A Phase II, Randomized, Double-blind, Controlled, Single-centre 21-day Study to Investigate the Efficacy of AllerPops to Reduce Nasal Symptoms in Adult Volunteers With Seasonal/Year-long Nasal Allergies
Phase: PHASE2
Conditions: Allergic Rhinitis
Sponsor: AllerPops Corp

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CLINICAL PROTOCOL COVER PAGE 
Protocol Title: A Phase II, randomized, double-blind, controlled, single-centre 21-day study to 
investigate the efficacy of AllerPops to reduce nasal symptoms in adult 
volunteers with seasonal/year-long nasal allergies.  
Protocol Number: 
21-SAHSE-01 
Protocol Date: 
February 14, 2022 
Version: 
 
4 
Study Design: 
Phase II, randomized, controlled 
Sponsor: 
 
SSH Corp. 
505 Oppenheimer Drive, Suite 205 
Los Alamos, NM 
87544 
USA 
CRO:   
 
dicentra Inc. 
 
 
 
603-7 Saint Thomas Street 
 
 
 
Toronto, ON 
 
 
 
M5S 2B7 
Canada 
Site: 
 
 
Vitalabs 
 
 
 
607-7 Saint Thomas Street 
 
 
 
Toronto, ON 
 
 
 
M5S 2B7 
Canada 
Principal Investigator: 
Dr. Gurinder Rai, MD, CCFP, ABFM, ACSM 
 
 
 
 
 

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Protocol Signatures: 
Name 
Signature 
Date 
Sponsor: 
Dr. Cliff Han 
SSH Corp. 
505 Oppenheimer Drive, Suite 205 
Los Alamos, NM 
87544 
USA 
 
 
CRO: 
Peter Wojewnik 
Vice President 
dicentra Inc. 
7 Saint Thomas Street, Suite 603 
Toronto, ON M5S 2B7 
Canada 
 
 
Principal Investigator: 
Dr. Gurinder Rai, MD, CCFP, 
ABFM, ACSM 
dicentra Inc. 
7 Saint Thomas Street, Suite 603 
Toronto, ON M5S 2B7 
Canada 
 
 
 
Protocol Revisions: 
Version 
# 
Description of Changes 
Date 
Signature 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
1. 
List of Abbreviations ............................................................................................................. 5 
2. 
Protocol Synopsis ................................................................................................................... 7 
2.1. 
Inclusion Criteria .................................................................................................................. 7 
2.2. 
Exclusion Criteria ................................................................................................................. 9 
2.3. 
Schedule of Assessments .................................................................................................... 11 
3. 
Background ........................................................................................................................ 110 
4. 
Study Objectives ................................................................................................................ 132 
5. 
Selection of Study Population ........................................................................................... 154 
5.1. 
Inclusion Criteria .............................................................................................................. 154 
5.2. 
Exclusion Criteria ............................................................................................................... 16 
5.3. 
Concomitant Medications ................................................................................................. 16 
5.4. 
Early Withdrawal ............................................................................................................... 16 
6. 
Investigational Product ....................................................................................................... 17 
6.1. 
Investigational Product Details ........................................................................................ 17 
6.2. 
Manufacturing and Storage ............................................................................................. 17 
6.3. 
Labelling ................................................................................................................................ 17 
6.4. 
Directions .............................................................................................................................. 17 
6.5. 
Randomization ..................................................................................................................... 19 
6.6. 
Blinding and Unblinding ................................................................................................... 19 
7. 
Study Design (Flow chart) .................................................................................................. 21 
8. 
Planned Study Visits .......................................................................................................... 210 
9. 
Clinical Assessments and Procedures ................................................................................ 26 
9.1. 
Height and Weight .............................................................................................................. 26 
9.2. 
Biometric Measurements .................................................................................................. 25 
9.3. 
Urine Sample Collection .................................................................................................... 25 
9.4. 
Blood Sample Collection.................................................................................................... 25 
9.5. 
Questionnaires ..................................................................................................................... 25 
9.6. 
Peak Nasal Inspiratory Flow (PNIF) measurement ................................................... 25 
9.7. 
Amplicon Metagenomics Sequencing Collection ......................................................... 26 
9.8. 
Compliance ........................................................................................................................... 26 
9.9. 
Laboratory Analysis ........................................................................................................... 26 

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9.10. 
Termination of the Trial .................................................................................................... 27 
10. 
Safety Instructions and Guidance .................................................................................. 27 
10.1. 
Adverse Events .................................................................................................................... 27 
10.3. 
Serious Adverse Events ..................................................................................................... 29 
10.4. 
Laboratory Test Abnormalities ....................................................................................... 30 
11. 
Statistical Evaluation ....................................................................................................... 29 
11.1. 
Determination of Sample Size .......................................................................................... 31 
11.2. 
Study Population ................................................................................................................. 31 
11.3. 
Analysis Plan .................................................................................................................... 3231 
12. 
Protocol Deviations .......................................................................................................... 33 
13. 
Protocol Amendments ................................................................................................... 332 
14. 
Data Collection and Storage ......................................................................................... 332 
15. 
Ethical Considerations................................................................................................... 343 
15.1. 
IRB Approval ....................................................................................................................... 34 
15.2. 
Informed Consent Form .................................................................................................. 343 
15.3. 
Risks and Procedures to Minimize Risk ...................................................................... 343 
16. 
Quality Assurance and Quality Control ........................................................................ 35 
16.1. 
Auditing ............................................................................................................................... 354 
16.2. 
Monitoring ............................................................................................................................ 34 
16.3. 
Data Management ............................................................................................................. 354 
17. 
References ......................................................................................................................... 37 
18. 
Appendix 1: Questionnaires ............................................................................................ 40 
 
 
 
 
 
 
 
 
 

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1. List of Abbreviations 
ADA  
Anti-Drug Antibodies 
ADR  
Adverse Drug Reaction 
AE  
 
Adverse Event  
ALT   
Alanine aminotransferase  
ANOVA 
Analysis of Variance 
AST   
Aspartate aminotransferase  
BMI   
Body Mass Index  
BPM  
Beats per minute 
BUN  
Blood urea nitrogen 
CBC   
Complete Blood Count  
CRF   
Case Report Form  
CTMS  
Clinical Trial Management Software  
Cl  
 
Chloride  
Cr 
 
Creatinine 
eCRF   
Electronic Case Report Form  
EDTA  
Ethylenediaminetetraacetic acid  
ET  
 
Early Termination  
GCP   
Good Clinical Practices  
GLP 
 
Good Laboratory Practices 
GMP  
Good Manufacturing Practices 
GGT   
Gamma glutamyl transpeptidase/transferase 
h or hr  
Hour 
HCT   
Hematocrit  
Hb  
 
Hemoglobin  
HIV   
Human Immunodeficiency Virus  
ICF  
 
Informed Consent Form  
ICH   
International Council for Harmonisation  
ID 
 
Identification 
IP  
 
Investigational Product  
IRB  
 
Institutional Review Board  
IUD 
 
Intrauterine Device 
K  
 
Potassium  
Kg  
 
kilogram  
m 
 
Meter  
MCH   
Mean corpuscular hemoglobin  
MCHC  
Mean corpuscular hemoglobin concentration  
MCV   
Mean corpuscular volume  
Na  
 
Sodium  
NCS   
Not clinically significant  
OTC  
Over the counter 
PD  
 
Protocol Deviation  
PI  
 
Principal Investigator  
PV  
 
Protocol Violation  
RBC   
Red Blood Cell  
SAE   
Serious Adverse Event  

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SAP 
 
Statistical Analysis Plan 
SOP 
 
Standard Operating Procedure 
WBC   
White Blood Cell 
EDA                Exploratory Data Analysis 
 
 

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2. Protocol Synopsis 
 
Title: A randomized, double-blind, controlled, single-centre, 21-day study to investigate the 
efficacy of AllerPops to reduce nasal symptoms in adult volunteers with seasonal/year-long nasal 
allergies. 
Phase: Phase II  
Duration: Up to 30 days between Screening (V1) and Baseline (V2), and a 21-day intervention 
period, with dosing occurring every other day for a minimum of 3 doses, and thereafter until the 
participant is satisfied with the relief of the nasal allergy symptoms. The suitable season for the 
trial will be determined based on the seasonal variation measures.  
Primary Objectives: To assess the effectiveness of AllerPops on relieving nasal symptoms 
compared to the control group in volunteers with seasonal/year-long allergies during the first 7 
days of the 21-day intervention period.   
Secondary Objective: 
1. To evaluate the safety of AllerPops administration in volunteers with seasonal/year-long 
allergies during a 21-day intervention period.  
2. To assess the duration of effectiveness of AllerPops in relieving nasal symptoms 
compared to the control group in volunteers with seasonal/year-long allergies during a 
21-day intervention period (exploratory). 
3. To evaluate the effect of the AllerPops administration on the oral microbial 
presentation/microbiota using Amplicon Metagenomics Sequencing test through saliva 
samples during a 21-day intervention period (exploratory). 
4. To evaluate the effect of the AllerPops administration on the IgE (total) blood level 
during a 21-day intervention period (exploratory). 
 
Study Population: Seventy-two participants with seasonal/year-long nasal allergies. 
2.1.Inclusion Criteria 
Participants must meet all of the following criteria to be considered eligible for admission to the 
study.  
1. Participants will be clinically diagnosed with persistent or intermittent allergic rhinitis, 
according to the Allergic Rhinitis and Its Impact on Asthma (ARIA) classification. 
(The guidelines of Allergic Rhinitis and its Impact on Asthma (ARIA) group, 
classified it to intermittent (less than 4 days per week and for less than 4 weeks) and 
persistent (more than 4 days per week or lasting more than 4 weeks regardless of the 
number of days per week). 
2. Male or female seasonal/year-long nasal allergy sufferers (as assessed by a 
questionnaire at screening) between the ages of 18 and 70.     

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3. Females who are not of childbearing potential (post-menopausal defined as those with 
amenorrhea for at least 2 years). Females of childbearing potential should be either 
sexually inactive (abstinent) for 60 days prior to the first dose of the study, throughout 
the study and for 30 days after completion of the study, or be using one of the 
following acceptable methods of birth control:   
i. 
Surgically sterile (bilateral tubal-ligation, hysterectomy, bilateral oophorectomy) 
for at least 90 days prior to the first dose of the study.   
ii. 
IUD in place for at least 60 days prior to the first dose of the study, throughout the 
study and for 30 days after completion of the study.   
iii. 
Barrier methods (condom, diaphragm) with spermicide for at least 60 days prior 
to the first dose of the study, throughout the study and for 30 days after study 
completion.   
iv. 
Hormonal contraceptives for at least 90 days prior to the first dose of the study, 
throughout the study, and for 30 days after study completion.   
*Changes to the method of birth control while participating in the study will be judged by the PI 
 
for acceptability.  
4. Written informed consent obtained and signed by participant.   
5. BMI between 18.5 and 29.9 kg/m2, with a stable weight over the last 3 months. (A 
stable weight is defined as <5% of total body weight change in the last 3 months). 
6. Agrees not to use any over the counter, prescription, health supplement or dietary 
supplement from at least 14 days prior to screening until the end of the study. 
7. Agrees to maintain current dietary habits, level of physical activity, occupational and 
living environment for the trial duration.   
8. Does not regularly consume more than 2 standard* alcoholic beverages a day as 
assessed through verbal confirmation at screening, and agrees not to consume >2 
standard* alcoholic beverages per day for the trial duration.   
9. Non-smoker within 12 months prior to dosing as assessed by verbal confirmation. 
10. Stable medical conditions that do not require medication use routinely and do not 
affect or involve the immune systems as determined by medical history, physical 
examination, clinical chemistry performed at screening, and as assessed by the 
Principal Investigator. 
11. Agrees not to use nasal steroid spray from at least 14 days prior to screening until the 
end of the study. 
12. Agrees not to use neti-pot and oil-pulling for at least 7 days prior to screening until the 
end of the study. 
13. .  
14. Have access to a microwave. 
* A standard alcoholic beverage is defined as 12 ounces of beer, 5 ounces, of wine, or 1.5 ounces 
of liquor 
 
 

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2.2.Exclusion Criteria 
Participants meeting any of the following criteria will not be eligible for admission to the study:   
 
1. Participants who are pregnant/lactating or planning to become pregnant during the course 
of the clinical trial. 
2. Participants who have any sings of active or recurrent upper airway infection 
(bacterial/viral). 
3. Participants who have a known sensitivity or allergy to any of the study products, or 
ingredients.   
4. Participation in another research study within 30 days prior to enrollment in this clinical 
trial.   
5. Participants who are not able to tolerate venipuncture and/or have poor venous access.   
6. Participants dependent on decongestants (nasal or oral) or receiving allergen-specific 
immunotherapy. 
7. Participants who have been diagnosed with other clinical forms of rhinitis such as 
infectious rhinitis, rhinitis of pregnancy, food and alcohol-induced rhinitis, atrophic 
rhinitis, vasomotor rhinitis, rhinosinusitis and age-related rhinitis. 
8. Participants who have receive previous acupuncture treatment or alternative medicine for 
AR in the last three months or planned in the next two years. 
9. Participants who have received allergy desensitization therapy (current, during the past 
two years, or planned in the next two years). 
10. Participants who have had any major surgery within 1 year of enrollment into the clinical 
trial or have any anticipated major surgeries intended to occur during the clinical trial.   
11. Participants who have received a blood transfusion within 8 weeks of enrollment in the 
clinical trial.   
12. Participants who have donated blood or plasma to a blood bank or clinical study within 8 
weeks of enrollment and during the study except venipuncture as part of clinical trial.    
13. Participant has known severe medical conditions, such as cardiovascular, liver or renal 
dysfunction, diabetes mellitus, cancers, cerebrovascular diseases, blood system diseases 
which in the opinion of the Principal Investigator, may preclude safe study participation, 
or interfere with study objectives.   
14. Participants who are immunocompromised or have been diagnosed HIV/AIDS, Hepatitis 
B, or untreated Hepatitis C.  
15. Participant has a history of alcohol or drug addiction treatment within the last 2 years 
prior to inclusion in the study, or any current addiction on alcohol or drugs. 
16. Participants with Grade II or III septum deviation and/or presence of nasal polyps or 
other conditions that lead to nasal obstruction. 
17. Participant has any other medical, social or other condition that, in the opinion of the 
Principal Investigator, would make participation in the study unsafe, complicate 
interpretation of study outcome data, or otherwise interfere with achieving the study 
objectives.   
18. Participants with allergic asthma and/or moderate to severe atopic dermatitis. 
19. History of anaphylactic reactions. 

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20.  Participants with any risk of developing dental cavity or on-going oral health issue, as 
assessed during their regular dentist visit in past 6 months. 
21. Participants who brush more than twice a day and/or mouthwash more than once a day 
and/or floss more than once a day. 
 
 

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2.3. Schedule of Assessments 
 
Assessment 
Visit 1 
Screening 
Day -30 to Day 0 
Visit 2 
Baseline 
Day 1 
Visit 3 
Follow-Up  
Day 7 
Visit 4 
 Follow-Up 
 Day 14 
Visit 5  
End of Study 
Day 21 
Informed Consent 
X 
 
 
 
 
Physical Exam 
X 
 
 
 
 
Medical History and 
Concomitant 
Medications 
X 
 
 
 
 
Temperature, blood 
pressure, heart rate 
measurements taken 
X 
X 
X 
 
 
X 
Questionnaires 
administered 
X 
X 
X 
X 
X 
Peak Nasal 
Inspiratory Flow 
(PNIF) Assessment  
 
X 
X 
X 
X 
Urine Sample 
Collected (for females 
of childbearing 
potential) 
X 
X 
X 
 
X 
Blood Draw – study 
endpoint related 
 
X 
X 
 
X 
Blood Draw - safety 
X 
 
 
 
X 
Saliva Sample – 
Amplicon 
Metagenomics 
Sequencing 
 
 
X 
 
X 
 
X 
Dispense Study 
Product 
 
 
X 
 
 
 
 
Dispense Study Diary 
 
X 
 
 
 
Calculate Compliance 
 
 
X 
 
 
Collect Unused Study 
Product (if applicable) 
 
 
 
 
X 
Collect Study Diary 
 
 
X 
X 
X 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
Concomitant 
Medication Review 
 
 
X 
X 
X 
X 
Study Exit 
Assessments 
 
 
 
 
 
X 
 
3. Background 
 
Allergic rhinitis (AR) was described in 1929 as a process which included three cardinal 
symptoms: sneezing, nasal obstruction, and mucus discharge [1]. AR is clinically defined as a 
symptomatic disorder of the nose induced by an IgE-mediated inflammation after allergen 
exposure of the membranes lining the nose.  AR is a widely prevalent condition in Canada (20-

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25%) [2] and other countries; it is often accompanied with significant physical sequelae and 
recurrent or persistent morbidities.  Increasing literature in animals and humans has implicated 
changes in the gut microbiome with the development of allergic disease [3]–[7], which were 
shown to be associated with reduced early microbial exposure [6], [8], [9]. Changes of the nasal 
[10]–[15] and oral microbiota [16]–[18] were found as well.  
Some investigations have shown that the oral administration of probiotics and prebiotics may 
benefit allergic rhinitis patients [19]–[22]. The local nasal administration of Lactococcus lactis 
NZ9000 can affect the local and systemic immune responses against Streptococcus pneumonia 
[23]. Probiotics seem a promising therapeutic approach for allergic airway diseases, however, 
clinical benefit of probiotic therapy depends upon numerous factors, such as type of bacterium, 
dosing regimen, delivery method and other underlying host factors, e.g. the age and diet of the 
host [22]. Among mechanisms of action underlying modulation of immune responses by 
microbial species, are reduction of permeability of gut barrier and systemic penetration of 
antigens [22], [24], generation of pro- and anti-inflammatory cytokines in the gut [25]–[27], and 
modulation of proliferation of immune cells [22], [28], [29]. 
AllerPops is Natural Health Product in a lozenge dosage form indicated for the alleviating 
(seasonal) AR. Immune-mediated disorders such as allergic rhinitis is being linked to reduced 
early microbial exposure [6], [8], [9], dysbiosis of the gut [6], [7], the nasal [10]–[12] and oral 
microbiota [16]–[18]. The medicinal ingredient was chosen based on its capability to provide 
balanced nutritional support to the oral microbiota, and thereby restore its presentation and the 
normal function. The active ingredient, L-Arginine, 5.04%, is used in the formula with the 
purpose of reducing the nasal symptoms of allergy.  
 
There will be 2 groups of participants in the study (investigational and control). For the 
investigational group; the method of use of the lozenge product will include two steps: 1) 
mechanical cleaning of the mouth, followed by 2) slow consumption of the investigational 
product with the target of its natural dissolution in the mouth after 60 minutes. The purpose of 
the first step is to remove the biofilm from the teeth and tongue and to provide an unoccluded 
surface for targeted bacteria to grow.The purpose of the second step is proposed to provide 
nutrition to the oral bacteria and thereby to restore their balance. 

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For the control group, the same investigational product will be administered, however the 
procedure for use will be modified as follows: There will be no mouth cleaning before the 
product consumption (No step 1 as mentioned above). The product will be swallowed instead of 
dissolved in the mouth, in order to reduce its presence in the mouth as much as possible. The 
purpose of this control group is to support the effect of use of the entire two-step method as 
compared to the investigational group. 
 
The active ingredient, L-Arginine is known to Health Canada.  L-Arginine is listed in the 
NHPID, and allowed for use in NHPs under proposed here conditions of use. Safety of the of 
current ingredient combination, while allowed for use separately, will also be tested under 
proposed conditions of use. 
The Rationale for Performing Research:  
Increase in immune-mediated conditions  [30]–[32](Allergic rhinitis is one of them) and the few 
medical solutions available (each of which is associated with side effects) prompted this research 
and clinical study. The medicinal ingredient, L-Arginine, in the formulation of AllerPops is a 
well-known Natural Health Product Ingredient with history of human use.  
4. Study Objectives 
 
Objectives: 
Primary Objective: To assess the effectiveness of AllerPops on relieving nasal symptoms 
compared to the control group in volunteers with seasonal and perennial (or intermittent and 
persistent) allergic rhinitis during the first 7 days of the 21-day intervention period.  
 
Secondary Objectives:  
1. To evaluate the safety of AllerPops administration in volunteers with seasonal/year-long 
allergies during a 21-day intervention period. 
2. To assess the duration of effectiveness of AllerPops in relieving nasal symptoms 
compared to the control group in volunteers with seasonal/year-long allergies during a 
21-day intervention period (exploratory). 

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3. To evaluate the effect of the AllerPops administration on the oral microbial 
presentation/microbiota using Amplicon Metagenomics Sequencing test through saliva 
samples during a 21-day intervention period (exploratory). 
4. To evaluate the effect of the AllerPops administration on the IgE (total) blood level 
during a 21-day intervention period (exploratory). 
Endpoints: 
Primary Endpoint: The reduction of nasal allergic symptoms during the first 7 days of the 21-
day intervention period (once every other day – D1, D3, D5). The reduction of symptoms will be 
measured using the following assessments. 
• Total Nasal Symptoms Score (TNSS) Questionnaire: This assessment will be 
conducted at the V1, V2, and V3.  
• Peak Nasal Inspiratory Flow (PNIF): Measures nasal flow for assessing nasal 
airway patency. This assessment will be conducted at the baseline D1 and D7. 
Secondary Endpoint(s):  
1. To evaluate the safety of the AllerPops product during a 21-day intervention period. The 
safety evaluation will be measured based on the following assessments: 
a. Safety will be assessed by collecting vital signs, the emergence of adverse events, 
and clinical chemistry (CBC and a comprehensive safety panel) and PI 
assessment. 
2. The exploratory study of the effect of AllerPops in relieving nasal symptoms compared to 
the control group during a 21-day intervention period. The reduction of symptoms will be 
measured based on the following assessments: 
a. Total Nasal Symptoms Score (TNSS) questionnaire: This will be assessed at D14 
(V4) and D21 (V5). 
b. Peak Nasal Inspiratory Flow (PNIF) measurement:  This will be assessed at D14 
and D21. 
3. The exploratory study of the effect of AllerPops in oral microbial presentation/microbiota 
through Amplicon Metagenomics Sequencing test which is a rRNA gene sequencing 
method in saliva. The evaluation will be measured at D1, D7 and D21. 
4. The exploratory study of the effect of AllerPops on the IgE (total) blood level through 
blood samples during a 21-day intervention period. The evaluation will be measured at 
D1, D7 and D21. 
 
 

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5. Selection of Study Population 
 
5.1.Inclusion Criteria 
Participants must meet all of the following criteria to be considered eligible for admission to the 
study.  
1. Participants will be clinically diagnosed with persistent or intermittent allergic rhinitis, 
according to the Allergic Rhinitis and Its Impact on Asthma (ARIA) classification. The 
guidelines of Allergic Rhinitis and its Impact on Asthma (ARIA) group, classify 
intermittent as less than 4 days per week and for less than 4 weeks and persistent as more 
than 4 days per week or lasting more than 4 weeks regardless of the number of days per 
week). 
2. Male or female seasonal/year-long nasal allergy sufferers (as assessed by a questionnaire 
at screening) between the ages of 18 and 70.     
3. Females who are not of childbearing potential (post-menopausal defined as those with 
amenorrhea for at least 2 years). Females of childbearing potential should be either 
sexually inactive (abstinent) for 60 days prior to the first dose of the study, throughout the 
study and for 30 days after completion of the study, or be using one of the following 
acceptable methods of birth control:   
v. 
Surgically sterile (bilateral tubal-ligation, hysterectomy, bilateral oophorectomy) 
for at least 90 days prior to the first dose of the study.   
vi. 
IUD in place for at least 60 days prior to the first dose of the study, throughout the 
study and for 30 days after completion of the study.   
vii. 
Barrier methods (condom, diaphragm) with spermicide for at least 60 days prior 
to the first dose of the study, throughout the study and for 30 days after study 
completion.   
viii. 
Hormonal contraceptives for at least 90 days prior to the first dose of the study, 
throughout the study, and for 30 days after study completion.   
*Changes to the method of birth control while participating in the study will be judged by the PI 
for acceptability.  
4. Written informed consent obtained and signed by participant.   
5. BMI between 18.5 and 29.9 kg/m2, with a stable weight over the last 3 months. (A stable 
weight is defined as <5% of total body weight change in the last 3 months). 
6. Agrees not to use any over the counter, prescription, health supplement or dietary 
supplement from at least 14 days prior to screening until the end of the study. 
7. Agrees to maintain current dietary habits, level of physical activity, occupational and 
living environment for the trial duration.   
8. Does not regularly consume more than 2 standard* alcoholic beverages a day as assessed 
through verbal confirmation at screening, and agrees not to consume >2 standard* 
alcoholic beverages per day for the trial duration.   
9. Non-smoker within 12 months prior to dosing as assessed by verbal confirmation. 

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10. Stable medical conditions that do not require medication use routinely and do not affect 
or involve the immune systems as determined by medical history, physical examination, 
clinical chemistry performed at screening, and as assessed by the Principal Investigator. 
11. Agrees not to use nasal steroid spray from at least 14 days prior to screening until the end 
of the study. 
12. Agrees not to use neti-pot and oil-pulling for at least 7 days prior to screening until the 
end of the study. 
13. .  
14. Have access to a microwave. 
* A standard alcoholic beverage is defined as 12 ounces of beer, 5 ounces, of wine, or 1.5 ounces 
of liquor 
5.2 Exclusion Criteria 
Participants meeting any of the following criteria will not be eligible for admission to the study:   
 
1. Participants who are pregnant/lactating or planning to become pregnant during the course 
of the clinical trial. 
2. Participants who have any sings of active or recurrent upper airway infection 
(bacterial/viral). 
3. Participants who have a known sensitivity or allergy to any of the study products, or 
ingredients.   
4. Participation in another research study within 30 days prior to enrollment in this clinical 
trial.   
5. Participants who are not able to tolerate venipuncture and/or have poor venous access.   
6. Participants dependent on decongestants (nasal or oral) or receiving allergen-specific 
immunotherapy. 
7. Participants who have been diagnosed with other clinical forms of rhinitis such as 
infectious rhinitis, rhinitis of pregnancy, food and alcohol-induced rhinitis, atrophic 
rhinitis, vasomotor rhinitis, rhinosinusitis and age-related rhinitis. 
8. Participants who have receive previous acupuncture treatment or alternative medicine for 
AR in the last three months or planned in the next two years. 
9. Participants who have received allergy desensitization therapy (current, during the past 
two years, or planned in the next two years). 
10. Participants who have had any major surgery within 1 year of enrollment into the clinical 
trial or have any anticipated major surgeries intended to occur during the clinical trial.   
11. Participants who have received a blood transfusion within 8 weeks of enrollment in the 
clinical trial.   
12. Participants who have donated blood or plasma to a blood bank or clinical study within 8 
weeks of enrollment and during the study except venipuncture as part of clinical trial.    
13. Participant has known severe medical conditions, such as cardiovascular, liver or renal 
dysfunction, diabetes mellitus, cancers, cerebrovascular diseases, blood system diseases 

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which in the opinion of the Principal Investigator, may preclude safe study participation, 
or interfere with study objectives.   
14. Participants who are immunocompromised or have been diagnosed HIV/AIDS, Hepatitis 
B, or untreated Hepatitis C.  
15. Participant has a history of alcohol or drug addiction treatment within the last 2 years 
prior to inclusion in the study, or any current addiction on alcohol or drugs. 
16. Participants with Grade II or III septum deviation and/or presence of nasal polyps or 
other conditions that lead to nasal obstruction. 
17. Participant has any other medical, social or other condition that, in the opinion of the 
Principal Investigator, would make participation in the study unsafe, complicate 
interpretation of study outcome data, or otherwise interfere with achieving the study 
objectives.   
18. Participants with allergic asthma and/or moderate to severe atopic dermatitis. 
19. History of anaphylactic reactions. 
20. Participants with any risk of developing dental cavity or on-going oral health issue, as 
assessed during their regular dentist visit in past 6 months. 
21. Participants who brush more than twice a day and/or mouthwash more than once a day 
and/or floss more than once a day. 
 
 
5.3 Concomitant Medications 
Apart from the dispensed IP(s), any medication taken by the participant throughout the study 
period will be regarded as concomitant treatment. During the study, participants shall be 
instructed not to take medications unless absolutely necessary. If the use of any concomitant 
treatment becomes necessary during the study, the treatment will be recorded, including the 
name of the drug or treatment, indication for use, dosage, route, date, and time of treatment.  
5.4 Early Withdrawal 
Removal of Study Participants:  
The removal of a study participant will be based on the Clinical, and Protocol Violation 
conditions outlined below. If possible, any evaluations or assessments planned for the end of 
the study will be completed at an Early Termination (ET) Visit. Criteria for participant 
removal at the PI’s discretion are:  
Removal by Principal Investigator  
The removal of a study participant by the principal investigator will be based on the Clinical 
and Protocol Violation conditions outlined below. If possible, any evaluations or assessments 
planned for the end of the study will be completed at an Early Termination (ET) Visit. 
Criteria for participant removal at the PI’s discretion are:  
 
Clinical  
A participant may be withdrawn from the study if, in the opinion of the PI, it is not in the best 
interest of the participant to continue. Participants who experience an adverse event (AE) or 

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severe adverse event (SAE) will be assessed by the PI and determine if removal from the 
study is necessary. Participants experiencing a SAE will be follow up by PI until resolution 
of SAE. Any female who becomes pregnant during the course of the study will be removed 
and followed-up with accordingly.  
 
Protocol Violation  
Protocol violations may be a result of the above inclusion/exclusion criteria. Violations will 
be assessed by the PI on a case-by-case basis with removal from the study, if necessary. 
Participants can be withdrawn from the study at the discretion of the Sponsor. Participants 
who are deemed to be a protocol violation will not be followed up on. 
6. Investigational Product 
6.1 Investigational Product Details 
Unit dose: 1 lozenge (8g) 
Package size: 1 box containing 8 lozenges 
Ingredients: sucrose (cane sugar), L-arginine, honey, trehalose, lactose, inulin, D-mannose, 
corn syrup, coconut oil, calcium gluconate, calcium lactate, carrageenan, cocoa powder, 
sodium chloride (salt), cinnamon, vanilla extract. 
6.2 Manufacturing and Storage 
AllerPops is manufactured at: 
QINGDAO XIZHITANG FOOD CO., LTD.  
No. 998 Wangsha Road 
Chengyang District 
Qingdao, Shandong, China 
The product will be shipped by the Sponsor to the CRO prior to trial commencement. The CRO 
will be responsible for storing, maintaining, and dispensing the product accordingly. The 
product will be stored at room temperature in a limited-access location. Temperature of the 
storage location will be checked and recorded as per the site’s SOPs.  
6.3 Labelling 
The IP will be labelled according to Health Canada and ICH-GCP E6(R2) guidelines and will 
contain the following information in both official languages (English and French): 
• a statement indicating that it is an investigational product to be used only by a qualified 
investigator 
• the brand name or code of the study product(s) 
• the expiry date 
• the storage conditions 
• the lot number 

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• the name and address of the manufacturer and the sponsor  
• the protocol code or identification 
Written instructions on how to use the investigational product will be provided to the participant 
as part of the Informed Consent Form.  
6.4 Directions 
 
IMPORTANT: Must be fasting for at least 4 hours before taking the study product.  
Directions for the Investigational Group: 
1. Brush teeth with tap water (no toothpaste). 
2. Scrub tongue with disposable tongue scraper provided. (Caution: reaching too far may 
cause a gag reflex.) 
3. Gargle and swish hot (optimal 120°F) water for 10-20 seconds. Spit out and repeat 
gargling over the next 5 minutes. The tongue should be red and without any biofilm. If it 
is not, repeat Step 2, and gargle once more.  
4. Self-administer one lozenge. Let the lozenge slowly melt in the mouth. Do not chew or 
swallow whole. This may take up to 60 minutes. Discard if it is not fully dissolved after 
60 minutes. Wait at least 30 minutes before eating your next meal. 
5. Repeat Step 1 to Step 5 every other day for a minimum of 3 doses.  
6. After the 3rd dose, you may repeat Step 1 to Step 5 every other day until you are satisfied 
with the symptom relief up to and including Day 13. Do not take the product on Day 14 
onwards and return all remaining product at Visit 4.  
 
          Directions for the Control Group:  
1. A box containing 8 units of the Investigational Product will be dispensed. This box will 
only be dispensed once, at visit 2.  
2. Microwave: heat the product in 5 second increments until soft. (Caution: more than 10 
seconds of microwaving the product may cause it to burn). 
3. Cut: cut the product into smaller pieces those are the size of your usual 
medication/supplement. 
4. Swallow: Participant will be instructed to swallow each of the small pieces over time 
with plenty of warm water. The participant will also be allowed to have a few sips of 
water to moisten the mouth and throat prior to swallowing the control product, if they feel 
it is necessary. Wait at least 30 minutes before eating your next meal. For next 2 doses, 
you must repeat Step 2 to Step 4 once every other day (day 3 and day 5). 
5. After the 3rd dose, you may choose to use additional doses until you are satisfied with the 
symptom relief. If you choose to continue using the product, you must repeat Step 2 to 
Step 6 once every other day up to (and including) day 13. Maximum dose expected 
during day 1 to 13 is 7. Do not take the product on day 14 onwards and return all 
remaining product at visit 4.  

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6.5 Randomization 
After eligibility for participants has been confirmed, they will be allocated to a study arm 
(Investigational or control). Participants will then be randomized accordingly to ensure an 
equal and unbiased distribution of products. The master randomization list will only be 
accessible to the designated unblinded personnel at the site until the database is locked. 
Participants will be given an envelope containing a detailed dosing instruction sheet. They 
will be instructed to take this home and open it, read and understand the procedure, and 
contact the site if they have any questions. The contact information for the site will be that of 
the designated unblinded personnel – these individuals will be able to answer any questions 
the participants may have about their assigned dosing instructions. Participants will be asked 
to not disclose information about their assigned dosing instructions to any study staff except 
the unblinded personnel whose contact information is contained in the detailed dosing 
instruction sheet.  
6.6 Blinding and Unblinding 
Blinding of study products will be maintained by appropriately delegated study staff. 
Designated unblinded personnel will randomize the groups using block randomization 
ensuring an equal distribution in each group. All site staff (excluding designated unblinded 
personnel) will remain blinded throughout the study until the data-lock and study-closeout 
stage.  
Since both groups will be receiving identical products (with different instructions of use for 
each group), emergency unblinding will not be applicable to this trial.  

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7. Study Design (Flow chart) 
 
8. Planned Study Visits 
Pre-Screening Telephone Call: 
Potential participants who will be contacted to participate in this study will be pre-screened over 
the phone. They will be asked a series of questions about their health and lifestyle.   As part of 
that telephone pre-screening the following questions will be asked regarding their allergy 
symptoms: 
1- How do you score your nasal congestion (0-5, with 5 being the worst)?  
2- How do you score your Nasal Discharge or sneezing (0-5, with 5 being the worst)?  
3- How do you score your watery or itchy eyes (0-5, with 5 being the worst)?  
4- How many times do you brush your teeth a day (0-3, 0,1,2,3 or more)? 
5- How many times do you use mouthwash a day (0-2, 0,1,2 or more)?  
6- How many times do you floss your teeth  a day (0-2, 0,1,2 or more)? 
Scoring Standards: Total score ≥ 7 in question 1-3 and Total score ≤ 4 in question 4-6 will be 
booked for Screening (V1). Potential participants with a total score of < 7 in question 1-3 and/or 
total score > 4 in question 4-6 will not pass the telephone pre-screening and will not be booked 
for Visit 1.  
Visit 1 – Screening 
Participants will not be required to fast prior to this visit. The delegated study staff will present 
the ICF, and review its contents with the participant. The study staff will answer any questions 
the participant may have.  
 

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The Informed Consent Form (ICF) will be provided to the participant. After a sufficient period of 
reflection, the written and informed consent of the participant will be sought. Each page of the 
ICF will be initialed and the last page will be signed by the participant. Once signed and attested 
to by the PI or delegate, a copy of the signed original ICF will be provided to the participant.  
 
After informed consent has been obtained, the PI and/or delegated research site staff will collect 
demographic information, complete a thorough medical history which will include the review of 
existing medical records to confirm inclusion/exclusion criteria. Biometric measurements (body 
temperature, SSH blood pressure, heart rate), anthropometric measurements (height, weight, 
calculated BMI) will be taken and a short questionnaire to assess allergy symptoms will be 
conducted. If none of the collected information excludes participation, screening clinical 
chemistry assessments will be conducted. 
 
The screening information will be reviewed by the PI and/or delegate to determine if the 
participant is to be scheduled for a physical examination* and a final eligibility assessment. 
 
*Physical exam will be done before dosing. This may be scheduled on another day.  
 
Participants that have met all of the inclusion criteria and none of the exclusion criteria will 
proceed to the next scheduled visit, and TNSS questionnaire will be administered. 
For females of childbearing potential, a urine sample will be collected for a urine pregnancy test.  
 
Blood samples to be collected will be analyzed for the following:  
• CBC [Includes: White Blood Cell Count (WBC), Red Blood Cell Count (RBC), 
Hemoglobin (HB), Hematocrit (HCT), MCV, MCH, MCHC, Platelet Count]  
• Aspartate aminotransferase (AST) 
• Sodium  
• Potassium 
• Chloride  
• Serum creatinine  
• Alanine Amino Transferase (ALT)  
• Alkaline Phosphatase (ALP) 
• Bilirubin Total   
• Gamma Glutamyl Transpeptidase (GGT)  
 
Visit 2 – Baseline – Day 1 
These assessments may not be completed in the order shown below.   
Participants:  
1. Must be at least 8 hours fasting (no food, only water) prior to visit. 
2. Will have any changes to health reviewed by delegated study staff. 
3. For females of childbearing potential, a urine sample will be collected for a urine 
pregnancy test. 
4. Will have the following measurements taken: temperature, blood pressure, heart rate. 

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5. Will have the following saliva test: 
• Amplicon Metagenomics Sequencing 
6. Will complete the following assessments: 
• Total nasal symptoms score (TNSS) questionnaire (appendix 2). 
• Peak nasal inspiratory flow (PNIF) measurement.  
7. Will have the following blood tests:  
• CBC (WBC, RBC, Hb, HCT, MCV, MCH, MCHC, Platelet Count) 
• Aspartate aminotransferase (AST) 
• Alanine aminotransferase (ALT) 
• Bilirubin 
• Gamma-glutamyl transferase (GGT) 
• Alkaline phosphatase (ALP) 
• Serum creatinine 
• Potassium 
• Chloride 
• Sodium 
• IgE (total) 
8. Be provided with a paper/electronic diary – IP dosing, adverse events, concomitant 
medication.  
9. Be provided with the IP (and oral hygiene kit if applicable) and instructions on dosing. 
10. Be provided with dates/times of subsequent visit(s). 
11. Review of all information for the visit by the PI and/or delegate prior to the next study 
visit to determine continued safe participation. 
 
The participant will be given a paper/electronic daily diary in order to record the use of 
concomitant medications, IP dosing, symptoms, and any adverse events (such as fatigue, fever or 
headache) that may have occurred. The diary will be collected and/or reviewed at the research 
site at each visit as indicated on the Schedule of Assessments.  
 
The participant should take the IP after this visit at home. The participant should take AllerPops 
at a maximum frequency of once every other day until the next study visit (Day 7). The 
participant should not take the product the morning of the next visit. The designated maximum 
dose until the next visit on day 7, is 3 doses.  
 
Visit 3 – Follow-Up – Day 7 ± 1 
These assessments may not be completed in the order shown below. 
Participants: 
1. Must be at least 8 hours fasting (no food, only water) prior to visit. 
2. Will have any changes to health reviewed by delegated study staff. 
3. Study diary will be collected and/or reviewed by delegated study staff for completion, 
and any AEs and/or concomitant medications. 
4. For females of childbearing potential, a urine sample will be collected for a urine 
pregnancy test.  

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5. Will have the following measurements taken: temperature, blood pressure, heart rate. 
6. Will have the following saliva test: 
• Amplicon Metagenomics Sequencing 
7. Will complete the following assessments: 
• Total nasal symptoms score (TNSS) questionnaire  
• Peak nasal inspiratory flow (PNIF) measurement 
8. Will have the following blood tests:  
• CBC (WBC, RBC, Hb, HCT, MCV, MCH, MCHC, Platelet Count) 
• Aspartate aminotransferase (AST) 
• Alanine aminotransferase (ALT) 
• Bilirubin 
• Gamma-glutamyl transferase (GGT) 
• Alkaline phosphatase (ALP) 
• Serum creatinine 
• Potassium 
• Chloride 
• Sodium 
• IgE (total) 
9. Be reminded to complete daily diary. 
10. Review of all information for the visit by the PI and/or delegate prior to the next study 
visit to determine continued safe participation. 
 
After completion of treatment dose, the participants are allowed for extra 4 maintenance doses, at 
a maximum frequency of once every other day (on day 7, 9, 11, and 13). Participant will not take 
the product on day 14 and onwards, and must return all remaining product at visit 4. Between day 
7 and day 13, the participants may take AllerPops with any recurrence of nasal allergy symptoms 
or until the participant is satisfied with the relief of the nasal allergy symptoms, as long as the 
minimal interval of alternate day dosing is not violated. The participant will continue to fill out a 
daily diary to indicate the time of dosing, symptoms, AEs (such as fatigue, fever or headache), and 
concomitant medications, if applicable.  
 
Visit 4 – Follow-Up – Day 14 ± 2 
These assessments may not be completed in the order shown below. 
Participants: 
1. Do not need to fast prior to this visit. 
2. Will have any changes to health reviewed by delegated study staff. 
3. Study diary will be collected and/or reviewed by delegated study staff for completion, 
and any AEs and/or concomitant medications. 
4. Will have the following measurements taken: temperature, blood pressure, heart rate. 
5. Will complete the following assessments: 
• Total nasal symptoms score (TNSS) questionnaire  
• Peak nasal inspiratory flow (PNIF) measurement 
6. Be reminded to complete daily diary. 
 

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The participant will continue to fill out a daily diary to indicate symptoms, AEs (such as fatigue, 
fever or headache), and concomitant medications, if applicable. 
 
After this visit, the participant will not continue taking the IP. Any remaining IP will be collected 
from the participant at this visit.  
 
Visit 5 – End of Study – Day 21 ± 2 
These assessments may not be completed in the order shown below. 
Participants: 
1. Must be at least 8 hours fasting (no food, only water) prior to visit. 
2. Will have any changes to health reviewed by delegated study staff. 
3. Study diary will be collected and reviewed by delegated study staff for completion, and 
any AEs and/or concomitant medications. 
4. For females of childbearing potential, a urine sample will be collected for a urine 
pregnancy test.  
5. Will have the following measurements taken: temperature, blood pressure, heart rate. 
6. Will have the following saliva test: 
• Amplicon Metagenomics Sequencing 
7. Will complete the following assessments: 
• Total nasal symptoms score (TNSS) questionnaire  
• Peak nasal inspiratory flow (PNIF) measurement 
8. Will have the following blood tests:  
• CBC (WBC, RBC, Hb, HCT, MCV, MCH, MCHC, Platelet Count) 
• Aspartate aminotransferase (AST) 
• Alanine aminotransferase (ALT) 
• Bilirubin 
• Gamma-glutamyl transferase (GGT) 
• Alkaline phosphatase (ALP) 
• Serum creatinine 
• Potassium 
• Chloride 
• Sodium 
• IgE (total) 
9. Review of all information for the visit by the PI and/or delegate to determine further 
action, if necessary. 
 
The results of the clinical chemistry will be assessed by the PI. The clinical chemistry parameters 
must be within the reference value ranges and/or deemed by the PI as not clinically significant. 
Otherwise, the participant will be contacted by the PI or delegated site staff to further assess and 
determine an appropriate course of action. 
 
 

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9. 
Clinical Assessments and Procedures 
 
9.1. Height and Weight 
Height and weight measurements will be performed as per the site’s SOPs. Participants will 
be weighed on a calibrated scale at specified visits.  
9.2. Biometric Measurements 
Blood pressure, heart rate, and temperature will be measured at each visit. All measurements 
will be done according to the site’s applicable SOP. Calibrated equipment will be used at 
every visit. Manual measurements may be taken for particular parameters where required by 
the PI and/or delegate. 
9.3. Urine Sample Collection 
A urine pregnancy test will be done for females of childbearing potential at Visit 1. If any 
pregnancies arise the participant will be screen-failed and therefore not be enrolled in the 
study.  
9.4. Blood Sample Collection 
 
Blood draws will be done for participants at all visits. Blood will be drawn by delegated site 
personnel from the antecubital site into the appropriate vacutainers as per the schedule of 
assessments, study visit details, and in accordance with the site’s SOPs. The samples will be 
stored and/or sent for analysis as indicated in the Laboratory Manual. The total volume of 
blood to be collected (for safety parameters) from each participant over the course of the trial 
is 240 millilitres (approximately 16 tablespoons) and approximately 48 mL from each 
participant at each visit. 
 
9.5. Questionnaires 
• Total Nasal Symptoms Score (TNSS) Questionnaire: a method developed to assess 
allergic rhinitis symptoms, based on the administration of a questionnaire [33]. 
According to this method, allergic rhinitis symptoms are scored from 0 to 3 (4 grades 
of severity), and the differences between groups will be statistically assessed.  
 
9.6. Peak Nasal Inspiratory Flow (PNIF) measurement 
The assessment of allergic rhinitis [34] . Using this method (PNIF manual), the nasal volume 
and flow for assessing nasal airway patency will be measured. 
9.7. Amplicon Metagenomics Sequencing Collection 
This rRNA gene sequencing method would allow for the assessment of the effect of the 
treatment on the microbial diversity in saliva. Previous evidence has been given to suggest 
that allergic rhinitis may be associated with dysbiosis of the oral microbiota [16], [17], [18]. 
Changes in the parameters of microbiota will be analyzed. 

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9.8. Compliance 
The participant will receive counselling and reminders pertaining to IP compliance and 
protocol requirements from delegated research site personnel.  
Each participant will be required to complete a daily study diary to record the daily intake of 
the IP, concomitant medications, and record the occurrence of any adverse events. The 
participant will be required to return the IP to the research site for the IP compliance 
calculation using the following formula: 
 
(%) as [(doses taken/doses intended) x 100] 
In the event the IP is returned to the study site compliance outside of 80-120% will be treated 
as a protocol deviation.  
This compliance calculation will only apply to Visit 3. 
9.9. Laboratory Analysis 
All laboratory samples will be collected, processed, and stored until shipment or destruction 
by delegated personnel.  
9.9.1. Endpoint-Related Samples 
 
The following endpoints will be collected for each visit during the trial life cycle: 
  
• V1-screening: Vital signs (Body temperature, blood pressure, and heart rate) will be 
measured and Blood Clinical Chemistry samples will be collected. Total Nasal 
Symptoms Score (TNSS) will be administered. A physical examination will be 
completed.  
• V2-Baseline (D1): Total Nasal Symptoms Score (TNSS), Peak Nasal Inspiratory Flow 
(PNIF) values, Saliva sample collection for Amplicon Metagenomics Sequencing test, 
Vital signs (Body temperature, blood pressure, and heart rate) will be measured and 
Blood Clinical Chemistry samples will be collected. 
• V3- Follow up (D7): Total Nasal Symptoms Score (TNSS), Peak Nasal Inspiratory 
Flow (PNIF) values, Saliva sample collection for Amplicon Metagenomics Sequencing 
test, Vital signs (Body temperature, blood pressure, and heart rate) will be measured 
and Blood Clinical Chemistry samples will be collected. 
• V4- Follow up: Total Nasal Symptoms Score (TNSS), Peak Nasal Inspiratory Flow 
(PNIF) values, and Vital signs (Body temperature, blood pressure, and heart rate) will 
be measured. 
• V5- End of study (D21): Total Nasal Symptoms Score (TNSS), Peak Nasal Inspiratory 
Flow (PNIF) values, Saliva sample collection for Amplicon Metagenomics Sequencing 
test, Vital signs (Body temperature, blood pressure, and heart rate) will be measured 
and Blood Clinical Chemistry samples will be collected. 
 
 

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9.9.2. 
Clinical Chemistry 
Clinical chemistry parameters will be analyzed by a local analytical laboratory. For each 
laboratory parameter, results will be assessed by the PI. All in-study out-of-range and 
clinically significant laboratory results will be identified on the lab report by the 
analytical laboratory and/or PI and documented as adverse events, as applicable.  
9.10. Termination of the Trial 
The trial may be terminated at any time by the Sponsor, PI, or applicable regulatory authority 
(Health Canada and/or IRB). If the trial is terminated prematurely, the PI, participants, and 
the regulatory authorities must all be notified of the termination promptly. Upon termination 
of the trial whether premature, or due to completion, site-closeout activities will be initiated 
including regulatory closeout to the appropriate authorities.  
10. Safety Instructions and Guidance 
 
10.1. 
Adverse Events 
Definition: 
An unexpected event (i.e., medical occurrence, sign, or symptom) that happens during the 
study period with an investigational product. Adverse event (AE) may be mild, moderate, or 
severe, and may be caused by something other than the drug or therapy being given. Adverse 
events must be followed-up to resolution or when the condition is deemed stable by the PI.  
10.2. 
Collecting, Recording, and Reporting of AEs 
Collection: 
The PI of delegated study staff must record all adverse events in an AE form with 
information about: 
• Details of adverse event 
• Date of onset (time can be recorded, if applicable) 
• Intensity (mild, moderate, severe) 
• Causal relationship to trial involvement (probable, possible, unlikely, not related) 
• Other actions taken 
• Date and time of outcome 
• Outcome 
Reporting: 
The following timelines apply to the reporting of AEs/SAEs as applicable: 
• Within 24 hours of the PI becoming aware of the event if it results in death of a 
participant 

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• Within 2 weeks (10 business days) after becoming aware of the event if: 
o It is an AE which is related to the conduct of the study; 
o It is an AE that is expected (listed in the ICF as a potential side effect) but is 
occurring more frequently than expected; 
o It is an unexpected AE/SAE that is related to the conduct of the study but is 
not life-threatening 
• Annually (together with the Study Status Report) if: 
o It is an expected AE (listed in the ICF as a potential side effect); 
o It is an unexpected AE that is unlikely to be related to the conduct of the study 
and is not life-threatening. 
Severity Assessment 
All clinical events will be graded as mild, moderate, or severe according to the following scale: 
Mild - The adverse event does not interfere in a significant manner with the subject’s 
normal functioning level. 
Moderate -The adverse event produces some impairment of functioning but is not 
hazardous to the subject’s health. 
Severe -The adverse event produces significant impairment of functioning and may be 
 
potentially hazardous to the subject’s health. 
 
 
Causality Assessment: 
Certain – An adverse event that cannot be explained by disease or any other drugs.  
Probably/Likely – An adverse event that follows a known, expected or suspected 
response pattern of the drug and is unlikely to be explained by any other factors or 
another etiology. 
Possible – An adverse event that follows a known, expected or suspected response 
pattern of the drug but could readily have been produced by a number of other factors or 
explained by another etiology. 
Unlikely – An adverse event that does not follow a known, expected, or suspected 
response pattern of the drug and could readily have been produced by a number of other 
factors or explained by another etiology. 
Conditional/Unclassified – An adverse event that requires more data for proper 
assessment or there is additional data under examination.  
Un-assessable/Unclassifiable – An adverse event that cannot be judged because 
information is insufficient or contradictory.  
 

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10.3. Serious Adverse Events 
Definition: 
A Serious Adverse Event (SAE) or reaction is any untoward medical occurrence that at any 
dose: 
• Results in death;  
• Is life-threatening;  
• Requires inpatient hospitalization;  
• Results in persistent or significant disability/incapacity or; 
• Is a medical event that may jeopardize the patient/participant and may require 
medical or surgical intervention. 
Reaction Reporting: 
(1) During the course of a clinical trial, the sponsor shall notify the Minister of Health of 
any serious adverse reaction and any serious unexpected adverse reaction to the natural 
health product that has occurred inside Canada as follows: 
(a) if it is neither fatal nor life threatening, within 15 days after the day on which 
the sponsor becomes aware of the information; and 
(b) if it is fatal or life threatening, within seven days after the day on which the 
sponsor becomes aware of the information. 
(2) The sponsor shall, within eight days after the day on which the Minister is notified under 
paragraph (1)(b), provide the Minister with a complete report in respect of that information 
that includes an assessment of the importance and implication of any findings made. 
10.4. 
Laboratory Test Abnormalities 
Occurrences of adverse events (serious and non-serious) will be assessed by the PI and/or 
delegate. For this purpose, a blood sample will be collected along with a clinical examination 
(to measure and assess vital signs), an interview of the participant for changes in health or 
concomitant medications, and a review of the participant’s daily diary will be carried out to 
assess the occurrence of adverse events.  
10.5. 
Treatment and Follow-Up of Laboratory Abnormalities 
All events will be treated in accordance with GCP to resolution or until stabilized as deemed 
by the PI and/or delegate 
11. Statistical Evaluation 
11.1. Determination of Sample Size 
Seventy-two participants will be participating in the study. The sample size was chosen based 
on the G*Power calculator in order to detect an effect of 0.6 (Medium effect size) considering 
80% power in t tests. Parametric statistical techniques including, but not limited to t tests - 

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Means: Difference between two independent means (two groups) will be performed on data sets 
which meet all requirements for normality and variance. The application of non-parametric 
techniques might be used for relevant data sets. Should any of the statistical methods proposed 
prove unsuitable during the final analysis, more appropriate methods will be used, and any 
changes will be documented in the clinical study report, including the rationale for use. These 
include the transformation of the data (for example to a logarithmic scale) in order to satisfy 
model assumptions, if applicable. A p-value of < 0.05 will indicate statistical significance for all 
tests. An exploratory data analysis (EDA) will be performed for the exploratory study part to 
analyze and investigate data sets and summarize the main characteristics, employing data 
visualization methods. 
 
 
Figure 1:Analysis: A priori: Compute required sample size. 
 
11.2. Study Population 
Intention-to-treat (ITT) analysis will be considered in this study. ITT analysis includes every 
subject who is randomized according to randomized treatment assignment. The ITT analysis 
includes all randomized patients in the groups to which they were randomly assigned, regardless 
of their adherence with the entry criteria, regardless of the treatment they actually received, and 
regardless of subsequent withdrawal from treatment or deviation from the protocol. ITT analysis 
reflects the practical clinical scenario because it admits noncompliance and protocol deviations. 
ITT analysis maintains prognostic balance generated from the original random treatment 
allocation and it gives an unbiased estimate of treatment effect. 
 
 

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11.3. Analysis Plan 
11.3.1. Primary Variables 
• 
 The Total Nasal Symptoms Score (TNSS) change from the screening (V1), baseline by 
comparing D1(V2) and D7(V3) for each group and the differences between groups 
(investigational and control) will be statistically assessed. 
• 
Peak Nasal Inspiratory Flow (PNIF) values change from the baseline by comparing D1 
and D7 for each group and the differences between groups (investigational and control) 
will be statistically assessed. 
 
11.3.2. Secondary Variables 
1. Safety of the AllerPops product during a 21-day intervention period. Safety will be 
assessed by collecting vital signs, the emergence of adverse events, clinical chemistry 
(CBC and a comprehensive safety panel) and PI assessment. 
2. The change of nasal symptoms will be measured based on the following variables during 
a 21-day intervention period: 
• The Total Nasal Symptoms Score (TNSS) score change will be assessed by 
comparing control group and investigational group.  
• Peak Nasal Inspiratory Flow (PNIF) values change will be assessed by comparing 
control group and investigational group.  
3. Amplicon Metagenomics Sequencing values change during a 21-day intervention period 
will be assessed by comparing control group and investigational group.  
4. IgE (total) blood level change during a 21-day intervention period will be assessed by 
comparing control group and investigational group. 
11.3.3. Data Analysis  
A descriptive statistics study will be performed for the primary variables. Continuous variables 
will be presented with the average and standard deviation or median range, as appropriate, and 
categorical variables will be presented as proportions. Parametric or non-parametric independent 
or related samples tests will be used, according to whether the distribution of the data in each 
variable is normal or not. A p-value < 0.05 is considered statistically significant. An EDA will be 
performed for the secondary variables (except safety) to analyze and investigate data sets and 
summarize their main characteristics, employing data visualization methods. 
11.3.4. Safety Analysis  
The safety evaluation will include assessment of AEs, vital signs, clinical laboratory safety tests, 
and physical examination findings. 
For each continuous laboratory parameter, results will be categorized as low, normal, or high based 
on the laboratory normal ranges, if applicable. Frequencies and percentages will be presented by 

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gender and BMI group for participants who had a shift to low and for participants who had a shift 
to high from baseline to any post-dosing assessment, if applicable.  
The number and percentage of participants with normal and abnormal physical examination results 
will be presented for evaluations at baseline, each indicated visit and final visit, if applicable. 
Individual and summary clinical laboratory data will be presented in tabular form with mean, 
median, standard deviation, and range (minimum and maximum) as appropriate.  
12. Protocol Deviations 
Protocol Deviation (PD) forms must be filed for any deviation from this protocol. PDs which 
place participants at increased risk of harm, or affect data integrity may be considered Protocol 
Violations (PVs) and must be reported to the appropriate regulatory authorities no later than 2 
weeks (10 business days) from the time of identification. PDs will be filed in the applicable 
participant chart, and in the Trial Master File upon study closeout. PDs will be filed and signed 
by delegated study staff and reviewed and signed by the PI. The PI will determine if the PD is 
reportable to the IRB based on an assessment of the participant’s safety and/or the effects on the 
integrity of the study data.  
13. Protocol Amendments 
Any changes to the protocol must be tracked and documented in the form of an amendment after 
it has been reviewed by the appropriate regulatory bodies. The reasons for change must be 
documented in writing and provided to the regulatory bodies and included in the Trial Master 
File (TMF). These changes will be subject to regulatory approval prior to implementation. All 
amendments will be documented in the study report.  
14. Data Collection and Storage 
The PI and/or delegated site staff agree to maintain accurate CRFs and source documentation. 
Source documents are the originals of any documents which will be used by the site that allow 
verification of the existence of the participant and substantiate the integrity of the data collected 
during the trial.  
dicentra will supply either paper or electronic CRFs for each participant. CRFs will be completed 
only by persons delegated by the PI. Corrections will be made so as not to obliterate original data 
and will be identified and dated by the person who made the correction. The PI will allow 
designated representatives and regulatory bodies to have direct access to the source documents to 
verify the data reported in the CRFs.  
All study records will be retained by the site for a period of 25 years after study completion. 
An independent, third-party clinical trial management system (CTMS) software vendor may be 
used at the site for laboratory report data and participant-associated document storage. All 
activities and actions performed on the vendor platform will be tracked and will product an 
electronic audit-trial in accordance to regulatory standards.  

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Paper documents will be used in the event that the CTMS system is not used due to any 
unforeseen or incidental circumstance causing disruption to data collection. All paper 
documentation will be subject to ICH-GCP E6(R2) and applicable guidelines.  
All site-specific documentation generation and management, including documents shared with 
the Sponsor prior to the start of the study follow internal SOPs for version control and approval 
for implementation. All procedural SOPs, reports and source documents that will be shared with 
the Sponsor during and after the study, including those that require changes during the course of 
the study, will be reviewed and approved by the appropriate site staff in accordance with site 
approval processes and SOPs.  
15. Ethical Considerations 
15.1. IRB Approval 
All necessary forms, advertisements, and subject-facing study documents will be compiled into 
a submission to an Institutional Review Board (IRB) for approval prior to the conduct of the 
study. No conduct of the trial will commence until written approval has been obtained from the 
IRB. dicentra must adhere to the requirements of the IRB and notify them of any study 
document changes, protocol amendments, and reportable protocol deviations/violations. Study 
termination must be reported to the IRB, and renewal of study approval must be obtained 
annually (or as per IRB’s stipulations).  
15.2. Informed Consent Form 
Informed consent will be obtained from participants by delegated study staff. The staff will 
explain the study and review each page of the consent document. Participants will then be 
asked to review the consent document, initial each page, and sign the appropriate section(s). 
The Informed Consent Form (ICF) will contain pertinent study details, a statement indicating 
the participant is free to withdraw from the study at any point and for any reason, contact 
information of the IRB (to report ethical concerns), local and applicable regulations 
surrounding disclosure of personal and health information of the participants, compensation 
information, and a section explaining the potential risk(s) of participating in the study.  
15.3. Risks and Procedures to Minimize Risk 
Potential risks are disclosed to the study participants in the ICF prior to their participation in 
the study. The potential risks associated with the study include venipuncture and associated 
risks. The risks of venipuncture (at the site) include: 
• Pain 
• Bruising 
• Infection 
All venipuncture will be performed by certified phlebotomists and all applicable procedures 
will be carried out to minimize risk of infection.  

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The major active ingredient in the product, L-Arginine (402.81mg per dosage unit), does not 
affect endocrine, hepatic or renal function and can be safely used in adults. However, the 
individual with or at risk or cancer are excluded due to possible increased risk of adverse event 
occurrence. 
The potential risks associated with the study product include development of low-grade fever, 
feeling tiredness or low-energy, and mild headache. Emergence of adverse events will be 
assessed at each visit.  
16. Quality Assurance and Quality Control 
16.1. Auditing 
All material used in this clinical trial will be subject to quality control. This study will be 
conducted in accordance with ICH-GCP E6(R2) and all applicable Regulations and local laws. 
Quality assurance audits may be performed by the Sponsor or any health authority during the 
course of the study or after its completion.  
The PI and site agree to comply with the Sponsor and regulatory requirements for auditing the 
study. This includes access to the source documents for source data verification.  
16.2. Monitoring 
Prior to the start of the study, the Sponsor representatives, site personnel, and any third-party 
vendor representatives will hold at least one meeting to go over the details of the study design 
and plans for study execution. During the study, the Sponsor may arrange the visit of appointed 
site monitors to ensure that the execution of the study plan by the site meets the Sponsor’s 
expectations and follows the study protocol objective. The site’s delegated staff will monitor 
the conduct of the study and documentation throughout the course of the trial.  
16.3. Data Management 
 
16.3.1. Source Data and Source Documents 
As defined by the International Conference on Harmonization (ICH), source data are defined 
as all information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical study necessary for the reconstruction 
and evaluation of the study. 
All source data and source documents will be stored and archived according to local 
regulatory requirements. For this study, source data and documents include, but are not 
limited to: 
• 
Signed and dated Informed Consent Form (ICF); 
• 
Name, gender, date of birth and other personal information/demographic 
information; 
• 
Participant ID; 
• 
Date and time of each visit; 

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• 
All clinical measurements and laboratory results; 
• 
Status of participant throughout the study; 
• 
Paper-based or electronic daily diary (to record any concomitant medications, pre-
emergent adverse events, changes in health, dosing time, and adverse events); 
• 
Reason for discontinuation/withdrawal, if applicable. 
 
16.3.2. Case Report Forms (CRFs) 
Case report forms will be created following protocol finalization and approval to capture 
study data. These forms may be in the form of paper, or may be electronic (e-CRFs). An 
eCRF system, provided by an independent third-party vendor, may be used to capture data. 
Prior to deployment of the study, the eCRF system will be validated and specified to address 
source documentation, in accordance with Sponsor and regulatory requirements.  
16.3.3. Data Storage and Access 
In case of eCRF, data will be entered into the CTMS system, checked for discrepancies and 
queried for any issues in accordance to site-approved SOPs. The database housing the eCRF 
input will be hosted by the eCRF vendor and paper CRFs will be used as the backup plan, if 
deemed necessary and applicable. Official corrections and/or modifications during the trial 
will be automatically tracked by an audit trail detailing the date, time, and personnel 
involved/approving the modification of the eCRF. All vendor data access and entry can only 
be performed by authorized users, using a unique user login and password. The Sponsor and 
dicentra will permit trial-related monitoring, audits, IRB review, and regulatory inspections, 
providing direct (read-only) access to source data/documents. Paper CRFs will be monitored 
for completion, queried through internal review by delegated site staff, identified items 
resolved and documented where applicable, and any required data from source documents 
will be entered into the final database prior to locking.  
16.4. 
Data Quality Assurance 
Data cleaning will be performed to check for completeness and consistency of data using 
both programmed and manual edit checks. Discrepancies in data will be resolved through 
querying, delegation and resolution in accordance to site SOPs. Actions changing original 
data collection will be recorded using an electronic audit trail or done manually for paper 
CRFs according to ICH-GCP E6(R2).  
16.5. 
Confidentiality of Participant Data 
The PI and/or delegated site staff will ensure that the confidentiality of the participant’s data 
will be preserved to the extent permitted by law. In any documents collected after enrollment 
into the study, the participants will only be identified by their participant ID; the ID consists 
of the participant’s initials and an assigned number related to the sequence of received ICFs 
for the study. Documents that house participant information, such as signed ICFs and 
personal information/demographic forms will be maintained and store by delegated site staff 
under strict access.  

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17. References 
 
[1] 
F. K. Hansel, “Clinical and histopathologic studies of the nose and sinuses in allergy,” J. 
Allergy, vol. 1, no. 1, pp. 43–70, Nov. 1929, doi: 10.1016/S0021-8707(29)90083-6. 
[2] 
P. K. Keith, M. Desrosiers, T. Laister, R. R. Schellenberg, and S. Waserman, “The burden 
of allergic rhinitis (AR) in Canada: perspectives of physicians and patients,” Allergy, 
Asthma Clin. Immunol., vol. 8, no. 1, p. 7, Jun. 2012, doi: 10.1186/1710-1492-8-7. 
[3] 
B. T. Prince, M. J. Mandel, K. Nadeau, and A. M. Singh, “Gut Microbiome and the 
Development of Food Allergy and Allergic Disease,” Pediatric Clinics of North America, 
vol. 62, no. 6. W.B. Saunders, pp. 1479–1492, Dec. 01, 2015, doi: 
10.1016/j.pcl.2015.07.007. 
[4] 
S. K. Wise et al., “International Consensus Statement on Allergy and Rhinology: Allergic 
Rhinitis,” Int. Forum Allergy Rhinol., vol. 8, no. 2, pp. 108–352, Feb. 2018, doi: 
10.1002/alr.22073. 
[5] 
L. C. F. L. Melli, M. S. do Carmo-Rodrigues, H. B. Araújo-Filho, D. Solé, and M. B. de 
Morais, “Intestinal microbiota and allergic diseases: A systematic review,” Allergologia et 
Immunopathologia, vol. 44, no. 2. Elsevier Doyma, pp. 177–188, Mar. 01, 2016, doi: 
10.1016/j.aller.2015.01.013. 
[6] 
C. E. West, M. C. Jenmalm, and S. L. Prescott, “The gut microbiota and its role in the 
development of allergic disease: A wider perspective,” Clinical and Experimental Allergy, 
vol. 45, no. 1. Blackwell Publishing Ltd, pp. 43–53, Jan. 01, 2015, doi: 
10.1111/cea.12332. 
[7] 
L. Zhu et al., “Gut microbial characteristics of adult patients with allergy rhinitis,” 
Microb. Cell Fact., vol. 19, no. 1, Sep. 2020, doi: 10.1186/s12934-020-01430-0. 
[8] 
J.-F. Bach, “The Effect of Infections on Susceptibility to Autoimmune and Allergic 
Diseases,” N. Engl. J. Med., vol. 347, no. 12, pp. 911–920, Sep. 2002, doi: 
10.1056/nejmra020100. 
[9] 
D. P. Strachan, “Hay fever, hygiene, and household size,” Br. Med. J., vol. 299, no. 6710, 
pp. 1259–1260, 1989, doi: 10.1136/bmj.299.6710.1259. 
[10] N. A. Abreu et al., “Sinus microbiome diversity depletion and Corynebacterium 
tuberculostearicum enrichment mediates rhinosinusitis,” Sci. Transl. Med., vol. 4, no. 151, 
pp. 151ra124-151ra124, Sep. 2012, doi: 10.1126/scitranslmed.3003783. 
[11] M. Hoggard, K. Biswas, M. Zoing, B. Wagner Mackenzie, M. W. Taylor, and R. G. 
Douglas, “Evidence of microbiota dysbiosis in chronic rhinosinusitis,” Int. Forum Allergy 
Rhinol., vol. 7, no. 3, pp. 230–239, Mar. 2017, doi: 10.1002/alr.21871. 
[12] D. Lal et al., “Mapping and comparing bacterial microbiota in the sinonasal cavity of 
healthy, allergic rhinitis, and chronic rhinosinusitis subjects,” Int. Forum Allergy Rhinol., 
vol. 7, no. 6, pp. 561–569, Jun. 2017, doi: 10.1002/alr.21934. 
[13] F. Lan, N. Zhang, E. Gevaert, L. Zhang, and C. Bachert, “Viruses and bacteria in Th2-

SSH Corp./Protocol Number 21-SAHSE-01 
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Version 4.0 
 
Page 38 of 40 
biased allergic airway disease,” Allergy: European Journal of Allergy and Clinical 
Immunology, vol. 71, no. 10. Blackwell Publishing Ltd, pp. 1381–1392, Oct. 01, 2016, 
doi: 10.1111/all.12934. 
[14] T. Shiomori, S. ichi Yoshida, H. Miyamoto, and K. Makishima, “Relationship of nasal 
carriage of Staphylococcus aureus to pathogenesis of perennial allergic rhinitis,” J. 
Allergy Clin. Immunol., vol. 105, no. 3, pp. 449–454, 2000, doi: 
10.1067/mai.2000.104256. 
[15] T. Van Zele et al., “Staphylococcus aureus colonization and IgE antibody formation to 
enterotoxins is increased in nasal polyposis [6],” Journal of Allergy and Clinical 
Immunology, vol. 114, no. 4. J Allergy Clin Immunol, pp. 981–983, Oct. 2004, doi: 
10.1016/j.jaci.2004.07.013. 
[16] S. J. Arbes and E. C. Matsui, “Can oral pathogens influence allergic disease?,” J. Allergy 
Clin. Immunol., vol. 127, no. 5, pp. 1119–1127, May 2011, doi: 
10.1016/j.jaci.2011.03.023. 
[17] J. W. Card et al., “Modulation of allergic airway inflammation by the oral pathogen 
Porphyromonas gingivalis,” Infect. Immun., vol. 78, no. 6, pp. 2488–2496, Jun. 2010, doi: 
10.1128/IAI.01270-09. 
[18] K. Wongkamhaeng, O. Poachanukoon, and S. Koontongkaew, “Dental caries, cariogenic 
microorganisms and salivary properties of allergic rhinitis children,” Int. J. Pediatr. 
Otorhinolaryngol., vol. 78, no. 5, pp. 860–865, 2014, doi: 10.1016/j.ijporl.2014.03.001. 
[19] D. J. Costa et al., “Efficacy and safety of the probiotic Lactobacillus paracasei LP-33 in 
allergic rhinitis: A double-blind, randomized, placebo-controlled trial (GA2LEN Study),” 
Eur. J. Clin. Nutr., vol. 68, no. 5, pp. 602–607, 2014, doi: 10.1038/ejcn.2014.13. 
[20] S. Kawamoto et al., “Sake lees fermented with lactic acid bacteria prevents allergic 
rhinitis-like symptoms ige-mediated basophil degranulation,” Biosci. Biotechnol. 
Biochem., vol. 75, no. 1, pp. 140–144, 2011, doi: 10.1271/bbb.100541. 
[21] A. C. Ouwehand, M. Nermes, M. C. Collado, N. Rautonen, S. Salminen, and E. Isolauri, 
“Specific probiotics alleviate allergic rhinitis during the birch pollen season,” World J. 
Gastroenterol., vol. 15, no. 26, pp. 3261–3268, Jul. 2009, doi: 10.3748/wjg.15.3261. 
[22] Ö. Özdemir, “Various effects of different probiotic strains in allergic disorders: An update 
from laboratory and clinical data,” Clinical and Experimental Immunology, vol. 160, no. 
3. Wiley-Blackwell, pp. 295–304, Jun. 2010, doi: 10.1111/j.1365-2249.2010.04109.x. 
[23] M. Medina, J. Villena, S. Salva, E. Vintiñi, P. Langella, and S. Alvarez, “Nasal 
administration of Lactococcus lactis improves local and systemic immune responses 
against Streptococcus pneumoniae,” Microbiol. Immunol., vol. 52, no. 8, pp. 399–409, 
Aug. 2008, doi: 10.1111/j.1348-0421.2008.00050.x. 
[24] N. Sudo, S. Sawamura, K. Tanaka, Y. Aiba, C. Kubo, and Y. Koga, “The requirement of 
intestinal bacterial flora for the development of an IgE production system fully susceptible 
to oral tolerance induction.,” J. Immunol., vol. 159, no. 4, 1997. 
[25] H. R. Christensen, H. Frøkiær, and J. J. Pestka, “Lactobacilli Differentially Modulate 

SSH Corp./Protocol Number 21-SAHSE-01 
Mar 1, 2022 
Version 4.0 
 
Page 39 of 40 
Expression of Cytokines and Maturation Surface Markers in Murine Dendritic Cells,” J. 
Immunol., vol. 168, no. 1, pp. 171–178, Jan. 2002, doi: 10.4049/jimmunol.168.1.171. 
[26] L. E. M. Niers et al., “Identification of strong interleukin-10 inducing lactic acid bacteria 
which down-regulate T helper type 2 cytokines,” Clin. Exp. Allergy, vol. 35, no. 11, pp. 
1481–1489, Nov. 2005, doi: 10.1111/j.1365-2222.2005.02375.x. 
[27] C. B. M. Maassen et al., “Strain-dependent induction of cytokine profiles in the gut by 
orally administered Lactobacillus strains,” Vaccine, vol. 18, no. 23, pp. 2613–2623, May 
2000, doi: 10.1016/S0264-410X(99)00378-3. 
[28] H. H. Smits et al., “Selective probiotic bacteria induce IL-10-producing regulatory T cells 
in vitro by modulating dendritic cell function through dendritic cell-specific intercellular 
adhesion molecule 3-grabbing nonintegrin,” J. Allergy Clin. Immunol., vol. 115, no. 6, pp. 
1260–1267, Jun. 2005, doi: 10.1016/j.jaci.2005.03.036. 
[29] H. Braat, J. Van Den Brande, E. Van Tol, D. Hommes, M. Peppelenbosch, and S. Van 
Deventer, “Lactobacillus rhamnosus induces peripheral hyporesponsiveness in stimulated 
CD4+ T cells via modulation of dendritic cell function,” Am. J. Clin. Nutr., vol. 80, no. 6, 
pp. 1618–1625, 2004, doi: 10.1093/ajcn/80.6.1618. 
[30] C. W. Schmidt, “Pollen overload: Seasonal allergies in a changing climate,” Environ. 
Health Perspect., vol. 124, no. 4, pp. A71–A75, Apr. 2016, doi: 10.1289/ehp.124-A70. 
[31] Z.-J. Xie, K. Guan, and J. Yin, “Advances in the clinical and mechanism research of 
pollen induced seasonal allergic asthma.,” Am. J. Clin. Exp. Immunol., vol. 8, no. 1, pp. 1–
8, 2019, Accessed: Jun. 11, 2021. [Online]. Available: 
http://www.ncbi.nlm.nih.gov/pubmed/30899604. 
[32] W. R. L. Anderegg, J. T. Abatzoglou, L. D. L. Anderegg, L. Bielory, P. L. Kinney, and L. 
Ziska, “Anthropogenic climate change is worsening North American pollen seasons,” 
Proc. Natl. Acad. Sci. U. S. A., vol. 118, no. 7, p. 2013284118, Feb. 2021, doi: 
10.1073/pnas.2013284118. 
[33] H. Chajra, G. Redziniak, D. Auriol, K. Schweikert, and F. Lefevre, “Trihydroxybenzoic 
acid glucoside as a global skin color modulator and photo-protectant,” Clin. Cosmet. 
Investig. Dermatol., vol. 8, pp. 579–589, Nov. 2015, doi: 10.2147/CCID.S93364. 
[34] S. de Souza Campos Fernandes, C. R. De Andrade, and C. da C. Ibiapina, “Application of 
Peak Nasal Inspiratory Flow reference values in the treatment of allergic rhinitis,” 
Rhinology, vol. 52, no. 2, pp. 133–136, 2014, doi: 10.4193/Rhino13.158. 
 
 
 
 

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Appendix 1: Questionnaires TNSS Questionnaire