofenadine hydrochloride) tablets should be stored at 15°C to 25°C in a dry 
place. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received, and any discrepancies are reported and 
resolved before use of the study drug. 
Until provided to the participants, all study drugs must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area at the study site in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized study site 
staff. Only participants enrolled in the study may receive study drug, and only authorized 
study site staff may provide study drug to the participants. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
The Investigator, a member of the study site staff, or a hospital pharmacist must maintain an 
adequate record of the receipt and distribution of all study drug using the Drug Accountability 
Form. These forms must be available for inspection at any time. 
Any unused/returned study drug should be destroyed at the study site, as per site’s standard 
operating procedures, after study drug accountability, at the end of the study and with 
Sponsor’s approval. 


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6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Randomization  
The subject randomization list will be supplied to the study site by the clinical research 
organization (CRO).   
Day 1 to Day 3 (double-blind, placebo-controlled part): 
All participants will be centrally assigned to randomized study drug at Visit 3 (Day 1) as per 
the randomization list. The study site staff will record the subject number allocated at the time 
of screening and wallet number in the electronic case report form (eCRF). After the individual 
study drug wallets are assigned, the dispensing staff can ensure their numbers are correct and 
the participant has not already been randomized. Individual study drug wallets (containing 
3 tablets of either fexofenadine or placebo – 2 doses and 1 additional tablet in case of loss) 
will be dispensed to the participants as assigned. The participants will be instructed by the 
study staff, to consume 1 tablet of study drug, each on Day 2 and Day 3 at home. The 
participant will return the used study drug wallet (containing 1 remaining tablet) when they 
return to the study site on Day 4, before the pollen challenge. Returned study drug should not 
be re-dispensed. 
Day 4 (open-label part, post pollen challenge): 
The participants will be exposed to a 3-hour pollen challenge at Visit 4 (Day 4). The study site 
staff will provide a commercial pack of fexofenadine 180 mg to each participant and instruct 
the participants to consume only one tablet from the pack. At H3, post pollen challenge, each 
participant will take the study drug at exactly the same time in the EEU. This time point will 
be recorded by study staff. The commercial pack of fexofenadine 180 mg with remaining 
tablets will be returned to the study site staff by each participant before leaving the EEU after 
completing all assessments at H6.  
Stratification 
Participants will be randomized to study drug at Visit 2. Stratification of 
TNSS-3 ≤7/TNSS-3 >7 will be documented in the Statistical Analysis Plan (SAP). 
6.3.2 
Blinding 
This study includes a double-blind study part on Day 1 through Day 3, with limited access to 
the randomization code. From Day 4 onwards, active study drug will be administered in an 
open-labeled manner. 
Fexofenadine HCl 180 mg and matching placebo will be provided as identical film-coated 
tablets and packaged in study drug wallets, as described in Table 2. The study site will receive 
the study drug (fexofenadine and placebo) from the Sponsor. Each study drug wallet will be 


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labeled in accordance with local Health Authority and Institution requirements. Each study 
drug wallet will be assigned a Unique Treatment Assignment Number at the time of 
randomization. 
In accordance with the double-blind design, the participants and Investigator will remain 
blinded to study drug assigned and will not have access to the randomization information 
(treatment codes) except under circumstances described below. 
In case of an AE, the code must only be broken in circumstances when knowledge of the 
study drug is required for treating the subject. If the code is broken, withdrawal should be 
discussed on a case-by-case basis. Code breaking can be performed at any time via code-break 
envelopes. If the blind is broken, the Investigator must document the date, time of day and 
reason for code breaking. 
Method for breaking 
blind 
Example text to use: 
Blind break 
(envelopes) 
This is a double-blind study in which participants and Investigators are blinded to 
study drug taken on Day 2 and Day 3. A sealed envelope that contains the study 
drug assignment for each participant will be provided to the Investigator. The 
sealed envelope will be retained by the Investigator (or representative) in a 
secured area. In case of an emergency, the Investigator has the sole responsibility 
for determining if unblinding of a participant’s intervention assignment is 
warranted. Participant safety must always be the first consideration in making 
such a determination. If the Investigator decides that unblinding is warranted, the 
Investigator may, at his/her discretion contact the Sponsor to discuss the situation 
prior to unblinding a participant’s study drug assignment unless this could delay 
emergency treatment for the participant. If a participant’s study drug assignment 
is unblinded, the Sponsor must be notified within 24 hours of this occurrence. 
Once the study is complete, all envelopes (sealed and opened) must be inventoried 
and returned to the Sponsor. 
Sponsor safety staff may unblind the intervention assignment for any participant with an SAE. 
If the SAE requires that an expedited regulatory report be sent to one or more regulatory 
agencies, a copy of the report, identifying the participant’s intervention assignment, may be 
sent to the Investigator in accordance with local regulations and/or Sponsor policy.  
6.4 
Study Drug Compliance 
All used study drug wallets will be collected by study staff at Visit 4, before pollen challenge, 
to ensure compliance by tablet counts. Similarly, after the pollen challenge at Visit 4, all 
open-label, used study drug packs will be collected by study staff to ensure compliance by 
tablet counts (ie, only 1 tablet taken out of the 5 provided to participants). 


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The prescribed dosage, timing, and mode of administration may not be changed. Any 
departures from the intended regimen must be recorded in the eCRF. 
Noncompliance is defined as taking fewer/more doses than prescribed in the protocol. 
A record of the quantity of fexofenadine tablets dispensed to and administered by each 
participant must be maintained and reconciled with study drug and compliance records. 
Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions will also be recorded. 
6.5 
Dose Modification 
Dose modifications are not planned or allowed in this study. 
6.6 
Continued Access to Study Drug after the End of the Study 
The Sponsor will not provide any additional care to participants after they leave the study 
because such care should not differ from what is normally expected for participants with SAR. 
6.7 
Management of Overdose 
For this study, any dose of fexofenadine HCl greater than 180 mg within a 24-hour time 
period will be considered an overdose. An overdose (accidental or intentional), ie, 
symptomatic overdose (serious or nonserious) with the study drug is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic pills count) 
and defined as above the maximum recommended dose of 180 mg according to the 
Allegra®/Telfast® labeling. Of note, asymptomatic overdose should be reported as a standard 
AE. 
The Sponsor recommends that any overdose should be managed by the Investigator as 
follows:  
• Contact the medical monitor immediately. 
• Evaluate the participant to determine, in consultation with the medical monitor, whether 
study drug should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE via a follow-up phone call with the 
participant until 7 days after Day 5 for AEs and 30 days after Day 5 for both SAEs and 
AEs of special interest (AESIs). 
• Document the quantity of the excess dose as well as the duration of the overdose. 


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6.8 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
• For vaccines (if applicable) include brand name and manufacturer (plus lot number if 
available) 
Any concomitant medications may be considered on a case-by-case basis by the Investigator 
in consultation with the medical monitor. 
6.8.1 
Prohibited Medications 
The following treatments/nutriments are forbidden before each pollen challenge (See 
Exclusion criteria 9): 
• Antihistamines: within 3 days for first-generation antihistamines, within 2 days for 
second-generation antihistamines 
• Intranasal or inhaled corticosteroids: 7 days 
• Ocular, intranasal or inhaled sodium cromoglycate: 14 days 
• High doses of systemic corticosteroids: 30 days 
• Leukotriene antagonists: 30 days 
• Intranasal or systemic decongestants: 3 days 
• Tricyclic antidepressants: 7 days 
• Any citrus fruits (grapefruit, orange, etc.) or their juices, as well as all fruit juices: 5 days 
• Aluminum-and-magnesium containing antacids: 7 days 
• Omalizumab/dupilumab: within 6 months 
The following medications are prohibited during the study: 
• Any antihistamine (during the washout period)  
• Beta blockers 
• Tricyclic antidepressants 


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• Monoamine oxidase inhibitors 
• Vaccination with live vaccines while on study is prohibited. Administration of inactivated 
vaccines is allowed (eg, inactivated influenza vaccines or SARS-CoV-2 vaccines). 
• Intranasal or inhaled corticosteroids 
• Ocular, intranasal or inhaled sodium cromoglycate 
• Systemic corticosteroids 
• Leukotriene antagonists 
• Intranasal or systemic decongestants 
• Any consumption of citrus fruits (grapefruit, orange, etc.) or their juices, as well as all fruit 
juices within 5 days before and during the treatment visit. 
• Any administration of aluminum-and-magnesium-containing antacids. 
6.8.2 
Rescue Medicine 
Rescue medication (eg, cetirizine) will be provided to the participants at the discretion of the 
Investigator, as per clinical judgment in order to manage symptoms. Rescue medication will 
not be blinded. Separate, open-label packets of marketed drug will be purchased locally by the 
study site and given to the participants by the study site staff/Investigator, as and when 
needed. 


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7.0 DISCONTINUATION OF STUDY DRUG AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Discontinuation of specific study sites or of the study as a whole are detailed in 
Section 10.1.11. 
7.1 
Discontinuation of Study Drug 
It may be necessary for a participant to permanently discontinue study drug if any of the 
following criteria are met: 
• Important Protocol violation 
• Withdrawal of consent by a participant 
• Participant is lost to follow-up 
• Inadvertent enrollment of a participant 
• Pregnancy – see Section 8.3.5 
• Termination of the study by the Sponsor 
If study drug is permanently discontinued, the participant will remain in the study until EOS 
on D5. See Section 1.3 for data to be collected at the time of discontinuation of study drug and 
follow-up and for any further evaluations that need to be completed. 
If a participant who does not meet enrollment criteria is inadvertently enrolled, that participant 
must be discontinued from study drug and the Sponsor, or Sponsor designee, must be 
contacted. An exception may be granted in rare circumstances for which there is a compelling 
safety reason to allow the participant to continue. In these rare cases, the Investigator must 
obtain documented approval from the Sponsor, or Sponsor designee, to allow the participant 
to continue in the study. 
Participants who discontinue study drug will not be replaced. 
7.1.1 
Temporary Discontinuation 
It may be necessary for a participant to temporarily discontinue study drug, which will be 
managed by the Investigator on a case-by-case basis. 
7.1.2 
Rechallenge 
It may be necessary for a participant to restart the study drug after temporarily 
discontinuation, which will be managed by the Investigator on a case-by-case basis. 


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7.2 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
compliance, positive COVID-19 test or suspected SARS-CoV-2 infection, or administrative 
reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted, as shown in the schedule of activities (SoA; Section 1.3). See SoA for data to 
be collected at the time of study discontinuation and follow-up and for any further evaluations 
that need to be completed.  
The participant will be permanently discontinued from the study drug and the study at that 
time. 
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the study site study records. 
Participants who voluntarily withdraw are termed dropouts. Dropouts and participants 
withdrawn due to protocol violations may be replaced following discussion with the Principal 
Investigator and Sponsor. 
Participants withdrawn due to an AE will not be replaced. Subjects who have withdrawn from 
the study cannot be re-randomized (treated). Their subject and randomization numbers must 
not be reused. 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The study site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, via telephone calls, and 
if necessary, a certified letter to the participant’s last known mailing address or local 


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equivalent methods). These contact attempts should be documented in the participant’s 
study record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
• Study site personnel, or an independent third party, will attempt to collect the vital status 
of the participant within legal and ethical boundaries for all participants randomized, 
including those who did not get study drug. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented, and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 


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8.0 STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers 
or exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
drug. 
Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Safety results that could unblind the study will not be reported to study sites or other blinded 
personnel until the study has been unblinded. 
8.1 
Efficacy Assessments 
Participants will score their symptoms as per the United States Food and Drug Administration 
2018 guidelines (see Section 10.4), on a scale from zero to 3, where: 
• 0 = absent symptoms (no sign/symptom evident)  
• 1 = mild symptoms (sign/symptom present, but minimal awareness; easily tolerated)  
• 2 = moderate symptoms (definite awareness of sign/symptom that is bothersome but 
tolerable) 
• 3 = severe symptoms (sign/symptom that is hard to tolerate; causes interference with 
activities of daily living [ADL] and/or sleeping)  
The symptoms to be evaluated are rhinorrhea, sneezing, nasal itching, nasal congestion, 
red/burning eyes, tearing, itchy/watery eyes, and itching of ears/palate or throat. 
Composite scores will be determined as per the following: 
• Total nasal symptoms score (TNSS-3): the sum of rhinorrhea, sneezing, and nasal 
itching scores (maximum 9). 
• Total ocular symptoms score (TOSS): the sum of red/burning eyes, tearing, 
itchy/watery eyes scores (maximum 9). 


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• Total symptoms score (TSS): the sum of rhinorrhea, sneezing, nasal itching, and nasal 
congestion; red/burning eyes, tearing, and itchy/watery eyes; and itching of ears/palate 
or throat scores (maximum 27). 
8.2 
Safety Assessments 
The Principal Investigator and staff must register and assess the following variables: AEs, 
SAEs, AEs leading to discontinuation, and AESIs. 
Symptoms assessed for efficacy (including changes in severity): rhinorrhea, sneezing, nasal 
itching, nasal congestion, red/burning eyes, tearing, itchy/watery eyes, and itching of 
ears/palate or throat to be considered as AEs as per Investigator’s clinical judgment. 
8.2.1 
Physical Examinations 
Physical examination includes at a minimum: head and neck examination, heart and 
respiratory auscultation; peripheral lymph nodes and abdomen examination. 
8.2.2 
Nasal Examination 
Nasal examination will be performed as follows: 
• External inspection: skin changes (eg, skin lesions/ erythema), deformity. 
• Internal inspection: nasal mucosa inspection for any abnormalities, nasal cavities 
alignment: 
o Nasal vestibule: skin changes (eg, ulceration)/ swelling/ asymmetry, 
o Nasal septum: polyps/deviation, 
o Inferior turbinates: asymmetry/inflammation/ polyps. 
• Palpation of nasal bones and cartilage for: 
o Alignment, 
o Tenderness or irregularity (if suspicious of fracture in trauma). 
• Nasal airflow assessment 
8.2.3 
Vital Signs 
Vital signs include oral body temperature, heart rate, respiratory rate, systolic and diastolic 
blood pressure. Heart rate, respiratory rate, systolic and diastolic blood pressure will be 
measured after at least 3 minutes in sitting position. 
Vital sign assessments will consist of 1 pulse and 1 blood pressure measurement. 


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8.2.4 
Electrocardiograms 
Electrocardiograms will be performed if deemed necessary, as per the Investigator’s 
discretion. 
8.2.5 
Clinical Safety Laboratory Tests 
Routine clinical laboratory testing will be conducted if deemed necessary, as per the 
Investigator’s discretion. A rapid antigen test will be performed before EEU entry, for 
SARS-CoV-2 infection. 
If laboratory values from non-protocol-specified laboratory tests performed at the institution’s 
local laboratory require a change in participant management or are considered clinically 
significant by the Investigator (eg, SAE or AE or dose modification), then the results must be 
recorded. 
8.2.6 
Pregnancy Testing 
Women of childbearing potential should only be included after a confirmed menstrual period 
and a negative highly sensitive urine pregnancy test. 
Additional pregnancy testing is not required for this study. 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of AEs and SAEs can be found in Section 10.2. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up all SAEs, AEs related to study drug, or AEs that lead to discontinuation from the 
drug or study (see Section 7.0). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.2. 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information 
All AEs and SAEs will be collected from the signing of the informed consent form (ICF) until 
EOS, at the time points specified in the SoA (Section 1.3). 
Medical occurrences that begin before the start of study drug but after obtaining informed 
consent will be recorded as medical history/current medical conditions, not as AEs. 


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All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of the Investigator’s awareness of the event, as 
indicated in Section 10.2 and Section 10.3. The Investigator will submit any updated SAE data 
to the Sponsor or designee within 24 hours of their awareness of the updated information. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion 
of the study participation. However, if the Investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 
event/cause of death to be reasonably related to the study drug or study participation, the 
Investigator must promptly notify the Sponsor or designee. 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting safety reports are provided in Section 10.2 and 
Section 10.3. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and AESIs (as defined in Section 8.3.6) 
will be followed via a follow-up phone call with the participant until 7 days after Visit 5 for 
AEs and 30 days after Visit 5 for both SAEs and AESIs. Further information on follow-up 
procedures is provided in Section 10.2 and Section 10.3. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study drug under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study drug under clinical investigation. The Sponsor 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, European Union Eudravigilance Database (as applicable), Institutional 
Review Boards (IRBs)/ Independent Ethics Committee (IECs), and Investigators. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then 


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file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) and unanticipated adverse device events according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
8.3.5 
Pregnancy 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study drug and until 4 days after D5. 
If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor or designee within 24 hours of learning of the 
female participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) pregnancy and should follow the procedures 
outlined in Section 10.3. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication (or 
elective termination) of a pregnancy for medical reasons will be reported as an AE or SAE. 
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (ie, 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus, stillbirth, or neonatal death]) the Investigator will report according to the SAE 
reporting procedures described in Section 10.3. 
The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant/pregnant 
female partner and the neonate and the information will be forwarded to the Sponsor or 
designee. 
Any post-study pregnancy-related SAE considered reasonably related to the study drug by the 
Investigator will be reported to the Sponsor as described in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study 
participants/pregnant female partner, he or she may learn of an SAE through spontaneous 
reporting. 
Any female participant who becomes pregnant while participating in the study will 
discontinue study drug or be withdrawn from the study.  
Prior to continuation of study drug following pregnancy, the following must occur: 
• The Sponsor and the relevant IRB/IEC give written approval. 
• The participant gives signed informed consent. 


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• The Investigator agrees to monitor the outcome of the pregnancy and the status of the 
participant and her offspring. 
8.3.6 
Adverse Events of Special Interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by 
the Investigator to the Sponsor is required. Such events may require further investigation in 
order to characterize and understand them. Adverse events of special interest may be added, 
modified or removed during a study by protocol amendment. 
Specific AESI(s) for this study include systemic hypersensitivity reactions with manifestations 
such as angioedema, chest tightness, dyspnea, flushing, and systemic anaphylaxis. Subjects 
with this diagnosis from Investigator during treatment period are to be advised to avoid use of 
fexofenadine in the future. 
8.3.7 
Treatment Satisfaction and Recommendation 
The participant’s satisfaction of the efficacy of this pre-treatment approach (comparing active 
drug versus placebo group) will be recorded using a 4-point Numerical Rating Scale: 
• 1 = very satisfied 
• 2 = satisfied 
• 3 = dissatisfied 
• 4 = very dissatisfied.  
The participant’s intention of recommending the pre-treatment approach will be either ‘yes’ or 
‘no’.  
8.4 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.5 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.6 
Genetics 
Genetics are not evaluated in this study. 
8.7 
Biomarkers 
Biomarkers are not evaluated in this study. 


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8.8 
Immunogenicity Assessments 
Immunogenicity is not evaluated in this study.  
8.9 
Health Economics 
Health economics parameters are not evaluated in this study. 


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9.0 STATISTICAL CONSIDERATIONS 
The SAP will be finalized prior to database lock, and it will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints including primary 
and key secondary endpoints. 
9.1 
Statistical Hypotheses 
In order to evaluate the additional benefit in term of efficacy of 2 days pre-treatment before 
the allergen exposure, the mean area under the plasma concentration-time curve (AUC) of 
TNSS-3 will be compared between Arm A and Arm B at V4, the following statistical null 
hypothesis and alternative will be tested: 
• H0: AUC0-6 TNSS-3 of A = AUC0-6 TNSS-3 of B  
• H1: AUC0-6 TNSS-3 of A ≠ AUC0-6 TNSS-3 of B 
The study will be positive if the null hypothesis (H0) is rejected, and the active pre-treatment 
leads to lowering the symptoms compared to placebo. 
9.1.1 
Multiplicity Adjustment 
The following multiplicity testing procedures will be used to control the type I error: 
• The secondary efficacy endpoints will be tested only if the primary endpoint is 
significant. 
• The multiplicity of secondary efficacy endpoints will be handled using Hochberg’s 
step-up test. 
• For the other secondary efficacy endpoints and the exploratory efficacy endpoints, 
p-values will be provided for descriptive purpose only. 
• The number of AEs defined as other secondary endpoint will be analyzed only with 
descriptive statistics (no p-value will be provided). 
9.2 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
• Safety population is defined as randomized participants who did receive at least one 
dose of study drug analyzed according to the treatment actually received. 
• The intent-to-treat population will include eligible participants who have been 
allocated to a randomized treatment regardless of whether the study drug wallet was 
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• The mITT population will comprise all eligible, randomized, and treated participants 
with TNSS-3 evaluation at H0 at V4 and at least a further time point at V4 (main 
analysis population for the efficacy endpoints). 
9.3 
Statistical Analyses 
9.3.1 
General Considerations 
In general, the descriptive summary for continuous data will include the number of 
non-missing observations (n), mean, standard deviation, median, 25th percentile and 75th 
percentile, minimum, and maximum. The number of subjects with missing data will be 
displayed when relevant. 
In general, categorical data will be summarized for each treatment group using counts (n) and 
percentages (%). The number of subjects with missing data will be displayed when relevant, 
but it will not be included in the denominator for the calculation of percentages unless 
otherwise specified. 
Evaluable participants are defined as those who received the Ragweed pollen challenge, with 
TNSS evaluations at H0 and at least 1 further time point. 
The extent of study drug exposure and compliance will be assessed and summarized by actual 
treatment received within the safety population. 
In case of any regional or national emergency declared by a governmental agency during the 
study, the impact on study conduct will be summarized (eg, study discontinuation or 
discontinuation/delay/omission of or changes to challenge procedures due to the emergency). 
Any additional analyses and methods required to evaluate the impact on efficacy (eg, missing 
data due to the emergency) and safety will be detailed in the SAP. 
9.3.2 
Primary Endpoint Analysis 
All efficacy endpoints analysis will be performed on the mITT population. 
The primary analysis will be the comparison of the primary efficacy endpoint (ie, AUC of the 
TNSS-3 from H0 to H6) between Arm A and Arm B, using an analysis of covariance 
(ANCOVA) with treatment group as fixed effect and the baseline value of TNSS-3 (ie, at H0 
at V4) as covariate. This primary analysis will be conducted on mITT analysis population. 




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values as covariate. The analysis of secondary endpoints will be conducted on the mITT 
analysis population. 
The TNSS-3, TOSS, TSS, and individual symptom score by time point will be analyzed given 
the mean and 95% confidence interval (CI). 
The representation of mean and 95% CI (TNSS-3, TSS, TOSS, and individual symptom 
score) versus time, by treatment group will be analyzed using Mixed Models for Repeated 
Measures, with treatment, time point, and treatment group by time point interaction as fixed 
effect with their respective H0 scores as baseline covariate. 
9.3.4 
Exploratory Endpoint(s) Analysis 
 
 
 
 
 
 
 
 
9.3.5 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. 
The pre-treatment period starts the day of the signed informed consent and ends before 
administration of study drug. 
The treatment-emergent AE period starts at time of administration of study drug ends 3 days 
after administration of study drug. 
All AEs diagnosed by the Investigator will be reported and described. 
All AEs will be coded using the version of the Medical Dictionary for Regulatory Activities 
currently in effect with the Sponsor at the time of the considered database lock. 
9.3.6 
Study Drug Compliance 
A participant will be considered noncompliant if they did not take the planned doses of study 
drug as required by the protocol. No imputation will be made for participants with missing or 
incomplete data. The prepared treatment individual package number that has been allocated as 
per the randomization process and that has actually been administered to the participant will 
be reported in the eCRF. 


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Treatment compliance will be summarized by the number and percentage of participants 
compliant per Arm. 
9.4 
Interim Analysis 
No interim analysis is planned. 
9.5 
Sample Size Determination 
Number of subjects (N) = 96 randomized participants (86 evaluable participants) 
All eligible participants will be randomized into 1 out of 2 Arms with the randomization ratio 
allocation 1:1 as follows: 
• Arm A: two days of pre-treatment with fexofenadine, then fexofenadine 180 mg 
during the test pollen challenge.  
• Arm B: two days of pre-treatment with placebo, then fexofenadine 180 mg during the 
test pollen challenge. 
The primary efficacy endpoint is the AUC of TNSS-3 (including rhinorrhea, sneezing, and 
nasal itching, where each symptom is scored from 0 to 3) from H0 to H6 at Visit 4. The 
maximum score of TNSS-3 is 9.2 
The expected benefit of the pre-treatment or the variability of the pre-treatment using the 
AUC of the TNSS-3 were not published in the literature when the pre-treatment with 
fexofenadine before allergen exposure has been evaluated.20 Therefore, given the previous 
study LPS15332 using TNSS-3, the mean (SD) of the AUCh2-h12 of the TNSS-3 has been 
estimated to be equal to 26.34 (16.66) on the placebo group and 18.53 (13.73) on the 
fexofenadine group after 3 hours of pollen exposure in the period 3, thus a common SD, 
estimated to be equal to 15, has been used for the sample size calculation.14 An MCID is 
commonly defined as a 0.55 change on Total Nasal Symptoms Score of 4 symptoms 
(TNSS-4) when 4 individual symptoms (ie, rhinorrhea, nasal congestion, nasal itching, and 
sneezing) are measured.16 
Assuming a common SD=15 and a targeted effect size of 0.70 for the primary endpoint, it will 
correspond to a difference of AUC of TNSS-3 between Arm A and Arm B of 10.5, which may 
be interpreted as a difference of TNSS-3 around 2 points between 2 Arms at each time point 
(which is higher than the MCID of TNSS-3 with 3 individual symptoms). Therefore, at least 
86 evaluable patients in both, Arm A and B (ie, included in the mITT population, meaning 
43 patients in each arm) are needed to detect a 0.70 effect size for the additional benefit of two 
days of pre-treatment with fexofenadine on the SAR symptoms with 90% of power and a 
2-sided type I error of 5%, using a 2-sample t-test which is assumed to be roughly equivalent 


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to the primary analysis that will be planned. This sample size has been calculated using 
EAST6.5 software. 
Considering a potential dropout rate of 10% before assessing the primary endpoint, 
10 additional patients should be randomized to reach the targeted a total of 86 patients in the 
mITT population, thus approximately 96 patients will be randomized. 


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10.0 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
international ethical guidelines 
• Applicable ICH GCP guidelines 
• Applicable laws and regulations. 
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs, or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the study site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations. 
After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative. The study will not start at any study 
site at which the Investigator has not signed the protocol. 


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10.1.2 
Adequate Resources 
The Investigator is responsible for supervising any individual or party to whom the 
Investigator delegates study-related duties and functions conducted at the study site. 
If the Investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the Investigator/institution should ensure this individual or 
party is qualified to perform those study-related duties and functions and should implement 
procedures to ensure the integrity of the study-related duties and functions performed and any 
data generated. 
10.1.3 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
10.1.4 
Insurance 
Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the participants in this study. The terms of the insurance will be kept in the study 
files. 
10.1.5 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study, including the 
risks and benefits, to the participant and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy, and data protection requirements, where applicable, 
and the IRB/IEC or study site. 
The study record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICF. 


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10.1.6 
Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant who will be required to give consent for their data to be 
used as described in the informed consent. 
• The participant must be informed that his/her study records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.7 
Committees Structure 
No review committee has been appointed for this study.  
10.1.8 
Dissemination of Clinical Study Data 
The results of the study should be reported within 1 year from the end of the clinical study. 
Irrespective of the outcome, the Sponsor will submit to any relevant database a summary of 
the results of the clinical study within 1 year from the end of the global clinical study. It shall 
be accompanied by a summary written in a manner that is understandable to laypersons. 
10.1.9 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
• Guidance on completion of eCRFs will be provided in the eCRF completion guidelines. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Quality tolerance limits will be predefined in the Clinical Monitoring Plan to identify 
systematic issues that can impact participant safety and/or reliability of study results. 
These predefined parameters will be monitored during the study, and important deviations 
from the quality tolerance limits and remedial actions taken will be summarized in the 
clinical study report. 
• Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 


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requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the Clinical Monitoring Plan. 
• Details of study monitoring, including action required due to SARS-CoV-2 (COVID-19), 
will be included in a separate Clinical Operation Plan. 
• The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals (eg, 
contract research organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after the completion or 
discontinuation of the clinical study. 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. 
10.1.10 
Source Documents 
The Investigator/institution should maintain adequate and accurate source documents and 
study records that include all pertinent observations on each of the study site’s participants. 
Source data should be attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original entry, 
and should be explained if necessary (eg, via an audit trail). 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the study site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. Source data is all information in original records and 
certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the reconstruction and evaluation of the study. Source data are 
contained in source documents. Source documents are original documents, data and records 
such as hospital records, clinic and office charts, laboratory notes, memoranda, pharmacy 
dispensing records, recorded data from automated instruments, subject’s identity, medical 
history, nursing notes, physician’s notes, etc. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized study site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 


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All data collected in the eCRF should be transcribed directly from source documents. This 
includes:  
• Agreement, date, and signature of informed consent mentioning the study 
identification 
• Subject identification, medical history, associated diseases, and data related to the 
studied pathology 
• Contraception methods for WOCBP 
• Previous and concomitant medications 
• Study identification 
• Date and time of the randomization and study drug administration 
• Dates of visits and assessments including the examination report 
• Vital signs 
• E-diary dispensation date 
• E-diary return date 
• Study e-diary including symptoms scoring by the subject 
• Any AE and follow-up: 
- 
In case of SAE, the study site staff must file in the source document at least copies 
of the hospitalization reports and any relevant examination reports documenting 
the follow-up of the SAE. The study site staff should make every effort to obtain 
details of all consultations, hospital records, etc. to document the event. All 
attempts to obtain information should be noted in the source documents. 
• Date of premature study discontinuation (if any) and reason. 
10.1.11 
Start and Closure of Study and Study Site 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study/Site Termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 


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Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to: 
• For study termination: 
o Discontinuation of further study drug development. 
• For study site termination: 
o Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor’s procedures, or GCP 
guidelines 
o Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
o Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the Regulatory Authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
10.1.12 
Publication Policy 
The study will be performed according to the local legislations and the outcomes will be 
communicated in congress and in a peer review publication. 
The data generated by this study are confidential information of the Sponsor. The Sponsor will 
make the results of the study publicly available. The publication policy with respect to the 
Investigator and study site will be set forth in the Clinical Trial Agreement. 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments. 
The Sponsor will comply with the requirements for publication of study results.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
 
 












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• 
Serious  
• 
Unexpected (ie, is not consistent with the currently applicable summary of product 
characteristics)  
• 
There is at least a reasonable possibility that there is a causal relationship between the event 
and the study drug  
will be classified as SUSARs and should be reported to the relevant ethics committee and to the 
relevant Health Authorities in accordance with applicable regulatory requirements for expedited 
reporting. It is the Sponsor’s responsibility to report SUSARs to central Ethics Committee and 
relevant Health Authorities. 
 
 


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10.3 Appendix 3: Contraceptive and Barrier Guidance and Collection of 
Pregnancy Information 
10.3.1 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
a) Documented hysterectomy. 
b) Documented bilateral salpingectomy. 
c) Documented bilateral oophorectomy. 
NOTE: Documentation can come from the study site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female: 
d) A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
e) Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
10.3.2 
Contraception Guidance 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
below. 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta  
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulationb  
• 
Oral. 
• 
Intravaginal. 


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• 
Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral. 
• 
Injectable.  
Highly Effective Methods That Are User Independenta  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal occlusion. 
Sexual abstinence  
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 drug. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.  
NOTES:  
a 
Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants participating in 
clinical studies.  
b 
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the 
efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be 
utilized during the treatment period and for at least 4 days after study completion.  
 
Pregnancy Testing: 
• A WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test. 
• Additional pregnancy testing should be performed at times specified in the SoA and as 
required locally. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
• Pregnancy testing, with a sensitivity of 25 mIU/mL (urine test) will be performed at the 
study site. 
Collection of Pregnancy Information 
Female Participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor or designee within 24 hours of learning of a 
participant’s pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor or designee. Generally, 
follow-up will not be required for longer than 6 to 8 weeks beyond the estimated delivery 


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date. Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (ie, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly [including that in an aborted fetus, stillbirth, or neonatal death]), the 
Investigator will report according to the SAE reporting procedures described in 
Section 10.2. 
• Any post-study pregnancy-related SAE considered reasonably related to the study drug by 
the Investigator will be reported to the Sponsor or designee as described in Section 10.2. 
While the Investigator is not obligated to actively seek this information in former 
participants, he or she may learn of an SAE through spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study drug or be withdrawn from the study. 
Reporting Pregnancy Information 
Email transmission of the paper Pregnancy Report Form is the preferred method to transmit 
safety event information to IQVIA with facsimile as a back-up method, if necessary. A study 
specific mailbox will be set up and EDC will be programmed to fire email trigger notifications 
to the mailbox and the study sites will be given the email address to forward pregnancy 
reports when EDC is down. All pregnancy events should be reported to IQVIA at:  
Email:  
   
 
 


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10.4 Appendix 4: Evolution of Seasonal Allergic Rhinitis Symptoms, 
Following United States Food and Drug Administration Guidelines 
2018 
Instantaneous Symptoms Scores 
Participants will evaluate their symptoms intensity and will score their symptoms using the 
below rating scale: 
• 0 = absent symptoms (no sign/symptom evident)  
• 1 = mild symptoms (sign/symptom present, but minimal awareness; easily tolerated)  
• 2 = moderate symptoms (definite awareness of sign/symptom that is bothersome but 
tolerable) 
• 3 = severe symptoms (sign/symptom that is hard to tolerate; causes interference with 
activities of daily living and/or sleeping)  
Symptoms to be evaluated: rhinorrhea, sneezing, nasal itching, nasal congestion, red/burning 
eyes, tearing, itchy/watery eyes, and itching of ears/palate or throat. 
Composite scores: 
• Total Nasal Symptoms Score (TNSS-3): the sum of rhinorrhea, sneezing, and nasal 
itching scores (maximum 9). 
• Total Ocular Symptoms Score (TOSS), the sum of red/burning eyes, tearing, 
itchy/watery eyes scores (maximum 9). 
• Total Symptoms Score (TSS): the sum of rhinorrhea, sneezing, nasal itching, and nasal 
congestion; red/burning eyes, tearing, and itchy/watery eyes; and itching of ears/palate 
or throat scores (maximum 27). 
 
Treatment Satisfaction and Recommendation 
Participant satisfaction of the efficacy of this pre-treatment approach (compared with the first 
challenger) will be rated using a 4-point Numerical Rating Scale 
• 1 = ‘very satisfied’ 
• 2 = ‘satisfied’ 
• 3 = ‘dissatisfied’ 
• 4 = ‘very dissatisfied’ 
At the end of the study, the participant’s intention of recommending the pre-treatment 
approach: ‘yes’ or ‘no’. 
 


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10.5 Appendix 5: Abbreviations   
Abbreviation 
Definition 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANCOVA 
Analysis of covariance 
AR 
Allergic rhinitis 
AUC 
Area under the plasma concentration-time curve 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEU 
Environmental Exposure Unit 
EoS 
End-of-Study 
e-PRO 
electronic Patient-Reported Outcome 
DSUR 
Development Safety Update Report 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
H 
Hour 
H1R 
histamine H1 receptor 
HRT 
Hormone replacement therapy 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IRB 
Institutional Review Board 
MCID 
minimum clinically important difference 
mITT 
modified intent-to-treat 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 


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Abbreviation 
Definition 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
Seasonal allergic rhinitis 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD 
Standard deviation 
SoA 
SmPC 
Schedule of activities 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
TNSS-3 
Total Nasal Symptoms Score of 3 symptoms 
TOSS 
Total Ocular Symptoms Score 
TSS 
Total Symptom Score 
V 
Visit 
WOCBP 
Women of childbearing potential 
 
 
 
 
 


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11.0 REFERENCES 
1. AAAAI.org accessed December 2020. 
2. Allergic rhinitis: Developing drug products for treatment. Guidance for industry. U.S. 
Department of Health and Human Services. Food and Drug Administration. Center for 
Drug Evaluation and Research (CDER). September 2018. 
3. Meltzer EO, Farrar JR, Sennett C. Findings from an online survey assessing the burden 
and management of seasonal allergic rhinoconjunctivitis in US patients. J Allergy Clin 
Immunol Pract. 2017;5(3):779-789. 
4. Okubo K, Kurono Y, Ichimura K, et al. Japanese guidelines for allergic rhinitis 2017. 
Allergol Int. 2017;66(2):205-219. 
5. Zhang Y, Bielory L, Mi Z, Cai T, Robock A, Georgopoulos P. Allergenic pollen 
season variations in the past two decades under changing climate in the United States. 
Glob Chang Biol. 2015; 21(4):1581–1589. 
6. Pfaar O, Bastl K, Berger U, et al. Defining pollen exposure times for clinical trials of 
allergen immunotherapy for pollen-induced rhinoconjunctivitis – an EAACI position 
paper. Allergy. 2017;72:713-722. 
7. Kurowski M1, Kuna P, Górski P. Montelukast plus cetirizine in the prophylactic 
treatment of seasonal allergic rhinitis: influence on clinical symptoms and nasal 
allergic inflammation. Allergy. 2004 Mar;59(3):280-288. 
8. Pitsios C, Chliva C, Mikos N, Kompoti E, Nowak-Wegrzyn A, Kontou-Fili K. Bee 
pollen sensitivity in airborne pollen allergic individuals. Ann Allergy Asthma Immunol. 
2006;97(5):703-706. 
9. Kitamura Y, Mizuguchi H, Ogishi H, Kuroda W, Hattori M, Fukui H. Preseasonal 
prophylactic treatment with antihistamines suppresses IL−5 but not IL-33 mRNA 
expression in the nasal mucosa of patients with seasonal allergic rhinitis caused by 
Japanese cedar pollen. Acta Oto-Laryngologica. 2012;132(4):434-438. 
10. Kitamura Y, Nakagawa H, Fujii T2, Sakoda T, Enomoto T, Mizuguchi H, et al. Effects 
of antihistamine on up-regulation of histamine H1 receptor mRNA in the nasal mucosa 
of patients with pollinosis induced by controlled cedar pollen challenge in an 
environmental exposure unit. J Pharmacol Sci. 2015;129(3):183-187.  
11. Mizuguchi H, Orimoto N, Kadota T, et al. Suplatast tosilate alleviates nasal symptoms 
through the suppression of nuclear factor of activated T-cells-mediated IL-9 gene 
expression in toluene-2,4-diisocyanate-sensitized rats. J Pharmacol Sci. 
2016;130(3):151-158. 
12. Mizuguchi H, Kitamura Y, Kondo Y, et al. Preseasonal prophylactic treatment with 
antihistamines suppresses nasal symptoms and expression of histamine H₁ receptor 
mRNA in the nasal mucosa of patients with pollinosis. Methods Find Exp Clin 
Pharmacol. 2010;32(10):745-748. 
13. Leurs R, Hoffmann M, Alewijnse AE, Smit MJ, Timmerman H. Methods to determine 
the constitutive activity of histamine H2 receptors. Methods Enzymol. 
2002;343:405-416. 


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14. Barbot A, Lheritier-Barrand M, Leonett M, et al. In vitro human nasal epithelium 
model establishment to study histamine effect and fexofenadine benefit as inverse 
agonist. BSCAI-WAO 2022;p129, Abstract 064. 
15. Ellis AK, Steacy LM, Hobsbawn B, Conway CE, Walker TJ. Clinical validation of 
controlled grass pollen challenge in the Environmental Exposure Unit (EEU). Allergy 
Asthma Clin Immunol. 2015;11(1):5. 
16. Barnes ML, Vaidyanathan S, Williamson PA, Lipworth BJ. The minimal clinically 
important difference in allergic rhinitis. Clin Exp All. 2010;40(2):242-250. 
17. McLeod LD, Coon CD, Martin SA, Fehnel SE, Hays RD. Interpreting patient-reported 
outcome results: US FDA guidance and emerging methods. Expert Rev Pharmacoecon 
Outcomes Res. 2011;11(2):163-169. 
18. Devillier P, Chassany O, Vicaut E, et al. The minimally important difference in the 
Rhinoconjunctivitis Total Symptom Score in grass-pollen-induced allergic 
rhinoconjunctivitis. Allergy. 2014;69(12):1689-1695. 
19. Yamamoto H, Yonekura S, Sakurai D, et al. Comparison of nasal steroid with 
antihistamine in prophylactic treatment against pollinosis using an environmental 
challenge chamber. Allergy Asthma Proc. 2012;33(5):397-403. 
20. Berkowitz BR, Braker S, Lutz C, et al, Efficacy of fexofenadine in the prophylactic 
control of cat allergen–induced allergic rhinitis. Ann Allergy Asthma Immunol. 
2006;96(2):327–333. 
 
 


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Protocol LPS17180 (FEXPRESAR), Original Protocol 
 
 
 
Signature of Investigator 
PROTOCOL TITLE: A Phase IIIb, single-center, double-blind, two-arms, placebo-controlled, 
randomized, parallel-group clinical trial to evaluate the efficacy and safety of 2-day 
pre-treatment with fexofenadine in patients suffering from Seasonal Allergic Rhinitis  
PROTOCOL NO: 
LPS17180 (FEXPRESAR) 
VERSION:  
 
Original Protocol  
This protocol is a confidential communication of The Sponsor. I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol. I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki and 
that are consistent with Good Clinical Practices and the applicable laws and regulations. 
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from the 
Sponsor. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the 
study site in which the study will be conducted. Return the signed copy to IQVIA. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:      __________________________            Date:  ________ 
Printed Name:                                
  
Investigator Title:                           ___________________________ 
 
Name/Address of Center:               
 
Kingston, Ontario, K7L 2V7, CANADA. 
 
 

SAP_001.pdf: 
Opella Healthcare Group SAS 
PROTOCOL LPS17180 (FEXPRESAR) 
 
Statistical Analysis Plan 
Page 1 of 35 
 
Document: 
 
 
Author: 
 
Version Number: 
 
 
Version Date:  
[17Feb2023] 
Template No.:  
 
Reference:  
 
Effective Date: 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
LPS17180 (FEXPRESAR) 
 
A Phase IIIb, single-center, double-blind, two-arms, placebo-controlled, randomized, parallel-group clinical trial to 
evaluate the efficacy and safety of 2-day pre-treatment with fexofenadine in patients suffering from Seasonal 
Allergic Rhinitis 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: FINAL V1.0 17Feb2023 
 
 
 


Opella Healthcare Group SAS 
PROTOCOL LPS17180 (FEXPRESAR) 
 
Statistical Analysis Plan 
Page 2 of 35 
 
Document: 
 
 
Author: 
 
Version Number: 
 
 
Version Date:  
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan Final V1.0 (Dated 17Feb2023) for Protocol LPS17180 dates 21st September 2022. 
 
Name 
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Date (DDMmmYYYY) 
Author: 
 
 
 
 
Position: 
 
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
 
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MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
Draft 1.0 
21Dec2022 
 
Not Applicable – First Version 
Final 1.0 
17Feb2023 
 
Updated as per sponsor comments on Draft 
Version 1. 
 
 


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TABLE OF CONTENTS 
1. 
INTRODUCTION............................................................................................................. 10 
2. 
STUDY OBJECTIVES AND ESTIMANDS .................................................................. 10 
2.1. 
Primary Objective ......................................................................................................................................... 10 
2.2. 
Secondary Objectives .................................................................................................................................... 10 
2.3. 
Exploratory Objectives ................................................................................................................................. 10 
2.4. 
Safety Objectives ............................................................................................................................................ 10 
2.5. 
Estimands ....................................................................................................................................................... 11 
3. 
STUDY DESIGN ............................................................................................................... 12 
3.1. 
General Description ....................................................................................................................................... 12 
3.2. 
Schedule of Events ......................................................................................................................................... 12 
3.3. 
Changes to Analysis from Protocol .............................................................................................................. 13 
4. 
PLANNED ANALYSES ................................................................................................... 13 
4.1. 
Data Monitoring Committee (DMC) ............................................................................................................ 13 
4.2. 
Interim Analysis ............................................................................................................................................. 13 
4.3. 
Final Analysis ................................................................................................................................................. 13 
5. 
ANALYSIS SETS.............................................................................................................. 14 
5.1. 
Process for Analysis Set Assignment ............................................................................................................ 14 
5.2. 
All Subjects Enrolled Set [ENR] ................................................................................................................... 14 
5.3. 
Intent-To-Treat Analysis Set [ITT] .............................................................................................................. 14 
5.4. 
Per Protocol Analysis Set [PPAS] ................................................................................................................. 14 
5.5. 
Safety Analysis Set [SAF] .............................................................................................................................. 14 


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5.6. 
Modified Intent-To-Treat Analysis Set [mITT] .......................................................................................... 14 
6. 
GENERAL CONSIDERATIONS ................................................................................... 15 
6.1. 
Reference Start Date and Study Day ........................................................................................................... 15 
6.2. 
Baseline ........................................................................................................................................................... 15 
6.3. 
Derived Timepoints ....................................................................................................................................... 15 
6.4. 
Unscheduled Visits and Early Termination Data ....................................................................................... 15 
6.5. 
Windowing Conventions ............................................................................................................................... 16 
6.6. 
Statistical Tests .............................................................................................................................................. 16 
6.7. 
Common Calculations ................................................................................................................................... 16 
6.8. 
Software Version ............................................................................................................................................ 16 
7. 
STATISTICAL CONSIDERATIONS ............................................................................ 16 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses ....................................................... 17 
7.2. 
Multicenter Studies ........................................................................................................................................ 17 
7.3. 
Missing Data ................................................................................................................................................... 17 
7.4. 
Intercurrent Events ....................................................................................................................................... 18 
7.5. 
Multiple Comparisons/ Multiplicity ............................................................................................................. 18 
7.6. 
Active-Control Studies Intended to Show Non-inferiority or Equivalence .............................................. 18 
7.7. 
Examination of Subgroups ............................................................................................................................ 18 
8. 
OUTPUT PRESENTATIONS ......................................................................................... 18 
9. 
DISPOSITION AND WITHDRAWALS ........................................................................ 18 
9.1. 
Disposition ...................................................................................................................................................... 19 
9.2. 
Protocol Deviations ........................................................................................................................................ 19 


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10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 19 
10.1. 
Derivations ................................................................................................................................................. 20 
11. 
MEDICAL HISTORY ...................................................................................................... 20 
12. 
CONCOMITANT ILLNESSES ...................................................................................... 20 
13. 
CONCOMITANT MEDICATIONS ............................................................................... 21 
14. 
STUDY MEDICATION EXPOSURE ............................................................................ 21 
14.1. 
Derivations ................................................................................................................................................. 21 
15. 
STUDY MEDICATION COMPLIANCE ...................................................................... 21 
15.1. 
Derivations ................................................................................................................................................. 22 
16. 
EFFICACY OUTCOMES................................................................................................ 22 
16.1. 
Primary Efficacy ........................................................................................................................................ 22 
16.1.1. 
Primary Efficacy Variable & Derivation ................................................................................................. 22 
16.1.2. 
Intercurrent Event Handling and Data Imputation for Primary Efficacy Variable(s) .............................. 22 
16.1.3. 
Primary Analysis of Primary Efficacy Variable(s) .................................................................................. 22 
16.1.4. 
Supplementary Analysis of Primary Efficacy Variable(s) ....................................................................... 23 
16.1.5. 
Sensitivity Analysis of Primary Efficacy Variable(s) .............................................................................. 23 
16.2. 
Secondary Efficacy .................................................................................................................................... 23 
16.2.1. 
Secondary Efficacy Variables & Derivations .......................................................................................... 23 
16.2.2. 
Intercurrent Event Handling and Data Imputation for Secondary Efficacy Variable(s) .......................... 23 
16.2.3. 
Analysis of Secondary Efficacy Variables............................................................................................... 23 
16.2.3.1. 
Analysis of Secondary Variables based on AUC ............................................................................. 23 
16.2.3.2. 
Analysis of TNSS-3, TOSS, and TSS .............................................................................................. 24 
16.3. 
Exploratory Efficacy ................................................................................................................................. 24 
16.3.1. 
Exploratory Efficacy Variables & Derivations ........................................................................................ 24 
16.3.2. 
Intercurrent Event Handling and Data Imputation for Exploratory Efficacy Variable(s) ........................ 25 
16.3.3. 
Analysis of Exploratory Efficacy Variables ............................................................................................ 25 
17. 
QUALITY OF LIFE ANALYSIS .................................................................................... 25 
18. 
SAFETY OUTCOMES .................................................................................................... 25 
18.1. 
Adverse Events ........................................................................................................................................... 26 
18.1.1. 
All TEAEs ............................................................................................................................................... 26 
18.1.1.1. 
Severity ............................................................................................................................................ 26 


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18.1.1.2. 
Relationship to Study Medication .................................................................................................... 26 
18.1.2. 
TEAEs Leading to Discontinuation of Study Medication ....................................................................... 27 
18.1.3. 
Serious Adverse Events ........................................................................................................................... 27 
18.1.4. 
Adverse Events Leading to Death............................................................................................................ 27 
18.1.5. 
Adverse Events Of Special Interest ......................................................................................................... 27 
18.1.6. 
CTC Grading for Adverse Events ............................................................................................................ 27 
18.2. 
Deaths ......................................................................................................................................................... 28 
18.3. 
Laboratory Evaluations ............................................................................................................................ 28 
18.3.1. 
Laboratory Specific Derivations .............................................................................................................. 28 
18.3.2. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ............................................................ 28 
18.3.3. 
CTC Grading for Laboratory Data ........................................................................................................... 28 
18.4. 
ECG Evaluations ....................................................................................................................................... 29 
18.5. 
Vital Signs ................................................................................................................................................... 29 
18.6. 
Physical Examination ................................................................................................................................ 29 
18.7. 
Other Safety Assessments ......................................................................................................................... 29 
19. 
PHARMACOKINETIC ANALYSIS .............................................................................. 29 
20. 
GENETIC ANALYSIS ..................................................................................................... 30 
21. 
DATA NOT SUMMARIZED OR PRESENTED .......................................................... 30 
22. 
REFERENCES .................................................................................................................. 31 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS .............................. 31 
IQVIA Output Conventions...................................................................................................................................... 31 
Dates & Times ............................................................................................................................................................ 31 
Spelling Format.......................................................................................................................................................... 31 
Presentation of Treatment Groups .......................................................................................................................... 31 
Presentation of Visits ................................................................................................................................................. 32 
Listings ....................................................................................................................................................................... 32 
APPENDIX 2. PARTIAL DATE CONVENTIONS ............................................................. 33 
Algorithm for Treatment Emergence of Adverse Events: ..................................................................................... 33 


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Algorithm for Prior / Concomitant Medications: ................................................................................................... 34 
 
 


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LIST OF ABBREVIATIONS  
 
ANCOVA 
Analysis of Covariance 
AR (1) 
first order Autoregressive 
AUC 
Area under the curve 
CI 
Confidence Interval 
CS 
Compound Symmetric 
CTCAE 
Common Terminology Criteria for Adverse Events 
EEU 
Environmental Exposure Unit 
H 
Hour 
ITT 
Intent-to-Treat 
LS 
Least Squares 
mITT 
modified Intent-to-Treat 
MMRM 
Mixed Models for Repeated Measures 
NIC 
National Cancer Institute 
PPAS 
Per Protocol Analysis Set 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SAR 
Seasonal allergic rhinitis 
SE 
Standard Error 
SOC 
System Organ Class 
STL 
Statistical Team Lead 
TNSS-3 
Total Nasal Symptoms Score of 3 symptoms 
TOSS 
Total Ocular Symptoms Score 
TSS 
Total Symptoms Score 
V 
Visit 
 


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1. INTRODUCTION 
This statistical analysis plan (SAP) describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data for Protocol LPS17180 (FEXPRESAR). It describes the data to be summarized and 
analysed, including specifics of the statistical analyses to be performed. 
 
This SAP is based on protocol version 1.0 dated 21 September 2022. 
2. STUDY OBJECTIVES AND ESTIMANDS 
2.1. 
Primary Objective 
To evaluate the efficacy of fexofenadine 180 mg when started 2 days before the exposure to the allergen in patients 
suffering from seasonal allergic rhinitis (SAR). 
2.2. 
Secondary Objectives 
• 
To evaluate the efficacy of fexofenadine when started 2 days before the exposure to the allergen in patients 
suffering from SAR in terms of preventing nasal and ocular symptoms of rhinorrhea, sneezing, and nasal 
itching, red/burning eyes, tearing, and itchy/watery eyes. 
• 
To evaluate the safety of fexofenadine when started 2 days before the exposure to the allergen in patients 
suffering from SAR. 
2.3. 
Exploratory Objectives 
• 
To evaluate the efficacy for total score and all individual symptoms: nasal, ocular, throat (9 symptoms in total: 
nasal and ocular symptoms of rhinorrhea, sneezing, nasal itching, and nasal congestion; red/burning eyes, 
tearing, and itchy/watery eyes; and itching of ears/palate or throat). 
• 
To assess the proportion of satisfaction in the 2 groups. 
• 
To assess the use of rescue medication in the 2 groups. 
2.4. 
Safety Objectives 
• 
To evaluate the safety of fexofenadine when started 2 days before the exposure to the allergen in patients 


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suffering from SAR. 
2.5. 
Estimands 
Not applicable. 
 
 


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3. STUDY DESIGN 
3.1. 
General Description 
This is a Phase IIIb, randomized, double-blind, single-center, two-arm, parallel-group, placebo-controlled, proof-of-
concept study, outside of Ragweed pollen season. Two Arms are planned: 
• Arm A (active 2 days): two days of pre-treatment with fexofenadine, then fexofenadine 180 mg during the test 
pollen challenge 
• Arm B (placebo 2 days): two days of pre-treatment with placebo, then fexofenadine 180 mg during the test pollen 
challenge 
A total of 5 visits to the study site or the environmental exposure unit (EEU) are planned per participant. An 
adequate number of participants will be screened to achieve 96 participants randomized (86 evaluable participants). 
 
Table A: 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2. 
Schedule of Events 
Schedule of events can be found in Section 1.3 of the protocol. 


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3.3. 
Changes to Analysis from Protocol 
 The SAP supersedes the statistical methods described in the clinical study protocol. Analysis methods that 
summarize and evaluate study efficacy endpoints for statistical significance will be implemented as described in the 
SAP. 
An additional exploratory analysis as in primary analysis will be performed stratified by baseline TNSS-3 ≤7, 
TNSS-3 >7.  
4. PLANNED ANALYSES 
The following analyses will be performed for this study: 
• 
Final Analysis  
4.1. 
Data Monitoring Committee (DMC)  
There will be no DMC for this study. 
4.2. 
Interim Analysis  
No interim analysis is planned. 
4.3. 
Final Analysis  
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics following Sponsor 
Authorization of this Statistical Analysis Plan, Database Lock, Sponsor Authorization of Analysis Sets and 
Unblinding of Treatment. 
 
 


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5. ANALYSIS SETS  
5.1. 
Process for Analysis Set Assignment 
The subjects will be assigned to the analysis sets programmatically as per the definitions below. 
5.2. 
All Subjects Enrolled Set [ENR] 
The all subjects enrolled (ENR) set will contain all subjects who provide informed consent for this study. 
5.3. 
Intent-To-Treat Analysis Set [ITT] 
The intent-to-treat analysis set (ITT) will contain all eligible subjects (passed screening and confirmation challenge) 
who have been allocated to a randomized treatment regardless of whether study drug wallet was used or not.  
Subjects will be classified according to randomized treatment. 
5.4. 
Per Protocol Analysis Set [PPAS] 
Not applicable. 
5.5. 
Safety Analysis Set [SAF] 
The safety analysis set (SAF) will contain all subjects in the ITT set who receive at least one dose of study 
medication and subjects will be classified according to treatment received.  
If there is any doubt whether a subject was treated or not, they will be assumed treated for the purposes of analysis.  
5.6. 
Modified Intent-To-Treat Analysis Set [mITT] 
The modified intent-to-treat analysis set (mITT) will contain all eligible, ITT, and treated subjects with Total Nasal 
Symptoms Score of 3 symptoms (TNSS-3) evaluation at H0 at V4 and at least a further time point at Visit 4.  
Subjects will be classified according to randomized treatment. 


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6. GENERAL CONSIDERATIONS 
6.1. 
Reference Start Date and Study Day 
Study Day will be calculated from the reference start date and will be used to show start/stop day of assessments and 
events. It will appear in every listing where an assessment date or event date appears. 
 
Reference start date is defined as the day of randomization (Day 1 is the day of randomization).  
• 
If the date of the event is on or after the reference date, then:  
• 
Study Day = (date of event – reference date) + 1.  
• 
If the date of the event is prior to the reference date, then:  
• 
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, and 
Study Day, and any corresponding durations will be presented based on the imputations specified in APPENDIX 2; 
Partial Date Conventions. 
6.2. 
Baseline 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to reference start 
date (including unscheduled assessments). Baseline of the symptoms scoring will be H0 at visit 4 value according to 
the analysis. 
6.3. 
Derived Timepoints 
Not applicable. 
6.4. 
Unscheduled Visits and Early Termination Data 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled measurements 
will not be included in by-visit summaries. 
  
Listings will include scheduled, unscheduled, and early discontinuation data. 


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6.5. 
Windowing Conventions  
No visit windowing will be performed for this study. 
6.6. 
Statistical Tests 
The default significant level will be (5%); CIs (confidence intervals) will be 95% and all tests will be two-sided, 
unless otherwise specified in the description of the analyses. 
6.7. 
Common Calculations 
For quantitative measurements, change from baseline will be calculated as: 
 
• 
Test Value at Visit X – Baseline Value 
6.8. 
Software Version 
All analyses will be conducted using SAS version 9.4 or higher.  
7. STATISTICAL CONSIDERATIONS 
Unless otherwise specified, all statistical tables will be provided by treatment group and will first present the results 
in the active group (FEXPRESAR) and then the results in the placebo group. The column ‘overall’ displaying all 
patients (all treatment groups combined) will be presented where appropriate. 
 
The descriptive summary for continuous data will include the number of non-missing observations (n), mean, 
standard deviation, median, 25th percentile and 75th percentile, minimum, and maximum. The number of subjects 
with missing data will be displayed when relevant. 
Categorical data will be summarized for each treatment group using counts (n) and percentages (%). The number of 
subjects with missing data will be displayed when relevant, but it will not be included in the denominator for the 
calculation of percentages unless otherwise specified. 
 
If the original data has N decimal places, then the summary statistics will have the following decimal places: 
• 
Minimum and maximum: N 
• 
Mean, median, percentiles, confidence intervals, ratios: N + 1 


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• 
SD: N + 2 
 
Percentages will be reported to one decimal place. P-values should be reported to three decimal places, except 
values <1.000 but >0.999 will be presented as ‘>0.999’ (e.g., 0.9998 is presented as >0.999); and values <0.001 will 
be presented as ‘<0.001’ (e.g., 0.0009 is presented as <0.001) 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses 
The following covariates and factors are used in the analyses. For details of their inclusion in the models, see the 
specific analysis section. 
• 
TNSS-3 at Day 1/Visit 4 H0 
• 
(Total Ocular Symptoms Score) TOSS at Day 1/Visit 4 H0 
• 
(Total Symptoms Score) TSS at Day 1/Visit 4 H0 
• 
Individual symptoms score at Day 1 
• 
Treatment group (Fexofenadine 180 mg, Placebo) 
• 
Time point (H0 to H12) 
• 
Treatment group by time point 
• 
Stratification factor – Visit 2 TNSS-3 (TNSS-3 ≤7, TNSS-3 >7) 
7.2. 
Multicenter Studies 
Not applicable. 
7.3. 
Missing Data 
Missing safety data will not be imputed.  
  
A missing symptom score will be imputed using linear interpolation between the last available preceding value and 
the first following non missing value; if no following non-missing value is available, the last available value will be 
carried forward up to H+12. Baseline value will not be extended in case of all post baseline values are missing. 
 


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7.4. 
Intercurrent Events 
Not applicable. 
7.5. 
Multiple Comparisons/ Multiplicity 
The following multiplicity testing procedures will be used to control the type I error: 
• 
The secondary efficacy endpoints will be tested only if the primary endpoint is significant. 
• 
The multiplicity of secondary efficacy endpoints will be handled using Hochberg’s step-up test. 
• 
For the other secondary efficacy endpoints and the exploratory efficacy endpoints, p-values will be provided for 
descriptive purpose only. 
• 
The number of Adverse Events defined as other secondary endpoint will be analysed only with descriptive 
statistics (no p-value will be provided). 
7.6. 
Active-Control Studies Intended to Show Non-inferiority or 
Equivalence 
Not applicable. 
7.7. 
Examination of Subgroups 
No subgroup analyses will be performed for this study. 
8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore the format and content 
of the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
All subjects who provide informed consent will be accounted for in this study.  


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9.1. 
Disposition 
Subject disposition and withdrawals, and reasons for exclusion from each analysis set, including inclusion and 
exclusion criteria will be summarized for the ENR set. The primary reason for discontinuation of study, including 
any of the following, will be summarized by treatment group: 
• 
Screen Failure 
• 
Adverse Event 
• 
EEU challenge intolerance 
• 
Poor Compliance to Protocol 
• 
Study Terminated by Sponsor 
• 
Patient Withdrew Consent 
• 
Investigator Decision 
• 
Death 
• 
Other 
A listing of all subjects who discontinued from the trial and their reason for discontinuation will be provided. 
9.2. 
Protocol Deviations 
Protocol deviation data will be obtained via Clinical Trial Management System Protocol Deviations (CTMS PD) 
log. Deviation data will be categorized as Critical, Major and Minor based on Severity. The number and percentage 
of subjects with any important protocol deviations will be presented for the SAF Analysis Set by treatment group. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the ITT and mITT. 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic and other baseline characteristics will be reported for this study: 
• 
Age (years)  
• 
Sex 
• 
Race  
• 
Ethnicity 
• 
Weight (kg) 


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• 
Height (cm) 
• 
BMI (kg/m2) 
• 
Allergic symptoms scoring (TNSS-3, TOSS, TSS) 
• 
Skin prick test (Allergen and Reaction diameter(mm)) 
• 
Patients with only ragweed positive (monosensitized) and patients with at least one allergen test positive with 
another allergen than ragweed (polysensitized). 
• 
Duration of Allergic Rhinitis (years) 
• 
Severity symptom scoring (4-7 and 8-9), which is TNSS-3 ≤7, TNSS-3 >7 at visit 2 
Age, Weight, Height,  BMI, Skin prick test – Reaction diameter, and Duration to Allergic Rhinitis will be 
summarized using descriptive statistics by treatment group. Sex, Race, Ethnicity, Allergic symptoms score, and Skin 
prick test – Allergen will be summarized with the number and percentages by treatment group. 
10.1. Derivations 
• 
BMI (kg/ m2) = weight (kg)/ height (m)2 
• 
Duration of Allergic Rhinitis (years) = {(Date of Visit 1 – Start date of Allergic Rhinitis) +1}/365.25 
 
Note: The Start date of Allergic Rhinitis will be taken from the Allergic Medical History eCRF page. 
11. MEDICAL HISTORY 
Medical History including Allergic Medical History information will be presented for the SAF by treatment group.  
• 
Medical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 25.1 
o 
Medical History conditions are defined as those conditions which stop prior to or at Screening.  
o 
Presented by SOC and PT.  
12. CONCOMITANT ILLNESSES 
Not applicable. 


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13. CONCOMITANT MEDICATIONS 
Medications or vaccines will be presented for the SAF and coded using WORLD HEALTH ORGANIZATION-DRUG 
DICTIONARY (WHO-DD) version currently in effect. 
See APPENDIX 2 for handling of partial dates for medications, in the case where it is not possible to define a 
medication as prior, concomitant, or post treatment, the medication will be classified by the worst case, i.e., 
concomitant.  
• 
‘Prior’ medications are medications which started and stopped prior to the first dose of study medication.  
• 
‘Concomitant’ medications are any treatments received by the subject concomitantly to the IMP or study 
procedure, from day 1 until day 5. 
14. STUDY MEDICATION EXPOSURE 
The extent of exposure will be assessed and summarized by actual treatment received within the safety population. 
The duration of exposure to pollen at visit 2 and visit 4 will also be presented. 
14.1. Derivations 
• 
Duration of exposure (days) = date of last study medication administration – date of first study medication 
administration + 1.  
 
• 
Duration of exposure to Pollen (hours) = (End time of the challenge -Start time of the challenge)/60*60 
15. STUDY MEDICATION COMPLIANCE  
Compliance to study medication will be presented for the SAF.  
A participant will be considered noncompliant if they did not take the planned doses of study drug as required by the 
protocol. Treatment compliance will be summarized by randomized, double-blind, placebo-control study part and by 
post pollen challenge, open-label study part  by number and percentage of participants compliant per arm.   
For Randomized, double-blind, placebo-control study part:  
0% (missed both the doses), 50% (missed one dose), 100% (took both the dose), >100% (took additional dose)  
For Open label study part:   
0% (missed dose), 100% (took dose), >100% (took additional dose) 


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The descriptive statistics of compliance percentage will be presented by treatment group. 
15.1. Derivations 
Randomized, double-blind, placebo-control study part:  
Compliance percentage = (Number of tablets taken/2) *100  
 
Open label study part: 
Compliance percentage = (Number of tablets taken) *100  
16. EFFICACY OUTCOMES  
16.1. Primary Efficacy 
16.1.1. 
Primary Efficacy Variable & Derivation 
The primary efficacy endpoint is AUC (Area under the curve) of TNSS-3 from H0 to H6 at Visit 4.  
 
The TNSS-3 is a composite score calculated as the sum of rhinorrhea, sneezing, and nasal itching scores (maximum 
9). The individual scores are collected in e-diary. 
The AUC will be computed using the linear trapezoidal method provided in reference section 22 (Ref 3) (22). 
16.1.2. 
Intercurrent Event Handling and Data Imputation for Primary Efficacy 
Variable(s) 
Not applicable. 
16.1.3. 
Primary Analysis of Primary Efficacy Variable(s) 
The primary efficacy analysis will be performed for the mITT. 
The primary analysis will be the comparison of the primary efficacy endpoint (ie, AUC of the TNSS-3 from H0 to 
H6 at V4) between fexofenadine and placebo, using an analysis of covariance (ANCOVA) with treatment group as 
fixed effect and the baseline value of TNSS-3 (i.e., at H0 at V4) as covariate. The mean TNSS-3 and its 95% CI will 
be plotted across time from H0 to H6 at Visit 4. This plot will also include the LS mean and 95% CI of the AUC. 


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16.1.4. 
Supplementary Analysis of Primary Efficacy Variable(s) 
Not applicable. 
16.1.5. 
Sensitivity Analysis of Primary Efficacy Variable(s) 
The primary analysis will be performed for observed cases. 
16.2. Secondary Efficacy 
The secondary efficacy analyses will be performed for the mITT. 
16.2.1. 
Secondary Efficacy Variables & Derivations 
The TOSS is a composite score calculated as the sum of red/burning eyes, tearing, itchy/watery eyes scores 
(maximum 9). The individual scores are collected in e-diary. The AUC will be computed using the linear trapezoidal 
method (22) for all the variables below. The mean score and its 95% CI will be plotted across respective timepoints. 
This plot will also include the LS mean and 95% CI of the AUC. 
• 
AUC of TOSS from H0 to H6 at V4  
• 
AUC of TNSS-3 from H0 to H12 at V4 
• 
AUC of TOSS from H0 to H12 at V4 
• 
AUC of TNSS-3 from randomization (D1) to V4 (D4) 
• 
AUC of TOSS from randomization (D1) to V4 (D4) 
16.2.2. 
Intercurrent Event Handling and Data Imputation for Secondary Efficacy 
Variable(s) 
Not Applicable. 
16.2.3. 
Analysis of Secondary Efficacy Variables 
16.2.3.1. 
ANALYSIS OF SECONDARY VARIABLES BASED ON AUC 
 
All secondary endpoints based on the AUC (i.e., TNSS-3 and TOSS) will be analysed using an ANCOVA model, 


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with treatment group as fixed effect and the baseline values as covariate. For the AUC assessment starting from 
Randomization (D1) to D4, symptom scoring at D1 will be used as baseline. 
16.2.3.2. 
ANALYSIS OF TNSS-3, TOSS, AND TSS 
 
The TNSS-3, TOSS, TSS, and individual symptom score by time point will be analysed given the mean and 95% 
confidence interval (CI).  
The TNSS-3, TOSS, and TSS will be analysed using MMRM (Mixed Models for Repeated Measures), with 
treatment, time point and treatment group by time point interaction as fixed effect with their respective H0 scores as 
baseline covariate. The MMRM model will be run using PROC MIXED procedure with an unstructured correlation 
matrix to model the within-subject errors. If unstructured fails to converge, the following covariance structures will 
be tested: CS (compound symmetric) first, and then AR (1) (first-order autoregressive). Denominator degrees of 
freedom will be estimated using the Satterthwaite’s approximation.  
The descriptive statistics (number, mean, SD, median, Q1 and Q3, minimum, and maximum) of AUC and the 
statistics from the MMRM, least square (LS) means, standard errors (SEs) and 95% confidence intervals (CIs)) will 
be provided. 
16.3. Exploratory Efficacy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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16.3.2. 
Intercurrent Event Handling and Data Imputation for Exploratory Efficacy 
Variable(s) 
Not applicable. 
16.3.3. 
Analysis of Exploratory Efficacy Variables 
 
 
  
 
 
 
 
17. QUALITY OF LIFE ANALYSIS  
Not applicable. 
18. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF.  


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There will be no statistical comparisons between the treatment groups for safety data, unless otherwise specified 
with the relevant section.  
18.1. Adverse Events 
Adverse Events (AEs) will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 25.1. 
 
The pre-treatment period starts the day of the signed informed consent and ends before administration of study drug. 
The treatment-emergent AE period starts at time of administration of study drug ends 3 days after administration of 
study drug.  
 
See Appendix 2 for handling of partial dates for AEs.  In the case where it is not possible to define an AE as 
treatment emergent or not, the AE will be classified by the worst case, i.e., treatment emergent.  
An overall summary of number of subjects within each of the categories described in the sub-section below, will be 
provided as specified in the templates.  
Listings will include pre-treatment AEs and TEAEs. 
18.1.1. 
All TEAEs 
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and broken down 
further by maximum severity and relationship to study medication. 
18.1.1.1. 
SEVERITY 
Severity is classed as mild/ moderate/ severe (increasing severity). TEAEs starting after the first dose of study 
medication with a missing severity will be classified as severe. If a subject reports a TEAE more than once within 
that SOC/ PT, the AE with the worst-case severity will be used in the corresponding severity summaries. 
18.1.1.2. 
RELATIONSHIP TO STUDY MEDICATION 
Relationship, as indicated by the Investigator, is classed as “Related” “Not Related”. TEAEs with a missing 
relationship to study medication will be regarded as “Related” to study medication. If a subject reports the same AE 
more than once within that SOC/ PT, the AE with the worst-case relationship to study medication will be used in the 
corresponding relationship summaries.  


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18.1.2. 
TEAEs Leading to Discontinuation of Study Medication 
TEAEs leading to permanent discontinuation of study medication will be identified by using the “Action taken” 
filed from the adverse events page of the eCRF.  
For TEAEs leading to discontinuation of study medication, summaries of incidence rates (frequencies and 
percentages) by SOC and PT will be prepared. 
18.1.3. 
Serious Adverse Events 
Serious adverse events (SAEs) are those events recorded as “Yes” on “Serious” field on the Adverse Events page of 
the eCRF. A summary of serious TEAEs by SOC and PT will be prepared. 
18.1.4. 
Adverse Events Leading to Death 
TEAEs leading to Death are those events which are recorded as “Yes” on “Death” filed on the Adverse Events page 
of the CRF. A summary of TEAEs leading to death by SOC and PT will be prepared. 
18.1.5. 
Adverse Events Of Special Interest  
Adverse events of special interest may be added, modified, or removed during a study by protocol amendment. 
Specific AESI(s) for this study include systemic hypersensitivity reactions with manifestations such as angioedema, 
chest tightness, dyspnea, flushing, and systemic anaphylaxis. A summary by SOC and PT will be prepared. 
18.1.6. 
CTC Grading for Adverse Events  
AEs will be graded using the NCI CTCAE v5.0 
(https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/CTCAE v5 Quick Reference 5x7.pdf). 
For AEs that are not adequately addressed in the NCI CTCAE, the Investigator should classify the intensity of the AE 
using the following guidelines: 
• 
Grade 1: Mild: Aware of sign or symptom, but easily tolerated; no intervention needed. 
• 
Grade 2: Moderate: Discomfort enough to cause interference with usual activity, minimal non-invasive 
intervention indicated (e.g., short course of antibiotics). 
• 
Grade 3: Severe: Medically significant but not immediately life-threatening; incapacitation with inability to 
work or do usual activity. 
• 
Grade 4: Life-threatening: Refers to an event in which the participant was at risk of death at the time of the 


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event, as judged by the Investigator; urgent/emergent intervention indicated. This category should not be used 
for an event that hypothetically might have caused death if it were more severe. 
• 
Grade 5: Fatal outcome. 
 
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) ,broken down by 
maximal grading. 
18.2. Deaths 
If any subjects die during the study as recorded in the Adverse Events page in eCRF, the information will be 
presented in a summary table and a data listing. 
18.3. Laboratory Evaluations 
A rapid antigen test will be performed before EEU entry, for SARS-CoV-2 infection.  
Women of childbearing potential should only be included after a confirmed menstrual period and a negative highly 
sensitive urine pregnancy test. 
 
The following listings will be provided for laboratory data: 
• 
COVID-19 tests 
• 
Urine Pregnancy test 
18.3.1. 
Laboratory Specific Derivations 
Not applicable. 
18.3.2. 
Laboratory Reference Ranges and Markedly Abnormal Criteria 
Not applicable. 
18.3.3. 
CTC Grading for Laboratory Data  
Not applicable. 


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18.4. ECG Evaluations 
Not Applicable. 
18.5. Vital Signs 
The following Vital Signs measurements will be reported for this study: 
• 
Systolic Blood Pressure (mmHg) 
• 
Diastolic Blood Pressure (mmHg) 
• 
Heart Rate (BEATS/MIN) 
• 
Respiratory Rate (BREATHS/MIN) 
• 
Oral Body Temperature (⁰C) 
• 
Weight (kg) 
• 
Height (cm) 
Summary table and listing will be presented for vital signs data. 
18.6. Physical Examination  
The following summaries will be provided for physical examination data: 
• 
Incidence of abnormalities at screening and Visit 4 H6. 
• 
Listing will be provided for physical examination.  
18.7. Other Safety Assessments 
The following will be presented: 
• 
Nasal Examination: Incidence of abnormalities at screening and Visit 4 H6 and Listing 
• 
Skin Prick Test: Summary of allergen and reaction diameter with data listing. 
19. PHARMACOKINETIC ANALYSIS  
Not applicable. 


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20. GENETIC ANALYSIS 
Not applicable. 
21. DATA NOT SUMMARIZED OR PRESENTED 
Not applicable. 
 
 
 


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22. REFERENCES  
1.A Phase IIIb, single-center, double-blind, two-arms, placebo-controlled, randomized, parallel-
group clinical trial to evaluate the efficacy and safety of 2-day pre-treatment with fexofenadine 
in patients suffering from Seasonal Allergic Rhinitis; Protocol Number: LPS17180 
(FEXPRESAR)2. LPS17180_eCRF Version 2.0_20Oct2022 - Unique Forms 
3. Yeh, Shi-Tao & Collegeville, GlaxoSmithKline. (1991). Using trapezoidal rule for the area 
under a curve calculation. 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 


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APPENDIX 2. PARTIAL DATE CONVENTIONS 


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