Conditions: Seasonal Allergic Rhinitis
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 216
Healthy volunteers: no

Brief summary:
This study is to assess the onset of action of fixed drug combination of azelastine hydrochloride and fluticasone propionate nasal spray (Dymista) in treating the nasal symptoms of seasonal allergic rhinitis (SAR) induced by an allergen challenge in an Environmental Exposure Unit (EEU).

Detailed description:

Arms:
arm 1: Fixed drug combination of Azelastine hydrochloride 137 μg / Fluticasone propionate 50 μg nasal spray and Placebo nasal spray arm 2: Placebo nasal spray and Fixed drug combination of Azelastine hydrochloride 137 μg / Fluticasone propionate 50 μg nasal spray

Interventions: intervention 1: Treatment A (Dymista): Fixed drug combination of azelastine hydrochloride and fluticasone propionate nasal spray at Visit 3 intervention 2: Treatment B (Placebo): Nasal spray with no active dose (Dymista vehicle) at Visit 5 intervention 3: Treatment A (Dymista): Fixed drug combination of azelastine hydrochloride and fluticasone propionate nasal spray at Visit 5 intervention 4: Treatment B (Placebo): Nasal spray with no active dose (Dymista vehicle) at Visit 3
Intervention descriptions: intervention 1: Single dose, one spray in each nostril of Dymista nasal spray, approximately 137 μg of azelastine hydrochloride and 50 μg of fluticasone propionate per actuation, at Visit 3 intervention 2: Single dose, one spray in each nostril of Placebo nasal spray at Visit 5 intervention 3: Single dose, one spray in each nostril of Dymista nasal spray, approximately 137 μg of azelastine hydrochloride and 50 μg of fluticasone propionate per actuation, at Visit 5 intervention 4: Single dose, one spray in each nostril of Placebo nasal spray, at Visit 3

Protocol document:
Prot_000.pdf: 
Version 3.0, 27 Jul 2021
Confidential
AZFL-AES-4-001 / C1D00571
CLINICAL STUDY PROTOCOL
Protocol Title
Clinical Trial to Assess Onset of Action of Azelastine Hydrochloride and 
Fluticasone Propionate Nasal Spray Delivered in a Single Spray (Dymista) 
in the Treatment of Allergen-Induced Allergic Rhinitis Symptoms in 
Comparison to Placebo in an Environmental Exposure Unit (EEU)
Short Title
Dymista Allergen Chamber
Protocol Number
AZFL-AES-4-001
Cliantha Study 
Code
C1D00571
Product
Dymista
Study Type
Phase IV (post-authorization)
Version
3.0
Protocol Date
27 Jul 2021
EudraCT no.
Not applicable
IND no.
077363
Legal/Filing 
Sponsor
Meda Pharma GmbH & Co. KG (A Viatris company)
Benzstrasse 1, 61352 Bad Homburg, Germany
Confidentiality:
This protocol is the confidential, intellectual property of Meda Pharma GmbH & Co. KG (A 
Viatris company). It should not be disclosed to a third party with the exception of regulatory 
agencies and study audit personnel that being Viatris employees, representatives, agents 
and/or contractors responsible for conducting the clinical study/trial, audits. Reproduction, 
modification, or adaption in part or in total is strictly forbidden without prior written approval 
by Meda Pharma GmbH & Co. KG (A Viatris company).
ClinicalTrials.gov Identifier: NCT04652245 


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DOCUMENT HISTORY
Document 
Version, Date
Summary of Changes with Rationale
1.0
21 October 2020
Original
2.0 
03 March 2021

To keep generalised wording for COVID-19 testing

To adapt planned study period

To correct end of study defininition in Section 4.1

To update e-mail addresses from ‘mylan.com’ to ‘viatris.com’
3.0
27 Jul 2021

To include wash-out period for COVID-19 vaccination

To adapt planned study period

To change signatures from Adobe signature to electronic
signature in the sponsor’s document manangement system

To perform administrative changes (update company name from
‘Mylan’ to ‘Viatris’, remove company logo, update department
names and job titles, minor clarifications and removal of
typographical errors)


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PROTOCOL REVISION HISTORY
The following table summarizes the updates made from Protocol Version 1.0 (21 Oct 2020) to 
Protocol Version 2.0 (03 Mar 2021)
Section: Protocol Synopsis
From: 
Study Period Planned: 
December 2020 – April 2021
To: 
Study Period Planned: 
December 2020 – July 2021
Rationale to change:  Recruitment is delayed due to COVID-19 restrictions and study period needs 
to be extended to reach the planned number of subjects.  
Section: Study Diagram and Study Schedule of Activities
Table 0-1 Study Schedule (Footnote 11)
From: 
Will be performed within 5 days prior to Visit 2 
and Visit 4 to ensure the subjects safety prior to 
entering the EEU
To: 
Will be performed within 5 days prior to Visit 2 
and Visit 4 or on the day of Visit 2 and 4 for a 
COVID-19 test to ensure the subjects safety prior 
to entering the EEU
Rationale to change:  So as to add an option for COVID-19 testing to be done on the day of Visit 2 
and Visit 4 using Health Canada approved Rapid testing kit. 
4.1  Study Population
From: 
The duration of the study from screening 
(Visit 1) to end of study (Visit 5) will last up to 
56 days for each subject (duration may be 
longer if re-priming is required).
To: 
The duration of the study from screening (Visit 1) 
to end of study (telephone follow-up) will last up to 
56 days for each subject (duration may be longer if 
re-priming is required).
Rationale to change:  Correction of the explanation for the end of study given in brackets in 
accordance with other sections of the protocol (e.g. Synopsis and Section 3.4).  Up to now Note to 
File note was issued for this correction.
6.2.1 Priming/Screening (Period 1, Visit 2) – Day -1
From: 
A COVID screening questionnaire with oral 
temperature will be performed and results of 
COVID test (PCR) performed within 5 days 
prior to this visit will be checked. 
To:
A COVID screening questionnaire with oral 
temperature will be performed and results of 
COVID test performed within 5 days prior to this 
visit or on the day of Visit 2 will be checked.
Rationale to change:   So as to add an option for COVID-19 testing to be done on the day of Visit 2 
and Visit 4 using Health Canada approved Rapid testing kit.


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6.2.3 Priming EEU (Period 2, Visit 4) – Day 13 (+ 5 Days)
From:
A COVID screening questionnaire with oral 
temperature will be performed and results of 
COVID test (PCR) performed within 5 days 
prior to this visit will be checked.
To:
A COVID screening questionnaire with oral 
temperature will be performed and results of 
COVID test performed within 5 days prior to this 
visit or on the day of Visit 4 will be checked.
Rationale to change:   So as to add an option for COVID-19 testing to be done on the day of Visit 2 
and Visit 4 using Health Canada approved Rapid testing kit.
Table 7.3 1 Clinical Laboratory Variables
From:

Pregnancy3 (urine): females of childbearing 
potential only

FSH2 (blood): if necessary to document 
postmenopausal status

COVID4 (nasopharyngeal/oropharyngeal)
To:
Pregnancy3 (urine): females of childbearing 
potential only
FSH2 (blood): if necessary to document 
postmenopausal status
COVID4 (nasopharyngeal/oropharyngeal/nasal)
Rationale to change:   COVID -19 rapid test are conducted using in nasal swab.
Table 7.3 1 Clinical Laboratory Variables (Footnote 4)
From:
Performed within 5 days prior to Visit 
2 and Visit 4
To:
Performed within 5 days prior to Visit 2 and Visit 4 or on 
the day of Visit 2 and 4
Rationale to change:   So as to add an option for COVID-19 testing to be done on the day of Visit 2 
and Visit 4 using Health Canada approved Rapid testing kit.
Other Changes 

Table of content and abbrevations list updated along with the version and date of the protocol.

E-mail addresses updated from ‘mylan.com’ to ‘viatris.com’ throughout the protocol.


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The following table summarizes the updates made from Protocol Version 2.0 (03 Mar 2021) to 
Protocol Version 3.0 (27 Jul 2021)
Section: Protocol Synopsis and 4.2.2 Exclusion Criteria (Table for prohibited medication)
Addition:
Prohibited medication
Prior to Screening
During study
COVID-19 vaccination
No restrictions
Within 3 days prior to each 
allergen challenge2
2
If there is a conflict with the next allergen challenge due to COVID-19 vaccination, a delay of up to 3 days for 
Visit 2 or Visit 4 is allowed. However, the interval between Visit 2 and Visit 3 or Visit 4 and Visit 5 must not 
be changed.
Rationale for the addition:  Added due to increasing COVID vaccinations in the Canadian 
population. A 3 days washout after COVID vaccination is considered to rule out possible systemic 
adverse events that may arise due to the vaccination. Clinically, during this period  a subject can 
possibly experience a systemic side effect to vaccine that can impact their study participation. Any 
local reaction to the vaccination site is not an issue and can be deemed acceptable for subject to 
continue with the study.
Section: Protocol Synopsis
From: 
Study Period Planned: 
December 2020 –July 2021
To: 
Study Period Planned: 
December 2020 – January 2022
Rationale to change:  Recruitment was delayed due to COVID-19 restrictions and it was not 
possible to randomize the planned number of subjects within the seasonal non-allergy period. 
Therefore, it was decided to set the study on hold and to resume after the end of this year’s ragweed 
season (i.e. September 2021 at the earliest). 
Section: Protocol Approval
From: 
Electronic signature
To: 
See Electronic Signature Manifestation
Rationale to change: According to sponsor’s SOP, signatures should be undertaken within the 
document management system. 
Other Changes (Administrative)

Removed company logo from the header throughout the protocol.

Updated company name from ‘Mylan’ to ‘Viatris’ throughout the protocol.

Updated department names and job titles on the Protocol Approval page.

Minor clarifications and removal of typographical errors.


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PROTOCOL SYNOPSIS
Protocol Title
Clinical Trial to Assess Onset of Action of Azelastine Hydrochloride and 
Fluticasone Propionate Nasal Spray Delivered in a Single Spray (Dymista) in the 
Treatment of Allergen-Induced Allergic Rhinitis Symptoms in Comparison to 
Placebo in an Environmental Exposure Unit (EEU)
Short Title
Dymista Allergen Chamber
Protocol 
Number
AZFL-AES-4-001
Cliantha 
Study Code
C1D00571
Study Sites
Headquarters: 
Cliantha Research
1310 Fewster Drive
Mississauga, ON L4W 1A4, Canada
Location of the allergen chamber:
Cliantha Research
4500 Dixie Road 
Mississauga, ON L4W 1V7, Canada
Study Period 
Planned
December 2020 – January 2022
Duration of 
Individual 
Treatment
The duration of the study will last up to 56 days for each subject (duration may 
be longer if re-priming is required). In the study, there will be single dose 
administrations on two separate occasions with at least 14 days wash-out 
between each treatment
End of Study
Date of last contact of the last subject undergoing the trial
Background 
and Rationale
Patients with allergic rhinitis have high expectations of anti-allergic treatment 
(Hellings et al. 2012). Highly effective medications with early onset of action 
may improve patient’s compliance with therapy. Pivotal trials showed that under 
clinical conditions, Dymista becomes efficacious within the first 30 minutes and 
more effective than the monoproducts (M1). However, these studies were 
standard phase III allergic rhinitis efficacy trials and they were not specifically 
designed to assess onset of action, the primary endpoint was treatment effect 
over 2-week treatment. The assessment of onset of action was done during 4-
hour observation period following the initial administration of trial drug at study 
sites under indoor conditions with considerably low pollen exposure. Therefore, 
clinical trial X-03065-3311 using a standardized EEU (synonym to 
environmental exposure chamber - EEC) model with measurement timepoints 
starting from 5 minutes after administration was performed. The EEU was used 
to promote a uniform aerosolization of allergen over time in a highly controlled 


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manner with limited confounding environmental factors. In this trial, Dymista 
started relieving nasal symptoms within 5 min and ocular symptoms within 10 
minutes of dosing. All individual nasal and ocular symptoms reached first 
statistical significance at early time points and thus contributed to the overall 
effects of Dymista (Bousquet et al. 2018, O1).
The aim of the current study is to replicate the results of the fast onset of action 
for Dymista in a second onset of action study using an EEU model with a similar 
design but without an active control.
The study design and requirements have been adapted from Principles of the 
U.S. FDA draft guidance “Allergic Rhinitis: Developing Drug Products for 
Treatment Guidance for Industry” September 2018 for evaluating onset of 
efficacy (R1).
Primary 
Objective

To assess the onset of action of a fixed combination of azelastine 
hydrochloride and fluticasone propionate nasal spray (Dymista) in relieving 
the nasal symptoms of seasonal allergic rhinitis (SAR) induced by an 
allergen challenge in an Environmental Exposure Unit (EEU)
Primary 
endpoint
For onset of action assessment:

Changes from baseline in TNSS at each post-dose assessment time point 
(0 to 4 hours p.a.)
Secondary 
Objectives

To assess onset of action of Dymista in relieving the ocular symptoms of 
SAR induced by an allergen challenge in an EEU

To assess onset of action of Dymista in relieving the combined nasal and 
ocular symptoms of SAR induced by an allergen challenge in an EEU

To compare overall efficacy (0-4 hours after dosing) of Dymista in relieving 
the nasal symptoms (TNSS) with that of placebo 

To compare overall efficacy (0-4 hours after dosing) of Dymista in relieving 
the ocular symptoms (TOSS) with that of placebo

To compare overall efficacy (0-4 hours after dosing) of Dymista in relieving 
the combined nasal and ocular symptoms (T7SS) with that of placebo

To compare overall efficacy (0-4 hours after dosing) of Dymista in relieving 
the individual nasal and ocular symptoms with that of placebo 

To evaluate time to relevant response to therapy (30% and 50% reduction of 
TNSS)
Secondary 
Endpoints
Efficacy:

Changes from baseline in TOSS and total 7 symptoms score (T7SS) at each 
post-dose assessment time point (0 to 4 hours p.a.)

Time courses of TNSS, TOSS, and T7SS during the 6.5-hour EEU session

Change from baseline in individual nasal symptom scores (itchy nose, nasal 
congestion, runny nose, sneezing) and ocular symptom scores (itchy eyes, 
watery eyes, eye redness) at each post-dose assessment time point (0 to 4 
hours p.a.)
Safety and tolerability:

Adverse events (AEs)

Vital signs


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Methodology 
The study will be a single-center, randomized, placebo-controlled, double-blind, 
and two-period cross-over trial.
The study will consist of a screening visit (Visit 1), which will take place on Day 
-28 to Day -2. A priming/screening visit will be performed at Visit 2 (Day -1), 
where subjects will record their individual nasal and ocular symptoms using an 
electronic diary (ePDATTM) prior to EEU entry and during a 2-hour ragweed 
EEU session (see Table 0-2 for time points). At Visit 2, if subjects meet a 
minimum threshold total nasal symptom score (TNSS) response of ≥ 6 out of a 
possible of 12 at least twice, with at least one occurring during the last 2 time 
points, as well as a score of at least 2/3 for runny nose at least twice, with at least 
one occurring during the last 2 time points, during hours 0-2 in the EEU, they 
will be eligible to attend Visit 3. 
At Visit 3 (Day 1), subjects will record their individual nasal and ocular 
symptoms using an electronic diary (ePDATTM) prior to EEU entry and during 
the ragweed EEU session (see Table 0-3) for the first 2 hours. Subjects who 
meet the predetermined minimum TNSS of ≥ 6 out of a possible 12 at least 
twice, with at least one occurring during the last 2 time points, as well as a score 
of at least 2/3 for runny nose at least twice, with at least one occurring during the 
last 2 time points, during hours 0-2 in the EEU, and with nasal passages that are 
not completely blocked on either one or both sides as assessed by the 
Investigator within 30 minutes prior to dosing, will be randomized to a treatment 
sequence. They will receive a single-dose of the first study treatment 
approximately 2.5 hours after entering the EEU. The ragweed EEU session will 
be continued over the next 4 hours with subjects recording their individual nasal 
and ocular symptoms using an electronic diary (ePDATTM) (see Table 0-3).
Subjects will return to the study site after a period of at least 12 days (+ 5 days). 
The procedures at Visits 4 and 5 (Period 2) will be identical to Visit 2 and Visit 
3, respectively, except that subjects will not need to meet a minimum threshold 
value for TNSS. Subjects will be assessed for complete nasal blockage within 30 
minutes prior to dosing. Any evidence of complete nasal blockage on one or 
both sides prior to dosing should be documented in the eCRF. Subjects will 
receive the alternate study treatment in the second period. Throughout the study, 
the Investigator will adequately treat and follow up on adverse events.
Study 
Treatment
Study Treatment 
Dose and Mode of Administration
Dymista = fixed drug combination of 
azelastine hydrochloride and 
fluticasone propionate nasal spray
Active Drug: 1 spray per nostril of 
Dymista for a total dose of 274 mcg 
azelastine hydrochloride plus 100 
mcg of fluticasone propionate 
Placebo = nasal spray with no active 
dose (Dymista vehicle)
Placebo: 1 spray per nostril of 
placebo nasal spray 
The blinded study treatment will be given to suitable subjects on Visits 3 and 5 
approximately 2.5 hours after the start of the EEU session. 
Inclusion/ 
exclusion 
criteria
Inclusion criteria:
To be eligible for the study, a subject must comply with all of the following 
criteria at screening (Visit 1):


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1.
Provide written informed consent.
2.
Male or female subjects (childbearing and non-childbearing potential, non-
childbearing potential defined as females with no menstruation for at least 
1 year at screening and documented FSH > 35 IU/L) aged 18 to 55 years 
(inclusive) at screening.
3.
History of SAR to ragweed pollen for at least the previous 2 ragweed pollen 
seasons.
4.
Positive skin prick test (SPT) response to ragweed pollen (allergen induced 
wheal diameter at least 3 mm larger than the negative control). A test 
performed at Cliantha Research in the previous 12 months may be used to 
qualify the subject. 
5.
Willingness to complete all study visits.
To be eligible for Visit 2 EEU, a subject must additionally comply with the 
following criteria:
6.
Asymptomatic or with mild symptoms during the baseline recording of 
symptoms prior to start of the screening EEU (Visit 2): 

TNSS ≤ 3/12 with the score for each symptom being less than 2.
To be eligible for Visit 3, a subject must additionally comply with the following 
criteria during Visit 2 EEU:
7.
Demonstrate adequate symptomology:

TNSS ≥ 6/12 on at least two ePDATTM time point assessments 
during hours 0-2 in the EEU (Visit 2), with at least one occurring 
during the last two time points. Additionally, subjects will be 
required to meet a score of at least 2/3 for runny nose at least twice 
during hours 0-2 in the EEU, with at least one occurring during the 
last two time points. 
To be eligible for randomization (Visit 3), a subject must additionally comply 
with the following criteria:
8.
Demonstrate adequate symptomology:

TNSS ≥ 6/12 on at least two ePDATTM time point assessments 
during hours 0-2 in the EEU (Visit 3), with at least one occurring 
during the last two time points. Additionally, subjects will be 
required to meet a score of at least 2/3 for runny nose at least twice 
during hours 0-2 in the EEU, with at least one occurring during the 
last two time points. 

No evidence of complete nasal blockage on either one or both sides 
on anterior rhinoscopy within 30 minutes prior to dosing.
Exclusion criteria:
A subject is ineligible and must not enter the study if any of the following 
criteria is met:
Safety concerns:
1.
History of allergic reaction to azelastine hydrochloride or fluticasone 
propionate or one of the excipients of the study treatments (e.g. 
benzalkonium chloride, phenylethyl alcohol, microcrystalline cellulose) or a 
component of the container.
2.
History of anaphylaxis, cardiovascular, pulmonary, hepatic, renal, 
gastrointestinal, hematological, endocrine, metabolic, psychiatric, 


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neurological, or other disease at screening that may affect subject safety 
during the study or evaluation of the study endpoints at the discretion of the 
Investigator and/or designee.
3.
Subjects with a current diagnosis of asthma or subjects with measured FEV1 
<75% of the predicted value using Global Lung Function Initiative set from 
2012 for references. 
4.
Pregnant, breast-feeding, or planning a pregnancy during the study and 
women of childbearing potential not using adequate contraception. Women 
of childbearing potential not abstinent or using a highly effective method of 
birth control defined as those which result in a low failure rate (i.e. <1% per 
year) when used consistently and correctly such as implants, injectables, 
combined oral contraceptives, hormonal IUDs, barrier methods, or tubal 
ligation started at least 4 weeks prior to screening. 
Lack of suitability for the study:
5.
Previous and concomitant treatments: use of prohibited therapies as 
specified in the following table; use of any medication considered to have an 
influence on the outcome of the study during the EEU session, at the 
discretion of the Investigator and/or designee.
Prohibited medication
Prior to Screening
During study
Antihistaminic agents, all 
presentations
1 week
Not allowed
Theophylline, all presentations
1 week
Not allowed
Cromolyn sodium, 
all forms Nedocromil sodium
24 hours
24 hours prior to 
each allergen 
challenge
Salbutamol, all presentations
No restrictions
6 hours prior to each 
allergen challenge
Leukotriene modifiers, all 
presentations
1 week
Not allowed
Corticosteroids
(inhaled, oral, intravenous)
4 weeks
Not allowed
Topical corticosteroids 
(ocular, intranasal)
2 weeks
Not allowed
Corticosteroids, 
(intramuscular or intra-articular)
12 weeks
Not allowed
Decongestants, all forms
24 hours
Not allowed
Immunotherapy
6 months
Not allowed 
Systemic antibiotics
1 week
Within 1 week prior 
to each visit day
Tricyclic antidepressants and 
MAO inhibitors1
2 weeks
Not allowed
Any cytochrome P450 3A4 
inhibiting or inducing drug (e.g. 
ritonavir, cobicistat, 
ketoconazole, itraconazole, 
erythromycin, cimetidine, 
14 days
Not allowed


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rifampicin, St. John’s wort 
(Hypericum perforatum) etc.)
COVID-19 vaccination
No restrictions
Within 3 days prior 
to each allergen 
challenge2
1 
Antidepressants devoid of anticholinergic effects: Fluctin (Fluoxetine), 
Seroxat (Paroxetine), and Trevilor (Venlafaxine) are permitted during the 
study period provided the subject has been on a stable dose for 4 weeks prior to 
screening and there is no change in the dose or regimen during the entire study. 
2
If there is a conflict with the next allergen challenge due to COVID-19 
vaccination, a delay of up to 3 days for Visit 2 or Visit 4 is allowed. However, 
the interval between Visit 2 and Visit 3 or Visit 4 and Visit 5 must not be 
changed.
6.
Subjects with (expected) clinically relevant symptoms at the timing of the 
scheduled EEU assessments due to concomitant allergies, i.e. history of 
allergic response to the causative allergen, at the discretion of the 
Investigator. Subjects with a positive SPT for cats and/or dogs are 
acceptable if the subject avoids cats and/or dogs for the duration of the 
study.
7.
Concomitant diseases: abnormalities during the screening visit (Visit 1) or 
Visit 2 that might interfere with study results as determined by the 
Investigator and/or designee.
8.
Presence of a severely deviated septum, septal perforation, structural nasal 
defect or large nasal polyps causing obstruction as determined by the 
Investigator.
9.
Acute conditions: any acute illness within 7 days prior to the screening visit 
(Visit 1) or Visit 2, including acute conjunctivitis or any other ocular 
infection, at the discretion of the Investigator and/or designee.
10. History of increased ocular pressure, glaucoma, cataracts, and/or central 
serous chorioretinopathy (CSCR).
11. Presence of or ongoing tuberculosis, untreated local or systemic fungal or 
bacterial infections, systemic viral or parasitic infections or ocular herpes 
simplex. 
12. Recent nasal ulcers, mucosal erosion, nasal surgery, or nasal trauma, that 
might interfere with study results as determined by the Investigator and/or 
designee. 
13. Exposure to chickenpox or measles within 4 weeks prior to the screening 
visit or during the study. 
14. Acute or chronic sinusitis or non-allergic rhinitis, at the discretion of the 
Investigator and/or designee.
15. Exposure to another investigational product within the last 30 days prior to 
screening. 
16. History of malignancy within the past five years, except for basal cell skin 
carcinomas that have been treated with no recurrence for at least 3 months.
17. Neurological or psychiatric disease or drug or alcohol abuse which would 
interfere with the subject’s proper completion of the protocol assignment. 
Subjects with a positive urine drug screen will be excluded. 
18. Subjects undergoing surgical procedures with general anaesthesia within 90 


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days prior to screening or who plan to undergo surgery/hospitalization 
during the study. 
Administrative reasons:
19. Vulnerable subjects (such as persons who are institutionalized).
20. Positive alcohol or drug test during screening visit (Visit 1)
21. Public health emergency (e.g. COVID-19): subjects not complying to Public 
health guidelines (e.g. self isolation etc.), at the discretion of the 
Investigator’s and/or designee, or subjects with a positive COVID-test at 
Visit 2. 
Planned 
Number of 
Subjects
A total of 216 subjects are to be randomized in the study to show an onset of 
action at 
Statistical 
Methods
Sample size estimation: 
 
 
 
 
 
 a total of 216 randomized subjects should be included in this study.
Statistical analyses :
Adequate descriptive statistics will be provided for each endpoint. Time 
courses will be displayed graphically. For all endpoints, baseline is defined as 
the average of the last 2 assessments in the EEU prior to dosing with study 
treatment.
Primary onset analysis (by time point): Analysis of changes from baseline at 
each post dose assessment time point in 0 to 4 hours will be performed using a 
mixed effect Analysis of Covariance model based on all subjects in FAS 
population (proc mixed). 
 
 
For the active treatment, the onset of action will be defined as the first time point 
after initiation of treatment when the product demonstrates a greater change 
from baseline in the primary efficacy endpoint compared to the placebo 
treatment that proves durable from this point until the end of the last assessed 
time point (4h). 
Other secondary onset analyses: Following secondary endpoints will be 
analyzed and reported similar to the analysis method and reporting of the 
primary endpoint as described above using only the FAS population:

Changes from baseline in TOSS and total 7 symptoms score (T7SS) at 
each post-dose assessment time point (0 to 4 hours p.a.)

Change from baseline in individual nasal symptom scores (itchy nose, 
nasal congestion, runny nose, sneezing) and ocular symptom scores 
(itchy eyes, watery eyes, eye redness) at each post-dose assessment time 
point (0 to 4 hours p.a.)


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Overall efficacy: 
 
Responder analysis: Time to relevant response to therapy (30% and 50% 
reduction of TNSS) will be analysed.
Safety analysis: Safety analysis will include descriptive analysis according to 
received treatment. 
Populations for statistical analyses:
Safety (SAF) population: all subjects who administered at least one dose of 
study treatment. Subjects will be categorized according to the treatment that they 
actually received.
Full analysis set (FAS) population: This will be the intention to treat (ITT) 
population (all randomized patients).
The per-protocol (PP) set of subjects will be a subset of the FAS population 
excluding the subjects with major protocol violations that may affect the results 
of the primary variables.
FAS Subgroup with Moderate/Severe Ocular Symptoms: all FAS subjects with 
baseline TOSS at Visit 3 ≥4.


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STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures. 
Refer to the Study Conduct Section (6.0) for detailed information on each procedure and 
assessment required for compliance with the protocol.


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Table 0-1
Study Schedule
Study treatment
Screening
Period 1
Period 2
EOS/ET
Visit No
1
2
3
4
5
51
Study procedures
Day (window)
-28 to -2
-1
12
13 (+5) 15 (+5)2 15 (+5)
Confirm subject ID 





3
COVID screening questionnaire and oral temperature





3
Written Research Subject informed consent

Review inclusion/exclusion criteria



Demographic information/social history

Vital signs

4
4
4
4
5
Paper diary training6 and dispensing 




3
Paper diary review and collection




3
Prior and concomitant medication assessment





3
Urine pregnancy test (females of childbearing potential only)



Physical examination, incl. measurement of height and weight

Placebo nasal spray administration training 


Verbal reminder of dosing technique


Nasal inspection with anterior rhinoscopy

7
7
Adverse events (AEs) monitoring8






Allergic skin prick test (SPT)9

Medical history
10
Blood and urine sample for clinical laboratory tests


Spirometry 

Urine drug & alcohol screen

COVID test
11
11
Randomization

Treatment administration 
Dispensing study treatment


Dosing


EEU
ePDATTM training and dispensing




Nasal symptoms using ePDATTM 
12
13
12
13
Ocular symptoms using ePDATTM 
12
13
12
13
At-home
Record AEs/concomitant medication in the paper diary





3
1
May be performed as part of the procedures at Visit 5, if done on the same day. 
2
The treatment administration visit (Visit 3 and Visit 5) should take place 2 days after the priming visit in the respective period (Visit 2 
and Visit 4), with one day in between the treatment administration visit and the priming visit. If a subject cannot make Visit 3 or 5 as 
scheduled because of emergency, re-priming is allowed once per period with a wash-out period of at least 5 days between the priming 
visits.
3
Will be performed unless EOS occurs on the same day as Visit 5
4
Vital signs (blood pressure and heart rate) will be measured in a seated position (after at least 2 minutes of rest) prior to and after the EEU 
session.
5
Conducted as part of Visit 5 after the EEU session or at early termination, if applicable.
6
Training will be provided only at screening 
7
Performed within 30 minutes to dosing. 
8
The adverse event collection period begins at signing of informed consent and ends 5 to 7 days after the last treatment administration. 
Adverse events collection after EOS/ET visit will be done by phone. An adverse event is considered treatment emergent when occurring 
in the period from administration of study medication until 5 days (120 h) thereafter.
9
If documentation within 12 months of screening is not available. 
10
Brief medical history will be sufficient at Visit 1 if medical history was already assessed at general screening within 60 days prior to 
Visit 2.
11
Will be performed within 5 days prior to Visit 2 and Visit 4 or on the day of Visit 2 and 4 for a COVID-19 test to ensure the subjects 
safety prior to entering the EEU
12
Individual nasal and ocular symptoms will be assessed within 10 minutes prior to the EEU session and during the EEU session at 30, 60, 
75, 90, 105, and 120 minutes (+ 5 minutes).
13
Individual nasal and ocular symptoms will be assessed within 10 minutes prior to entering the EEU session, after entering the EEU 
session at 30, 60, 75, 90, 105 and 120 minutes (+ 5 minutes) and after dosing at 5, 10, 15 minutes (+ 2 minutes), 30, 60, 90, 120, 150, 
180, 210 and 240 minutes (+ 5 minutes).


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Table 0-2
Schedule of Assessments in the EEU at Visit 2 and Visit 4
Time [min]
Pre-EEU
30* 
60*
75*
90*
105*
120*
Post-
EEU
Vital Signs


ePDATTM training and dispensing 

Placebo nasal spray administration training

Nasal symptoms using ePDATTM







Ocular symptoms using ePDATTM







* Deviation window of + 5 minutes
Table 0-3
Schedule of Assessments in the EEU at Visit 3 and Visit 5 
Time [min]
Pre-
EEU
30*€ 60*€ 75*€ 90*€ 105*
€
120*
€
150/0§
5¥
10¥
15¥
30€
60€
90€
120€ 150€ 180€ 210€ 240€ Post-
EEU
Administration of study treatment

Vital Signs


ePDATTM training and dispensing 

Nasal symptoms using ePDATTM


















Ocular symptoms using ePDATTM


















* Prior to dosing
€ Deviation window of + 5 minutes
¥ Deviation window of + 2 minutes
§ Deviation window of ± 5 minutes


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Figure 0-1
Study Schematic


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PROTOCOL APPROVAL
Protocol Title
Clinical Trial to Assess Onset of Action of Azelastine 
Hydrochloride and Fluticasone Propionate Nasal Spray 
Delivered in a Single Spray (Dymista) in the Treatment of 
Allergen-Induced Allergic Rhinitis Symptoms in Comparison to 
Placebo in an Environmental Exposure Unit (EEU)
Protocol Number
AZFL-AES-4-001 / C1D00571
Version
3.0
Protocol Date
27 Jul 2021
EudraCT no.
Not applicable
IND no.
077363
Clinical Science Program Lead:
 
 Clinical Development 
Lead Allergy, Anaphylaxis
Global Clinical Development 
See Electronic Signature Manifestation
Clinical Safety Lead:
Global Safety 
Surveillance, Risk Management 
and Clinical Safety 
Global PSRM
See Electronic Signature Manifestation
Statistical Lead:
 
Statistician
Global Clinical Operations
See Electronic Signature Manifestation
Clinical Science Study Lead:
Clinical Development 
 
Urology, Allergy
Global Clinical Development
See Electronic Signature Manifestation
Clinical Operations Study Lead:
 Clinical Project Manager
Global Clinical Operations
See Electronic Signature Manifestation


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Functional Department Lead:
 
Global Clinical Development 
 Allergy, Dermatology, 
CV and Pain
See Electronic Signature Manifestation
Sponsor GCD Representative:
 Global Clinical 
Development
See Electronic Signature Manifestation


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TABLE OF CONTENTS
DOCUMENT HISTORY.........................................................................................................2
PROTOCOL REVISION HISTORY.....................................................................................3
PROTOCOL SYNOPSIS ........................................................................................................6
STUDY DIAGRAM AND STUDY SCHEDULE OF ACTIVITIES.................................14
PROTOCOL APPROVAL....................................................................................................18
TABLE OF CONTENTS.......................................................................................................20
LIST OF COMMONLY USED ABBREVIATIONS..........................................................25
1.0
INTRODUCTION.......................................................................................................27
1.1
Indication ...................................................................................................................27
1.2
Background and Rationale.........................................................................................27
1.3
Investigational Product ..............................................................................................28
1.3.1
Dymista ......................................................................................................................28
1.3.2
Azelastine hydrochloride ...........................................................................................28
1.3.3
Fluticasone propionate ..............................................................................................29
1.4
Ethics and Benefit-Risk Considerations ....................................................................29
1.4.1
Ethics..........................................................................................................................29
1.4.2
Benefit-Risk Considerations.......................................................................................29
2.0
OBJECTIVES AND ENDPOINTS ...........................................................................30
2.1
Objectives ..................................................................................................................30
2.1.1
Primary objective.......................................................................................................30
2.1.2
Secondary Objectives.................................................................................................30
2.2
Endpoints ...................................................................................................................30
2.2.1
Primary Endpoint.......................................................................................................30
2.2.2
Secondary Endpoints .................................................................................................31
3.0
STUDY DESIGN.........................................................................................................31
3.1
Overall Design ...........................................................................................................31
3.2
Rationale for Study Design........................................................................................31
3.3
Environmental Exposure Unit (EEU) ........................................................................32
3.4
End of Study Definition.............................................................................................32
4.0
STUDY POPULATION..............................................................................................32
4.1
Study Population........................................................................................................32


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4.2
Inclusion and Exclusion Criteria................................................................................32
4.2.1
Inclusion Criteria.......................................................................................................32
4.2.2
Exclusion Criteria......................................................................................................33
4.2.3
Randomization Criteria .............................................................................................35
4.2.4
Screening Failures.....................................................................................................36
4.2.5
Criteria for study drug termination, withdrawal from the study and study 
termination.................................................................................................................36
4.3
Replacement Policy ...................................................................................................37
4.4
Lifestyle Guidelines...................................................................................................37
4.5
Contraception.............................................................................................................37
4.5.1
Females - Non-childbearing Potential.......................................................................37
4.5.2
Females - Childbearing Potential..............................................................................37
4.6
Pregnancy Testing......................................................................................................38
5.0
STUDY DRUG ............................................................................................................38
5.1
Investigational Drug...................................................................................................38
5.1.1
Administration of Study Drugs...................................................................................39
5.2
Drug Inventory...........................................................................................................40
5.3
Study Medication/Device Complaints .......................................................................40
5.4
Storage, Disposition of Unused Study Drug and Drug Accountability.....................41
5.4.1
Retained Drug Samples..............................................................................................41
5.5
Randomization ...........................................................................................................41
5.6
Breaking the Blind .....................................................................................................42
5.7
Rescue Medication.....................................................................................................43
5.8
Concomitant Medications ..........................................................................................43
5.9
Recommended Procedure in a Subject Experiencing Adverse Effects Secondary to 
Excessive Pharmacological Effects of Study Drug ...................................................43
5.10
Treatment Compliance...............................................................................................44
5.11
Therapy at End of Study for compassionate use........................................................44
6.0
STUDY CONDUCT....................................................................................................44
6.1
Screening Procedures.................................................................................................45
6.1.1
Screening (Visit 1)......................................................................................................45
6.2
Treatment phase.........................................................................................................46
6.2.1
Priming/Screening (Period 1, Visit 2) – Day -1 ........................................................46
6.2.2
Randomization and Treatment Administration (Period 1, Visit 3) – Day 1 ..............47


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6.2.3
Priming EEU (Period 2, Visit 4) – Day 13 (+ 5 Days)..............................................49
6.2.4
Treatment Administration (Period 2, Visit 5) – Day 15 (+5 Days)...........................50
6.2.5
Early study drug Termination (ET) visit....................................................................51
6.3
End of Study (EOS) Visit - Day 15 (+5 Days) ..........................................................52
6.4
Follow up (telephone call) .........................................................................................52
7.0
TREATMENT PROCEDURES AND ASSESSMENT CRITERIA ......................53
7.1
Efficacy Assessment ..................................................................................................53
7.1.1
Total Nasal Symptom Score (TNSS) and Total Ocular Symptom Score (TOSS) and 
Total symptom score (T7SS) ......................................................................................53
7.2
Safety Assessment .....................................................................................................54
7.2.1
Adverse Event Assessment .........................................................................................54
7.2.2
Vital Signs ..................................................................................................................55
7.3
Other Aspects.............................................................................................................55
7.3.1
Clinical Laboratory Tests ..........................................................................................55
7.3.2
Spirometry..................................................................................................................56
7.3.3
Demographic Data and Social History......................................................................56
7.3.4
General Medical History, Concomitant Diseases .....................................................56
7.3.5
Skin Prick Test ...........................................................................................................56
7.3.6
Physical Examination ................................................................................................57
7.3.7
Anterior Rhinoscopy ..................................................................................................57
7.3.8
Pregnancy Testing .....................................................................................................57
7.3.9
Blood Volume.............................................................................................................58
7.4
Restrictions ................................................................................................................58
7.5
Mitigation in the event of a public health emergency................................................58
7.5.1
Pandemic COVID-19 Response Plan ........................................................................58
8.0
DATA MANAGEMENT ............................................................................................59
9.0
STATISTICAL CONSIDERATIONS ......................................................................60
9.1
Sample Size Determination........................................................................................60
9.2
Populations for Analyses ...........................................................................................60
9.3
Statistical Analyses ....................................................................................................61
9.3.1
Definition of the Primary Efficacy Endpoint .............................................................61
9.3.2
Primary Analysis of Primary Endpoint......................................................................61
9.3.3
Secondary/Sensitivity Analysis of Primary Endpoint ................................................62
9.3.4
Definition and Analysis of the Secondary Endpoints.................................................62


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9.3.5
Missing Data..............................................................................................................62
9.3.6
Sub-Group Analyses...................................................................................................62
9.3.7
Safety Analyses...........................................................................................................62
9.3.7.1
Adverse Events ...........................................................................................63
9.3.7.2
Vital Signs...................................................................................................63
9.3.8
Planned Interim Analyses ..........................................................................................63
10.0
ADMINISTRATIVE PROCEDURES ......................................................................63
10.1
Source Documentation Forms....................................................................................63
10.2
Access to Data/Source Documentation......................................................................64
10.3
Final Clinical Study Report and Case Report Forms (CRFs)....................................64
10.4
Adherence to Protocol................................................................................................64
10.5
Investigator’s qualification ........................................................................................64
10.6
Data Handling and Record Retention ........................................................................65
10.7
Monitoring .................................................................................................................66
10.8
Confidentiality ...........................................................................................................66
10.9
Ethics and Regulatory Authorities.............................................................................67
10.9.1
Institutional Review Board/Ethics Committee...........................................................67
10.9.2
Regulatory Authority..................................................................................................67
10.10
Informed Consent.......................................................................................................67
10.11
Trial Registration .......................................................................................................68
10.12
Disclosure and Publication of Clinical Study Data....................................................68
10.13
Financing and Insurance ............................................................................................68
10.14
Quality assurance and management...........................................................................68
10.15
End of Trial................................................................................................................69
11.0
ADVERSE EVENTS AND SAFETY REPORTING...............................................69
11.1
Definitions..................................................................................................................69
11.2
Special Situations:......................................................................................................72
11.3
Collection and Recording of Adverse Events............................................................72
11.4
Classification of an Adverse Event............................................................................73
11.4.1
Severity.......................................................................................................................73
11.4.2
Causality ....................................................................................................................73
11.4.3
Expectedness..............................................................................................................75
11.4.4
Outcome .....................................................................................................................75


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11.4.5
Action Taken with the Study Treatment .....................................................................76
11.5
Reporting of Serious Adverse Events and Pregnancy Exposures..............................76
11.5.1
Investigator reporting: notifying the study sponsor...................................................76
11.5.2
Follow-up...................................................................................................................77
11.5.3
Investigator reporting: Notification of Ethics Committee .........................................77
11.5.4
Investigator Reporting of Pregnancy - notifying the study sponsor ..........................77
12.0
REFERENCE LIST....................................................................................................79
12.1
Published Literature...................................................................................................79
12.2
Product Information...................................................................................................80
12.3
Regulatory Documents...............................................................................................80
12.4
Other Proprietary Study Reports and Documents......................................................80
LIST OF TABLES
Table 0-1
Study Schedule.................................................................................................15
Table 0-2
Schedule of Assessments in the EEU at Visit 2 and Visit 4............................16
Table 0-3
Schedule of Assessments in the EEU at Visit 3 and Visit 5............................16
Table 5.1-1
Composition and Storage Conditions of Dymista and Placebo.......................39
Table 5.1-2
Treatment Administration................................................................................40
Table 5.5-1
Randomization Sequence.................................................................................42
Table 7.1-1
Allergic Rhinitis Symptoms.............................................................................53
Table 7.1-2
Allergic Rhinitis Symptoms.............................................................................54
Table 7.1-3
Ocular Redness Score ......................................................................................54
Table 7.3-1
Clinical Laboratory Variables..........................................................................56
LIST OF FIGURES
Figure 0-1
Study Schematic...............................................................................................17
Figure 7.1-1
Ocular Redness Scores.....................................................................................54


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LIST OF COMMONLY USED ABBREVIATIONS
Abbreviation
Description
ADR
Adverse Drug Reaction
AE
Adverse Event
ANCOVA
Analysis of Covariance
AR
Allergic Rhinitis
ARIA
Allergic Rhinitis and its Impact on Asthma
COVID
Corona Virus Disease
CRF
Case Report Form
CRO
Contract Research Organization
CSCR
Central Serous Chorioretinopathy
DMP
Data Management Plan
EC
Ethics Committee
EDC
Electronic Data Capture
EEC
Environmental Exposure Chamber
EEU
Environmental Exposure Unit
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EOS
End of Study
EU
European Union
EudraCT
European Clinical Trials Database
ePDATTM
Electronic Patient Data Acquisition Tablet
ET
Early Termination
FAS
Full Analysis Set
FEV1
Forced Expiratory Volume in 1 Second
FDA
Food and Drug Administration
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice
GDPR
General Data Protection Regulation
H1A
H1-Antihistamine
HEPA
High Efficiency-Particulate Air(filter)
ICF
Informed Consent Form
ICH
International Council for Harmonisation (of Technical 
Requirements for Pharmaceuticals for Human Use
ICTRP
International Clinical Trials Registry Platform
ID
Identification
IEC
Independent Ethics Committee
IgE
Immunglobulin E
INCS
Intranasal Corticosteroid
IRB
Institutional Review Board
ISF
Investigator’s Site File


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ITT
Intent-to-Treat (Population)
IUD
Intrauterine Device
LEC
Local Ethics Committee
MAO
Monoamine Oxidase
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed Model for Repeated Measures
p.a.
(post applicationem) post-administration
PAF
Platelet-activating Factor
PI
Principal Investigator
PP
Per-Protocol (Population)
PSRM
Product Safety and Risk Management
QA
Quality Assurance
QC
Quality Control
SAE
Serious Adverse Event
SAF
Safety (Population)
SAP
Statistical Analysis Plan
SAR
Saisonal Allergic Rhinitis
SD
Standard Deviation
SDV
Source Data Verification
SE
Standard Error
SOP
Standard Operating Procedure
SPT
Skin Prick Test
T7SS
Total 7 Symptom Score (TNSS + TOSS)
TEAE
Treatment Emergent Adverse Event
TMF
Trial Master File
TNSS
Total Nasal Symptom Score
TOSS
Total Ocular Symptom Score
TX
Treatment
U.S .
United States
WHO
World Health Organization


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1.0 INTRODUCTION
1.1
Indication
Allergic rhinitis (AR) is an upper airway inflammatory disease of the nasal mucosa, resulting 
from an IgE-mediated immunological response following an allergen exposure. Symptoms of 
AR include rhinorrhea, sneezing, nasal itching, congestion as well as non-nasal symptoms 
such as itchy eye, watery eye, red eye and throat and palate itching (Small & Kim 2011). AR 
is one of the most common of atopic diseases, but by itself, is not life threatening unless 
accompanied by asthma (Dixon et al. 2006 , Kim et al. 2008). However, AR can affect 
between 10% and 25% of the world’s population and epidemiologic studies indicate that the 
prevalence of AR is on the rise. Moreover AR causes significant morbidity, substantial 
economic burden and impairment in quality of life (Stewart et al. 2010).
Seasonal allergic rhinitis (SAR) is typically caused by pollens of specific seasonal plants 
including tree, grass and ragweed (Small & Kim 2011, Ihler & Canis 2015, Day et al. 2006, 
Jacobs et al. 2012). Early-phase symptoms occur within minutes of exposure to the allergen 
in a sensitized individual. Cross-linking of allergen-specific IgE to the surface of mast cells in 
the nasal mucosa can trigger a cascade of instantaneous events including mast cell 
degranulation and the immediate release of Type I hypersensitivity mediators such as 
histamine, leukotrienes and prostaglandins, which can induce acute nasal symptoms (Small & 
Kim 2011, Sin & Togias 2011, Pawankar et al. 2011). Approximately 30 to 40% of sensitive 
individuals develop late-phase reaction occurring 4 to 5 hours after the initial allergen 
exposure. Indolent symptoms can continue due to the continued upregulation of a variety of 
recruited Type 2 T-helper cells and the production of cytokines (Small & Kim 2011, Min 
2010, Pipet et al. 2009). Repeated allergen exposure or “priming” can lead to the 
development of mucosal inflammation and increased nasal hyper-responsiveness (Sin & 
Togias 2011, Pawankar et al. 2011).
Therapeutic options available for treatment of AR include avoidance measures, oral/ 
intranasal antihistamines, intranasal corticosteroids, leukotriene receptor antagonists and 
allergen immunotherapy. The recently updated Allergic rhinitis and its impact on asthma 
(ARIA) Guidelines (Bousquet et al. 2020) recommend the use of a combination of intranasal 
H1A and INCS for initial therapy as well as for patients previously not sufficiently treated 
with H1A and INCS alone. This applies to all AR patients, independent of symptom severity 
and type of AR (seasonal and/or perennial). Most relevantly, the ARIA guidelines highlight 
that the combination of intranasal antihistamine and INCS is more effective than INCS alone 
and is effective within minutes whereas the INCSs may need day(s) to work.
1.2
Background and Rationale
Patients with allergic rhinitis have high expectations of anti-allergic treatment (Hellings et al. 
2012). Highly effective medications with early onset of action may improve patient’s 
compliance with therapy. Pivotal trials showed that under clinical conditions, Dymista 
becomes efficacious within the first 30 minutes and more effective than the monoproducts 
(M1). However, these studies were standard phase III allergic rhinitis efficacy trials and they 
were not specifically designed to assess onset of action, the primary endpoint was treatment 
effect over 2-week treatment. The assessment of onset of action was done during 4-hour 


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observation period following the initial administration of trial drug at study sites under indoor 
conditions with considerably low pollen exposure. Therefore, clinical trial X-0365-3311 
using a standardized EEU (synonym to environmental exposure chamber – EEC) model with 
measurement timepoints starting from 5 minutes after administration was performed. The 
EEU was used to promote a uniform aerosolization of allergen over time in a highly 
controlled manner with limited confounding environmental factors. In this trial, Dymista 
started relieving nasal symptoms within 5 min and ocular symptoms within 10 minutes of 
dosing. All individual nasal and ocular symptoms reached first statistical significance at early 
time points and thus contributed to the overall effects of Dymista (Bousquet et al. 2018, O1).
The aim of the current study is to replicate the results of the fast onset of action for Dymista 
in a second onset of action study using an EEU model with a similar design but without an 
active control.
The study design and requirements have been adapted from Principles of the U.S. FDA draft 
guidance “Allergic Rhinitis: Developing Drug Products for Treatment Guidance for Industry” 
September 2018 for evaluating onset of efficacy (R1).
1.3
Investigational Product
1.3.1
Dymista 
Dymista is comprised of two active ingredients, azelastine hydrochloride and fluticasone 
propionate. It is indicated in Canada for the symptomatic treatment of moderate to severe 
seasonal allergic rhinitis (SAR) and associated ocular symptoms in adults, adolescents, and 
children aged 6 years and older for whom monotherapy with either antihistamines or 
intranasal corticosteroids is not considered sufficient (M1) and in the US for the relief of 
symptoms of seasonal allergic rhinitis in patients 6 years of age and older who require 
treatment with both azelastine hydrochloride and fluticasone propionate for symptomatic 
relief (M2). It is also indicated for relief of the symptoms of perennial allergic rhinitis in 
many other countries worldwide as well as for symptomatic treatment of allergic rhinitis and 
rhino-conjunctivitis.
The approved daily dose for Dymista in Canada (M1), in the US (M2), and other countries 
worldwide is one actuation in each nostril twice daily (morning and evening). The use of 
Dymista within this trial is in line with the approved dosage recommendation. Subjects will 
apply Dymista as a single dose of 1 spray per nostril; each spray delivers 137 μg of azelastine 
hydrochloride and 50 μg of fluticasone propionate. 
Warnings and precautions, as well as common side effects of the drug, can be found in the 
Canadian product monograph (M1).
The components of Dymista, azelastine hydrochloride and fluticasone propionate, possess 
different modes of action in the treatment of AR symptoms (M1). 
1.3.2
Azelastine hydrochloride
Azelastine is a phthalazinone derivative and is classified as a potent long-acting anti-allergic 
compound that has selective H1-antagonist, mast cell stabilizing and anti-inflammatory 


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properties. Azelastine has been shown to inhibit the synthesis or release of chemical 
mediators involved in early and late stage allergic reactions, e.g. leukotrienes, histamine, 
platelet-activating factor (PAF) and serotonin (M1).  
The azelastine hydrochloride in Dymista is administered as a racemic mixture, which 
possesses no difference in pharmacologic activity. The major metabolite, 
desmethylazelastine, also possesses H1-receptor antagonist activity (M1). 
1.3.3
Fluticasone propionate
Fluticasone propionate is a synthetic trifluorinated corticosteroid with powerful anti-
inflammatory action with a high affinity for the glucocorticoid receptor (M1). 
The exact mechanism by which fluticasone propionate affects symptoms of AR is not known. 
Corticosteroids have been shown to have a wide range of effects on multiple cell types, such 
as mast cells, eosinophils, neutrophils, macrophages, and lymphocytes, as well as mediators, 
such as histamine, and cytokines, involved in inflammation (M1). 
1.4
Ethics and Benefit-Risk Considerations
1.4.1
Ethics
The study will be conducted in agreement with the following directives, laws, and guidelines: 

Declaration of Helsinki (R2).

ICH guideline on Good Clinical Practice (ICH E6 (R2)) Addendum (R3).

Regulation (EU) 2016/679 of 27 April 2016 (General Data Protection Regulation (R4)

Applicable regulatory and national legislations.
Cliantha Research will apply for authorisation by competent authorities, as applicable, and 
for favourable opinion by the IRB. The study will be notified to other locally responsible 
authorities as applicable. Meda will provide a power of attorney for delegation of 
responsibilities to authorised persons / institutions.
1.4.2
Benefit-Risk Considerations
The EEU is an established model to assess onset of action of anti-allergic medications. 
Cliantha Research and its founders have over 15 years of experience in conducting EEU 
studies. The risks associated with exposure to ragweed pollen in the EEU are limited. While 
subjects are in the EEU, they will be exposed to ragweed allergens and are expected to 
experience AR symptoms typically experienced during the ragweed pollen season. In 
instances where either no treatment or a placebo treatment is administered, the symptoms will 
not be alleviated during allergen exposure. 
Before subjects are exposed to ragweed pollen in the EEU, they will be examined by the 
study staff for adverse events and administration of concomitant medications and their vital 
signs will be taken. They will be monitored throughout their stay in the EEU. If subjects 


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experience any significant changes in their symptoms and well-being, they will be treated as 
judged necessary by the Investigator and/or designee. 
The subjects will also be exposed to: 

The known risks related to the study treatments or the study procedures, and

Unknown risks that might be related to study treatments or to the study procedures.
The subjects are comprehensively informed about these aspects, and the study is conducted 
under conditions to ascertain onset of action of the study treatments and to further evaluate 
the efficacy of the treatments. 
Common side effects of Dymista can be found in the Canadian product monograph (M1).
The subjects may indirectly benefit from the study by advancing medical knowledge about 
the study treatments.  
2.0 OBJECTIVES AND ENDPOINTS
2.1
Objectives
2.1.1
Primary objective
To assess the onset of action of a fixed combination of azelastine hydrochloride and 
fluticasone propionate nasal spray (Dymista) in relieving the nasal symptoms of seasonal 
allergic rhinitis (SAR) induced by an allergen challenge in an Environmental Exposure Unit 
(EEU)
2.1.2
Secondary Objectives

To assess onset of action of Dymista in relieving the ocular symptoms of SAR
induced by an allergen challenge in an EEU

To assess onset of action of Dymista in relieving the combined nasal and ocular
symptoms of SAR induced by an allergen challenge in an EEU

To compare overall efficacy (0-4 hours after dosing) of Dymista in relieving the nasal
symptoms (TNSS) with that of placebo

To compare overall efficacy (0-4 hours after dosing) of Dymista in relieving the
ocular symptoms (TOSS) with that of placebo

To compare overall efficacy (0-4 hours after dosing) of Dymista in relieving the
combined nasal and ocular symptoms (T7SS) with that of placebo

To compare overall efficacy (0-4 hours after dosing) of Dymista in relieving the
individual nasal and ocular symptoms with that of placebo

To evaluate time to relevant response to therapy (30% and 50% reduction of TNSS)


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2.2
Endpoints
2.2.1
Primary Endpoint
For onset of action assessment:
a) Changes from baseline in TNSS at each post-dose assessment time point (0 to 4
hours p.a.)
2.2.2
Secondary Endpoints
Efficacy:
b) Changes from baseline in TOSS and total 7 symptoms score (T7SS) at each post-
dose assessment time point (0 to 4 hours p.a.)
c) Time courses of TNSS, TOSS, and T7SS during the 6.5-hour EEU session
d) Change from baseline in individual nasal symptom scores (itchy nose, nasal
congestion, runny nose, sneezing) and ocular symptom scores (itchy eyes, watery
eyes, eye redness) at each post-dose assessment time point (0 to 4 hours p.a.)
Safety and tolerability:
e) Adverse events (AEs)
f)
Vital signs
3.0 STUDY DESIGN
3.1
Overall Design
This study will be a therapeutic study performed as a single-center, randomized, placebo-
controlled, double-blind, and two-period cross-over trial.
3.2
Rationale for Study Design
The aim of the current study is to replicate the results of the fast onset of action for Dymista 
from study X-03065-3311 in a second onset of action study using an EEU model with a 
similar design but without an active control. 
An EEU is used to promote a uniform aerosolization of allergen over time in a highly 
controlled manner. As the assessments will be conducted with limited confounding 
environmental factors and with consistent allergen exposure, the use of an EEU model is 
expected to provide a more effective method to assess the onset of efficacy of Dymista 
compared to a field trial. 
The choice of dosage and route of administration is based on study X-03065-3311 and the 
approved and marketed dosage forms for Dymista used in the study (M1).


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The study design and requirements have been adapted from Principles of the U.S. FDA draft 
guidance “Allergic Rhinitis: Developing Drug Products for Treatment Guidance for Industry” 
September 2018 for evaluating onset of efficacy (R1).
3.3
Environmental Exposure Unit (EEU)
The EEU is equipped with an environmental control unit / air handling system which 
provides temperature and humidity controlled HEPA-filtered air into the EEU to create the 
optimal conditions for aerosolization. Pollen counts are obtained as per Cliantha SOPs 
regarding EEU operation.
During the EEU sessions, subjects will be exposed to airborne ragweed pollen at an average 
concentration of 3500 ± 500 grains/m3 for approximately 2 or 6.5 hours, depending on the 
visit. While in the EEU, ragweed-allergic subjects are expected to experience nasal and 
ocular allergy symptoms typically experienced during the ragweed pollen season. Deviations 
in EEU conditions including pollen counts should be reported to the Sponsor.
3.4
End of Study Definition
A participant is considered to have completed the study if he or she has completed all phases 
of the study including the end of study (EOS) visit and last phone contact. Subjects who 
prematurely terminate from the study will have an Early Termination (ET) visit scheduled as 
soon as possible. 
The end of study is defined as the date of final contact of the last subject undergoing the trial.
4.0 STUDY POPULATION
4.1
Study Population
A total of approximately 216 male and female subjects will be randomized into the study. 
Subjects will be selected from non-institutionalized volunteers consisting of members of the 
community at large. 
The duration of the study from screening (Visit 1) to end of study (telephone follow-up) will 
last up to 56 days for each subject (duration may be longer if re-priming is required). In the 
study, there will be single dose administrations on two separate occasions with at least 14 
days wash-out between each treatment. 
4.2
Inclusion and Exclusion Criteria
4.2.1
Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before subjects are included in the study.
To be eligible for the study, a subject must comply with all of the following criteria at 
screening (Visit 1):


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1. Provide written informed consent.
2. Male or female subjects (childbearing and non-childbearing potential, non-childbearing 
potential defined as females with no menstruation for at least 1 year at screening and 
documented FSH >35 IU/L) aged 18 to 55 years (inclusive) at screening.
3. History of SAR to ragweed pollen for at least the previous 2 ragweed pollen seasons.
4. Positive skin prick test (SPT) response to ragweed pollen (allergen induced wheal 
diameter at least 3 mm larger than the negative control). A test performed at Cliantha 
Research in the previous 12 months may be used to qualify the subject. 
5. Willingness to complete all study visits.
To be eligible for Visit 2 EEU, a subject must additionally comply with the following criteria:
6. Asymptomatic or with mild symptoms during the baseline recording of symptoms prior to 
start of the screening EEU (Visit 2): 

TNSS ≤ 3/12 with the score for each symptom being less than 2.
To be eligible for Visit 3, a subject must additionally comply with the following criteria 
during Visit 2 EEU:
7. Demonstrate adequate symptomology:

TNSS ≥ 6/12 on at least two ePDATTM time point assessments during hours 0-2 in 
the EEU (Visit 2), with at least one occurring during the last two time points. 
Additionally, subjects will be required to meet a score of at least 2/3 for runny 
nose at least twice during hours 0-2 in the EEU, with at least one occurring during 
the last two time points. 
To be eligible for randomization (Visit 3), a subject must additionally comply with the 
following criteria:
8. Demonstrate adequate symptomology:

TNSS ≥ 6/12 on at least two ePDATTM time point assessments during hours 0-2 in 
the EEU (Visit 3), with at least one occurring during the last two time points. 
Additionally, subjects will be required to meet a score of at least 2/3 for runny 
nose at least twice during hours 0-2 in the EEU, with at least one occurring during 
the last two time points. 

No evidence of complete nasal blockage on either one or both sides on anterior 
rhinoscopy within 30 minutes prior to dosing.
4.2.2
Exclusion Criteria
A subject is ineligible and must not enter the study if any of the following criteria are met:
Safety concerns:
1. History of allergic reaction to azelastine hydrochloride or fluticasone propionate or one of 
the excipients of the study treatments (e.g. benzalkonium chloride, phenylethyl alcohol, 
microcrystalline cellulose) or a component of the container.


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2.
History of anaphylaxis, cardiovascular, pulmonary, hepatic, renal, gastrointestinal,
hematological, endocrine, metabolic, psychiatric, neurological, or other disease at
screening that may affect subject safety during the study or evaluation of the study
endpoints at the discretion of the Investigator and/or designee.
3.
Subjects with a current diagnosis of asthma or subjects with measured FEV1 <75% of the
predicted value using Global Lung Function Initiative set from 2012 for references.
4.
Pregnant, breast-feeding, or planning a pregnancy during the study and women of
childbearing potential not using adequate contraception. Women of childbearing potential
not abstinent or using a highly effective method of birth control defined as those which
result in a low failure rate (i.e. <1% per year) when used consistently and correctly such
as implants, injectables, combined oral contraceptives, hormonal IUDs, barrier methods,
or tubal ligation started at least 4 weeks prior to screening.
Lack of suitability for the study:
5.
Previous and concomitant treatments: use of prohibited therapies as specified in the
following table; use of any medication considered to have an influence on the outcome of
the study during the EEU session, at the discretion of the Investigator and/or designee.
Prohibited medication
Prior to Screening
During study
Antihistaminic agents, all presentations
1 week
Not allowed
Theophylline, all presentations
1 week
Not allowed
Cromolyn sodium, 
all forms Nedocromil sodium
24 hours
24 hours prior to each 
allergen challenge
Salbutamol, all presentations
No restrictions
6 hours prior to each 
allergen challenge
Leukotriene modifiers, all presentations
1 week
Not allowed
Corticosteroids
(inhaled, oral, intravenous)
4 weeks
Not allowed
Topical corticosteroids 
(ocular, intranasal)
2 weeks
Not allowed
Corticosteroids, 
(intramuscular or intra-articular)
12 weeks
Not allowed
Decongestants, all forms
24 hours
Not allowed
Immunotherapy
6 months
Not allowed 
Systemic antibiotics
1 week
Within 1 week prior to each 
visit day
Tricyclic antidepressants and 
MAO inhibitors1
2 weeks
Not allowed
Any cytochrome P450 3A4 inhibiting or 
inducing drug (e.g. ritonavir, cobicistat, 
ketoconazole, itraconazole, erythromycin, 
cimetidine, rifampicin, St. John’s wort 
(Hypericum perforatum) etc.)
14 days
Not allowed
COVID-19 vaccination
No restrictions
Within 3 days prior to each 
allergen challenge2


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1 
Antidepressants devoid of anticholinergic effects: Fluctin® (Fluoxetine), Seroxat® (Paroxetine), and 
Trevilor® (Venlafaxine) are permitted during the study period provided the subject has been on a stable 
dose for 4 weeks prior to screening and there is no change in the dose or regimen during the entire study. 
2
If there is a conflict with the next allergen challenge due to COVID-19 vaccination, a delay of up to 3 days 
for Visit 2 or Visit 4 is allowed. However, the interval between Visit 2 and Visit 3 or Visit 4 and Visit 5 
must not be changed.
6.
Subjects with (expected) clinically relevant symptoms at the timing of the scheduled
EEU assessments due to concomitant allergies, i.e. history of allergic response to the
causative allergen, at the discretion of the Investigator. Subjects with a positive SPT for
cats and/or dogs are acceptable if the subject avoids cats and/or dogs for the duration of
the study.
7.
Concomitant diseases: abnormalities during the screening visit (Visit 1) or Visit 2 that
might interfere with study results as determined by the Investigator and/or designee.
8.
Presence of a severely deviated septum, septal perforation, structural nasal defect or large
nasal polyps causing obstruction as determined by the Investigator.
9.
Acute conditions: any acute illness within 7 days prior to the screening visit (Visit 1) or
Visit 2, including acute conjunctivitis or any other ocular infection, at the discretion of
the Investigator and/or designee.
10. History of increased ocular pressure, glaucoma, cataracts, and/or central serous
chorioretinopathy (CSCR).
11. Presence of or ongoing tuberculosis, untreated local or systemic fungal or bacterial
infections, systemic viral or parasitic infections or ocular herpes simplex.
12. Recent nasal ulcers, mucosal erosion, nasal surgery, or nasal trauma, that might interfere
with study results as determined by the Investigator and/or designee.
13. Exposure to chickenpox or measles within 4 weeks prior to the screening visit or during
the study.
14. Acute or chronic sinusitis or non-allergic rhinitis, at the discretion of the Investigator
and/or designee.
15. Exposure to another investigational product within the last 30 days prior to screening.
16. History of malignancy within the past five years, except for basal cell skin carcinomas
that have been treated with no recurrence for at least 3 months.
17. Neurological or psychiatric disease or drug or alcohol abuse which would interfere with
the subject’s proper completion of the protocol assignment. Subjects with a positive
urine drug screen will be excluded.
18. Subjects undergoing surgical procedures with general anaesthesia within 90 days prior to
screening or who plan to undergo surgery/hospitalization during the study.
Administrative reasons:
19. Vulnerable subjects (such as persons who are institutionalized).
20. Positive alcohol or drug test during screening visit (Visit 1)
21. Public health emergency (e.g. COVID-19): subjects not complying to Public health
guidelines (e.g. self isolation etc.), at the discretion of the Investigator’s and/or designee,
or subjects with a positive COVID-test at Visit 2.


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4.2.3
Randomization Criteria
To be eligible for randomization (Visit 3), a subject must comply with the criteria for 
randomization mentioned in Section 4.2.1.
4.2.4
Screening Failures
To allow a rough description of the reasons to fail screening, at least the following items need 
to be documented for these patients in the eCRF: age, sex, ethnicity, race, adverse events, 
concomitant medications (only if in context with adverse events) and the main reason for not 
being enrolled / randomized.
4.2.5
Criteria for study drug termination, withdrawal from the study and study 
termination
Subjects may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study center. Every effort should be 
made to retain subjects in the study. When available, a reason for not completing the study 
will be recorded in the subject source documents and transcribed into the electronic case 
report form (eCRF).
Withdrawal is understood as premature discontinuation from study procedures after 
randomization. Drop-outs before randomization are considered as screening failures (see 
Section 4.2.4). A decision of withdrawal should be communicated with the Sponsor in a 
timely manner.
If, a subject discontinues from the study prematurely, due to any reason as provided in the 
below withdrawal criteria, the site should make every effort to follow-up the subject to 
perform safety and efficacy assessments as per the Study Schedule (Table 0-1). 
A subject may be required to terminate study drug for reasons including the following:

The subject withdraws consent.

For female subjects, diagnosis of pregnancy or stated intention to become pregnant.
All efforts should be made by the site to obtain consent from the pregnant women, so
that they are followed until delivery or termination.

Despite education/reinforcement, the subject shows persistent inadequate compliance
with required study visits/procedures, potentially compromising safety monitoring
while on study drug based on Investigator’s discretion.

The subject takes prohibited treatment presenting a safety concern to continued
dosing with study drug.

At the Investigator’s discretion (it is recommended that the investigator discusses with
medical monitor prior to decision), if it is in the subject’s best interest due to
occurrence of an AE and/or other findings considered to present a safety concern to
continued dosing with study drug, and warrants treatment withdrawal.

If the blind is broken for a subject by the Investigator


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The Principal Investigator and/or the Sponsor reserve the right to terminate the study for any 
reason.
The study will be terminated early if there are significant safety concerns.
Subjects who prematurely terminate from the study will have an Early Termination (ET) visit 
scheduled as soon as possible.
4.3
Replacement Policy
Subjects who are withdrawn from the study after randomization and after administration of 
the first treatment will not be replaced. 
For subjects who dropped out before randomization due to other reasons than safety and SAR 
symptoms qualification, re-screening may be possible following discussion with Sponsor or 
designee or according to pre-defined written procedures, if applicable. If re-screening occurs 
this will be clearly documented within the site file.
4.4
Lifestyle Guidelines
No specific interaction studies with Dymista and food have been performed. Subjects do not 
have to follow specific dietary restriction throughout the conduct of study. 
In clinical trials, the occurrence of somnolence has been reported in some patients (0.7% of 
patients) taking Dymista. In isolated cases fatigue, weariness, exhaustion, dizziness or 
weakness that may also be caused by the disease itself, may occur when using Dymista nasal 
spray. In these cases, the ability to drive and use machines may be impaired. Alcohol and 
other central nervous system depressants may enhance this effect and should be avoided 
(M1).
4.5
Contraception
4.5.1
Females - Non-childbearing Potential
Female subjects of non-childbearing potential must meet at least one of the following criteria:
1. Postmenopausal females, defined as females who have been amenorrheic for at least 1 
year and documented FSH > 35 IU/L at screening.
2. Females who have a reported or documented hysterectomy and/or bilateral 
oophorectomy more than 90 days prior to Visit 3.
All other females will be considered to be of childbearing potential.
4.5.2
Females - Childbearing Potential
Female subjects of child-bearing potential must use an acceptable, highly effective method of 
contraception (i.e., a method with a failure rate <1% per year when used consistently and 
correctly) starting at least 4 weeks prior to screening and continuing at least 5 days following 
the last treatment, such methods include at least one of the following:


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
Abstinence (periodic abstinence is not acceptable)

Tubal ligation

Intrauterine device of intrauterine system

Barrier method, like condom, with spermicide

Male partner who has had a vasectomy for at least 6 months. Male partners with
vasectomies of <6 months are NOT considered protected

Hormonal contraceptives (oral, injected, transdermal or implanted) with the exception
of low dose gestagens, i.e. only containing lynestrenol or norethisterone, since they do
not inhibit ovulation and are therefore not considered as highly-effective. The subject
must remain on the hormonal contraceptive throughout the study and must have been
using hormonal contraceptives for an adequate period prior to the study to ensure
effectiveness (e.g., 3 months)
4.6
Pregnancy Testing
Urinary pregnancy testing will be performed on all females of childbearing potential as 
described in the schedule of activities (results will be reviewed and must be negative prior to 
dosing). In the event of a positive test, the subject will be withdrawn from the study (or will 
not enter the study if during screening).
Any pregnancy occurring after randomization to study drug will be followed up and reported 
to the Sponsor as per Section 11.5.4.
5.0 STUDY DRUG
5.1
Investigational Drug
Dymista nasal spray (azelastine hydrochloride and fluticasone propionate nasal spray) will be 
supplied in glass bottles containing 23 g suspension fitted with a metered-dose nasal spray 
pump. Each bottle contains at least 120 metered sprays. After priming, the nasal spray pump 
delivers approximately 137 μg of azelastine hydrochloride and 50 μg of fluticasone 
propionate per actuation.
The placebo nasal spray will be also supplied in glass bottles containing 23 g suspension 
fitted with a metered-dose nasal spray pump. Each bottle contains at least 120 metered 
sprays. 
The composition of Dymista and the placebo nasal spray is listed in Table 5.1-1 below.


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Table 5.1-1
Composition and Storage Conditions of Dymista and Placebo
Dymista
Placebo nasal spray 
(Dymista vehicle)
Active 
substance(s)
Azelastine hydrochloride 137 μg and 
Fluticasone propionate 50 μg
-
Excipients
Benzalkonium chloride, Disodium 
edetate, Glycerol, Microcrystalline 
cellulose and carmellose sodium, 
Phenylethyl alcohol, Polysorbate 80 and 
Purified Water
Benzalkonium chloride, Disodium 
edetate, Glycerol, Microcrystalline 
cellulose and carmellose sodium, 
Phenylethyl alcohol, Polysorbate 80 and 
Purified Water
Store between 15°C-30°C
Store between 8°C-25°C
Storage 
Storage condition to be applied to the blinded study drug is Store between 15-25°C
Marketing 
authorization 
holder
MEDA Pharmaceuticals Ltd.
-
Canadian commercial Dymista nasal spray will be purchased for use in the study. The 
placebo nasal spray will be provided by the Sponsor. 
The study treatments will be labelled according to Cliantha Research SOPs. The approved 
labels in the local language(s) will be filed in the TMF of the Investigator and the Sponsor.
The study drugs must not be used after the retest or expiry date. The study monitor will check 
these dates accordingly and will initiate appropriate measures in due time if study drugs will 
be needed after that date. 
For placebo nasal spray, the certificate of analysis will be filed in the TMF of the Sponsor. 
Respective documentation (i.e. the "final release" form and study drug shipment record) in 
the TMF of the Investigator will specify batch number(s), retest date(s), and reference 
number(s) of the certificate(s) of analysis.
For Canadian commercial Dymista nasal spray, respective documentation (i.e. purchase 
records and documents specifying batch numbers, expiry dates and the certificate(s) of 
analysis, if available.) will be filled in the TMF of the Investigator and Sponsor.  
5.1.1
Administration of Study Drugs
In each period for Visit 3 and Visit 5, after an approximately 2.5-hour session in the ragweed 
EEU, each subject will be administered with either one of the following treatments as 
described in Table 5.1-2 below and according to randomization.  


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Table 5.1-2
Treatment Administration
Period 1 (Visit 3)
Period 2 (Visit 5)
Treatment A: One spray in each nostril of Dymista 
nasal spray 
Treatment B: One spray in each nostril of placebo 
nasal spray 
Treatment B: One spray in each nostril of placebo 
nasal spray 
Treatment A: One spray in each nostril of Dymista 
nasal spray
The dosage instructions for Dymista are indicated in the respective Canadian product 
monograph (M1). Preparation of the spray (including priming the pump) should be done by 
the member of the study staff who dispenses and will otherwise not be involved in the 
conduct of the trial. 
In the event of any significant dosing errors, the Medical Monitor, or Sponsor study contact 
should be contacted immediately.
Subjects will be trained on how to use the nasal spray with a training placebo nasal spray at 
the end of the priming EEU session at Visit 2 andVisit 4.
5.2
Drug Inventory
Canadian commercial Dymista nasal spray will be purchased for use in the study. The 
placebo nasal sprays will be supplied by the Sponsor and shipped to Cliantha Reseach. 
5.3
Study Medication/Device Complaints
In the event the subject has a complaint/concern during study participation regarding the 
study supplied study medication, they should inform the study staff.
In the event of a complaint/concern regarding any study medication provided by the Sponsor 
for this study, as a minimum the following information should be sent by the site via e-mail 
to 

Study number

Principal Investigator name

Subject ID

Date of occurrence of incident/complaint

Description of incident/complaint (facts)

Confirmation if the complaint caused or resulted in a SAE? If “Yes”, confirmation
that the SAE has been reported
Additional information and potentially the return of study medication may be requested by 
the Sponsor in order to investigate the complaint.


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5.4
Storage, Disposition of Unused Study Drug and Drug Accountability
The Investigator, or an approved representative, e.g. pharmacist, will ensure that all 
investigational products are stored in a secured area under recommended storage conditions 
and in accordance with applicable regulatory requirements while at the Investigator site.
Study drug should be stored between 15-25°C.
Temperature of storage facilities should be monitored and recorded on a daily basis using 
validated devices that record maximum and minimum temperatures. Should the storage 
facility experience any excursion of temperature outside of the labelled storage condition this 
must be reported immediately to Sponsor or designee. At sites where daily monitoring and 
recording is not possible at weekends, then on the next working day after the weekend the 
temperature record (e.g. max/min thermometers) should be checked immediately for any 
temperature excursions. Devices used for temperature monitoring should be regularly 
calibrated. Affected material must be placed into quarantine until the impact of the excursion 
has been assessed and confirmed by Sponsor.
The Investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of the study drug. If Sponsor supplies drug accountability forms these must be 
used. Alternatively, Sponsor may approve use of standard institution forms. In either case, the 
forms must identify the study drug, including batch or code numbers, and account for its 
disposition on a subject-by-subject basis, including specific dates and quantities. The forms 
must be signed by the individual who dispensed the drug, and copies must be provided to 
Sponsor or designee.
At the end of the study, Sponsor will provide instructions as to disposition of any unused 
investigational product. If Sponsor authorizes destruction at the study site, the Investigator 
must ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Sponsor. 
Destruction must be adequately documented.
The study medication must not be used outside this protocol. 
5.4.1
Retained Drug Samples
Not applicable. 
5.5
Randomization 
At screening, each subject will be assigned a screening number and listed in the Subject 
Identification List and Screening/Enrolment Log (blank form in TMF of the Investigator). 
After review of all eligibility criteria and immediately before dispensing the randomized 
treatment, the subject will be assigned the next available randomization number according to 
the randomization scheme. The respective control label will be affixed in the respective place 
on the subject source document. 


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Cliantha Research will generate the randomization scheme. The randomization scheme will 
be generated by using SAS statistical software (Version 9.4 or higher; SAS Institute Inc., 
USA)
The randomization scheme will be kept in a locked cabinet within the pharmacy, with access 
limited to pharmacy staff only. The pharmacy staff involved in preparing and dispensing of 
investigational products will be accountable for ensuring compliance to the randomization 
scheme.  The Principal Investigator and study staff will not have access to the randomization 
scheme during the study conduct until unblinding.
All sequences will be balanced (i.e., the ratio of the sequences will be 1:1, meaning 108 
subjects per sequence). Table 5.5-1 represents the randomization sequences. 
Table 5.5-1
Randomization Sequence
Sequence
Period 1
Period 2
1
Treatment A : Dymista
Treatment B : Placebo
2
Treatment B : Placebo
Treatment A : Dymista
5.6
Breaking the Blind
Individual decoding may be requested by the Investigator from the pharmacy staff if 
necessary for medical reasons or regulatory requirements. The Investigator should unblind 
the individual treatment only to prevent immediate harm to the subject or on request by a 
regulatory authority or IRB. 
If time permits, the Investigator is encouraged to contact the Sponsor prior to breaking the 
blind. If the blind is broken for any reason, the Investigator must notify the Sponsor 
immediately about unblinding procedure without medication code (within 24 hours). Upon 
request by the Sponsor, the Investigator should provide the status of unblinding.
Emergency unblinding envelopes (one envelope for each subject) will be prepared by 
unblinded pharmacy staff using the randomization scheme. QC/QA of the preparation process 
will be performed by 1 or 2 additional unblinded staff members. To faciliatate emergency 
unblinding and ensure subject safety, unblinding envelopes will be kept in a secured area 
with access limited to Pharmacy staff, the PI and other key designated study staff as specified 
in the delegation log. Unblinding will be performed by breaking the seal of the envelope, for 
that specific subject of interest only, and retrieving the treatment code.
The name of the unblinding person, the reason, the subject randomization number, the date 
and time of unblinding will be documented and confirmed by a signature. The reasons for and 
the date of unblinding must also be documented in the subject source document and also in 
the eCRF (if applicable). If possible, all causality and expectedness assessments should be 
done before breaking the blind. The sole fact that an adverse event is considered serious does 
not provide sufficient rationale for breaking the blind for a given subject.


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5.7
Rescue Medication
Use of rescue medications may result in removal of the subject from the period/study at the 
discretion of the Investigator. Decision of withdrawal should be communicated with the 
Sponsor in timely manner. If subjects experience bronchospasm, salbutamol may be 
administered if judged necessary.
5.8
Concomitant Medications
All concomitant medications taken during the study (from signing informed consent to post-
study follow-up) must be recorded with indication, daily dose, and start and stop dates of 
administration in the subject source documents and transferred into the eCRF. All subjects 
will be questioned about concomitant medication at each clinic visit and at follow up.
Changes in concomitant treatments should be kept at a minimum to avoid or at least reduce 
confounding factors.
Indication specific medications taken prior to screening (Visit 1) will be documented as a 
prior medication.
Subjects will abstain from all prohibited medications as described in the exclusion criteria 
section of this protocol (Section 4.2.2). Use of prohibited medication during the study will be 
deemed a protocol deviation and such subjects will be assessed by the Sponsor or designee 
regarding potential need to early terminate study drug (e.g. for safety reasons – see 
Section 4.2.5).
For non-pharmacological treatment, procedure, or diagnostic measures, the indication, and 
start and stop dates will be recorded. Any change since start of screening should be 
documented as well. Times of hospitalisation (beyond emergency room) or prolongation of 
hospitalisation will be recorded as an SAE (see Section 11.1).
5.9
Recommended Procedure in a Subject Experiencing Adverse Effects Secondary to 
Excessive Pharmacological Effects of Study Drug
With the nasal route of administration, overdose reactions are not anticipated.
In the event of overdose after incidental oral uptake (of the whole bottle), disturbances of the 
central nervous system, which include drowsiness, confusion, coma, tachycardia and 
hypotension, caused by azelastine hydrochloride may occur based on the results of animal 
experiments (M1). Of note, in clinical studies, single oral use of azelastine up to 17.6 mg is 
not associated with relevant safety findings. 
There is no known antidote to Dymista. Close observation should be performed and adequate 
supportive care should be provided (M1) in the event of treatment emergent adverse events. 
Other expected adverse reactions associated with the use can be found in the Canadian 
product monograph (M1). 


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5.10 Treatment Compliance
All study treatments will be administered by trained subjects during the EEU session under 
the supervision of the Investigator or the study staff.
5.11 Therapy at End of Study for compassionate use
Not applicable.
6.0 STUDY CONDUCT
Subjects eligible for study recruitment will have the nature, purpose, and risks of the study 
explained to them by the Investigator and/or designee. They will be provided with a written 
copy of the informed consent form (ICF) for the study and given sufficient time to consider 
the study’s implications before deciding to participate. Subjects agreeing to participate in the 
study will sign the ICF and be given a duplicate copy before undergoing any screening 
procedures. Historical Data of Cliantha Research collected from General Screening may be 
used (if data obtained within 60 days prior to Visit 2 except for SPT which can be obtained 
12 months prior to Visit 2). The data may include: medical history, social history, 
demographics and SPT. At screening, each subject will be assigned a screening number and 
listed in the Subject Identification List and Screening/Enrolment Log (blank form in TMF of 
the Investigator). 
Once a subject enrolls in this trial the site will make every effort to retain the subject for the 
planned duration of the trial. Clinical trial site staff are responsible for developing and 
implementing support and retention plans. Elements of this plan may include the following :

Thorough explanation of the complete clinical trial visit schedule and procedural
requirements during the informed consent process and re-emphasis at each clinic visit.

A simple explanation of the key data and key time points that are critical for the trial's
successful analysis, and the importance of all the treatment groups to the overall
success of the trial.

Discussion at screening, and subsequent regular review of possible barriers to clinic
visit attendance and full study participation and compliance.

Collection and maintanance of contact information in the database for subjects which
is maintained by Cliantha .

Use of appropriate and timely study visit reminders.

In case of missed visits, at least 3 attempts at 3 different timings through phone and if
subject is not responding, he/she will declared as lost to follow up..
In cases where the subject does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the 
subject so that they can appropriately be withdrawn from the study. All contact attempts 
should be documented in the subject's source documents. Should the subject continue to be 
unreachable, then and only then will he/she be considered to have withdrawn from the study 
with a primary reason of "Lost to Follow-up." For all other subjects withdrawing from the 
study, an alternative reason for discontinuation should be recorded in the eCRF. Regardless 


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of site plans to support and retain subjects within the trial, subjects may voluntarily withdraw 
from the trial for any reason and at any time.
For a subject that completes the study and all procedures it is anticipated that the duration of 
study would be up to 56 days (duration may be longer if re-priming is required). 
For details and timings of assessments, refer to Section 7.0.
6.1
Screening Procedures
Each prospective subject must agree to participate in screening procedures by signing the 
most recent ICF before any screening or re-screening (if applicable) procedure is initiated. 
The Principal Investigator or Medical Sub-Investigator will review the inclusion and 
exclusion criteria to confirm eligibility of each subject prior to enrolment.
6.1.1
Screening (Visit 1)
Subjects will commence screening procedures on Day -28 to -2 to confirm that they meet the 
selection criteria for the study. 
The following procedures will be performed at screening: 

A government issued ID containing an image of the subject or a government issued
non-photo ID with a non-government photo ID of the subject will be used to confirm
the subject’s identification

A COVID screening questionnaire with oral temperature will be performed before
obtaining the Research Subject Informed Consent Form.

Subjects will be presented with and asked to sign the Research Subject Informed
Consent Form. Subjects can discuss issues of concern with the PI/designee. Only
patients who sign the informed consent will be evaluated for inclusion and exclusion
criteria.

Collect demographic information and social history

Record medical history (including surgical history, allergy history and history of
asthma) (brief medical history will be sufficient if medical history was already
assessed during general screening within 60 days prior to Visit 2)

Perform vital signs measurement (blood pressure, heart rate, oral temperature and
respiratory rate)

Assessment of any prior medication use within the last 6 months or longer as required
as per the table in the exclusion criteria

Physical examination including an examination of the ears, nose and throat and
measurements of height and weight

Perform a skin prick test (if documentation within 12 months is not available)

Nasal inspection with anterior rhinoscopy

Blood and urine samples will be collected for clinical laboratory testing

Spirometry will be performed


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
A urine drug & alcohol screen will be performed

A urine pregnancy test will be performed (females of childbearing potential only)

Subjects will be evaluated if they meet the inclusion/exclusion criteria

Subjects will be trained and provided with a paper diary card to record any adverse
events and use of any concomitant medications during their time at home. The
subjects will be asked to bring their diary cards with them to the next visit for the
review of adverse events and use of any concomitant medications during their time at
home.
6.2
Treatment phase
6.2.1
Priming/Screening (Period 1, Visit 2) – Day -1
If the subject meets the eligibility criteria during the screening visit, they will attend a 2-hour 
priming/screening visit in a ragweed EEU where they will be exposed to ragweed pollen at an 
average concentration of 3500 ± 500 grains/m3 for evaluation of the inclusion criteria. 
Subjects will be regarded to be suitable for this investigation if they are asymptomatic or with 
mild symptoms during the baseline recording of symptoms prior to start of the EEU session 
(TNSS of ≤ 3 out of a possible 12, with each symptom being less than 2).
The following assessments will be conducted: 

A government issued ID containing an image of the subject or a government issued
non-photo ID with a non-government photo ID of the subject will be used to confirm
the subject’s identification.

A COVID screening questionnaire with oral temperature will be performed and
results of COVID test performed within 5 days prior to this visit or on the day of Visit
2 will be checked.

The paper diary card will be collected and reviewed for any adverse events and if
subjects have taken any concomitant medications since the last visit. The paper diary
card will be stored with the subject source documents.

A urine pregnancy test will be performed (females of childbearing potential only).

Subjects will be trained on how to use the electronic diary (ePDATTM) to record their
allergy symptoms and the ePDATTM will be dispensed to subjects prior to the start of
the EEU session.

Subjects will record their nasal symptoms (itchy nose, nasal congestion, runny nose,
sneezing) and ocular symptoms (itchy eyes, watery eyes, eye redness) prior to
entering the EEU and 30, 60, 75, 90, 105 and 120 minutes (+ 5 minutes) after entering
the EEU.

Vital signs (blood pressure and heart rate) will be measured prior to entering the EEU
and after the EEU.

Subjects will be monitored for adverse events throughout the EEU sessions.
If subjects qualify for Visit 3, the following procedures will be performed after end of the 
EEU session:


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
Subjects will be trained on how to use the training placebo nasal spray.

Subjects will be provided with a new paper diary card to record any adverse events
and use of any concomitant medications during their time at home. The subjects will
be asked to bring their diary cards with them to the next visit for the review of adverse
events and use of any concomitant medications during their time at home.
The EEU sessions should begin at around the same time (± 2.0 hours) throughout the study 
for each subject. 
In order to be eligible for Visit 3, subjects will be required to meet a minimum threshold 
TNSS response of ≥ 6 out of a possible of 12 at least twice during hours 0-2 in the EEU, with 
at least one occurring during the last two time points. Additionally, subjects will be required 
to meet a score of at least 2/3 for runny nose at least twice during hours 0-2 in the EEU, with 
at least one occurring during the last two time points. These eligibility criteria do not need to 
be met at the same time point. Subjects will not be permitted to use rescue medications 
during the EEU session. If a subject cannot tolerate the EEU, they may leave at any time and 
will be observed in the clinic. If a subject leaves the EEU early, they will be excluded from 
the study. 
Use of rescue medication may result in the removal of the subject from the study at the 
discretion of the Investigator. 
Subjects are permitted to leave the EEU to use the restroom. Subjects will be advised not to 
leave the EEU during pollen sampling, within 10 minutes before or during their time point 
assessments. Subject restroom breaks will be monitored and documented by study staff.
During each EEU session, measurements at the same time point will be done in the following 
sequence: nasal symptoms and ocular symptoms.
For each EEU session, subjects will be instructed to report their own symptoms and will be 
informed about the importance of accurate symptom reporting. Subjects who are found to be 
discussing their symptoms during the EEU session will be reminded that everyone’s 
individual symptoms differ, and asked not to discuss with each other. 
6.2.2
Randomization and Treatment Administration (Period 1, Visit 3) – Day 1
Eligible subjects will proceed to Visit 3, where they will attend a visit in a ragweed EEU. The 
start of the EEU session should begin at around the same time (± 2.0 hours) throughout the 
study for each subject. The following assessments will be conducted prior to EEU entry: 

A government issued ID containing an image of the subject or a government issued
non-photo ID with a non-government photo ID of the subject will be used to confirm
the subject’s identification.

A COVID screening questionnaire with oral temperature will be performed.

The paper diary card will be collected and reviewed for any adverse events and if
subjects have taken any concomitant medications since the last visit. The paper diary
card will be stored with the subject source documents.


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
The use of the ePDATTM to record allergy symptoms will be reviewed and the
ePDATTM will be dispensed to subjects.

Subjects will record their nasal symptoms (itchy nose, nasal congestion, runny nose,
sneezing) and ocular symptoms (itchy eyes, watery eyes, eye redness).

A verbal reminder of the dosing technique will be given.

Vital signs (blood pressure and heart rate) will be measured.
Subjects will then enter the EEU for approximately 6.5 hours and will record their nasal and 
ocular symptoms. Subjects must meet the predetermined minimum TNSS of ≥ 6 out of a 
possible 12 at least twice during hours 0-2 in the EEU, with at least one occurring during the 
last two time points, to be randomized to a treatment sequence. Additionally, subjects will be 
required to meet a score of at least 2/3 for runny nose at least twice during hours 0-2 in the 
EEU, with at least one occurring during the last two time points. These eligibility criteria do 
not need to be met at the same time point. The Investigator or designee will also perform an 
anterior rhinoscopy within 30 minutes of dosing. If there is evidence of complete nasal 
blockage on either one or both sides, the subject will be reassessed just prior to dosing. If 
there is evidence of complete nasal blockage on one or both sides at the second assessment, 
the subject will be excluded from the study. After the first 2 hours in the EEU, if the subject 
is eligible for the study, randomization and drug administration will be done during the next 
30 minutes within the EEU. The allergen challenge will be then continued for further  4 
hours. Subjects that do not meet the eligibility criteria will not be dosed and will be 
withdrawn from the study. 
Subjects will have the following assessments conducted while in the EEU: 

Subjects will record their nasal symptoms (itchy nose, nasal congestion, runny nose,
sneezing) and ocular symptoms (itchy eyes, watery eyes, eye redness) at 30, 60, 75,
90, 105 and 120 minutes (+ 5 minutes) after entering the EEU.

Anterior rhinoscopy within 30 minutes prior to dosing.
Subjects who are deemed eligible to participate in the clinical trial will have the following 
further assessments conducted while in the EEU:

Administration of the randomized study treatment approximately 2.5 hours (± 5
minutes) after the start of the EEU session.

Subjects will continue to record their nasal and ocular symptoms after dosing at 5, 10,
15 (+ 2 minutes), 30, 60, 90, 120, 150, 180, 210 and 240 minutes (+ 5 minutes).

Vital signs (blood pressure and heart rate) will be measured after exposure in the
EEU.

Subjects will be monitored for adverse events throughout the EEU sessions.
The following procedures will be performed after end of the EEU session:

Subjects will be provided with a new paper diary card to record any adverse events
and use of any concomitant medications during their time at home. The subjects will


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be asked to bring their diary cards with them to the next visit for the review of adverse 
events and use of any concomitant medications during their time at home.
Subjects will not be permitted to use rescue medications during the EEU session. If a subject 
cannot tolerate the EEU, they may leave at any time and will be observed in the clinic. If a 
subject leaves the EEU early, they will be excluded or withdrawn from the study. 
Use of rescue medication may result in the removal of the subject from the study at the 
discretion of the Investigator. 
Subjects are permitted to leave the EEU to use the restroom. Subjects will be advised not to 
leave the EEU during pollen sampling, within 10 minutes before or during their time point 
assessments, or during the 30 minutes post dosing. Subject restroom breaks will be monitored 
and documented by study staff. 
6.2.3
Priming EEU (Period 2, Visit 4) – Day 13 (+ 5 Days)
Subjects will return to the study site after a period of at least 12 days. 
Subjects will attend a 2-hour priming visit in a ragweed EEU. The following assessments will 
be conducted:  

A government issued ID containing an image of the subject or a government issued
non-photo ID with a non-government photo ID of the subject will be used to confirm
the subject’s identification.

A COVID screening questionnaire with oral temperature will be performed and
results of COVID test performed within 5 days prior to this visit or on the day of
Visit 4 will be checked.

The paper diary card will be collected and reviewed for any adverse events and if
subjects have taken any concomitant medications since the last visit. The paper diary
card will be stored with the subject source documents.

A urine pregnancy test will be performed (females of childbearing potential only).

The use of the ePDATTM to record allergy symptoms will be reviewed and the
ePDATTM will be dispensed to subjects prior to the start of the EEU session.

Subjects will record their nasal symptoms (itchy nose, nasal congestion, runny nose,
sneezing) and ocular symptoms (itchy eyes, watery eyes, eye redness) prior to
entering the EEU and 30, 60, 75, 90, 105 and 120 minutes (+ 5 minutes) after entering
the EEU.

Vital signs (blood pressure and heart rate) will be measured prior to entering the EEU
and after the EEU.

Subjects will be monitored for adverse events throughout the EEU sessions.

At the end of the EEU session, subjects will be trained on how to use the training
placebo nasal spray.

Subjects will be provided with a new paper diary card to record any adverse events
and use of any concomitant medications during their time at home. The subjects will


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be asked to bring their diary cards with them to the next visit for the review of adverse 
events and use of any concomitant medications during their time at home.
The EEU sessions should begin at around the same time (± 2.0 hours) throughout the study 
for each subject.
Subjects do not need to meet a minimum threshold value for TNSS and will receive the next 
study treatment in the following EEU visit. 
Subjects will not be permitted to use rescue medications during the EEU session. If a subject 
cannot tolerate the EEU, they may leave at any time and will be observed in the clinic. If a 
subject leaves the EEU early, they will be withdrawn from the study. 
Use of rescue medication may result in the removal of the subject from the study at the 
discretion of the Investigator. 
Subjects are permitted to leave the EEU to use the restroom. Subjects will be advised not to 
leave the EEU during pollen sampling, within 10 minutes before or during their time point 
assessments. Subject restroom breaks will be monitored and documented by study staff.
6.2.4
Treatment Administration (Period 2, Visit 5) – Day 15 (+5 Days)
Subjects will proceed to Visit 5 where they will attend another visit in a ragweed EEU and 
for administration of the next scheduled study treatment. The visit should take place 2 days 
after Visit 4, with one day in between each visit. The start of the EEU session should begin at 
around the time (± 2.0 hours) throughout the study for each subject. 
The following assessments will be conducted prior to EEU entry: 

A government issued ID containing an image of the subject or a government issued
non-photo ID with a non-government photo ID of the subject will be used to confirm
the subject’s identification

A COVID screening questionnaire with oral temperature will be performed.

The paper diary card will be collected and reviewed for any adverse events and if
subjects have taken any concomitant medications since the last visit. The paper diary
card will be stored with the subject source documents.

The use of the ePDATTM to record allergy symptoms will be reviewed and the
ePDATTM will be dispensed to subjects.

Subjects will record their nasal symptoms (itchy nose, nasal congestion, runny nose,
sneezing) and ocular symptoms (itchy eyes, watery eyes, eye redness).

A verbal reminder of the dosing technique will be given.

Vital signs (blood pressure and heart rate) will be measured.
Subjects will then enter the EEU for approximately 6.5 hours and will record their nasal and 
ocular symptoms. The Investigator or designee will also perform an anterior rhinoscopy 
within 30 minutes of dosing. If there is evidence of complete nasal blockage on either one or 
both sides, the subject will be reassessed just prior to dosing. Any evidence of complete nasal 
blockage on one or both sides at the second assessment should be documented in eCRF. 


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Administration of the randomized study treatment will be done approximately 2.5 hours (± 5 
minutes) after the start of the EEU session. 
The following assessments will be conducted while in the EEU:

Subjects will record their nasal symptoms (itchy nose, nasal congestion, runny nose,
sneezing) and ocular symptoms (itchy eyes, watery eyes, eye redness) at 30, 60, 75,
90, 105 and 120 minutes (+ 5 minutes) after entering the EEU.

Anterior rhinoscopy within 30 minutes prior to dosing.

Administration of the next randomized study treatment approximately 2.5 hours (± 5
minutes) after the start of the EEU session.

Subjects will continue to record their nasal and ocular symptoms after dosing at 5, 10,
15 (+ 2 minutes), 30, 60, 90, 120, 150, 180, 210 and 240 minutes (+ 5 minutes).

Vital signs (blood pressure and heart rate) will be measured after exposure in the
EEU.
The following procedures will be performed after end of the EEU session (unless EOS occurs 
on the same day as Visit 5):

Subjects will be provided with a new paper diary card to record any adverse events
and use of any concomitant medications during their time at home. The subjects will
be asked to bring their diary cards with them to the next visit for the review of adverse
events and use of any concomitant medications during their time at home.
Subjects will be monitored for adverse events throughout the EEU sessions. Subjects will not 
be permitted to use rescue medications during the EEU session. If a subject cannot tolerate 
the EEU, they may leave at any time and will be observed in the clinic. If a subject leaves the 
EEU early, they will be withdrawn from the study. 
Use of rescue medication may result in the removal of the subject from the study at the 
discretion of the Investigator. 
Subjects are permitted to leave the EEU to use the restroom. Subjects will be advised not to 
leave the EEU during pollen sampling, within 10 minutes before or during their time point 
assessments, or during the 30 minutes post dosing. Subject restroom breaks will be monitored 
and documented by study staff. 
6.2.5
Early study drug Termination (ET) visit
Subjects may request termination of study drug or withdrawal from the study at any time, or 
be required to withdraw or terminate study drug by the Investigator or Sponsor for reasons as 
per Section 4.2.5. If study drug is terminated or the subject withdraws or is withdrawn, the 
reason for termination/withdrawal should be established and recorded. If a subject does not 
return for a scheduled visit, every effort should be made to contact the subject. In any 
circumstance, every effort should be made to document the outcome of subject contact 
attempt, if possible. The Investigator will contact Sponsor or designee in the event that a 
subject fails to complete the study or violates the protocol.


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If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected. The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Unless consent is withdrawn, subjects who prematurely terminate study drug will be asked to 
return to the clinic for an ET visit and will have this scheduled as soon as possible after their 
last dose of study drug. 
At the ET visit, the same assessments as mentioned for end of study (EOS) Visit in Section 
6.3 will be conducted. 
6.3
End of Study (EOS) Visit - Day 15 (+5 Days)
The end of study examination will be conducted following the EEU session in Visit 5 or on a 
separate day. 
The following assessments will be conducted:

A government issued ID containing an image of the subject or a government issued
non-photo ID with a non-government photo ID of the subject will be used to confirm
the subject’s identification (unless EOS occurs on the same day as Visit 5)

A COVID screening questionnaire with oral temperature will be performed (unless
EOS occurs on the same day as Visit 5).

Vital signs (blood pressure and heart rate) that are conducted as part of Visit 5 after
the EEU session or at early termination, if applicable.

Subjects will be monitored for adverse events.

Subjects will be asked if they have taken any concomitant medications (unless EOS
occurs on the same day as Visit 5).

The paper diary card will be collected and reviewed for any adverse events and if
subjects have taken any concomitant medications since the last visit. The paper diary
card will be stored with the subject source documents (unless EOS occurs on the same
day as Visit 5).

Collection of blood and urine for clinical laboratory assessments.
6.4
Follow up (telephone call)
Subjects will be followed-up by phone at within 5 to 7 days after last treatment 
administration. 
The following assessment will be conducted:

Subjects will be asked for occurrence of adverse events since last treatment
administration.

In case of an adverse event, subjects will be asked if they have taken any concomitant
medications since last treatment administration prior to or for treatment of the adverse
event.


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7.0 TREATMENT PROCEDURES AND ASSESSMENT CRITERIA
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the Investigator that may make it unfeasible to 
perform the test. In these cases, the Investigator or designated representative will take all 
steps necessary to ensure the safety and well-being of the subject. When a protocol required 
test cannot be performed the Investigator or designated representative will document the 
reason for this and any corrective and preventive actions which he/she has taken to ensure 
that normal processes are adhered to as soon as possible. The Sponsor study team will be 
informed of these incidents in a timely fashion.
Activities specific to this protocol are expanded upon further below.
7.1
Efficacy Assessment
For timing of methods and assessments see the study schedule in Table 0-1.
7.1.1
Total Nasal Symptom Score (TNSS) and Total Ocular Symptom Score (TOSS) 
and Total symptom score (T7SS)
The total nasal symptom score (TNSS) is comprised of 4 symptoms from the nose (Table 
7.1-1). The sum of the 4 symptom scores will be used as the TNSS. The total ocular symptom 
score (TOSS) is comprised of 3 symptoms from the eyes (Table 7.1-1). The sum of the 3 
symptom scores will be used as the TOSS. The sum of TNSS and TOSS will be used as the 
total symptom score (T7SS).
Table 7.1-1
Allergic Rhinitis Symptoms 
Symptom Class
Symptoms
Nasal Symptoms
Itchy nose, nasal congestion, runny nose, sneezing
Ocular Symptoms
Itchy eyes, watery eyes, eye redness
The nasal and ocular symptoms will be assessed by subjects on the ePDATTM diary prior to 
and during their exposure to ragweed allergen in the EEU in Visits 2, 3, 4, and 5 at the time 
periods specified in the schedule of assessments (Table 0-2 and Table 0-3). A mirror and a 
picture scale (Figure 7.1-1) will be provided to subjects for assessment of eye redness.
All individual allergic rhinitis symptoms and ocular redness score will be scored on a scale of 
0 to 3 as indicated in Table 7.1-2  and in Table 7.1-3 (accompanied with photographic scale 
in Figure 7.1-1), respectively. The sum of the TNSS will contribute to a score ranging from 0 
– 12 and the sum of the TOSS will contribute to a score ranging from 0 – 9. The total 7 
symptoms score (T7SS) will be the combination of the TNSS and TOSS, for a combined 
maximum score of 21. 


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Table 7.1-2
Allergic Rhinitis Symptoms 
Scale
Symptoms
0
None
(no sign/symptoms evident)
1
Mild
(sign/symptom clearly present, but minimal awareness; easily tolerated)
2
Moderate
(definite awareness of sign/symptoms that is bothersome but tolerable)
3
Severe
(sign/symptom that is hard to tolerate; causes interference with activities of daily 
living and/or sleeping)
Table 7.1-3
Ocular Redness Score 
Scale
Symptoms
0
None
(not experiencing any redness in your eyes)
1
Mild
(minimal redness in your eyes)
2
Moderate
(more than minimal redness, but you can still see some clear white in your eyes)
3
Severe
(Noticeably red or pink eyes or if the whites of your eyes are swollen)
Figure 7.1-1
Ocular Redness Scores
7.2
Safety Assessment
7.2.1
Adverse Event Assessment
If a subject reports any symptoms before drug administration, they will be evaluated by 
medical staff and necessary measurements will be performed. The Principal Investigator or 
Medical Sub-Investigator will be notified before dosing to determine the course of action.
    0
  1
 2
3
None
           Mild
       Moderate
         Severe
    0
  1
 2
3
None
           Mild
       Moderate
         Severe
    0
  1
 2
3
None
           Mild
       Moderate
         Severe


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Findings from screening procedures, e.g., laboratory tests or physical examinations will be 
recorded as medical history. Clinically significant worsening from the screening procedures 
will be recorded as adverse events.
Subjects will be routinely queried in regard to the presence or absence of adverse events 
using open ended questions. The clinic will provide documentation of any adverse events in 
the subject’s eCRF. The adverse event source documentation will minimally include the 
following information: date and time of assessment, the outcome of the response, and 
identification of the clinic staff member collecting the information.
No adverse events of special interest will be monitored in this study.
7.2.2
Vital Signs
At screening, vital signs to be recorded are systolic and diastolic blood pressure and heart 
rate, respiratory rate and oral temperature. Vital signs (blood pressure and heart rate) will also 
be measured at Visit 2, Visit 3, Visit 4, Visit 5, and EOS/ET visit. Vital signs will be 
performed before and after the EEU session in each visit. Blood pressure and heart rate will 
be measured in a seated position (after at least 2 minutes of rest).
Any clinically significant changes in blood pressure and heart rate should be recorded as an 
AE. If the findings contribute to a clinical diagnosis (such as tachycardia in case of an 
abnormally increased pulse) this diagnosis should be recorded as an AE. Determination of 
clinical significance and seriousness will be based on the Investigator's medical judgment.
7.3
Other Aspects
The following issues are not intended to directly contribute to the assessment of efficacy and 
safety of the study medication. They will be recorded from each subject at scheduled times 
during the study (see Table 0-1) and cannot be related to a single treatment period.
7.3.1
Clinical Laboratory Tests
Clinical laboratory tests will be assessed at screening and at the end of study (EOS) or early 
termination (ET). Additional tests (i.e. pregnancy test, FSH test, COVID test) will be 
performed during the study as described in Table 7.3-1. 
On the laboratory sheets, the Investigator must classify each value outside normal range into 
the following categories:

Invalid value; a reason for this judgement must be specified. This classification may 
require a repeated measurement (e.g. from the same blood sample or a repeated blood 
draw) depending on the assumed sources of inaccuracy.

No clinical significance, or attributed to an existing condition unrelated to study 
treatment. 

Clinical significance (e.g. serious, causing discontinuation, or requiring therapeutic 
measures) and a respective record in the source documents for AEs. If the findings 


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contribute to a clinical diagnosis this diagnosis should be recorded as an AE. Findings 
from screening procedures will be recorded as medical history.
The clinical laboratory tests include the following variables: 
Table 7.3-1
Clinical Laboratory Variables 
Theme
Variables
Hematology1
Leukocytes (white blood cell count) with differential, erythrocytes (red 
blood cell count), hemoglobin, hematocrit, thrombocytes (platelets)
Electrolytes1
Sodium, potassium, chloride 
Clinical Chemistry1
Blood urea nitrogen (BUN), creatinine, total bilirubin, alkaline 
phosphatase, aspartate aminotransferase (AST), alanine transaminase 
(ALT), glucose, albumin 
Urinalysis1
Glucose, protein, ketones, bilirubin, blood, nitrites, leukocyte, pH, 
specific gravity (if blood, nitrites, leukocytes are positive, a microscopic 
urinalysis will be performed)
Urine Drug & Alcohol 
Screen2
Amphetamines, cannabinoids, cocaine metabolites, opiates, 
phencyclidine, benzodiazepines, ethanol
Additional tests
Pregnancy3 (urine): females of childbearing potential only
FSH2 (blood): if necessary to document postmenopausal status
COVID4 (nasopharyngeal/oropharyngeal/nasal)
1 Performed at screening and EOS/ET
2 Performed at screening
3 Performed at screening, Visit 2 and Visit 4.
4 Performed within 5 days prior to Visit 2 and Visit 4 or on the day of Visit 2 and 4
7.3.2
Spirometry
At screening, spirometry will be performed on all subjects. Subjects must have FEV1 ≥ 75% 
of the predicted value to be enrolled in the study.
7.3.3
Demographic Data and Social History
During screening, age, sex, ethnic origin, height, and body weight will be recorded. Body 
weight will be assessed without shoes. During screening, social history (e.g. drug and alcohol 
abuse) will be collected. 
7.3.4
General Medical History, Concomitant Diseases
Clinically relevant medical history (including drug sensitivities and allergies, major 
surgeries) and any disease present during screening will be documented under medical 
history and updated until first exposure to study treatment.
Medical history mentioned in the exclusion criteria, Section 4.2.2, occurring before exposure 
to the study treatment will be recorded under medical history. 


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7.3.5
Skin Prick Test
At screening, if prior documentation within the previous 12 months is not available, a skin 
prick test for a panel of common allergens will be performed:
Positive Control
Negative Control
Short Ragweed
Cat
Dog
Alternaria
Aspergillus fumigatus
Cladosporium cladosporioides
American Elm
Sugar Maple
White Poplar
White Ash
White Birch
White Oak
D. Farinae
D. Pteronyssinus
Grass Mix
7.3.6
Physical Examination
At screening, a physical examination will be performed by the Investigator, or other qualified 
personnel under the direction of the Investigator. The physical examination will include: 
general appearance, skin, head, eyes, ears, nose, throat, neck, chest, and cardiovascular, 
abdominal, neurological, lymphatic, and musculoskeletal systems. The source document will 
contain the findings of the physical examination and whether or not there are clinically 
relevant findings and the eCRF will document completion of the examination. Any abnormal 
finding should be recorded under medical history.
7.3.7
Anterior Rhinoscopy
At screening, the Investigator or designee will perform an anterior rhinoscopy to assess if 
there are any nasal structural abnormalities that might interfere with study results. At Visit 3 
and Visit 5, the Investigator or designee will perform an anterior rhinoscopy within 30 
minutes of dosing. If there is evidence of complete nasal blockage on either or both sides, the 
subject will be reassessed just prior to dosing. Any evidence of complete nasal blockage on 
one or both sides at the second assessment should be documented in the eCRF.  


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7.3.8
Pregnancy Testing
A urine pregnancy test (females of childbearing potential only) will be performed at 
screening and Visit 2 and Visit 4. The results of each pregnancy test will be recorded in the 
subject source and the eCRF. Additional pregnancy tests may be performed if pregnancy is 
suspected. 
For consequences of a positive pregnancy test see Section 11.5.4.
7.3.9
Blood Volume
Total blood sampling volume for an individual subject is approximately 18 mL (9 mL at 
screening and 9 mL at EOS/ET). Additional blood samples may be taken for safety 
assessments, provided the total volume taken during the study does not exceed 500 mL 
during any period of 30 consecutive days, and the ethics committee/IRB is notified of the 
blood collection.
7.4
Restrictions
Study restrictions include all items listed in the Lifestyle Guidelines (Section 4.4) and the 
concomitant medications as described in the exclusion criteria section of this protocol 
(Section 4.2.2) and will be prohibited throughout the duration of the study. If concomitant 
medications change during the study, a discussion between the Principal Investigator or a 
Medical Sub-Investigator along with the Sponsor should occur, and a decision to continue or 
discontinue the subject will be made based on the medication’s pharmacology and 
pharmacokinetics.
7.5
Mitigation in the event of a public health emergency
In the event of any circumstances impacting the ability of enrolled subjects to attend for 
scheduled visits at the investigator site, such as travel restrictions imposed due to COVID-19, 
investigators must notify the Sponsor and make the necessary arrangements to ensure the 
safety of their enrolled subjects. They should also evaluate whether their subjects should 
continue in the clinical trial. Those that have not been randomized yet should not continue the 
study.
Protocol deviations arising under such circumstances (eg, missed or delayed visits, 
assessments not performed, etc) will be clearly documented in the eCRF and the reasons will 
be collected.
7.5.1
Pandemic COVID-19 Response Plan
Regulatory authorities have recognized that the Coronavirus Disease 2019 (COVID-19) 
pandemic may impact the conduct of clinical study. COVID-19 pandemic has created a lot of 
uncertainty in the current situation and has put subject’s safety, protocol compliance and data 
validity at high risk.
Due to COVID-19 pandemic, challenges may arise for clinical study conduct, for example, 
quarantines of site personnel/study participants, travel limitations, interruptions to the supply 


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chain for the IP(s), or other considerations if site personnel or study participants become 
infected with COVID-19. These challenges may lead to difficulties in meeting protocol 
specified procedures, including administration or use of investigational product, housing 
duration or adhering to protocol specified visits and laboratory/diagnostic testing. 
To accommodate these challenges and mitigate safety risks associated with COVID-19, 
changes may be required from approved protocol which include (but not limited to) 
conducting the study in multiple groups, change in study procedures timing, change in 
subject’s housing duration, additional test or parameter may be performed to standard 
inclusion or exclusion criteria at the discretion of Investigator/designee, etc. The changes 
made to the procedure will prioritize subject’s safety and data validity and integrity. For any 
significant change, as per regulatory guidelines, a planned protocol deviation will be filled and 
notified to IRB and/or local regulatory (as applicable).
All participants will be pre-screened prior to enrolment into the study and evaluated for risk 
factors and symptoms of COVID-19 according to the most recent regional Public Health 
guidelines available at the time of pre-screening. The screening is conducted through 
telephone at the time of appointment confirmation and again when the subject arrives at the 
clinic for any visit.
Additional health checks including body temperature or other vital sign monitoring, etc. may 
be performed during the study at the discretion of Investigator/designee, even if not specified 
in the protocol. Subject who is tested positive to COVID-19 during the study will be 
withdrawn from the study. This subject and other subjects in close contact will be handled as 
per applicable local Public Health Guidelines.
As the science and regulations are continuously being adapted to the evolving information 
around the pandemic, additional measures apart from the ones mentioned here may be 
undertaken to ensure subject safety and appropriate study conduct. The IRB and the sponsor 
would be informed for their review and approval as applicable. 
Risk Mitigation plan/Risk Evaluation and Mitigation strategy will be made to minimize the 
risk for COVID-19 exposure and to handle possible situations during COVID-19 pandemic. 
8.0 DATA MANAGEMENT
A database (EDC) will be created, which reflects the data required to be recorded and 
analyzed per protocol. 
The creation and validation of the EDC system and management of the data will be 
conducted in accordance with the Division 5 of the Canadian Food and Drug regulations and 
guidelines (R5) and CFR 21, part 11 of the US regulations (R6). Methods used to ensure the 
quality and integrity of the data will be documented in the Data Management Plan (DMP), 
which will be approved by data management and the Sponsor.
The information from the subject source documents will be entered into the EDC system by 
the site, reviewed by the site’s Quality Control group, compared and corrected accordingly. 
Computerised edit checks on completeness, correctness, plausibility (such as range checks, 
cross-checks) will be performed according to the study specific data management plan. All 


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identified discrepancies will be queried utilizing the EDCs query management system. No 
self-evident corrections (such as spelling and header corrections) will be made by the data 
manager. Any updates to the data, whether through updates on the page or through the query 
management system will be recorded in the EDC system’s audit trail.
The ePDATTM data will be transferred to the Cliantha Clinical Data Management group and 
integrated into the final datasets. 
The database will be soft-locked after all source data verification (SDV) has been completed 
and all SDV queries are resolved and the coding for medical terms (AEs, medical history) 
and concomitant treatments is completed. The database will be locked when the sets of 
subjects for analysis are determined. 
Unblinding of the study will only be performed after the database has been locked. For 
unblinding of individual cases see Section 5.6.
9.0 STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be dated and maintained 
by the Sponsor. This document may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. Any further change from final SAP will be reflected in the 
study Clinical Study Report (CSR).
Statistical analysis and the associated tables, listings and figures will be performed using 
SAS® (SAS Institute Inc., Cary, USA) version 9.4 or higher at 5% alpha level of significance 
unless specified.
9.1
Sample Size Determination
Assumptions for parameters were derived from a very similar chamber study of Dymista 
(X-03065-3311; Bousquet et al. 2018, O1).
 
 
 
 
 
a 
total of 216 randomized subjects should be included in this study.


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In case a substantial number of subjects could only participate at one treatment period of this 
cross over study due to public health emergency (COVID-19, etc.) a replacement of patients 
may be considered in a protocol amendment.
9.2
Populations for Analyses
Safety population (SAF) : all subjects having received at least one dose of the study 
treatment. The SAF will be used for the analysis of safety data and subjects will be 
categorized according to the treatment that they actually received.
Full analysis set (FAS) : This will be the intention to treat (ITT) population. These are all 
randomized patients including subjects who receive incorrect treatment, do not complete the 
study or do not comply to the protocol, and who are randomized but do not take any study 
medication..   
Per-protocol set (PP) : all subjects in the FAS who had no major protocol violation that 
would impact on the primary efficacy endpoint. Potential significant protocol deviations are 
listed below and will be further defined in the SAP. The list of major protocol deviations will 
be finalized prior to database lock and unblinding as part of the final blind data review 
(BDR). Data will be summarized and analyzed according to the treatment a subject actually 
received. 
Potential violations that may result in the exclusion of the subject from the per-protocol 
population include, but are not limited to:

Not fulfilling all of the inclusion and none of the exclusion criteria during 
randomization

Not receiving the treatment to which they were randomized

Taking prohibited concomitant medications that may affect the primary variables
FAS Subset with Moderate/Severe Ocular Symptoms: all FAS subjects with baseline 
TOSS at Visit 3 ≥4. 
9.3
Statistical Analyses
Adequate descriptive statistics will be provided for each endpoint. Mean time courses for raw 
values and changes from baseline will be displayed graphically. Demographic data and 
background characteristics will be displayed descriptively. Baseline measurements of the 
efficacy variables will be compared descriptively for both treatment periods. 
Baseline for each efficacy variable is defined per period (visit 3 and visit 5 separately) as 
average of the last 2 assessments (105 min and 120 min) of this variable prior to dosing with 
study treatment. In case one of these two assessments is missing, the baseline will be the 
remaining value. 


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9.3.1
Definition of the Primary Efficacy Endpoint
For onset of action assessment: 

Changes from baseline in TNSS at each post-dose assessment time point (0 to 4 hours
p.a.)
9.3.2
Primary Analysis of Primary Endpoint
 
 
 
 
 
The onset of action is defined as the first time point after initiation of treatment when the 
product demonstrates a greater change from baseline in compared to the placebo, which  
proves durable from this time point until the end of the last assessed time point (4h) of this 
study. Multiple comparisons are handled by hierachical testing from 4h backwards.
9.3.3
Secondary/Sensitivity Analysis of Primary Endpoint
The analysis of the PP population will serve as a sensitivity analysis. 
9.3.4
Definition and Analysis of the Secondary Endpoints
Following secondary endpoints will be analyzed and reported similar to the analysis method 
and reporting of the primary endpoint as described above using only the FAS population:

Changes from baseline in TOSS and total 7 symptoms score (T7SS) at each post-dose
assessment time point (0 to 4 hours p.a.)

Change from baseline in individual nasal symptom scores (itchy nose, nasal
congestion, runny nose, sneezing) and ocular symptom scores (itchy eyes, watery
eyes, eye redness) at each post-dose assessment time point (0 to 4 hours p.a.)
 
 
 
 
Responder analysis: Time to relevant response to therapy (30% and 50% reduction of TNSS) 
will be analysed by means of Kaplan Meier analysis.
Time course arithmetic mean ± SE curves for raw values (0-6.5 hours) and for change from 
baseline in TNSS for the post-dose time points 0 to 4 hour will be presented by treatments 
overlaid each other using the FAS Population.


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9.3.5
Missing Data
Missing data will not be replaced. More details might be specified in the SAP.
9.3.6
Sub-Group Analyses
Changes from baseline in TOSS and T7SS will be calculated in a subgroup of subjects with 
moderate/severe baseline TOSS at Visit 3 as defined in Section 9.2. 
9.3.7
Safety Analyses
Analysis of all safety data will be performed on the safety population (SAF) and will be 
presented by the treatment received. 
9.3.7.1 Adverse Events
Adverse events will be coded using latest version of Medical Dictionary for Regulatory 
Authorities (MedDRA). The occurrence of treatment emergent AEs (TEAEs) and SAEs will 
be summarized in terms of incidence, as well as in terms of total number of AEs. Analysis of 
AEs in terms of incidence by severity and by relatedness will also be provided.
Prior and concomitant medications will be listed by subject and coded using the latest version 
of the WHO Drug Dictionary . Medical history will be listed by subject and coded using the 
latest version of MedDRA and will be summarized.
9.3.7.2 Vital Signs
Summary statistics of vital signs will be presented for non-treatment days (Visit 1, Visit 2, 
Visit 4 and EOS/ET Visit ). For vital signs during the treatment periods, the Pre-EEU 
observation will be considered as baseline. During treatment periods, summary statistics for 
the observed data at Pre- and Post-EEU session as well as the change at Post-EEU session for 
Visit 3 and Visit 5 will be presented by treatments.
Blood Pressure and heart rate will be listed and descriptively summarized (N, mean, standard 
deviation, minimum and maximum) by treatment and visit. 
9.3.8
Planned Interim Analyses
No interim analysis is planned for this study.
10.0
ADMINISTRATIVE PROCEDURES
10.1 Source Documentation Forms
All clinical data will be recorded by the clinical staff on raw data sheets and/or recorded 
electronically using validated software. If computerized systems are used to create, modify, 
maintain, archive, retrieve or transmit source data, they must comply with the applicable 
regulatory regulations and/or guidance. The Investigator will assume responsibility for 


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ensuring the completeness and accuracy of all clinical documents independent if sourced on 
paper or electronically generated.
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
Each page of the subject source will be identifiable by the study number, an identifier for the 
version, the subject number, and a page number. Completed subject source documents must 
be dated and signed by the Investigator or authorised study personnel.
The nature and location of all source documents will be documented separately. Source data 
may be directly captured from devices, transferred from 3rd parties (e.g. laboratory data) or 
entered manually into eCRF/database.
10.2 Access to Data/Source Documentation
The Investigator or designated representative will permit full access to data and source 
documentation for the purpose of clinical monitoring, audits, IRB/IEC review and regulatory 
inspections.
10.3 Final Clinical Study Report and Case Report Forms (CRFs)
A written clinical study report will be provided in accordance with the International 
Conference on Harmonization (ICH) E-3 guidelines including Annex I (Synopsis) 
documenting the clinical execution of the study. This report will include a description of 
important protocol deviations. All protocol deviations will be listed in the appendix. The final 
report will also include reasons for withdrawals and any necessary treatment(s). The report 
will also include tables presenting demographics (separate summary tables for enrolled and 
completed subjects), and adverse events recorded during the study. In addition, the clinical 
study report will include a Quality Assurance statement, documenting that the report has been 
reviewed for completeness, accuracy, and compliance with the protocol and applicable local 
and federal regulations. For final clinical reporting purposes only, adverse events deemed 
“definite”, “probable” or “possible” will be included in the treatment-related 
summaries/listings.
Electronic Case Report Forms (eCRFs) containing data transcribed from subject source 
documents (as appropriate) and copies of other source documents will be supplied by the 
clinical site. All study staff will be trained to ensure that accurate, consistent, complete, and 
reliable data is entered into the eCRF unique for each subject. 
The Principal Investigator must sign each subject’s eCRF after completion of data entry, 
signifying that the data entered in the eCRF is complete and accurate. Electronic CRFs will 
be provided.
10.4 Adherence to Protocol
Except for an emergency situation in which proper care for the protection, safety and well-
being of the study subjects requires medical treatment, the study will be conducted as 


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described in the approved protocol (and amendments, if applicable), GCP and applicable 
SOPs. In addition, the study will be conducted in accordance with the applicable regulatory 
requirements of the country where the study is being conducted as well as the country where 
the study will be submitted. Any deviation(s) from the protocol will be recorded and 
presented in the final report (see Section 10.3).
All scheduled events in the study should be conducted at the time(s) specified. Allowed 
deviation windows are specified in the protocol (see Section 6.0). Tests conducted outside of 
the allowed deviation windows will be considered a protocol deviation.
10.5 Investigator’s qualification
In accordance with ICH E6 (R2), the Investigator(s) should be qualified by education, 
training, and experience to assume responsibility for the proper conduct of the trial, should 
meet all the qualifications specified by the applicable regulatory requirement(s), and should 
provide evidence of such qualifications through up-to-date curriculum vitae and other 
relevant documentation requested by the Sponsor, the IRB, or the competent authority.
The Investigator is responsible for supervising any individual or party to whom the 
Investigator delegates trial-related duties and functions conducted at the trial site. The 
Investigator/institution should ensure all individuals and parties retained to perform trial-
related duties are qualified to perform those trial-related duties and functions and should 
implement procedures to ensure the integrity of those study tasks and the generated data.
10.6 Data Handling and Record Retention
All clinical information shall be recorded, handled and stored in such a way that it can be 
accurately reported, interpreted and verified, while the confidentiality of records of the trial 
subjects remains protected. 
A eCRF is required to be completed for each subject. The eCRF is property of the Sponsor 
and the Investigator must review all eCRFs prior to submission to the Sponsor.
All data collected in the study will be captured and maintained in a secure and validated 
electronic data capture (EDC) system or collected electronically and provided to clinical data 
management. Study staff will enter the data into the database as indicated in Section 10.3 
with the exception of data collected through an electronic source (e.g., ePDATTM entries). 
The paper diaries are for cumulative documentation of adverse events and use of concomitant 
medication. They serve as basis of information for the Investigator to transfer relevant 
information to the eCRF and diary data will not be entered directly into the EDC. Completed 
diaries will be stored with the subject source documents.
The ePDATTM data will be transferred to the Cliantha Clinical Data Management group and 
integrated into the final datasets. In the event of an ePDATTM failure, paper diary cards will 
be used as a back-up to collect symptom scores.
Details for all data sources will be provided in the Data Management Plan (DMP).


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The Sponsor and the Investigator will each maintain a Trial Master File (TMF) for the 
“essential documents” as specified by ICH E6 (R2). Sponsor or its designated CRO will 
provide an Investigator’s Site File (ISF) as a part of the TMF to each PI containing a cover 
page with a description of the required contents for each binder section and any project 
specific standardized forms . The Sponsor and Investigator/institution should maintain a 
record of the location(s) of their respective essential documents including source documents. 
The storage system used during the study and for archiving (irrespective of the type of media 
used) should provide for document identification, version history, search, and retrieval.
When a copy is used to replace an original document (e.g., source documents), the copy 
should fulfil the requirements for certified copies as specified by ICH E6 (R2).
All records pertaining to the receipt and return of study supplies (particularly study 
medication) and copies of final case report forms, worksheets, and other pertinent source 
documents must be retained in accordance with ICH-GCP and the applicable regulatory 
requirements of the country where the study is being conducted as well as the country where 
the study will be submitted.
The Investigator must obtain in writing the Sponsor’s agreement to dispose of any records, 
even if the retention period has been reached.
10.7 Monitoring
Monitoring of the study will be performed by a monitor independent from the Investigator’s 
site. The Sponsor reserves the right to monitor and/or co-monitor the study in frame of 
Sponsor oversight.
The sponsor or designee will base the monitoring strategy on a systematic, prioritised, risk-
based approach. The extent and details of the monitoring as well as the rationale for the 
monitoring strategy will be documented in a monitoring plan tailored to the human subject 
protection and data integrity of the study.
One of the obligations of the monitors is to check the accuracy and completeness  of the 
source documents, the eCRF entries, and other trial-related records against each other (source 
data verification) as outlined in ICH E6 (R2), this can be completed on site or remotely. 
Obligations of the monitors are specified in a clinical monitoring plan.
The monitor informs the Investigator of any entry error, omission, or illegibility in the source 
documentation and eCRF. The monitor should ensure that appropriate corrections, additions, 
or deletions are made, dated, explained (if necessary), and initialled by the Investigator or by 
authorised study personnel. The Principal Investigator should guarantee that authorised study 
personnel are available during monitoring visits.
If noncompliance that significantly affects or has the potential to significantly affect human 
subject protection or reliability of trial results is discovered, the sponsor or designee should 
perform a root cause analysis and implement appropriate corrective and preventive actions.
Monitoring visits will be recorded in a Monitoring visit log at the center of the Investigator. 
The Monitoring Visit Log will be maintained in the sites ISF.  A copy  of the log will be 


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collected at close out and maintained in the Sponsor TMF. The original will be stored in the 
Investigator’s file.
10.8 Confidentiality
Information furnished to Clinical Investigators and IRBs/Ethics Committees will be 
maintained in confidence by the Clinical Investigator and IRB/Ethics Committee. By signing 
this protocol, the Investigator affirms to the Sponsor that he/she will maintain, in confidence, 
information furnished to the IRB/Ethics Committee relevant to this study under appropriate 
understanding of confidentiality with such IRB/Ethics Committee.
By signing the protocol, the Investigator agrees that within local regulatory restrictions and 
institutional and ethical considerations, the Sponsor may consult and/or copy source 
documents (e.g., laboratory reports,  workbooks, medical records) in order to verify eCRF 
data.
Data, including personal data, from source documents may be transferred to Viatris entities or 
service providers which may be located inside or outside of Canada including, but not limited 
to, the USA, the European Economic Area (EEA). In such cases, Sponsor ensures that such 
transfers are carried out in compliance with all applicable data protection laws and 
regulations and signed Informed Consent Form (ICF).
Personal study related data will be kept confidential. Study documents submitted to the 
Sponsor, e.g. eCRFs, etc., are only identifiable by pseudonym, i.e. the Subject No. The 
Investigator will keep in his/her TMF the original of the Subject Identification List and 
Screening/Enrolment Log (including complete name and date of birth of each subject). To 
allow compliance with GCP, each subject will be asked for consent regarding the access to 
his/her personal study related data for monitoring, audits, and inspections as well as regarding 
transmission and storage of his/her pseudonymous data; a respective statement will be part of 
the informed consent. The subject has the right to access and rectification of his/her personal 
data according to the General Data Protection Regulation (GDPR) (R4).
10.9 Ethics and Regulatory Authorities
Guidelines will be followed with regard to the treatment of human subjects in the study, in 
accordance with the requirements of the Declaration of Helsinki and International Conference 
on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (ICH E6 (R2)) (R3) in addition to the regulatory requirements of the country where the 
study is being conducted as well as the country where the study will be submitted.
10.9.1 Institutional Review Board/Ethics Committee
The Investigator is responsible for obtaining initial and continuing review (at intervals not 
more than once per year) of the study by an IRB/Ethics Committee, or in accordance with 
applicable government regulations of the country where the study is being conducted as well 
as the country where the study will be submitted. This study will not enroll any subjects until 
the IRB/Ethics Committee provides written approval of the protocol and the informed 
consent to the Investigator. In addition, a copy of the IRB/Ethics Committee approval 
documents must be provided to the Sponsor prior to enrolling any subjects into the study.


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10.9.2 Regulatory Authority
This clinical study protocol, title and a list of investigational sites, IEC(s)/IRB(s) approvals, 
as well as other relevant documentation will be submitted, as applicable, to the local 
Regulatory Authorities for review and approval or notification prior to trial start. Upon 
completion, the Regulatory Authorities will be notified the study has ended, as applicable. 
The study will only be undertaken in compliance with the local regulatory requirements.
10.10 Informed Consent
A properly executed, written informed consent in compliance with current GCP guidelines 
and ICH guidelines shall be obtained from each volunteer prior to entering the study. A copy 
of the informed consent document to be used will be submitted by the Investigator to an 
independent institutional review board (e.g. IRB or ethics committee) and the Sponsor and/or 
its agent for review and approval prior to the start of the study. The Investigator shall provide 
a copy of the signed and dated informed consent to the subject, and a signed and dated copy 
shall be maintained in the volunteer’s medical record.
10.11 Trial Registration
This clinical trial will be registered in a publicly accessible database, which is a primary or 
partner registry of, or a data provider to, the international clinical trials registry platform of 
the World Health Organization (WHO ICTRP), before start of recruitment.
10.12 Disclosure and Publication of Clinical Study Data
The disclosure and publication of clinical study data will be detailed in the clinical trial 
agreement with the Investigators.
10.13 Financing and Insurance 
The study will be financed by Meda Pharma GmbH & Co. KG (A Viatris company). 
For all patients participating in the trial the Sponsor or the designated CRO has taken out a 
study-specific insurance in accordance with national legislation, covering liability of the 
Investigator and Sponsor for damages that occurred in relation to the study. Particular 
reference is made to the obligations of the insured patient participating in the study, such as 
immediate notification of any injury that might have occurred during the trial. For further 
relevant insurance conditions please refer to the copy of the policy and conditions in the TMF 
of the Sponsor and Investigator.
10.14 Quality assurance and management
This clinical study will be conducted in accordance with Standard Operating Procedures 
(SOP) of the Sponsor (and/or representatives thereof) and Cliantha Research, the 
requirements of International Council for Harmonisation Good Clinical Practice Guidelines 
(ICH GCP (E6 R2), principles provided in Helsinki Declaration, as well as in accordance 
with the applicable local legislation and regulations of the country where the study is being 


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conducted. Compliance with the requirements may be provided by audits of the 
investigational sites and the data obtained in the study. 
Audits and inspections may be carried out by the Sponsor's quality assurance department or 
its designee, local authorities, or authorities, to whom information on this study has been 
submitted. All documents pertinent to the study must be made available for such inspection 
after an adequate announcement. Informed consent of patients participating in this study has 
to include the consent to this access to source documents.
A Quality Management system based on a risk-based approach according to ICH GCP E6 (R 
2) addendum (R3) will be implemented to manage quality throughout all steps of the clinical 
trial. It will include identification of critical processes and data, identification,  evaluation, 
control, review and reporting of risks using appropriate tools in cooperation with the CRO. 
Risks will be periodically reviewed during the study.
10.15 End of Trial
The end of trial is considered to be the date of last subject last contact or the date of early 
termination of the study whichever is the later.
11.0
ADVERSE EVENTS AND SAFETY REPORTING
The adverse event collection period begins at signing of informed consent and continues until 
5 to 7 days after the last dose of study medication. Adverse events occurring during this 
period need to be reported to the sponsor according to Section ‘Collection and Recording of 
Adverse Events.’ The investigator is also responsible for notifying the sponsor if he/she 
becomes aware of any adverse event after the study period has ended and it is considered 
related to the study medication (i.e. an adverse drug reaction). Once an AE is detected, it 
should be followed until its resolution or until it is judged by the principal investigator to be 
stable or permanent.
11.1 Definitions
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. 
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory or physical findings, symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product whether or not considered related to the 
medicinal product.
Clinically significant changes from baseline in laboratory assessments, vital signs, and 
physical examination are to be recorded as adverse events. Clinically significant 
abnormalities include:

a result associated with accompanying signs/symptoms 


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
a result that requires additional diagnostic testing or medical/surgical intervention 

a result that leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy 

a result considered to be an adverse event by the investigator or sponsor
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event. Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event. 

An abnormal safety assessment (e.g. laboratory, vital signs, ECG) associated with a 
clinical diagnosis that has been recorded as an AE does not require a separate AE 
entry

Events meeting the definition of an AE also include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug or drug-food 
interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. (Please refer to Section ‘Special Situations‘ 
for further details) 

A symptom or medical complication related to a protocol-mandated intervention, 
including screening procedures
Serious Adverse Event
Adverse events are classified as serious or non-serious. A serious adverse event is any AE 
that is: 

fatal

life-threatening
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 

requires inpatient hospitalisation or prolongation of existing hospitalisation
Note: In patient hospitalization is defined as 24 hours in a hospital or an overnight stay. An 
elective hospital admission to treat a condition present before exposure to the study drug or a 
hospital admission for a diagnostic evaluation of an AE, does not qualify the condition or 
event as an SAE. Further, an overnight stay in the hospital that is only due to transportation, 
organization or accommodation problems and without medical background does not need to 
be considered an SAE.
Events NOT to be reported as SAEs are hospitalizations for the following: 
o
Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition 


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o
Treatment, which was elective or pre-planned, for a pre-existing condition that 
is unrelated to the indication under study and did not worsen 
o
Admission to a hospital or other institution for general care due to social or 
economic reasons (e.g., no access to local ambulatory medical care) 
o
Treatment on an emergency, outpatient basis for an event not fulfilling any of 
the definitions of serious given above and not resulting in hospital admission 
Hospitalization also does not include the following: Rehabilitation facilities, Hospice 
facilities, Respite care (e.g., caregiver relief), Skilled nursing facilities, Nursing homes 

results in persistent or significant disability or incapacity

a congenital anomaly or birth defect

an important medical event. 
o
Note: medical and scientific judgment should be exercised in deciding whether 
it is appropriate to consider other situations serious, such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject and / or may require 
intervention to prevent one of the other outcomes listed in the definition 
above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug 
abuse. 
o
The seriousness criterion of “medically significant” should only be selected 
when none of the other seriousness criteria apply to the event but the 
investigator still considers the event as serious.
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events. 
Treatment emergent adverse events
Any adverse event that occurs or worsens during a given period after the study medication 
has been administered. In the present cross-over study an AE is considered treatment 
emergent when occurring in the period from administration of study medication until 5 days 
(120 h) thereafter.
Adverse drug reaction
All noxious and unintended responses to an investigational product related to any dose of the 
investigational product should be considered adverse drug reactions (ADRs). The phrase 
“responses to an investigational product” means that a causal relationship between an 
investigational product and an AE is at least a reasonable possibility. All AEs judged by 
either the reporting Investigator or the Sponsor as having a reasonable causal relationship to 
an investigational product will be designated as ADRs.
All AEs, with the causal relationship to the study drug reported as “possible”, “probable” or 
“definite” will be considered ADRs. If the relationship to the study drug is not given, then the 
AE must be treated as if the relationship were “possible.”


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Expected/Unexpected adverse event
An expected AE is defined as one whose nature, severity or outcome is consistent with the 
applicable reference safety information described of the study drugs. 
An AE is to be considered unexpected if the nature, severity or outcome is not consistent with 
the applicable product reference safety information.
Preexisting Condition
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline medical history and not reported as an AE. A baseline or preexisting 
condition should be recorded as an adverse event only if the frequency, intensity, or the 
character of the condition worsens during the study period.
General Physical Examination Findings
Any new clinically significant findings/abnormalities that meet the definition of an adverse 
event must also be recorded and documented as an adverse event. 
Post-study Adverse Event/Serious Adverse Event
At the last scheduled contact with the subject the investigator should instruct each subject to 
report any subsequent event(s) that the subject, or the subject’s personal physician, believes 
might reasonably be related to participation in this study. The investigator should notify the 
study sponsor of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be related to this study. 
The sponsor should also be notified if the investigator becomes aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has 
participated in this study. 
11.2 Special Situations:
The following situations may by associated with a serious outcome and should be evaluated 
for expedited reporting to the sponsor.

Any diagnosis of Cancer or Neoplasm is to be reported as a serious adverse event.

Emergency Room Visits: Events that result in emergency room visits that do not 
result in admission to the hospital are not routinely considered to be serious events; 
however, these events should be evaluated for one of the other serious outcomes (e.g., 
life-threatening, other serious [medically significant] events).

Overdose: Overdose per se will not be reported as an AE/SAE unless this is an 
intentional overdose taken with possible suicidal/self-harming intent; this should be 
reported regardless of sequelae. signs and symptoms associated with accidental 
overdose are to be recorded as adverse events or as serious AEs. If adverse events 
associated with overdose fulfil any of the serious criteria (as defined in section 
‘Serious Adverse Event’), a completed SAE report form is required to be submitted.

Reports of Drug-drug interaction and Drug Abuse and Medication Errors: drug 
interactions or abuse of the study medication must be recorded as AEs. Medication 


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errors will be captured as protocol deviations while any associated signs or symptoms 
must be recorded as AEs on the CRF. In addition, any serious consequence of drug 
interactions, drug abuse, or medication error must be reported immediately if these 
fulfil any of the SAE criteria.
11.3 Collection and Recording of Adverse Events
During the Adverse Event Reporting Period, the PI or designee (trained qualified study clinic 
staff) will record all adverse events. At each contact with the subject, the investigator must 
seek information on adverse events by specific questioning and, as appropriate, by 
examination. Information on all adverse events should be recorded immediately in the source 
document, and in the appropriate adverse event module of the case report form (CRF). 
Information to be collected includes AE name or term (in standard medical terminology) and 
final diagnosis, event description, time and date of onset, clinician’s assessment of severity, 
seriousness, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), action taken with the study drug, treatment for the event and 
time (if available) and date of resolution/stabilization of the event.
Any findings from protocol specified safety assessments that are associated with the 
indication being studied are not to be reported as AEs or SAEs, unless judged by the 
investigator to be more severe than expected for the subject’s condition. 
All clearly related signs, symptoms, and abnormal results of diagnostic procedures should be 
grouped under one diagnosis on the CRF where possible and appropriate.
The clinical course of each event should be followed until resolution or stabilisation. Adverse 
events that are still ongoing at the end of the study period must be followed up to determine 
the outcome. Any adverse event that occurs after the study period and is related to the study 
treatment or study participation should be recorded; and if serious, the investigator should 
also immediately report it to the Sponsor.
11.4 Classification of an Adverse Event
11.4.1 Severity
The Investigator will assign a severity rating to each AE. For purposes of consistency, the 
following scale is to be used:
Grade 1 - MILD
Does not interfere with subject's usual function.
Grade 2 - MODERATE
Interferes to some extent with subject's usual function.
Grade 3 - SEVERE
Interferes significantly with subject's usual function.
It is important to distinguish between severe AEs and Serious AEs. Severity is a classification 
of intensity, whereas an SAE is an AE that meets any of the regulatory specified criteria (see 
definitions, Serious Adverse Event)


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11.4.2 Causality
For all adverse events, sufficient information should be obtained by the investigator to 
determine the causality of the adverse event. The investigator is required to assess causality 
of each AE.
An Investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an AE. The 
Investigator must make an assessment of the relationship of each AE (serious and non-
serious) to the study treatment(s) and record this relationship in the CRF.
Factors that need to be considered when making a causality assessment include: Temporal 
relationship, Clinical and pathological characteristics of the event(s), Pharmacological 
plausibility, Exclusion of confounding factors (medical and medication history), Drug 
interactions, De-challenge/re-challenge, Dose relationship.
A suspected relationship (definite, probable, possible) between the events and the study 
medication means, in general, that there are facts (evidence) or arguments to suggest a causal 
relationship. Receipt of additional or clarifying information may warrant reassessment of 
causality. The Investigator is responsible for assessing relationship of AEs to study treatment 
in accordance with the following definitions:
Category
Causality
Description
DEFINITE
Causal relationship is 
certain
For example: the temporal relationship 
between drug exposure and the adverse 
event (AE) onset/course is reasonable, 
there is a clinically compatible response to 
de-challenge, other causes have been 
eliminated; the event must be definitive 
pharmacologically or phenomenologically, 
using a satisfactory re-challenge procedure 
if necessary.
PROBABLE
High degree of certainty 
for causal relationship
For example: the temporal relationship 
between drug exposure and AE 
onset/course is reasonable, there is a 
clinically compatible response to de-
challenge (re-challenge is not required), 
and other causes have been eliminated or 
are unlikely.
POSSIBLE
Causal relationship is 
uncertain
For example: the temporal relationship
between study treatment exposure and the 
AE onset/course is reasonable or 
unknown, dechallenge information is 
either unknown or


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equivocal; could also be explained by 
disease or other drugs.
UNLIKELY
Causal relationship is
improbable
Another explanation is more likely such as 
disease, environment, or other medication.
Does not represent a known reaction to 
study drug.
UNRELATED/NOT 
RELATED
No possible relationship
The temporal relationship between drug 
exposure and the AE onset/course is 
unreasonable or incompatible, or a causal 
relationship to study drug is impossible
For SAEs, if the relationship to the study treatment(s) is considered to be unlikely or not 
related, an alternative suspected etiology should be provided when possible (e.g., 
concomitant medications, intercurrent illness/events, study-related procedure).
11.4.3 Expectedness
The Sponsor or its designated representative will be responsible for determining whether an 
AE is expected or unexpected based on the reference safety information. The reference safety 
information mentioned in the approved Canadian Product Monograph (M1) will be used in 
this study for the expectedness assessment of SAEs.
11.4.4 Outcome
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Sponsor or its 
designated representative.
The outcome at the time of last observation will be classified as:
RECOVERED/RESOLVED where the subject recuperated and is free of any pathological 
conditions resulting from the prior disease or injury.
RECOVERED WITH SEQUELAE where the subject recuperated but retained pathological 
conditions resulting from the prior disease or injury. 
NOT RECOVERED/NOT RESOLVED (i.e. ongoing) where the subject has not recuperated 
from the condition or injury and the event is still considered ongoing
RECOVERING where the subject has begun to recuperate from the condition or injury but 
the event is considered ongoing at a reduced intensity


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FATAL the condition or injury results in the subject’s death. The investigator should identify 
the principal cause of death and assign Fatal outcome to that event. Other concurrent ongoing 
AE/SAEs present at the time of death would remain Not recovered/Not resolved.
UNKNOWN can be selected if none of the other situations apply or are known. Follow-up 
should be conducted to obtain one of the preceding outcomes.
11.4.5 Action Taken with the Study Treatment
Action
Description
Treatment interrupted
The treatment was temporarily discontinued
Treatment withdrawn
The treatment was permanently discontinued
Unknown
Not known, not observed, not recorded, or refused
No action taken
The AE did not result in any modification of dose or 
frequency of dosing
Not applicable
The AE occurred prior to first dose or following last 
scheduled dose
11.5 Reporting of Serious Adverse Events and Pregnancy Exposures
Investigators and the Sponsor or its designated representative must conform to the serious 
adverse event reporting timelines, formats and requirements of the various entities to which 
they are responsible. 
11.5.1 Investigator reporting: notifying the study sponsor
Immediate notification of SAEs by the investigator to Viatris PSRM is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
Viatris will comply with country specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Serious adverse events must be reported to the study sponsor within 24 hours of awareness. 
To report such events, a Serious Adverse Event (SAE) Report form must be completed and 
signed by the investigator or designee and forwarded to:
Viatris Global Product Safety and Risk Management (PSRM) 
Email: 
(primary)
Fax: 
(secondary)


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If the initial notification using the completed ‘SAE report form’ is not possible, the 
notification may be made via email/fax or over telephone with the following minimum 
necessary information

Study identifier

Study Center

Subject number

A description of the event

Current status (outcome of event-if known 
and 
whether 
study 
medication 
is 
continuing)

The reason why the event is classified as 
serious

Investigator assessment of the causality 
between the event and study treatment
The investigator should provide further information on the Serious Adverse Event as soon as 
possible, preferably within 48 hours of awareness. This should include a copy of the 
completed SAE Report form, and any other diagnostic information and medical records that 
will assist in the understanding of the event.
Subject identifying information must not be visible on SAE forms or any supporting 
documentation provided by the Investigator. Any information that could be used to identify 
the subject (e.g. name, address, medical record number) must be de-identified before 
submission to Viatris or its designee. The subject’s study specific ID number should be 
recorded on every page of documentation forwarded to the sponsor.
The PI should provide the final diagnosis as the SAE term whenever possible in the SAE 
report form and CRF. The signs and symptoms should be provided in the narrative only, not 
as SAE terms. The PI should only list all signs and symptoms as SAE terms if no diagnosis is 
available at the time of report.
11.5.2 Follow-up
New information and any important missing information from prior reports on a serious 
adverse event must be provided promptly to the study sponsor. In addition, the Investigator 
may be requested by Viatris/designee to obtain specific additional follow-up information in 
an expedited fashion. The investigator should respond to targeted follow-up requests as soon 
as possible and preferably within 48 hours from receipt of the request.
11.5.3 Investigator reporting: Notification of Ethics Committee
Investigators are responsible for safety reporting to their local Ethics Committee (LEC) and 
complying with their local EC’s reporting requirements. Copies of each report and 
documentation of LEC notification and receipt will be kept in the investigator’s study file.
11.5.4 Investigator Reporting of Pregnancy - notifying the study sponsor 
All subjects who participate in the study should be counseled on the need to practice adequate 
birth control and on the importance of avoiding pregnancy during study participation as 
detailed in the inclusion and exclusion criteria. Pregnancy testing will be conducted 
throughout the study, as detailed in the schedule of assessments.


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A subject who is found to be pregnant at the screening visit will be excluded from the study 
and will be a screening failure. 
Subjects who have been enrolled in the study should be instructed to contact the Investigator 
or study staff immediately if pregnancy occurs or is suspected. Early termination visit 
assessments are required as soon as possible after learning of the pregnancy. Pregnant 
females will be discontinued from study treatment by the Investigator. A male that has a 
partner that becomes pregnant during the study will not be discontinued from study treatment. 
Details of the pregnancy should be recorded on the Pregnancy Report form and reported to 
Viatris PSRM within 24 hours of awareness by email 
 (primary) or 
facsimile 
 from the time of initial awareness, even if beyond the closure of 
the clinical database. 
The Investigator is also responsible for following the pregnancy every 3 months or until 
delivery or termination and informing the Sponsor about its outcome. Reports where the 
embryo or foetus may have been exposed to the study drug(s), should be followed-up in order 
to collect information on the:

outcome of the pregnancy,

outcome for both mother and foetus (malformation/anomalies diagnosed since initial 
report)

development of the child after birth (developmental assessment, infant illnesses, 
hospitalisations, drug therapies, breastfeeding)
Healthy newborns should be followed-up at 1 month after birth to confirm no congenital 
anomalies were subsequently detected (if possible).
While pregnancy itself is not considered an AE or SAE, any pregnancy complication or 
termination of a pregnancy for medical reasons will be recorded as an AE or an SAE. A 
spontaneous abortion is always considered to be a SAE and will be reported to the Sponsor.
Elective termination (i.e., without medical reasons) of an uncomplicated pregnancy is 
considered an elective procedure and not an AE; nevertheless, Viatris requests the outcome 
(e.g., elective termination) be reported within 24 hours of awareness and sent as a follow-up 
on the Delivery and Infant Follow-up Form). 
Any SAE occurring in association with a pregnancy brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as at least 
possibly related to the study treatment, must be promptly reported to Viatris PSRM.
If the study center becomes aware of a pregnancy in a female partner of a male subject, study 
personnel should contact their clinical research associate to obtain a partner pregnancy ICF. 
Consent of the pregnant partner must be obtained before any details of the pregnancy can be 
shared with Viatris or its designated representative. If the pregnant partner provides consent 
to have the pregnancy followed, the study center should collect the information specified on 
the Pregnancy Report form and forward the completed form to Viatris PSRM every 3 months 
until the pregnancy outcome has been obtained. 


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12.0
REFERENCE LIST
12.1
Published Literature
Bousquet J, Meltzer EO, Couroux P, Koltun A, Kopietz F, Munzel U, Kuhl HC, Nguyen DT, 
Salapatek AM, Price D. Onset of Action of the Fixed Combination Intranasal Azelastine-
Fluticasone Propionate in an Allergen Exposure Chamber. J Allergy Clin Immunol Pract. 
2018 Sep - Oct;6(5):1726-1732.e6.
Bousquet J, Schünemann HJ, Togias A et al. Allergic Rhinitis and Its Impact on Asthma 
Working Group. Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) 
guidelines for allergic rhinitis based on Grading of Recommendations Assessment, 
Development and Evaluation (GRADE) and real-world evidence. J Allergy Clin Immunol. 
2020 Jan;145(1):70-80.e3.
Day, J. H., Ellis, A. K., Rafeiro, E., Ratz, J. D. & Briscoe, M. P. Experimental models for the 
evaluation of treatment of allergic rhinitis. Ann. Allergy. Asthma Immunol. 96, 263–277; 
quiz 277–278, 315 (2006).
Dixon, A. E. et al. Allergic rhinitis and sinusitis in asthma*: Differential effects on symptoms 
and pulmonary function. Chest 130, 429–435 (2006).
Hellings PW, Dobbels F, Denhaerynck K, Piessens M, Ceuppens JL, De Geest S. Explorative 
study on patient's perceived knowledge level, expectations, preferences and fear of side 
effects for treatment for allergic rhinitis. Clin Transl Allergy. 2012 May 29;2(1):9
Ihler, F. & Canis, M. Ragweed-induced allergic rhinoconjunctivitis: current and emerging 
treatment options. J. Asthma Allergy 8, 15–24 (2015).
Jacobs, R. L. et al. Responses to ragweed pollen in a pollen challenge chamber versus seasonal 
exposure identify allergic rhinoconjunctivitis endotypes. J. Allergy Clin. Immunol. 130, 122–
127.e8 (2012).
Kim, H., Bouchard, J. & Renzix, P. M. The link between allergic rhinitis and asthma: A role for 
antileukotrienes? Can. Respir. J. 15, 91–98 (2008).
Min, Y.-G. The Pathophysiology, Diagnosis and Treatment of Allergic Rhinitis. Allergy. 
Asthma Immunol. Res. 2, 65–76 (2010).
Pawankar, R., Mori, S., Ozu, C. & Kimura, S. Overview on the pathomechanisms of allergic 
rhinitis. Asia Pac. Allergy 1, 157–167 (2011).
Pipet, A., Botturi, K., Pinot, D., Vervloet, D. & Magnan, A. Allergen-specific immunotherapy in 
allergic rhinitis and asthma. Mechanisms and proof of efficacy. Respir. Med. 103, 800–812 
(2009). 
Sin, B. & Togias, A. Pathophysiology of Allergic and Nonallergic Rhinitis. Proc. Am. Thorac. 
Soc. 8, 106–114 (2011).
Small, P. & Kim, H. Allergic rhinitis. Allergy Asthma. Clin. Immunol. 7 Suppl 1, S3 (2011).
Stewart, M., Ferguson, B. J. & Fromer, L. Epidemiology and burden of nasal congestion. Int. J. 
Gen. Med. 3, 37–45 (2010).


Protocol AZFL-AES-4-001 / C1D00571
Page 80 of 80
Version 3.0, 27 Jul 2021
Confidential
12.2
Product Information 
M1
Canada : Product Monograph Dymista, Azelastine Hydrochloride and Fluticasone Propionate 
Suspension Nasal Spray, 137 mcg/50 mcg per metered spray. BGP Pharma ULC. Date of 
Revision: October 3, 2019. 
M2
US : Prescribing Information Dymista (azelastine hydrochloride and fluticasone propionate) 
nasal spray, for intranasal use. MEDA Pharmaceuticals Inc. Revised : 9/2018 
12.3
Regulatory Documents 
R1
FDA: Allergic Rhinitis: Developing Drug Products for Treatment. Guidance for Industry 
September 2018
R2
World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research 
Involving Human Subjects, amended by the 64th WMA General Assembly, Fortaleza 2013
R3
ICH E6 (R2): Guideline for Good Clinical Practice (Step 4: November 2016, step 5 (EU: 
CPMP/ICH/135/95: Note for Guidance on Good Clinical Practice)
R4
Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 
on the protection of natural persons with regard to the processing of personal data and on the 
free movement of such data, and repealing Directive 95/46/EC (General Data Protection 
Regulation) Official Journal of the European Union, Vol. L119 (4 May 2016), pp. 1-88
R5
Food and Drug Regulations (C.R.C., c. 870), Health Canada. Available at https://laws-
lois.justice.gc.ca/eng/regulations/c.r.c.,_c._870/page-1.html accessed on 8 Oct 2020.
R6
FDA : Code of Federal Regulations (CFR), Title 21, 21: Part 11 (October 6, 2020)
12.4
Other Proprietary Study Reports and Documents 
O1
Study X-03065-3311 
Authors: 
 
Principle investigator: 
 
Title: Clinical trial to assess onset of action of azelastine hydrochloride and fluticasone 
propionate nasal spray delivered in a single spray (MP-AzeFlu) in the treatment of allergen-
induced allergic rhinitis symptoms in comparison to placebo and free combination of 
fluticasone propionate nasal spray and oral loratadine Sponsor: MEDA Pharma GmbH & Co. 
KG, Report No.: 


Document Name : Protocol - AZFL-AES-4-001 - 001277005
Title : AZFL-AES-4-001 Protocol
Status : Approved
Electronic Signatures
User
Date
Justification
03-Aug-2021
15:46:47
Reviewer
03-Aug-2021
15:51:58
Author
03-Aug-2021
16:06:49
Approver
04-Aug-2021
01:16:18
Reviewer
04-Aug-2021
03:21:07
Reviewer
04-Aug-2021
04:04:06
Approver
05-Aug-2021
03:09:34
Reviewer

SAP_001.pdf: 
Statistical Analysis Plan 
Protocol No.: AZFL-AES-4-001 
Dymista 
SAP Version: 
V02 
Date: 01 Mar 22 
Page 1 of 23 
CONFIDENTIAL 
 STATISTICAL ANALYSIS PLAN 
Clinical Trial to Assess Onset of Action of Azelastine Hydrochloride and Fluticasone 
Propionate Nasal Spray Delivered in a Single Spray (Dymista) in the Treatment of 
Allergen-Induced Allergic Rhinitis Symptoms in Comparison to Placebo in an 
Environmental Exposure Unit (EEU). 
Clinical Study Protocol No. AZFL-AES-4-001 
(Version 3.0, dated 27 Jul 2021) 
Sponsored By: 
 Meda Pharma GmbH & Co.  
KG (A Viatris Company)  
Benzstrasse 1, 61352 Bad Homburg, 
 Germany  
Prepared By: 
Cliantha Research Limited 
Garden View Corporate House No.7 
Opp. AUDA Garden, Bodakdev, 
Ahmedabad – 380054, INDIA. 
T: +91-79-68221100 
Confidential and restricted circulation. 
This document contains confidential information of Cliantha Research and Viatris. 
Any viewing or disclosure of such information that is not authorized in writing by 
Cliantha Research or Viatris is strictly prohibited.  Such information may be used 
solely for the purpose of reviewing or performing this study. 
ClinicalTrials.gov Identifier: NCT04652245


 
Statistical Analysis Plan 
Protocol No.: AZFL-AES-4-001 
Dymista 
SAP Version: 
V02 
Date: 01 Mar 22 
Page 2 of 23 
 
 
CONFIDENTIAL 
 
 
 
SIGNATURE PAGE 
 
 
CRO’s Signatory 
Department: Biostatistics & Programming 
 
Name 
Prepared by 
Reviewed by 
 
 
Designation 
Biostatistician 
 Biometrics 
Signature & Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Protocol No.: AZFL-AES-4-001 
Dymista 
SAP Version: 
V02 
Date: 01 Mar 22 
Page 3 of 23 
 
 
CONFIDENTIAL 
 
 
 
 
Sponsor’s Signatory 
Meda Pharma GmbH & Co KG. 
Approved by 
Name 
  
 
Designation 
Statistician 
  
Signature & Date 
Name 
 
 
Designation 
Clinical Science Study 
 
 
Signature & Date 
 
 
 
Revision History 
VERSION DATE 
DESCRIPTION OF REVISIONS 
REVISED BY 
D01 
01 Jul 2021 
NA (first version) 
Cliantha 
D02 
02 Aug 2021 
Incorporation of Sponsor review 
Cliantha 
D03 
26 Aug 2021 
Incorporation of Sponsor review 
Cliantha 
D04 
30 Sep 2021 
Incorporation of Sponsor review 
Cliantha 
D05 
06 Oct 2021 
Incorporation of Sponsor review 
Cliantha 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan 
Protocol No.: AZFL-AES-4-001 
Dymista 
SAP Version: 
V02 
Date: 01 Mar 22 
Page 4 of 23 
 
 
CONFIDENTIAL 
 
 
V01 
24 Nov 2021 
Approved version for interim blind 
data review 
Cliantha/Viatris 
D1.1 
07 Feb 2021 
Incorporation of Sponsor Review, 
Update after interim blind data 
review 
Cliantha/Viatris 
D1.2 
26 Feb 2021 
Final review 
Cliantha/Viatris 
V02 
01 Mar 2022 
Approved version for final analysis  Cliantha 


Statistical Analysis Plan 
Protocol No.: AZFL-AES-4-001 
Dymista 
SAP Version: 
V02 
Date: 01 Mar 22 
Page 5 of 23 
CONFIDENTIAL 
TABLE OF CONTENTS 
List of Abbreviations and Definition of Terms....................................................................7 
1.
Introduction to the Statistical Analysis Plan ............................................................8 
2.
Objective of the Study .............................................................................................8 
2.1 
Primary Objective: ..............................................................................................8 
2.2 
Secondary Objectives: .........................................................................................8 
3.
Investigational Plan ..................................................................................................9 
3.1 
Overall Study Design ..........................................................................................9 
3.2 
Investigational Medicinal Products: ....................................................................9 
3.3 
Randomization Procedure ...................................................................................9 
3.4 
Sample Size Justification ....................................................................................9 
3.5 
Schedule of Events ............................................................................................10 
3.6 
Change to Analysis from Protocol ....................................................................10 
3.7 
Analysis Populations .........................................................................................10 
3.7.1 
Safety (SAF) population .......................................................................10 
3.7.2 
Full Analysis Set (FAS) Population .....................................................10 
3.7.3 
Per-Protocol (PP) Population................................................................11 
3.7.4 
FAS Subset with Moderate/Severe Ocular Symptoms .........................11 
3.8 
Population Derivation .......................................................................................11 
4.
Efficacy and Safety Variables ................................................................................11 
4.1 
Primary Efficacy Endpoint ................................................................................11 
4.2 
Secondary Efficacy Endpoints ..........................................................................11 
4.2.1 
Efficacy: ................................................................................................11 
4.2.2 
Safety and tolerability: ..........................................................................12 
4.3 
Safety Variables ................................................................................................12 
5.
Statistical Considerations .......................................................................................12 
5.1 
General Considerations .....................................................................................12 
5.2 
Derived Variable ...............................................................................................12 
5.3 
Reporting Precision ...........................................................................................13 
5.4 
Multiple Comparison/ Multiplicity ...................................................................13 
5.5 
Handling of  missing data..................................................................................13 
5.6 
Interim Analysis ................................................................................................14 
6.
Statistical Analysis .................................................................................................14 
6.1 
Subject Disposition and Withdrawals ...............................................................14 
6.2 
Demographic Characteristics ............................................................................15 
6.3 
Primary Efficacy Analysis ................................................................................15 
6.4 
Secondary Efficacy Analysis ............................................................................16 
6.4.1 
Efficacy: ................................................................................................16 
6.4.2 
Subgroup Analysis:...............................................................................18 
6.5 
Safety and Tolerability Assessment ..................................................................18 
6.5.1 
Overall Summary of AEs and TEAEs ..................................................18 
6.5.2 
Summary of TEAEs by SOC, PT .........................................................18 


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6.5.3 
Summary of SAE by SOC, PT .............................................................19 
6.5.4 
Summary of TEAE leading to discontinuation by SOC, PT ................19 
6.5.5 
Summary of TEAE leading to death by SOC, PT ................................19 
6.5.6 
Summary of incidence of TEAE by relatedness to study drug.............19 
6.5.7 
Summary of incidence of TEAE of any causality by treatment, SOC, 
PT and Severity ......................................................................................................19 
6.5.8 
Vital Signs ............................................................................................19 
6.5.9 
Laboratory Parameters ..........................................................................20 
6.6 
Physical Examination ........................................................................................20 
6.7 
Protocol Deviation.............................................................................................20 
6.8 
Medical and Social History ...............................................................................20 
6.9 
Prior and Concomitant Medication ...................................................................20 
6.10 
Rescue Medication .......................................................................................21 
7.
Summary of Analyses ............................................................................................22 
8.
Data Management Considerations .........................................................................23 
9.
Tables, Listings and Figures ..................................................................................23 
10.
References ..............................................................................................................23 


Statistical Analysis Plan 
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CONFIDENTIAL 
List of Abbreviations and Definition of Terms 
ANCOVA 
Analysis of Co-Variance 
AE 
Adverse Event 
BDR 
Blinded Data Review 
CI 
Confidence Interval 
COVID 
Corona Virus Disease 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CTP 
Clinical Trial Protocol 
DBL 
Data Base Lock 
EDC 
Electronic Data Capture 
EEU 
Environmental Exposure Unit  
EOS 
End of Study  
EOT 
End of Treatment 
ET 
Early Termination 
FAS 
Full Analysis Set (Population) 
ICH 
International Council for Harmonization 
IMPs 
Investigational Medicinal Products 
ITT 
Intent-to-Treat (Population)  
LSM 
Least Square Means 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
OOW 
Out Of Window 
PP 
Per Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAF 
Safety (Population) 
SAR 
Seasonal Allergic Rhinitis  
SD 
Standard Deviation  
SE 
Standard Error  
SOC 
System Organ Class 
T7SS 
Total 7 Symptom Score (TNSS + TOSS)  
TEAE 
Treatment Emergent Adverse Event  
TLFs 
Table Listing Figures 
TNSS 
Total Nasal Symptom Score  
TOSS 
Total Ocular Symptom Score 
OTC 
Over the Counter 
WHODrug 
World Health Organization Drug Global 


 
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1. Introduction to the Statistical Analysis Plan 
This Statistical Analysis Plan (SAP) provides a thorough description of statistical 
analysis methods and presentation of the study data from the clinical trial described in 
Study Protocol AZFL-AES-4-001, (Version no. 3.0) dated 27 Jul 2021.  
The SAP will be finalized prior to database lock (DBL) and statistical methods 
described in this document supersede the statistical section mentioned in the study 
protocol. Deviations to the protocol are described in section 3.6, if any. 
Mock shells for Table, Listing & Figure (TLFs) are only for template purpose, 
modifications might be done in final TLFs as identified during the review of data to 
have meaningful presentation of data.  
2. Objective of the Study  
The objectives of this study are:  
2.1 Primary Objective: 
· To assess the onset of action of a fixed combination of azelastine hydrochloride 
and fluticasone propionate nasal spray (Dymista) in relieving the nasal symptoms 
of seasonal allergic rhinitis (SAR) induced by an allergen challenge in an 
Environmental Exposure Unit (EEU)  
2.2 Secondary Objectives: 
· To assess onset of action of Dymista in relieving the ocular symptoms of SAR 
induced by an allergen challenge in an EEU  
 
· To assess onset of action of Dymista in relieving the combined nasal and ocular 
symptoms of SAR induced by an allergen challenge in an EEU  
 
· To compare overall efficacy (0-4 hours after dosing) of Dymista in relieving the 
nasal symptoms (TNSS) with that of placebo  
 
· To compare overall efficacy (0-4 hours after dosing) of Dymista in relieving the 
ocular symptoms (TOSS) with that of placebo  
 
· To compare overall efficacy (0-4 hours after dosing) of Dymista in relieving the 
combined nasal and ocular symptoms (T7SS) with that of placebo  
 
· To compare overall efficacy (0-4 hours after dosing) of Dymista in relieving the 
individual nasal and ocular symptoms with that of placebo  
 
· To evaluate time to relevant response to therapy (30% and 50% reduction of 
TNSS)  
 


 
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3. Investigational Plan 
3.1 Overall Study Design 
This study is a therapeutic study performed as a single-center, randomized, placebo-
controlled, double-blind, and two-period cross-over trial.  
The aim of the current study is to replicate the results of the fast onset of action for 
Dymista from study X-03065-3311 in a second onset of action study using an EEU 
model with a similar design but without an active control.  
An EEU is used to promote a uniform aerosolization of allergen over time in a highly 
controlled manner. As the assessments will be conducted with limited confounding 
environmental factors and with consistent allergen exposure, the use of an EEU model 
is expected to provide a more effective method to assess the onset of efficacy of 
Dymista compared to a field trial. 
 
3.2 Investigational Medicinal Products: 
Subjects were randomized to receive either one of the treatment sequence as AB or 
BA.  
Period 1 (Visit 3) 
Period 2 (Visit 5)  
Treatment A: One spray in each nostril of 
Dymista nasal spray for a total dose of 
274 mcg azelastine hydrochloride plus 
100 mcg of fluticasone propionate 
Treatment B: One spray in each nostril of 
placebo nasal spray  
Treatment B: One spray in each nostril of 
placebo nasal spray  
Treatment A: One spray in each nostril of 
Dymista nasal spray for a total dose of 
274 mcg azelastine hydrochloride plus 
100 mcg of fluticasone propionate 
The blinded study treatment was given to suitable subjects on Visits 3 and 5 
approximately 2.5 hours after the start of the EEU session.  
3.3 Randomization Procedure 
To be eligible for Randomization (Visit 3) a subject must comply with all inclusion 
criteria and must not meet any of the exclusion criteria for randomization mentioned 
in protocol sections # 4.2.1 and 4.2.2.  
3.4 Sample Size Justification 
 
 
 


 
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 a total of 216 randomized subjects should be included in this study. 
  
 
 
 
3.5 Schedule of Events 
The study visit schedule can be found in Table 0-1 of the protocol (Version 3.0: 27 
Jul, 2021). 
3.6 Change to Analysis from Protocol 
The following minor changes from the CTP were decided during the blind data 
review meeting:  
· It was decided to draw the figures with absolute values with standard deviation 
as error bar instead of standard error of means. The reason is, that SEM will be 
displayed already at the change from baseline figures and different error bars 
will provide more information.  
· Additional to the specification of the protocol, all symptom score assessments, 
which are out of the defined time windows as defined in the CTP, should be 
excluded from the per protocol analysis for the respective timepoint (compare 
also section 5.7).  
· Additional to the specification of the protocol, all patients, who do not have 
assessments for both periods in this cross over study (e.g., due to early 
discontinuation), should be excluded from the per protocol population. 
 
3.7 Analysis Populations 
3.7.1 Safety (SAF) population 
All subjects having received at least one dose of the study treatment. The SAF will be 
used for the analysis of safety data and subjects will be categorized according to the 
treatment that they actually received. In case the actually received treatment is not 
documented or could not unambiguously stated, the corresponding treatment period 
will be assigned to the active treatment and all safety analyses will be done with this 
classification. The denominator for incidences of AEs will not be changed.  
3.7.2 Full Analysis Set (FAS) Population 
This will be the intention to treat (ITT) population. These are all randomized subjects 
including subjects who receive incorrect treatment, do not complete the study or do 
not comply to the protocol, and who are randomized but did not take any study 
medication. 


 
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CONFIDENTIAL 
 
 
3.7.3 Per-Protocol (PP) Population 
The per-protocol (PP) set of subjects will be a subset of the FAS population excluding 
the subjects with major protocol violations that may affect the results of the primary 
efficacy endpoint. For out-of-window assessments see also section 5.7. 
Additionally, all patients who do not have assessments for both periods in this cross 
over study will be excluded from per protocol population. 
3.7.4 FAS Subset with Moderate/Severe Ocular Symptoms 
All FAS subjects with baseline TOSS at Visit 3 ≥4 (moderate or severe). 
3.8 Population Derivation 
Conditions for the population derivation: 
1) Has the subject been randomized? = “Yes” 
Subjects who satisfy conditions # 1 will be considered in FAS population. 
2) Subjects with baseline TOSS at Visit 3 is ≥4. 
Subjects who are in FAS population and satisfy condition # 2 will considered in FAS 
subgroup population. 
3) Date of dosing must be available for at least one visit (visit 3 and/or visit 5). 
Subjects who satisfy condition # 3 will be considered in Safety (SAF) population. 
4) Subjects should not have major protocol violations that may affect the results of the 
primary variables (as discussed in the blind data review meeting and stated in the 
blind data review report). Subjects should have data for both treatment periods of this 
cross over study. 
Subjects who are in the FAS population and satisfy conditions # 4 will be considered 
in PP population. 
4. Efficacy and Safety Variables 
4.1 Primary Efficacy Endpoint 
For onset of action assessment:  
· Changes from baseline in TNSS at each post-dose assessment time point (0 to 
4 hours p.a.)  
4.2 Secondary Efficacy Endpoints 
4.2.1 Efficacy: 
· Changes from baseline in TOSS and total 7 symptoms score (T7SS) at each 
post-dose assessment time point (0 to 4 hours p.a.). 
· Absolute values (time courses) of TNSS, TOSS, and T7SS during the 6.5-hour 
EEU session.  
· Change from baseline in individual nasal symptom scores (itchy nose, nasal 
congestion, runny nose, sneezing) and ocular symptom scores (itchy eyes, 


 
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CONFIDENTIAL 
 
 
watery eyes, eye redness) at each post-dose assessment time point (0 to 4 
hours p.a.). 
 
4.2.2 Safety and tolerability: 
· Adverse events (AEs)  
· Vital signs  
4.3  Safety Variables 
Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs). 
5. Statistical Considerations 
5.1 General Considerations 
General considerations are as follows: 
· Continuous variables will be summarized by descriptive statistics (Number of 
subjects, number of subjects with missing data, mean, median, standard deviation 
(SD) and range) and for categorical variables will be summarized as frequencies 
and percentages. 
· For all endpoints, baseline is defined per period as the average of the last 2 
assessments (105 and 120 min) in the EEU prior to dosing with study treatment. 
In case one of these two assessments is missing, the baseline will be the remaining 
value. 
· All the statistical analyses will be conducted at 5% alpha level of significance 
unless specified. 
· For Tables, Listings and Figures preparation, SAS® software (SAS institute, Inc. 
Cary, USA) version 9.4 or higher will be used.  
5.2 Derived Variable 
Following derivations will be utilized throughout the study. Formula used for 
calculation will be displayed in footnote of the table. 
 
· Change from baseline = Post Baseline value – Baseline value  
 
· TNSS = Itchy nose + nasal congestion + runny nose + sneezing 
 
· TOSS = Itchy eyes + watery eyes + eye redness 
 
· T7SS = TNSS + TOSS 
 
· %Reduction in TNSS = (change from baseline for TNSS / Baseline TNSS 
value)*100 
 
·  Time to 30% reduction in TNSS = first time point when the %Reduction is equal 
or more than 30% 


 
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· Time to 50% reduction in TNSS = first time point when the %Reduction is equal 
or more than 50% 
 
· Prior Medication = Medication consumed by subject prior to screening (Visit 1). 
 
· Concomitant Medication = Medication consumed by subject from signing 
informed consent to post-study follow-up. 
 
· Prior & Concomitant Medication = Medication consumed by subject prior to 
screening (Visit 1) and/or during the study period. 
 
5.3 Reporting Precision 
All outputs will be generated based on the specifications mentioned in the document 
of Mock TLFs. 
Summary statistics will be presented to the following degree of precision: 
Statistic 
Degree of Precision 
Mean and Median  
One more decimal place than the raw data 
Minimum and Maximum 
Same as the raw data 
Standard deviation, Standard error  
Two more decimal places than the raw data 
Percentage 
One decimal places 
p-value 
Four decimal places or as <.0001 
Examples for the Decimal Places: 
If percentage value is 0 or 100, it will be reported as ‘0’ and ‘100’ respectively. 
Ratios and/or Confidence Interval (CI) will be reported with at least 2 decimal places 
(e.g. xx.xx, (xx.xx, xx.xx)). 
5.4 Multiple Comparison/ Multiplicity 
 
 
5.5 Handling of missing data 
In case of a missing value at time point 105 min or 120 min which are required for 
baseline calculation, please see section 5.1. 
In an event of a single missing symptom item (1 out of 4 nasal symptoms per 
assessment or 1 out of 3 ocular symptoms missing), this will be replaced by the 
average of the previous and the following time point of this symptom item, if these 
two were present for the patient. In an event that before this replacement, two or more 
symptom items were missing or after this replacement one or more symptoms were 
still missing, the TNSS/TOSS at this time point will be regarded as missing.  


 
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This rule is not applicable for values used for baseline calculation and first assessed 
timepoint post dose (105 min, 120min pre-dose, 5 min post dose). 
T7SS will be calculated as the sum of the TNSS and TOSS. In an event that one or 
both of these is missing, the T7SS at this time point will be missing, too. 
 
5.6 Interim Analysis 
There is no interim analysis planned for the study. 
5.7 Out of window assessments 
Definition of out of window deviations. 
The primary endpoint of this study is the Total Nasal Symptom score (TNSS) 
including 4 nasal symptoms. All scheduled assessments should be conducted during 
the time windows specified in the CTP.  
However, as there are some assessments outside the defined windows a more precise 
definition of out-of-window-deviations is given in the following: 
If at least one of the 4 nasal symptoms is assessed inside the defined windows, which 
is specified in the CTP for the respective time point, the complete assessment of the 
TNSS (all 4 symptoms) is regarded as inside the window. In other words, only if all 4 
nasal symptoms are assessed outside the defined window for the respective time point 
the TNSS score will be classified as out-of-window (OOW). This is applicable for all 
nasal symptoms, all time points and irrespective if the assessment is before or after 
the defined window.  
 
Handling of out-of-window assessments: 
It is regarded, out-of-window assessments for single time points are considered minor 
in the sense, that this does not justify an exclusion of all assessments of this patient 
from per protocol analysis who otherwise assessed scores within the assessment 
windows at other timepoints.  
However, as the primary endpoint is a time-related assessment it is not deemed 
justified, that out of window deviations should be included in the per protocol 
analysis. Therefore, all OOW assessments will be excluded from the per protocol 
analysis of TNSS for the affected time points. Within window assessments of the 
same patient will be included for the analyses of other time points.  
The OOW assessments for a specified timepoint will be handled like missed 
assessments for the per protocol analysis of TNSS at this timepoint.  
Missed assessments: 
It is regarded, that missed assessments of single time points are considered minor and 
that it is not regarded as violation, which justifies the exclusion of the patient from the 
per protocol analysis. However, as there is no replacement of missing data, the 
missing timepoint will be kept as missing in the analysis of this specified time point.  
6. Statistical Analysis 
6.1 Subject Disposition and Withdrawals 
Frequency only of the following categories will be displayed as overall:  


 
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· Number of screening events (provided informed consents, since study protocol 
allows rescreening, a unique subject may have 1 to 2 screening events). 
· Number of unique subjects screened 
· Number of screen failure events by reason 
 
Following categories will be presented as overall using frequency and percentages: 
· Number of subjects in FAS Population 
· Number of subjects in Safety (SAF) Population 
· Number of subjects in PP Population 
· Number of subjects in FAS Subset Population 
· Number of subjects who completed the study 
· Subjects who discontinued early, as well as reasons for subject discontinuation 
 
The denominators for the percent calculations will be overall number of randomized 
subjects. 
Subjects’ discontinuation status will be listed by last administered treatment and will 
include subject number, date of completion or discontinuation and specific reason for 
discontinuation. 
6.2 Demographic Characteristics  
Demographic characteristics will be collected at screening. 
Demographic characteristics (age, sex, ethnic origin, race, height, body weight and 
BMI) will be summarized by number of subjects (n), mean, standard deviation, 
median, minimum and maximum for the continuous variables and number of subjects 
and percent of subjects for categorical variables. 
Demographic characteristics data will also be listed and summarized for Safety and 
FAS population. 
6.3 Primary Efficacy Analysis  
The primary endpoint of the study is, 
· 
Changes from baseline in TNSS at each post-dose assessment time point (0 to 4 
hours p.a.)  
 
 
 
 
 
 
  


 
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The onset of action is defined as the first time point after initiation of treatment when 
the product demonstrates a greater change from baseline compared to the placebo, 
which proves durable from this time point until the end of the last assessed time point 
(4h) of this study.  
Primary efficacy analysis will be performed on FAS population and sensitivity 
analysis of the primary efficacy endpoint will be performed on PP population. For PP 
analysis see also section 5.7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
6.4 Secondary Efficacy Analysis  
6.4.1  Efficacy: 
· Changes from baseline in TOSS and total 7 symptoms score (T7SS) at each 
post-dose assessment time point (0 to 4 hours p.a.)  
 
· Change from baseline in individual nasal symptom scores (itchy nose, nasal 
congestion, runny nose, sneezing) and ocular symptom scores (itchy eyes, 
watery eyes, eye redness) at each post-dose assessment time point (0 to 4 
hours p.a.)  
 
The analysis for these two secondary endpoints will be the same as for the primary 
endpoint analysis.  
 
Overall change from baseline in TNSS, TOSS, and T7SS and all individual symptoms (0 
to 4 hours after dosing) will be performed using all time points together and a mixed 
model repeated measurements analysis 
 
 
 
 
 
 
 
All secondary endpoints will be analysed on FAS population. 
 
 
 
 
 


 
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Time courses: Time courses of TNSS, TOSS, and T7SS during the 6.5-hour EEU 
session. Time courses will be displayed graphically. Time course arithmetic mean ± 
SE curves for raw values (0-6.5 hours) and for change from baseline in TNSS, TOSS, 
and T7SS for the post-dose time points 0 to 4 hour will be presented by treatments 
overlaid each other using the FAS Population. 
Responder analysis: Time to relevant response to therapy (30% and 50% reduction of 
TNSS) will be analysed by means of Kaplan Meier analysis.  
· 30% reduction in TNSS 
· 50% reduction in TNSS 
 
The time to 30% and 50% reduction in TNSS will be analysed using the survival 
analysis method. For a subject during a treatment period, if the time to 30% reduction 
in TNSS is not achieved before completion of 4 hour post dose time point in EEC or 
subject discontinue or withdrawn earlier than 4 hour post dose time point in EEC, the 
30% reduction time is unknown and will be considered as right-censored for the 
analysis of 30% reduction time. Similarly, the unknown response time for 50% 
reduction in TNSS will be considered as right-censored for the analysis of 50% 
reduction time. The censored observations from this study will be considered as 
random and uninformative type. 
The Kaplan-Meier method of calculation will be used for the cumulative survival 
probabilities. Cox proportional hazard model using the treatment and baseline TNSS 
scores will be used to evaluate and compare the treatments and the effect of baseline 
symptom score for the response time. The Efron method will be used to compute the 
partial likelihood estimates in case there are event times that are tied. 
The reported study results will include: 
· 
The Kaplan-Meier cumulative survival probabilities. 
· 
Summary of estimates of rate of change in log of the hazard 
corresponding to a one-unit change as well as the hazard ratio for each 
predictor variable Treatment and baseline TNSS. The hazard ratio for 
baseline TNSS will be expressed as percentages. 


 
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· 
Percentage of subjects with 30% and 50% reduction in TNSS figures by 
predictor variable Treatment groups from Cox proportional hazard 
model analysis. 
6.4.2 Subgroup Analysis: 
The subgroup analysis on FAS population for TOSS and T7SS with baseline TOSS at 
Visit 3 ≥4 (moderate or severe) will be performed. 
 
The onset of action and overall change from baseline in TOSS and T7SS for this 
subgroup will be analysed same as defined in section 6.3 and 6.4.1. 
 
6.5 Safety and Tolerability Assessment  
Following will be covered under safety assessment. 
AE: Any untoward medical occurrence reported by subject during study period (i.e. 
screening to end of study) and which does not necessarily have to have a causal 
relationship with this treatment. 
TEAE: The AE start date and treatment dosing dates are compared to attribute an AE 
to the last treatment just before the adverse event. An AE is considered treatment 
emergent when occurring in the period from administration of study medication until 
5 days (120 h) thereafter. Otherwise, the AE is not considered a Treatment Emergent 
Adverse Event. 
SAE: The adverse events which are Serious 
Adverse events will be coded using the latest version of Medical Dictionary for 
Regulatory Authorities (MedDRA). The occurrence of treatment emergent AEs 
(TEAEs) and SAEs will be summarized in terms of incidence, as well as in terms of 
total number of AEs. Analysis of AEs in terms of incidence by severity and by 
relatedness will also be provided. 
6.5.1 Overall Summary of AEs and TEAEs 
Following categories will be displayed considering Adverse Event, TEAE and SAE 
for each treatment and overall. 
 
· Total number of AE/TEAE/SAE (Counts only) 
· Number of subjects with at least one TEAE/SAE 
· Subjects discontinued due to TEAE 
· Number of subjects Died 
All subjects in Safety (SAF) population will be included while preparing the tables. 
6.5.2 Summary of TEAEs by SOC, PT  
Incidences of TEAE will be presented by number and percentages of subjects 
experience the TEAE and total number of events for SOC & PT by treatment.  
 


 
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If a subject has more than one occurrence of the same preferred term (PT) for an AE 
then the PT will be counted only once for that subject under the SOC at which it was 
experienced. 
6.5.3 Summary of SAE by SOC, PT  
A summary of number and percent of subjects who experienced at least one serious 
AE or TEAE as well as the number of events, number and percent of subjects who 
experienced each specific SOC and PT will be presented by treatment.  
 
If a subject has more than one occurrence of the same preferred term (PT) for an AE 
then the PT will be counted only once for that subject under the SOC at which it was 
experienced. 
6.5.4 Summary of TEAE leading to discontinuation by SOC, PT  
Incidences of TEAE leading to discontinue will be presented by number and 
percentages of subjects experienced TEAE and total number of occurrence. 
6.5.5 Summary of TEAE leading to death by SOC, PT  
Incidences of TEAE leading to death will be presented by number and percentages of 
subjects experienced TEAE and total number of occurrence. 
6.5.6 Summary of incidence of TEAE by relatedness to study drug 
All TEAE will be presented by relationship categories, in case any adverse event 
observed more than once in same subject then highest relationship only will be 
counted once for that subject and TEAE. Table will be presented for TEAE and 
Serious TEAE. 
6.5.7 Summary of incidence of TEAE of any causality by treatment, SOC, PT 
and Severity   
All TEAE will be presented by severity categories, in case any adverse event 
observed more than once in same subject then highest severity only will be counted 
once for that subject and TEAE. 
 
Adverse events listing and summary will be presented using safety (SAF) population. 
 
6.5.8 Vital Signs  
Summary statistics like n, mean, SD, median, minimum and maximum of vital signs 
will be presented for non-treatment days (Visit 1, Visit 2, Visit 4 and EOS/ET Visit). 
For vital signs during the treatment periods, the Pre-EEU observation will be 
considered as baseline. During treatment periods, summary statistics for the observed 
data at Pre- and Post-EEU session as well as the change at Post-EEU session for Visit 
3 and Visit 5 will be presented by treatments.  
Blood Pressure and heart rate will be listed and summarised. 
 
Vitals sign listing and summary will be presented by treatment and visit using Safety 
(SAF) population. 


 
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6.5.9 Laboratory Parameters 
All laboratory parameters will be listed with the subject number, visit, treatment 
sequence, date and time of sample collection, test name and results of test and will be 
presented using Safety (SAF) population. 
6.6 Physical Examination  
Physical examinations will be listed with the subject number, visit, treatment 
sequence, date of physical examination, results and clinical significance, if applicable. 
6.7 Protocol Deviation  
The list of major protocol deviations will be finalized prior to database lock and 
unblinding as part of the final blind data review (BDR).  
 
Potential violations that may result in the exclusion of the subject from the per-
protocol population include, but are not limited to: 
a) Not fulfilling all of the inclusion and none of the exclusion criteria during 
randomization. 
b) Not receiving the treatment to which they were randomized. 
c) Taking prohibited concomitant medications that may affect the primary 
variables.  
A list of all protocol deviations will be produced. A summary of protocol deviations 
will also be produced as frequency and percentages by treatment groups along with 
total. 
6.8 Medical and Social History 
Clinically relevant medical history (including drug sensitivities and allergies, major 
surgeries) and any medical condition present at the time that the subject is screened 
will be documented under medical history and updated until first exposure to study 
treatment.  
Medical and Social history term will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 23.1 or higher. 
Listing of medical and social history will include the parameters as subject number, 
medical or surgical term, system organ class/preferred term, start date, end date, 
ongoing and medication ongoing of the term.  
 
6.9 Prior and Concomitant Medication  
Any medication other than study drug, either prescription drug or OTC will be treated 
as concomitant medication.  
Medication/Therapy and indication code terms will be coded using the WHO Drug 
Dictionary (Version March 2019). 
Listing of prior and concomitant medication will include Medication/Therapy, 
Indication, Dose per administration, Unit, Dosage form, Frequency, Route, Start 
date/Stop date (if applicable)/ongoing, Prior/ Conmed/ Prior & Conmed/ Post EOT.  


 
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Listing of prior and concomitant non-pharmacological treatments will include 
Treatment Name/Procedure/Diagnostic Measures, Indication,  Start date/Stop date (if 
applicable), ongoing.  
No summary table will be generated. 
6.10 Rescue Medication 
In case rescue medication was used, this will be documented as concomitant 
medication. 


 
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7. Summary of Analyses 
Endpoint 
Analyses 
Population(s) 
Primary Endpoint:  
For onset of action assessment:  
· 
 Changes from baseline in TNSS at each 
post-dose assessment time point (0 to 4 
hours p.a.)  
 
 
ANCOVA model by 
timepoint 
 
 
 
 
 
FAS and PP 
Secondary Endpoints: 
· 
Changes from baseline in TOSS and total 
7 symptoms score (T7SS) at each post-
dose assessment time point (0 to 4 hours 
p.a.)  
 
· 
Time courses of TNSS, TOSS, and T7SS 
during the 6.5-hour EEU session and 
change from baseline (0-4h post dose)  
 
· 
Change from baseline in individual nasal 
symptom scores (itchy nose, nasal 
congestion, runny nose, sneezing) and 
ocular symptom scores (itchy eyes, watery 
eyes, eye redness) at each post-dose 
assessment time point (0 to 4 hours p.a.)  
 
· 
Overall change from baseline in TNSS, 
TOSS, and T7SS and all individual 
symptoms (0 to 4 hours after dosing) 
 
· 
Subgroup analysis on FAS population for 
TOSS and T7SS with baseline TOSS at 
Visit 3 ≥4 (moderate or severe) 
 
 
· 
Time to relevant response to therapy (30% 
and 50% reduction of TNSS) 
 
 
ANCOVA model by 
timepoint 
 
 
 
Figure: mean and SEM 
 
 
 
ANCOVA model by 
timepoint 
 
 
 
 
 
 
MMRM model 
 
 
 
ANCOVA model by 
timepoint and MMRM 
model 
 
 
 
Kaplan Meier analysis 
 
 
FAS  
 
 
 
 
FAS  
 
 
 
FAS 
 
 
 
 
 
 
 
FAS 
 
 
 
FAS subset 
 
 
 
 
 
FAS  
Safety variable: 
· 
Adverse events  
· 
Vital signs 
 
Frequency (%) 
Summary Statistics 
 
Safety  
Safety 
Disposition 
Frequency (%) 
All Screened 
Subjects 
Demographics 
Summary Statistics 
Safety 
FAS 
PP 


 
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Endpoint 
Analyses 
Population(s) 
Protocol deviations 
Frequency (%) 
All 
randomized 
Subjects 
8. Data Management Considerations 
All data entry shall be performed by the site staff into the EDC system using 
CodeAngelo version 1.0. The ePDATTM data will be transferred to the Cliantha Clinical 
Data Management group and integrated into the final database. Prior to performing the 
analyses, a series of checks will be performed to identify missing data, inconsistent 
data and errors in database. Protocol deviations will be identified. All reported 
adverse events (AEs) will be coded to standard ‘Preferred Terms’ and ‘System Organ 
Class’ using the Medical Dictionary for Regulatory Activities (MedDRA) version 
23.1 or higher. 
After all the modifications to the database are made, protocol deviations identified, 
and adverse events coded, database will be locked. All request to modify the database 
after treatment assignment is added will require the written approval of the Head of 
biometrics (Viatris).  
All summaries, statistical analyses, and individual subject data listings will be 
completed using Statistical Analytical System (SAS®) version 9.4, or higher SAS 
Institute, Cary, North Carolina, United States of America (USA). 
 
9. Tables, Listings and Figures 
The TLF shells for this study are provided in a separate document “SAP Mock 
Shells”. These shells may not be reflective of every aspect of this study but are 
intended to show the general layout of the Tables, Listings and Figures that will be 
included in the final report.  
TLFs are numbered following the ICH E3 “Structure and Content of Clinical Study 
Report”. 
10. References 
· ICH E3: Structure and Content of Clinical Study Reports, July 1996, CPMP. 
· ICH E9: Statistical Principles for Clinical Trials, September 1998, CPMP.