Clinical trial NCT04728711
Conditions: Atopic Asthma
Sponsor: Aldeyra Therapeutics, Inc.
Start date: 2021-01-09; Completion date: 2022-01-18
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A Double Masked, Placebo Controlled, Single Center, Randomized Clinical Trial to Assess the Safety and Efficacy of ADX-629 in Subjects with Mild Asthma Induced by the Bronchial Allergen Challenge (BAC)

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: ADX-629 intervention 2: Placebo
Intervention descriptions: intervention 1: ADX-629, 600 mg administered orally twice daily (PO bid) for a minimum of 1 week intervention 2: Placebo, 600 mg administered orally twice daily (PO bid) for minimum 1 week

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
This protocol is the confidential and proprietary information of 
 Limited doing business as 
 and 
Aldeyra Therapeutics, Inc. It was developed for Aldeyra Therapeutics, Inc. by 
 and should not be disclosed to a 
third party, with the exception of regulatory agencies and study audit personnel. 
 
 
 
 
 
 
 
                           
f 
 
A Double Masked, Placebo Controlled, Single Center, Randomized Clinical Trial 
to Assess the Safety and Efficacy of ADX-629 in Subjects with Mild Asthma 
Induced by the Bronchial Allergen Challenge (BAC) 
 
Name of Sponsor 
 
Aldeyra Therapeutics, Inc. 
131 Hartwell Avenue, Suite 320 
Lexington, MA 02421 
USA 
Protocol 
Identification (code 
or numbers) 
Sponsor Study Number: ADX‐629‐AA‐001 
 Study Number: C2D00212 
Study Product(s)  
Treatment A: ADX-629, 600 mg (2 x 300 mg tablets)  
Treatment B: Placebo, 600 mg (2 x 300 mg tablets)  
Clinical Research 
Organization 
 
 
  
 
Indication 
Mild asthma 
Clinical Trial Phase 
Phase 2 
Regulatory Agency 
Health Canada 
Protocol Version  
Final 5.0 
Protocol Date 
 19 May 2021 
 
 
 
 


 
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PROTOCOL VERSION CONTROL  
 
Version Number 
 
Date 
Final 1.0 
 
20 Aug 2020 
Final 2.0 
 
  
16 Nov 2020 
Final 3.0 
 
 
24 Feb 2021 
Final 4.0 
 
 
14 Apr 2021 
Final 5.0 
 
 
19 May 2021 
 
 
 


 
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PROTOCOL REVISION HISTORY 
The following table summarizes the updates made from Protocol Version 4.0 (14 Apr 2021) to 
Protocol Version 5.0 (19 May 2021). 


 
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The following table summarizes the updates made from Protocol Version 3.0 (24 Feb 2021) to 
Protocol Version 4.0 (14 Apr 2021). 


  
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The following table summarizes the updates made from Protocol Version 2.0 (16 Nov 2020) to 
Protocol Version 3.0 (24 Feb 2021). 


  
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SPONSOR APPROVAL/SIGNATURE PAGE 
 
Title: A Double Masked, Placebo Controlled, Single Center, Randomized Clinical Trial to 
Assess the Safety and Efficacy of ADX-629 in Subjects with Mild Asthma Induced by the 
Bronchial Allergen Challenge (BAC). 
 
I, on behalf of Aldeyra Therapeutics, Inc., approve the protocol and agree to conduct this clinical 
trial as outlined in the approved protocol and in accordance with the appropriate guidelines and 
all applicable federal government codes, acts and regulations, the ethical pricinples that have 
their origins in the Declaration of Helsinki and all amendments, Good Clinical Practice (GCP) 
requirements, The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidance E6 (R2) on Good Clinical Practice, and Tri-
Council Policy Statement (Canada). 
 
Sponsor Representative  
  
  
  
  
  
  
 
 
 
 
 
 


  
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PRINCIPAL INVESTIGATOR APPROVAL/SIGNATURE PAGE 
 
Title: A Double Masked, Placebo Controlled, Single Center, Randomized Clinical Trial to 
Assess the Safety and Efficacy of ADX-629 in Subjects with Mild Asthma Induced by the 
Bronchial Allergen Challenge (BAC). 
 
I agree to conduct this clinical trial as outlined in the approved protocol and in accordance with 
the Sponsor's guidelines and all applicable federal government codes, acts and regulations, the 
ethical pricinples that have their origins in the Declaration of Helsinki and all amendments, Good 
Clinical Practice (GCP) requirements, The International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guidance E6 (R2) on Good Clinical 
Practice, and Tri-Council Policy Statement (Canada) and to allow the Sponsor and applicable 
regulatory agencies the opportunity to inspect study facilities and pertinent records at 
reasonable times and in a reasonable manner that ensures subject confidentiality. 
Principal Investigator 
  
  
  
 
  
  
  
 
 
 
 


  
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ................................................................................................ 26 
2. 
SPONSOR REPRESENTATIVE ......................................................................................... 29 
3. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................................. 29 
 
Clinical Research Organization ................................................................................... 29 
 
Clinical Facilities .......................................................................................................... 29 
 
Principal Investigator ................................................................................................... 29 
 
Central Institutional Review Board (IRB) ..................................................................... 29 
 
Statistical Analyses ..................................................................................................... 30 
 
Medical Monitor ........................................................................................................... 30 
 
Clinical Laboratory Facility .......................................................................................... 30 
4. 
STUDY SUMMARY ............................................................................................................ 31 
5. 
STUDY SCHEMATIC .......................................................................................................... 40 
 
Schedule of Assessments ........................................................................................... 40 
 
Study Design ............................................................................................................... 43 
6. 
INTRODUCTION ................................................................................................................. 44 
 
Background and Study Rationale ................................................................................ 44 
 
ADX-629 ...................................................................................................................... 45 
 
Nonclinical Safety and Toxicology ............................................................................... 45 
 
Benefit/Risk Assessment ............................................................................................. 45 
 
Effects in Humans ....................................................................................................... 46 
 
Rationale for Dose Selection ....................................................................................... 48 
7. 
OBJECTIVES AND ENDPOINTS ....................................................................................... 49 
 
Study Objectives ......................................................................................................... 49 
 
Study Endpoints .......................................................................................................... 49 
8. 
CLINICAL TRIAL DESIGN ................................................................................................. 50 
9. 
SUBJECT SELECTION ...................................................................................................... 51 
 
Number of Subjects ..................................................................................................... 51 
 
Inclusion Criteria for Study Volunteers ........................................................................ 51 
 
Exclusion and Restriction Criteria for Study Volunteers .............................................. 52 
9.3.1 
Exclusion Criteria ................................................................................................ 52 
9.3.2 
Restrictions and Concomitant Medications ......................................................... 53 


  
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9.3.3 
Female Subjects of Childbearing Potential.......................................................... 55 
9.3.4 
Male Subjects ...................................................................................................... 56 
10. STUDY PRODUCT AND RANDOMIZATION ..................................................................... 57 
 
Study Product and Treatment ..................................................................................... 57 
 
Randomization Sequence ........................................................................................... 57 
 
Masking and Unmasking ............................................................................................. 58 
10.3.1 
Masking ............................................................................................................... 58 
10.3.2 
Emergency Unmasking ....................................................................................... 58 
11. STUDY CONDUCT ............................................................................................................. 59 
 
COVID-19 Screening ................................................................................................... 59 
 
Medical Screening: Visit 1 (Day - 28 to Day - 2) ......................................................... 59 
 
Pre-Treatment Period (3 consecutive days): Visit 2a, 2b and 2c (Day 1, 2 and 3) ..... 60 
 
Randomization Visit: Visit 3 (Day 17) .......................................................................... 62 
 
Treatment Period 1 (Day 17 to Day 23 [+3]) ............................................................... 63 
11.5.1 
Reminder Phone Calls - Treatment Period 1 ....................................................... 63 
 
Post-Treatment Period 1 (2 consecutive days): Visits 4a and 4b (Day 24 and 25) ..... 63 
 
Treatment Period 2 (2 weeks after Visit 4b) (Day 39 to Day 45) ................................. 65 
11.7.1 
Reminder Phone Calls - Treatment Period 2 ....................................................... 65 
 
Post-Treatment Period 2 (2 consecutive days): Visits 5a and 5b (Day 46 & 47) ......... 65 
 
Early Termination Visit (ETV) ...................................................................................... 65 
12. STUDY PROCEDURES AND SAFETY ASSESSMENTS ................................................. 66 
 
Study Procedures ........................................................................................................ 66 
12.1.1 
Skin Prick Test (SPT) .......................................................................................... 66 
12.1.2 
Spirometry ........................................................................................................... 66 
12.1.3 
Methacholine Challenge Test (MCT) ................................................................... 67 
12.1.4 
Multi-skin Prick Sensitivity Test ........................................................................... 67 
12.1.5 
Bronchial Allergen Challenge (BAC) ................................................................... 68 
12.1.6 
Fractional Exhaled Nitric Oxide (FeNO) .............................................................. 68 
12.1.7 
Sputum Analysis .................................................................................................. 69 
12.1.8 
Biomarkers .......................................................................................................... 69 
 
Safety Assessments .................................................................................................... 69 
12.2.1 
Clinical Laboratory Tests ..................................................................................... 69 


  
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12.2.2 
Demographics and Medical, Surgical and Social History .................................... 70 
12.2.3 
Physical Examination .......................................................................................... 70 
12.2.4 
Vital Signs ........................................................................................................... 70 
12.2.5 
Adverse Event Query/Concomitant Medication Query ........................................ 71 
12.2.6 
Paper Diaries ....................................................................................................... 71 
12.2.7 
Pharmacokinetic assessment .............................................................................. 71 
12.2.8 
Electrocardiogram ............................................................................................... 71 
13. ANALYSES AND REPORTS ............................................................................................. 72 
 
Handling of Dropouts or Missing Data ......................................................................... 72 
 
Final Integrated Report ................................................................................................ 72 
14. STATISTICAL CONSIDERATIONS ................................................................................... 72 
 
Statistical Plan ............................................................................................................. 72 
 
Sample Size Calculation ............................................................................................. 72 
 
Analysis Populations ................................................................................................... 72 
 
Statistical Analyses ..................................................................................................... 73 
14.4.1 
General Descriptive Statistics .............................................................................. 73 
14.4.2 
Efficacy Variables ................................................................................................ 73 
14.4.3 
Exploratory Variables .......................................................................................... 73 
14.4.4 
Statistical Analysis of Efficacy Data..................................................................... 73 
 
Safety Analysis ............................................................................................................ 74 
 
Interim Analyses .......................................................................................................... 74 
 
Sub-group Analyses .................................................................................................... 74 
 
Exploratory Analyses ................................................................................................... 74 
15. ADMINISTRATIVE STUDY RECORDS ............................................................................. 74 
 
Subject Enrollment and Identification .......................................................................... 74 
 
Study Charts/Records and Source Documents ........................................................... 75 
 
Retention and Availability of Investigational Records .................................................. 76 
16. DRUG ACCOUNTABILITY ................................................................................................. 76 
 
Product Shipment ........................................................................................................ 76 
 
Product Receipt ........................................................................................................... 76 
 
Product Storage .......................................................................................................... 76 
 
Drug Dose Package Labeling ...................................................................................... 77 


  
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Reserve Samples (if applicable) .................................................................................. 77 
17. SUBJECT SAFETY MONITORING AND ADVERSE EVENTS ......................................... 77 
 
Subject Safety Monitoring ........................................................................................... 77 
17.1.1 
Pregnancy ........................................................................................................... 77 
 
Adverse Events ........................................................................................................... 78 
17.2.1 
Recording Adverse Events .................................................................................. 78 
17.2.2 
Reporting Serious Adverse Events...................................................................... 80 
17.2.3 
Removal of Subjects from Clinical Trial ............................................................... 81 
17.2.4 
Termination of Study Due to Adverse Events ...................................................... 81 
18. ETHICS OF CONDUCT ...................................................................................................... 81 
19. QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 82 
 
Pandemic COVID-19 Response Plan ......................................................................... 82 
20. REGULATORY ................................................................................................................... 83 
 
Institutional Review Board/Health Canada .................................................................. 83 
 
Consent Document ...................................................................................................... 84 
 
Confidentiality .............................................................................................................. 85 
 
Investigator's Statement .............................................................................................. 85 
21. REFERENCES .................................................................................................................... 87 
22. APPENDICES ..................................................................................................................... 89 
Appendix 1: Asthma Control Questionnaire .......................................................................... 89 
Appendix 2: Asthma Action Plan ............................................................................................ 92 
 


  
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1. 
LIST OF ABBREVIATIONS  
TERM 
DEFINITION  
ºC 
Degrees Centigrade 
ºF 
Degrees Fahrenheit 
μg 
Microgram 
μmol 
Micromole 
μM 
micromolar 
ACQ 
Asthma Control Questionnaire 
ADaM 
Analysis Dataset Model 
ADRs 
Adverse Drug Reactions 
AE 
Adverse Event 
AHR 
Allergen-induced shift in airway Hyper Responsiveness 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
ATS 
American Thoracic Society 
AUC 
Area Under the Curve 
AUC0-t 
Area under the plasma concentration versus time curve, from time 0 to the 
‘t’ hour 
BAC 
Bronchial Allergen Challenge 
BAU 
Bioequivalent Allergy Unit 
bid  
Bis in die (twice a day) 
BMI 
Body Mass Index 
bpm 
Beats per minute 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CDISC 
Clinical Data Standards Interchange Consortium 
CFR 
Code of Federal Regulations 
Cmax 
Maximum Observed Concentration 
COVID-19 
Corona Virus Disease 2019 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CYP 
Cytochrome P450 
DMP 
Data Management Plan 
EAR 
Early Phase Asthmatic Response 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EDC 
Electronic Data Capture 
FeNO 
Fractional Exhaled Nitric Oxide 


  
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TERM 
DEFINITION  
ERS 
European Thoracic Society 
ETV 
Early Termination Visit  
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in one second 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transpeptidase 
GLP 
Good Laboratory Practice 
GSEM 
Geometric Standard Error of the Mean 
h 
Hour 
HDM 
House Dust Mite 
HNE 
4-Hydroxynonenal 
HR 
Heart Rate 
ICH 
International Council for Harmonisation 
ID 
Identification 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
kg 
Kilogram 
L 
Liter  
LAR 
Late Phase Asthmatic Response 
m 
Metre 
MAD 
Multiple Ascending Dose 
Mch 
Methacholine 
Mch PC20 
Provocative Methacholine Concentration that causes a ≥ 20% fall in FEV1 
from the post- saline value 
MCT 
Methacholine Challenge Test 
MDI 
Metered Dose Inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute(s) 
mL 
Millilitre 
mm 
Millimeter 
mmHg 
Millimetre of mercury 
MMRM 
Mixed effect Model for Repeated Measures 
ms 
Milliseconds 
ng 
Nanogram 
NOAEL 
No Observed Adverse Effect Level 
PK 
Pharmacokinetic 
PO 
Oral 
PP 
Per-Protocol 


  
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TERM 
DEFINITION  
QA 
Quality Assurance 
QTcF 
Corrected value by Fredericia’s formula of the interval between the Q and 
T waves on the electrocardiogram tracing 
RASP 
Reactive Aldehyde Species 
REB 
Research Ethics Board 
SABA 
Short-Acting Beta2-Agonist 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SAS 
Statistical Analysis Software 
SD 
Standard Deviation  
SDTM 
Study Data Tabulation Model 
SGOT 
Serum Glutamic Oxaloacetic Transaminase  
SGPT 
Serum Glutamic Pyruvic Transaminase  
SOP 
Standard Operating Procedure 
SPT 
Skin Prick Test 
SUSAR 
Suspected Unsuspected Serious Adverse Reaction 
TdP 
Torsades de Pointes  
TSH 
Thyroid Stimulating Hormone  
WOCBP 
Women of Childbearing Potential 
 


  
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2. 
SPONSOR REPRESENTATIVE 
  
  
 Aldeyra Therapeutics, Inc.  
 131 Hartwell Avenue, Suite 320  
 Lexington, MA 02421  
 USA  
 
 
3. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
 
Clinical Research Organization 
 
 
 
 
 
 
Clinical Facilities 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator 
Dr. Peter Couroux MD, FRCPC, CPI  
  
  
 
  
  
 
 
 
 
Central Institutional Review Board (IRB) 
            Advarra  
372 Hollandview Trail, Suite 300 
Aurora, ON L4G 0A5  
Canada  


  
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Phone: (905) 727-7989 
 
 
Statistical Analyses 
 
 
 
 
 
 
 
 
 
 
Medical Monitor 
 
 
  
 
 
Clinical Laboratory Facility 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
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4. 
STUDY SUMMARY 
Title 
 
A Double Masked, Placebo Controlled, Single Center, Randomized Clinical Trial to 
Assess the Safety and Efficacy of ADX-629 in Subjects with Mild Asthma Induced by the 
Bronchial Allergen Challenge (BAC) 
Protocol 
Identification 
(code or 
numbers) 
Sponsor Study Number: ADX‐629‐AA‐001 
 Study Number: C2D00212 
Study Phase 
Phase 2 
Study 
Objectives 
Primary objective: 
To assess the safety of ADX-629 in subjects with allergen-induced mild asthma. 
Secondary objective: 
To assess the clinical efficacy of ADX-629 in subjects with allergen-induced mild asthma. 
Study 
Endpoints 
Safety Endpoint: 
• 
Safety, as assessed by adverse events (AEs) and serious adverse events 
(SAEs) 
Efficacy Endpoints: 
• 
Change from baseline (within visit) in forced expiratory volume in one second 
(FEV1) to post-BAC (during 0-3 h post-BAC [Key Efficacy Endpoint] and 3-7 h 
post BAC). 
• 
Absolute count and percentage differential count of sputum eosinophils and 
neutrophils at approximately 7 h and 24 h post-BAC. 
• 
Allergen-induced shift in airway hyper responsiveness (AHR) as assessed by 
Methacholine PC20 (Mch PC20) post-BAC.  
• 
Change from baseline in fractional exhaled Nitric Oxide (FeNO) at approximately 
7 h and 24 h post-BAC. 
Exploratory Endpoints: 
• 
Biomarkers (Reactive Aldehyde Species [RASP] and endotoxin-induced cytokine 
release) pre-BAC (at approximately 1 hour post-dose) and 7 h post-BAC. 
• 
Area under curve (AUC) of FEV1 during 0-3 h post-BAC and/or 3-7 h post BAC. 
Study 
Population 
Adult subjects with mild asthma and positive skin prick test to cat or house dust mite 
(HDM). 
Study Design 
 
ADX-629-AA-001 is a double-masked, cross-over, placebo-controlled, single center, 
randomized clinical trial to assess the clinical safety and efficacy of ADX-629 compared 
to placebo in mild cat or HDM-induced asthmatics using the BAC model. The clinical trial 
will consist of 9 visits to the clinic (Visits 1, 2a, 2b, 2c, 3, 4a, 4b, 5a, and 5b) over a 


  
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period of approximately 75 days. During this period there will be 4 additional visits, 1 visit 
for safety lab and 3 visits for COVID-19 testing, as described below. 
Study Products 
and Treatment 
arms  
Treatment A: ADX-629, 600 mg (2 x 300 mg tablets), orally twice daily (PO bid) for 
minimum of 1 week (+3)  
Treatment B: Placebo, 600 mg (2 x 300 mg tablets), orally twice daily (PO bid) for 
minimum 1 week (+3)  
During Post-Treatment Period 1 and 2 (Visits 4a, 4b, 5a, and 5b), in lieu of the morning 
dose, 600 mg of the treatments will be administered approximately one hour prior to 
MCT or BAC testing.  
Route of 
Administration 
Oral  
Study 
population 
Enough subjects will be enrolled to ensure approximately 12 subjects complete the 
study. Subjects will be randomized (1:1) to one of the following sequences: 
1. 
AB (N= 6) 
2. 
BA (N= 6) 
Study Conduct 
I. Medical Screening- Visit 1 
All subjects will undergo a screening visit (Visit 1), which will include a written informed 
consent, demographics, medical/surgical/social/medication histories, vital signs, samples 
for standard clinical labs, Electrocardiogram (ECG), and a physical examination with 
height, weight and BMI. An asthma control questionnaire will be completed. A urine 
pregnancy test will be administered to women of childbearing potential (WOCBP). A skin 
prick test (SPT) will be performed to show positivity to cat or HDM allergen (≥ 3 mm 
wheal compared to negative control). Subjects will undergo spirometry to demonstrate 
baseline (pre-bronchodilator) FEV1 of ≥ 80% of the predicted value. All lung function 
tests will be conducted in accordance with the site standard procedures (which is based 
on the American Thoracic Society/European Thoracic Society [ATS/ERS] 
recommendations). Post-bronchodilator FEV1 will be measured within 15±5 minutes 
following 400 µg (4 puffs) of salbutamol inhalation and post-bronchodilator reversibility 
will be recorded.  
II. Pre-Treatment Period (For 3 consecutive days) –Visits 2a, 2b and 2c 
Subjects will return to the clinic for the pre-treatment period within approximately 4 weeks 
of the Screening visit. In all visits, staff will update the subjects’ concomitant medication 
and collect adverse events and vital signs. Eligibility criteria will be reviewed. 
At Visit 2a, asthma control questionnaire will be completed. Spirometry will be performed 
to ensure FEV1 ≥ 80% of the predicted value. Subjects will have a pre-BAC Methacholine 
challenge test (MCT) performed as per the site standard procedures. Subjects will inhale 
normal saline and have a baseline FEV1 established. Subjects will then be given 
subsequent doubling concentrations of Methacholine (Mch) as per the site standard 
procedures. FEV1 will be measured at approximately 30 and 90 seconds following 
nebulization. If the FEV1 drops < 20%, the subject will be given the next highest 
concentration and spirometry repeated. Mch doses will continue to be administered 
sequentially (max concentration 4 mg/mL) until FEV1 falls ≥ 20% of the baseline. At such 
time, the test will be terminated and subjects will be given 4 puffs of salbutamol, followed 
by a 15±5 minute waiting period prior to FEV1 measurement. Subjects whose FEV1 


  
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levels are not within 10% of their baseline will be given another dose of salbutamol and 
spirometry measurement repeated after 15±5 minutes. Mch PC20 will then be calculated. 
All MCT will be performed at the same time of the day within a timeframe of ±1.5 hours 
throughout the entire study. Those who qualify will undergo a multi-skin prick sensitivity 
test with doubling concentrations of cat/ HDM allergen extracts. A positive control and a 
negative control will also be administered. The wheal diameters will be measured as per 
the site standard procedures. Salbutamol inhaler with spacer (rescue medication) will be 
provided to the subject to take home at Visit 2a and rechecked at every Clinic Visit to 
ensure that the subjects have enough medication. The subjects will be issued a diary 
(including Asthma Action Plan) to keep a daily log of any changes in their health or 
medication use (including rescue medication) in their diary while at home. The subjects 
will be given the option to be confined at the study site in order to facilitate early morning 
visit on the next day. 
The next day (Visit 2b), subjects will undergo a BAC. At Visit 2b, the subjects’ old diary 
(including Asthma Action Plan) will be collected and the subjects will be issued a new 
diary to keep a daily log of any changes in their health or medication use (including 
rescue medication) while at home. Before the test can be performed, qualified personnel 
will explain the procedure and expected symptoms to the subjects. The allergen 
concentration to be administered will be determined based on the results from the MCT 
and allergy SPT titrations performed at Visit 2a.  
The concentration of the allergen provocative concentration (PC20) will then be predicted 
from the previous Mch PC20 and the skin sensitivity using the following logarithmic 
formula: 
  
Log10 (Allergen PC20) = 0.68 log10 (Mch PC20 x skin sensitivity).  
 
Where skin sensitivity is the skin prick test end point dilution titration which is the lowest 
concentration producing a ≥3 mm wheal.  
(This formula may be subject to modification and is dependent on the allergen PC20 
estimated in subjects). 
Following the calculation of the predicated allergen PC20, subjects will undergo BAC as 
per the Principal Investigator and Sponsor approved Manual of Procedures.  
Early phase asthmatic response (EAR) is defined as a ≥ 20% fall in FEV1 from the 
highest pre-inhalation FEV1 value on at least one occasion within 3 h after the inhalation 
of the final concentration of allergen. In order to assess the EAR, FEV1 will be measured 
at approximately 30, 60, 90, 120, and 180 minutes post allergen exposure. Late phase 
asthmatic response (LAR) is defined as a ≥ 15% fall in FEV1 from the highest pre-
inhalation FEV1 value on at least one occasion between 3 and 7 h after the inhalation of 
the final concentration of allergen. To assess the LAR, FEV1 will be measured every hour 
between 3 to 7 hours post allergen challenge.  
At the end of the monitoring period, 4 puffs of bronchodilator (salbutamol) will be 
administered to the subjects to restore FEV1 to 90% of pretest FEV1, if necessary. If 
FEV1 does not return to normal levels, the Investigator/medical designee will assess the 
subject. Following the test, sputum will be induced, collected, and processed 
(approximately 7 h post-BAC). The subjects will be given the option to be confined at the 
study site in order to facilitate early morning visit on the next day. 
The next day (Visit 2c) sputum induction and collection (approximately 24 h post-BAC) 
will be performed. Additionally, a blood sample will be taken and sent to analytical lab for 


  
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exploratory biomarkers (RASP and endotoxin-induced cytokine release). This will be 
considered as baseline value. 
At Visit 2c, the subjects’ old diary will be collected and the subjects will be issued a new 
diary to keep a daily log of any changes in their health or medication use (including 
rescue medication) while at home. Subjects will also receive an asthma action plan to 
monitor asthma symptoms. Subjects will be asked to return to the clinic after 
approximately 2 weeks. 
Note: Safety clinical laboratory tests will be repeated within 3 days prior to the first dose 
of study drug to ensure continued eligibility.   
III. Randomization Visit- Visit 3  
Following at least 2 weeks wash-out period, eligible subjects will return to the clinic for 
Visit 3 to participate in the treatment periods. Clinic staff will update the subjects’ 
concomitant medication and collect AEs and vital signs. Eligibility criteria will be 
reviewed. Diary cards including asthma action plan will be collected and reviewed and 
subjects will be issued a new diary. Asthma control questionnaire will be collected. A 
urine pregnancy test will be administered to WOCBP.  
 
Subjects will be randomized to either Sequence treatment AB or Sequence Treatment 
BA. Subjects will be dispensed ADX-629 or Placebo for at-home treatment with 
instructions for dosing. Subjects will receive their first dose on site.  
Blood sample will be collected for PK assessment at 1 hour (+5 minutes) post dose.  
An Electrocardiogram (ECG) will be performed at 1 hour (±15 minutes) post dose. 
IV. Treatment Period 1  
At home, subjects will take the treatment (Treatment A or Treatment B) orally twice per 
day, i.e. PO bid dosing for minimum 1 week (+3 days) and return to the Clinic for the 
Post-Treatment Period 1. Subjects will take the morning and evening dose at 
approximately the same time each day. Additionally, there will be a phone call during the 
treatment period to follow up on subject’s health and treatment compliance. 
Subjects will continue to keep a daily log of any changes in their health or medication use 
(including rescue medication) and time of dosing in their diary while at home. They will 
also continue to refer to the asthma action plan, if there is any worsening of asthma 
control. 
Additionally, subjects will receive a phone call on the last day of the treatment period to 
remind them that their morning dose (600 mg) of the treatment will be administered 
onsite next day.  
V. Post-Treatment Period 1 (For 2 consecutive days) - Visits 4a & 4b 
Subjects will not stop treatment in order to maintain steady state concentration of the 
drug during the Visits 4a and 4b. Hence subjects will continue to receive their respective 
treatments with same schedule. However, on the days of visits 4a and 4b, subjects will 
receive their morning dose (600 mg) of the treatment on site approximately one hour 
prior to MCT or BAC. 
Staff will update the subjects’ concomitant medication and collect AEs and vital signs. 
Asthma control questionnaire will be collected. Eligibility criteria will be reviewed. Diary 
cards including asthma action plan will be collected and reviewed and subjects will be 
issued a new diary. Blood and urine samples will be collected for safety clinical 


  
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laboratory tests (CBC with differential, electrolytes [Calcium, Sodium, Potassium, 
Chloride], eGFR, creatinine, BUN, ALT, AST, ALP, total bilirubin, albumin, total protein, 
glucose, total cholesterol, triglycerides, lipase and amylase and urinalysis including 
assessment of microalbuminuria).  
At Visit 4a, pre-BAC FeNO (baseline) and baseline FEV1 will be performed. Pre-BAC 
FeNO to be performed prior to baseline FEV1. At approximately 1 hour post-dose blood 
samples will be taken and sent to analytical lab for exploratory biomarkers (RASP and 
endotoxin-induced cytokine release) prior to BAC. An additional blood sample will be 
collected for PK assessment at 1 hour (+5 minutes) post dose. An ECG will be 
performed at 1 hour (±15 minutes) post dose. 
Subjects will then undergo BAC with the target allergen titer dilution identified in the pre-
treatment allergen challenge visit (Visit 2b). Approximately 7 h post-BAC, FeNO will be 
measured and then sputum will be induced, collected, and processed. FeNO to be 
performed prior to 7 h FEV1 measurements. Additionally, blood samples will be taken 
and sent to analytical lab for exploratory biomarkers (RASP and endotoxin-induced 
cytokine release), at approximately 7 h post-BAC. The subjects will be given the option to 
be confined at the study site in order to facilitate early morning visit on the next day. At 
home treatment will be dispensed and/or collected based on subject’s decision regarding 
confinement. 
Once all procedures are completed, subjects will be reminded to take their next day 
morning dose on site approximately one hour prior to MCT. 
The following day (Visit 4b), subjects will undergo post-BAC MCT, FeNO and sputum 
testing (approximately 24 h post-BAC). FeNO will be performed before any other 
procedure on Visit 4b. Procedures for MCT (including baseline FEV1) will be repeated as 
described in Visit 2a, except that the maximum concentration of Mch used in this visit will 
be up to16 mg/mL. Following MCT, sputum will be induced, collected, and processed 
(approximately 24 h post-BAC). Any remaining at home treatment will be collected. 
After completion of Visit 4b study procedures, subjects will be dispensed the second 
treatment according to their assigned sequence and new at-home diary cards and will be 
asked to follow the same instructions as previously directed. Following Visit 4b, subjects 
will complete 2 weeks of washout period. Subjects will continue to keep a daily log any of 
any changes in their health or medication use (including rescue medication) and time of 
dosing in their diary while at home. They will also continue to refer to the asthma action 
plan, if there is any worsening of asthma control. 
Subjects will receive a phone call approximately 1 day prior to their scheduled initiation of 
at-home dosing as a reminder to start treatment. Staff will update the subjects’ 
concomitant medication and rescue medication use and collect AEs.  
VII. Treatment Period 2  
At home, subjects will take the treatment (Treatment B or Treatment A) orally twice per 
day, i.e. PO bid dosing for minimum 1 week (+3 days) and return to the Clinic for the 
Post-Treatment Period 2. Subjects will take the morning and evening dose at the same 
time each day. Additionally, there will be a phone call during the treatment period to 
follow up on subject’s health and treatment compliance. 
Subjects will continue to keep a daily log of any changes in their health or medication use 
(including rescue medication) and time of dosing in their new diary while at home. They 


  
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will also continue to refer to the asthma action plan, if there is any worsening of asthma 
control. 
Additionally, subjects will receive a phone call on the last day of the treatment period to 
remind them that their morning dose (600mg) of the treatment will be administered onsite 
next day  
VIII. Post-Treatment Period 2 (For 2 consecutive days) –Visits 5a & 5b 
Subjects will return to the Clinic for the Post-Treatment Period 2 following approximately 
3 weeks (+3 days) later after having completed 2 weeks of washout and 1 week (+3 
days) of at-home dosing. At Visits 5a and 5b, subjects will follow same procedures as 
performed previously at Visits 4a and 4b, respectively. As with Visits 4a and 4b, on the 
days of visits 5a and 5b, subjects will receive their morning dose (600 mg) of the 
treatment on site approximately one hour prior to MCT or BAC.   
Additionally, at Visit 5b, paper diary cards including asthma action plan and any 
remaining at home treatment will be collected from the subjects and a urine pregnancy 
test will be administered to WOCBP. 
Subjects will complete a health check prior to clinical trial exit. 
IX. Early Termination Visit (ETV) 
Staff will update the subjects’ concomitant medication and collect any unused at home 
treatments, adverse events, asthma control questionnaire, and vital signs. Paper diaries 
will be collected and reviewed. Urine pregnancy test for WOCBP only will be done, if not 
performed before on the same day. 
Inclusion 
Criteria 
1. Male or non-pregnant female, between 18 to 65 years of age (inclusive) at Screening 
Visit. 
2. Subjects must give their signed and dated written informed consent (in English) to 
participate prior to commencing any study-related activities and must be willing to 
comply with study procedures, study restrictions, study protocol, and return for the 
required assessments. 
3. Female subjects of either non-childbearing potential or of child-bearing potential who 
commit to consistent and correct use of at least one highly effective or two effective 
forms of contraception starting at least 4 weeks prior to the Screening Visit and for at 
least 30 days post last dose of study drug. 
4. Generally healthy subjects with mild controlled asthma for 2 years at Screening Visit 
according to the Global Initiative for Asthma (GINA 2020) criteria.  
5. No concomitant asthma treatment, except inhaled SABA. 
6. 
 
 
  
7. 
 
8. 
 
  
9. Currently a non-smoker; having not used tobacco products (i.e. cigarettes, cigars, 
pipe tobacco) within the past year, and having ≤ 10 pack-years of historical use. Use 


  
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of electronic cigarettes or other inhaled nicotine delivery products, smoking and/or 
inhalation of cannabis using a device (e.g. vaping) will not be allowed during the 
study. 
10. Agree to limit caffeine and consumption of cruciferous vegetables and grilled meats. 
Agree to prohibit concomitant medications (strong CYP1A2, 2B6 and 3A4 inhibitors).  
11. Body mass index (BMI) within the range 18.5-35.0 kg/m2. 
12. Male subjects who commit to not father a child or donate sperm from first dose until 
3 months post-last dose. 
13. Male subjects (with female partners of childbearing potential) who commit to 
consistent and correct use of at least two effective methods of birth control for the 
duration of the study and 30 days after the last dose of study drug. 
14. AST, ALT, ALP, TSH, White Blood Count, hemoglobin, glucose, albumin, 
electrolytes, total proteins and total bilirubin within the normal range. 
15. Acceptable lipase, amylase, GGT, CPK, total cholesterol, triglycerides, and 
eosinophils levels as determined by the Investigator in consultation with the medical 
monitor. 
16. 
 
 
17. 
 
 
 
 
 
Exclusion 
Criteria 
1. History and presence of clinically significant cardiovascular, renal, neurologic, 
hepatologic, endocrinologic, gastrointestinal, genitourinary, autoimmune, 
hematological, or metabolic disease other than asthma, which in the opinion of 
Investigator may either put the subject at risk or influence the results during the 
study. 
2. Subjects with perennial allergy symptoms and/or possible exposure to perennial 
allergens (e.g. mold, dog) that occur or are anticipated to occur during the study at 
the discretion of the investigator. Subjects with seasonal allergy symptoms that occur 
or are anticipated to occur during the study should result in subject exclusion or 
rescheduling until the subject is out of the allergy season. 
3. Any relevant pulmonary disease within 1 year prior to dosing at the discretion of the 
investigator.  
4. Recent hospitalization with asthma in the last 6 months or any other medical 
condition that the Investigator deems incompatible with participation in the trial.  
5. Inability to tolerate temporary withdrawal of current asthma medication. 
6. Other co-morbid respiratory and sinus diseases. 
7. History of frequent asthma exacerbations in the previous year. 
8. The use of the following medications: beta blockers, tricyclic/polycyclic 
antidepressants, monoamine oxidase inhibitors within 14 days of the study.  
9. History or current evidence of clinically relevant allergies or idiosyncrasy to drugs. 


  
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10. Known intolerance or hypersensitivity to any component of the salbutamol MDI and 
intolerance to aerosolized β2-adrenergic agonists. 
11. Female subjects of child-bearing potential who are pregnant, lactating or using 
inadequate contraceptive measures. 
12. Subjects that have a history of alcohol, drug or medication abuse within the past year 
before the study. 
13. Subjects that lack cooperation or compliance, as judged by the Investigator. 
14. Subjects suffering from severe psychiatric, psychological, or neurological disorders.  
15. Subjects who are employees of the sponsor or CRO and/or 1st grade relatives or 
partners of the (principal) Investigator. 
16. Inability to demonstrate the proper use of the nebulizer as determined by the staff.  
17. Any clinically significant abnormal finding on the physical examination, vital signs or 
laboratory results at screening as deemed so by the Investigator.  
18. The use of any investigational drug within 30 days of the study.  
19. Allergen immunotherapy treatment with cat or HDM within the previous 5 years. 
20. Any clinically significant physical findings of nasal anatomical deformities (including 
the presence of nasal mucosal ulceration, nasal polyps, purulent secretions, septal 
perforation or any other major abnormalities in the nose), which at the discretion of 
the Investigator, would interfere with the study procedures. 
21. Any surgery requiring general anaesthesia three months before the Screening Visit 
or planned during the study period. 
22. Known hypersensitivity to ADX-629 or any of its components. 
23. History of anaphylaxis or angioedema. 
24. Previous history of life-threatening asthma and/or exacerbation of asthma within 6 
weeks prior to the Screening Visit. 
25. Previous history of respiratory tract infection within 2 weeks prior to the Screening 
Visit. 
26. History of risk factors for TdP (e.g., heart failure, hypokalemia, family history of long 
QT syndrome). 
27. Persistent systolic BP >140mmHg or diastolic BP > 90mmHg. 
28. 
 
29. Public health emergency (e.g., COVID-19): subject not complying with Public health 
guidelines (e.g., self-isolation), at the discretion of the Investigator and/or designee, 
or subjects with a positive COVID-19 test result up to 5 days prior to Visit 2a, Visit 4a 
or Visit 5a. 
 
Statistical 
Analysis 
The safety endpoint will be summarized descriptively. 
The key efficacy endpoint change from baseline in FEV1 during 0-3 h post-BAC may be 
analyzed using a mixed effect model for repeated measures (MMRM) with the following 
independent factors, within-visit baseline FEV1 as covariate, and sequence, visit, 
treatment, post-BAC assessment time, and interaction of treatment by post-BAC 
assessment time. Subject may be treated as a random effect. If deemed appropriate, 
baseline sputum eosinophil count may be included as an additional covariate in MMRM. 
AUCs may be analyzed using a mixed effect model with following terms: 


  
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• 
sequence, visit (i.e., period), treatment group  
• 
subject as random effect 
The other efficacy endpoints may be compared between treatments using appropriate 
statistical models. 
The Statistical Analysis Plan will detail all statistical procedures and will take precedence 
over any statistical descriptions herein. 
Safety Analysis 
All study subjects who receive at least one dose of any of the study products will be 
included in the comparative safety analysis. Adverse events will be classified using 
standard Medical Dictionary for Regulatory Activities (MedDRA) terminology Version 22 
or higher and presented by treatment group. Summary tables listing the type, date of 
onset, date and time of resolution, incidence, severity, outcome, action taken, and 
Investigator’s opinion of relationship to the study product will be presented by treatment 
group for AEs reported after randomization. 
Concomitant medication used during the study will be tabulated by treatment by subject. 
Sample Size 
Determination 
Based on repeatability analyses in allergen-induced airway inflammation responses, a 
sample size of 12 subjects yields more than 80% power to detect a difference of 0.1 with 
standard deviation of 0.1 in change from baseline FEV1 across treatment groups.  


 
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5. 
STUDY SCHEMATIC  
 
Schedule of Assessments 


 
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Study Design 
 
 
 
 
 
 
 
 


 
  
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6. 
INTRODUCTION 
 
Background and Study Rationale 
Type I allergy is an immune-disorder which results from the inappropriate formation of 
Immunoglobulin E (IgE) antibodies against proteins and glycoproteins from plants, insects, 
animals, and fungi, most of which are normally considered harmless. The cross-linking of IgE 
antibodies on effector B cells by allergens activates an immunological cascade leading to some 
or all of the symptoms of Type I allergy which may include rhinitis, conjunctivitis, asthma, and 
anaphylactic shock. 
Asthma is a serious global health problem and one of the most common diseases in the 
Western world. Allergic asthma is the most common form of asthma, with over 50% of the 
asthma population being affected by allergic asthma.1 Asthma is a chronic inflammatory 
disorder of the airways in which a variety of cell types and cellular elements play a role. Airway 
inflammation produces four forms of airflow limitations: acute bronchoconstriction, swelling of 
the airway wall, mucus hypersecretion, and airway wall remodeling. The chronic inflammation 
causes an associated increase in airway hyper-responsiveness that leads to recurrent episodes 
of wheezing, breathlessness, chest tightness, and coughing. These episodes are usually 
associated with widespread, but variable airflow obstruction that is often reversible, either 
spontaneously or with treatment.2 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
  
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ADX-629 
ADX-629 is a small molecule with a quinoline core that acts as a reactive aldehyde species 
(RASP) inhibitor by irreversibly binding to RASP. ADX-629 is being developed for the treatment 
of systemic immune-mediated and inflammatory diseases, including psoriasis, inflammatory 
bowel disease, asthma, ulcerative colitis, non-alcoholic steatohepatitis, and other diseases 
believed to be caused, or exacerbated, by elevated concentrations of RASP. In an animal model 
of cytokine release syndrome, ADX-629 treatment resulted in broad-based reduction in 
inflammatory cytokines, including TH2 cytokines that mediate allergy. In addition, ADX-629 has 
demonstrated activity in animal models of ulcerative colitis, multiple sclerosis, and non-alcoholic 
steatohepatitis. ADX-629 is a close structural analog of reproxalap, which is now in Phase 3 
clinical trials for the treatment of dry eye disease and allergic conjunctivitis, two ocular 
inflammatory diseases. 22 
 
 
Nonclinical Safety and Toxicology  
Nonclinical safety pharmacology and toxicology studies were conducted with ADX-629 in rats 
and dogs. After 28 days of oral administration in good laboratory practice (GLP) toxicology 
studies, the no adverse effect levels (NOAELs) for rats and dogs were 500 mg/kg/day and 100 
mg/kg/day, the highest doses tested.22 In vivo safety pharmacology studies have shown that 
ADX-629 is unlikely to affect central nervous system function, cardiovascular function, or 
respiratory function in humans at clinically relevant doses.22 
 
 
Benefit/Risk Assessment 
Free RASP (e.g., malondialdehyde [MDA] and 4-hydroxynonenal [HNE]) are toxic, leading to 
inflammation and molecular dysfunction by reacting with cellular biomolecules, and have been 
implicated in many immune-mediated and inflammatory diseases. ADX-629 binds to free RASP 
via a rapid, two-step reaction involving Schiff base formation followed by a ring closure, resulting 
in stable and non-reactive ADX-629-RASP adducts that are subsequently degraded.22  
The potential benefit of RASP inhibition in immune-mediated and inflammatory diseases has 
been demonstrated by the first-in-class RASP inhibitor reproxalap (ADX-102), which has been 
shown beneficial in treating ocular inflammation, including dry eye disease and allergic 
conjunctivitis across numerous Phase 2 and Phase 3 clinical trials, and is now in Phase 3 
clinical testing. ADX-629 is being investigated for the treatment of systemic, immune-mediated, 
and inflammatory conditions thought to be caused or exacerbated by elevated RASP levels.22 
 


 
  
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Secondary pharmacology studies, which include a large panel of ligand binding assays, ion 
channel assays, transporter assays, and enzyme inhibition studies, suggest that there is a low 
risk of off-target effects due to treatment with ADX-629. In addition, in vitro studies have shown 
that ADX-629 has a very low potential to inhibit the delayed rectifier potassium current. Results 
of preclinical studies demonstrate that ADX-629 has a low risk of genotoxicity.22 ADX-629 
plasma concentrations are projected to have reached at least 10 μM, exceeding reported levels 
of RASP in humans with inflammatory diseases. The data support the potential of ADX-629, and 
RASP inhibition in general, in treating inflammation and fibrosis. 22 
 
Genotoxicity studies have shown no potential for mutagenicity or clastogenicity of ADX-629. 22 
 
 
Effects in Humans 
The ADX-629 Phase 1 clinical trial was a first-in-human, randomized, double-blind, placebo-
controlled trial with a 3:1 randomization of ADX-629 and placebo. The clinical trial was 
comprised of single ascending dose (SAD) and multiple ascending dose (MAD) protocols. The 
MAD drug exposure was 10 days of twice -per-day (BID) administration. The clinical trial was 
performed with subjects housed in a clinical research unit; the drug compliance was 100%. 
Overall, ADX-629 was found to be safe and tolerable. The adverse event profile of ADX-629 
was favorable compared to placebo: A total of 6 (9.4%) subjects receiving ADX-629 had 
treatment emergent adverse events, compared to 4 (19.1%) subjects who received placebo. 
There were no interruptions or discontinuations of study drug administration. 22 
No clinically meaningful changes were observed in hepatic or renal analytes, including 
transaminases (ALT and AST), alkaline phosphatase (ALP), amylase, gamma-glutamyl 
transpeptidase (GGT), bilirubin, creatinine kinase and creatinine. No changes in serum glucose 
were observed. No clinically meaningful changes were observed in heart rate (HR), blood 
pressure (systolic, diastolic and orthostatic changes), respiratory rate, pulse oximetry, or 
temperature. No clinically significant hematological changes were observed. ADX-629 did not 
lead to QTcF prolongation. There were no subjects who had QTcF > 500 msec or a change of > 
60 msec from baseline. Five subjects had a change of >30 msec from baseline but did not 
require intervention or study drug interruption or discontinuation, and all subjects remained 
asymptomatic. Three of these five subjects were in the SAD portion of the study (one each in 
the 100 mg, 200 mg, and 700 mg dose cohorts) and the remaining two subjects were in the 
MAD portion of the study (one each in the 
150 mg BID and 300 mg BID dose cohorts). 22 
 
Healthy volunteers were dosed with 600 mg of ADX-629 BID for 10 days in the top (highest) 
dose cohort. The observed Cmax on Day 1 was 1920 ng/mL (67.4%CV) and 1458 ng/mL 
(46.6%CV) on Day 10. The 0 to 12 hour area under the curve (AUCtau) was 5710 h*ng/mL 
(61.5 %CV) on Day 1 and 6,800 h*ng/mL (37.9 %CV) on Day 10. The observed half-life of the 
drug was 3.98 h (22.9 %CV) on Day 1 and 4.56 h (12.1 %CV) on Day 10. Plots of the Data are 
shown in below figures: 22 
 
 
 
 


 
  
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Mean Concentration vs Time Plot by Dose in Healthy Volunteers on Day 1 and Day 10 of 
Dosing (Semi-Log) 
 
 
 
These results indicate that no cyp autoinduction was observed over the course of 10 days as no 
significant increase in clearance was observed between Day 1 and Day 10. Although 
pharmacokinetic (PK) variability was evident, a linear correlation was observed in Cmax and AUC 
as dose increased. The half-life (t1/2) was consistent across cohorts and days, and mean values 


 
  
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in multiple day exposures ranged between 3.07 to 6.20 hours. Little to no accumulation of the 
drug was seen across all cohorts. 22 
A decrease in free MDA levels was observed in the plasma of healthy volunteers over 10 days 
of dosing with ADX-629 600mg BID that was statistically greater than that of subjects treated 
with placebo. Following ingestion of a high-fat meal on Day 10 of dosing with 600 mg BID or 
placebo, levels of free fatty acids were statistically lower and levels of HDL were statistically 
higher in drug-treated subjects than in placebo-treated subjects, potentially representing 
additional anti-inflammatory activity of ADX-629. 22 
 
 
Rationale for Dose Selection 
Clinical development of ADX-629 in inflammatory disease is supported by safety testing in 
human healthy volunteers in single and multiple ascending dose (10 day), placebo-controlled 
Phase I trials. Overall, ADX-629 was found to be safe and tolerable at the doses explored, 
including the maximum dose of 600 mg BID. 22 
The dose for Phase 2 clinical trials of ADX-629 of 300 mg BID PO is based on conservative 
margins from 28-day nonclinical assessments and drug exposure in humans in the Phase 1 
clinical trial, which generally exceeds levels of RASP reported in human inflammatory disease.22 
 
 


 
  
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7. 
OBJECTIVES AND ENDPOINTS 
 
Study Objectives 
Primary objective: 
To assess the safety of ADX-629 in subjects with allergen-induced mild asthma. 
 
Secondary objective: 
To assess the clinical efficacy of ADX-629 in subjects with allergen-induced mild 
asthma. 
 
 
Study Endpoints 
Safety Endpoint: 
• 
Safety, as assessed by adverse events (AEs) and serious adverse events (SAEs) 
 
Efficacy Endpoints: 
• 
Change from baseline (within visit) in forced expiratory volume in one second (FEV1) 
to post-BAC (during 0-3 h post-BAC [Key Efficacy Endpoint] and 3-7 h post BAC). 
• 
Absolute count and percentage differential count of sputum eosinophils and 
neutrophils at approximately 7 h and 24 h post-BAC. 
• 
Allergen-induced shift in airway hyper responsiveness (AHR) as assessed by 
Methacholine PC20 (Mch PC20) post-BAC.  
• 
Change from baseline in fractional exhaled Nitric Oxide (FeNO) at approximately 7 h 
and 24 h post-BAC. 
 
Exploratory Endpoints 
• 
Biomarkers (RASP and endotoxin-induced cytokine release) pre-BAC (at 
approximately 1 hour post-dose) and 7 h post-BAC.  
• 
Area under curve (AUC) of FEV1 during 0-3 h post-BAC and/or 3-7 h post BAC. 
 
 


 
  
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8. 
CLINICAL TRIAL DESIGN 
ADX-629-AA-001 is double-masked, cross-over, placebo-controlled, single center, randomized 
clinical trial to assess the clinical safety and efficacy of ADX-629 compared to placebo in mild 
cat or HDM-induced asthmatics using the BAC model. The study will consist of 9 visits to the 
clinic (Visits 1, 2a, 2b, 2c, 3, 4a, 4b, 5a, and 5b) over a period of approximately 75 days (Please 
refer study design section 5.2). During this period there will be 4 additional visits, 1 visit for 
safety lab and 3 visits for COVID-19 testing, as described below. The clinical trial will be 
conducted as follows: 
 
1. Medical Screening: Visit 1 
2. COVID-19 test within 5 days prior to Pre-Treatment Period  
3. Pre-Treatment Period (For 3 consecutive days) 
i. 
Visit 2a 
ii. 
Visit 2b  
iii. 
Visit 2c 
4. Washout (2 weeks) 
5. Additional visit for safety sample blood collection within 3 days of Visit 3 
6. Randomization Visit: Visit 3 
7. Treatment Period 1 (at home treatment taken for 1 week [+ 3 days]) 
8. COVID-19 test prior to Post-Treatment Period 1 
9. Post-Treatment Period 1 (For 2 consecutive days):  
i. 
Visit 4a 
ii. 
Visit 4b 
10. Washout (2 weeks) 
11. Treatment Period 2 (at home treatment taken for 1 week [+ 3 days]) 
12. COVID-19 test prior to Post-Treatment Period 2 
13. Post-Treatment Period 2 (For 2 consecutive days):  
i. 
Visit 5a 
ii. 
Visit 5b 
A re-screening visit will be included to the subjects who failed under previous versions of the 
Protocol. 
The end of study is defined as the time at which the last subject has completed all study 
procedures in the clinical trial. Upon completion of the clinical trial, the study product will no 
longer be available to the subject but the Investigator can, at their discretion, discuss alternative 
treatments with the subject. 
 
 


 
  
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9. 
SUBJECT SELECTION 
 
Number of Subjects 
Enough subjects will be enrolled to ensure approximately 12 subjects complete the study. 
 
 
Inclusion Criteria for Study Volunteers 
1. Male or non-pregnant female, between 18 to 65 years of age (inclusive) at Screening Visit. 
2. Subjects must give their signed and dated written informed consent (in English) to 
participate prior to commencing any study-related activities and must be willing to comply 
with study procedures, study restrictions, study protocol, and return for the required 
assessments. 
3. Female subjects of either non-childbearing potential or of child-bearing potential who commit 
to consistent and correct use of at least one highly effective or two effective forms of 
contraception starting at least 4 weeks prior to the Screening Visit and for at least 30 days 
post last dose of study drug. 
4. Generally healthy subjects with mild controlled asthma for 2 years at Screening Visit 
according to the Global Initiative for Asthma (GINA 2020) criteria23.  
5. No concomitant asthma treatment, except inhaled SABA. 
6. 
 
  
7. 
 
8. 
 
  
9. Currently a non-smoker; having not used tobacco products (i.e. cigarettes, cigars, pipe 
tobacco) within the past year, and having ≤ 10 pack-years of historical use. Use of electronic 
cigarettes or other inhaled nicotine delivery products, smoking and/or inhalation of cannabis 
using a device (e.g. vaping) will not be allowed during the study. 
10. Agree to limit caffeine and consumption of cruciferous vegetables and grilled meats. Agree 
to prohibit concomitant medications (strong CYP1A2, 2B6 and 3A4 inhibitors). 
11. Body mass index (BMI) within the range 18.5-35.0 kg/m2. 
12. Male subjects who commit to not father a child or donate sperm from first dose until 
3 months post-last dose. 
13. Male subjects (with female partners of childbearing potential) who commit to consistent and 
correct use of at least two effective methods of birth control for the duration of the study and 
30 days after the last dose of study drug. 
14. AST, ALT, ALP, TSH, White Blood Count, hemoglobin, glucose, albumin, electrolytes, total 
proteins and total bilirubin within the normal range. 
15. Acceptable lipase, amylase, GGT, CPK, total cholesterol, triglycerides, and eosinophils 
levels as determined by the Investigator in consultation with the medical monitor. 


 
  
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16.
 
 
17. 
 
 
 
 
Exclusion and Restriction Criteria for Study Volunteers  
9.3.1 Exclusion Criteria 
1. History and presence of clinically significant cardiovascular, renal, neurologic, 
hepatologic, endocrinologic, gastrointestinal, genitourinary, autoimmune, hematological, 
or metabolic disease other than asthma, which in the opinion of Investigator may either 
put the subject at risk or influence the results during the study. 
2. Subjects with perennial allergy symptoms and/or possible exposure to perennial 
allergens (e.g. mold, dog) that occur or are anticipated to occur during the study at the 
discretion of the investigator. Subjects with seasonal allergy symptoms that occur or are 
anticipated to occur during the study should result in subject exclusion or rescheduling 
until the subject is out of the allergy season. 
3. Any relevant pulmonary disease within 1 year prior to dosing at the discretion of the 
investigator.  
4. Recent hospitalization with asthma in the last 6 months or any other medical condition 
that the Investigator deems incompatible with participation in the trial.  
5. Inability to tolerate temporary withdrawal of current asthma medication. 
6. Other co-morbid respiratory and sinus diseases. 
7. History of frequent asthma exacerbations in the previous year. 
8. The use of the following medications: beta blockers, tricyclic/polycyclic antidepressants, 
monoamine oxidase inhibitors within 14 days of the study.  
9. History or current evidence of clinically relevant allergies or idiosyncrasy to drugs. 
10. Known intolerance or hypersensitivity to any component of the salbutamol MDI and 
intolerance to aerosolized β2-adrenergic agonists. 
11. Female subjects of child-bearing potential who are pregnant, lactating or using 
inadequate contraceptive measures. 
12. Subjects that have a history of alcohol, drug or medication abuse within the past year 
before the study. 
13. Subjects that lack cooperation or compliance, as judged by the Investigator. 
14. Subjects suffering from severe psychiatric, psychological, or neurological disorders.  
15. Subjects who are employees of the sponsor or CRO and/or 1st grade relatives or 
partners of the (principal) Investigator. 
16. Inability to demonstrate the proper use of the nebulizer as determined by the staff.  


 
  
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17. Any clinically significant abnormal finding on the physical examination, vital signs or 
laboratory results at screening as deemed so by the Investigator.  
18. The use of any investigational drug within 30 days of the study.  
19. Allergen immunotherapy treatment with cat or HDM within the previous 5 years. 
20. Any clinically significant physical findings of nasal anatomical deformities (including the 
presence of nasal mucosal ulceration, nasal polyps, purulent secretions, septal 
perforation or any other major abnormalities in the nose), which at the discretion of the 
Investigator, would interfere with the study procedures. 
21. Any surgery requiring general anaesthesia three months before the Screening Visit or 
planned during the study period. 
22. Known hypersensitivity to ADX-629 or any of its components. 
23. History of anaphylaxis or angioedema. 
24. Previous history of life-threatening asthma and/or exacerbation of asthma within 6 weeks 
prior to the Screening Visit. 
25. Previous history of respiratory tract infection within 2 weeks prior to the Screening Visit. 
26. History of risk factors for TdP (e.g., heart failure, hypokalemia, family history of long QT 
syndrome). 
27. Persistent systolic BP >140mmHg or diastolic BP > 90mmHg. 
28. 
 
 
 
29. Public health emergency (e.g., COVID-19): subject not complying with Public health 
guidelines (e.g., self-isolation), at the discretion of the Investigator and/or designee, or 
subjects with a positive COVID-19 test result up to 5 days prior to Visit 2a, Visit 4a or 
Visit 5a. 
 
9.3.2 Restrictions and Concomitant Medications 
Once the clinical trial has begun, the subjects will be instructed to take only the study 
medication(s) described in the protocol. If the subject takes any other medication during the 
clinical trial, the Investigator will record the necessary information and may notify the Sponsor, if 
judged to be significant. 
Items restricted prior to and during the course of this clinical trial are described in the table 
below:  
 
 
Restricted Item 
Start of Restriction 
End of Restriction 
SABAs 
8 hours Prior to MCT, BAC  
- 
Long acting bronchodilators i.e. 
formeterol, salmeterol 
48 hours prior to MCT, BAC 
End of last study visit 
Ipratropium bromide 
24 hours prior to MCT, BAC 
End of last study visit 
Tiotropium 
72 hours prior to MCT, BAC 
End of last study visit 
Theophylline 
48 hours prior to MCT, BAC 
End of last study visit 


 
  
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Restricted Item 
Start of Restriction 
End of Restriction 
Leukotriene modifiers i.e., 
Singular (montelukast) 
7 days prior to MCT, BAC 
End of last study visit 
Cholinesterase inhibitor 
2 weeks prior to Screening 
End of last study visit 
Beta blockers, tricyclic/polycyclic 
antidepressants, monoamine 
oxidase inhibitors 
14 days before Medical 
Screening -Visit 1 
End of last study visit 
Antihistamines i.e., cetirizine, 
fexofenadine or loratadine 
7 days prior to the Medical 
Screening-Visit 1 and 
Visit 2a and 12 to 24 hours 
prior to MCT, BAC 
End of last study visit 
Cromolyn sodium 
8 hours prior to MCT, BAC 
End of last study visit 
Nedocromil 
48 hours prior to MCT, BAC 
End of last study visit 
Concomitant CYP1A2, 2B6 and 
3A4 Substrates 
24 hours prior to MCT, BAC 
End of last study visit 
Strong CYP1A2, 2B6 and 3A4 
inhibitors 
24 hours prior to MCT, BAC 
End of last study visit 
Acetaminophen  
72 hours before Medical 
Screening -Visit 1  
End of last study visit 
Coffee, tea, cola, caffeinated 
beverages, chocolate 
(No more than one serving per 
day) 
First dose of the study 
products for each treatment 
period   
Last dose of the study 
products for each treatment 
period   
Allergen immunotherapy 
treatment with cat or HDM 
5 years before Medical 
Screening Visit 1 
End of last study visit 
 Investigational drug/product  
30 days before Medical 
Screening Visit 1 
End of last study visit 
Smoking (used tobacco 
products i.e., cigarettes, cigars, 
pipe tobacco, electronic 
cigarettes or other inhaled 
nicotine delivery product) 
12 months before Medical 
Screening  Visit 1 
End of last study visit 
Smoking and/or inhalation of 
cannabis using a device (e.g., 
vaping) 
Screening Visit 1 
End of last study visit 
Alcohol 
12 hours before Medical 
Screening Visit 1 
End of last study visit 
Cruciferous vegetables 
(1-2 servings per week) 
First dose of the study 
products for each treatment 
period   
Last dose of the study 
products for each treatment 
period 


 
  
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Restricted Item 
Start of Restriction 
End of Restriction 
Grilled meats 
(1-2 servings per week) 
First dose of the study 
products for each treatment 
period   
Last dose of the study 
products for each treatment 
period 
Green leafy vegetables 
2 hours prior to FeNO 
- 
Eating and drinking anything 
1 hour prior to FeNO 
- 
Any surgery requiring general 
anaesthesia 
3 months before Medical 
Screening Visit 1 
End of the last study visit 
Oral corticosteroids 
30 days prior to Medical 
Screening-Visit 1 
End of the last study visit 
Intranasal corticosteroids 
2 weeks prior to Medical 
Screening-Visit 1 
End of the last study visit 
Inhaled corticosteroids 
2 weeks prior to Medical 
Screening-Visit 1 
End of the last study visit 
Exposure to perennial allergens 
(e.g. mold, dog) 
End of Medical 
Screening -Visit 1 
End of last study visit 
A complete listing of medications that are CYP Inhibitors and Inducers are available online at 
http://medicine.iupui.edu/clinpharm/ddis/main-table. 
 
No other concurrent medications, other than mentioned in the above restriction table, are 
allowed during the trial conduct unless deemed necessary per the investigator’s medical 
judgement.  
Subjects who violate any of the above restrictions may be excluded or dropped from the clinical 
trial at the discretion of the Investigator. Individual exceptions to the above restrictions may be 
approved by the Sponsor and/or Investigator. 
 
9.3.3 Female Subjects of Childbearing Potential 
A woman is considered of childbearing potential (WOCBP) if she is not postmenopausal, not 
congenitally sterile; not diagnosed as infertile (and not undergoing treatment to reverse 
infertility); or has not undergone successful surgical sterilization (such as tubal ligation, bilateral 
oophorectomy, or hysterectomy). A woman is considered of non-childbearing potential if she is 
postmenopausal (naturally postmenopausal [no menses] for at least 1 year), surgically sterile 
(tubal ligation, bilateral oophorectomy, or hysterectomy), congenital sterility, or diagnosed as 
infertile and not undergoing treatment to reverse infertility. 
WOCBP must commit to consistent and correct use of at least one highly effective or two 
effective forms of contraception starting at least 4 weeks prior to the Medical Screening Visit 
and until 30 days after the last administration of investigational product, such as total 
abstinence, intrauterine device, a double-barrier method, oral, transdermal, injected or 
implanted non- or hormonal contraceptive.  


 
  
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Subjects on hormonal contraceptives must have been on the same hormonal contraceptive 
for at least one month before the Medical Screening Visit and continue throughout the 
duration of the study. 
WOCBP will be instructed to contact the Investigator immediately if they suspect they might 
be pregnant. 
 
9.3.4 Male Subjects  
Male subjects must commit to not father a child or donate sperm from first dose until 3 months 
post-last dose. 
Male subjects (with female partners of childbearing potential) must commit to consistent and 
correct use of at least two effective methods of birth control from the Medical Screening Visit 
until 30 days after the last administration of investigational product. 
• 
Condom and diaphragm with spermicide (foam, cream, gel, sponge) 
• 
Condom and cervical cap with spermicide (foam, cream, gel, sponge) 
• 
Non-hormonal intrauterine device (IUD) 
Female partner(s) of male volunteers also have the option to use the following highly effective 
hormonal method of contraception: implants, injectables, combined oral contraceptives, and 
IUDs. 
 
 


 
  
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10. 
STUDY PRODUCT AND RANDOMIZATION  
 
Study Product and Treatment 
The following products will be used in the study: 
Test Product (Treatment A) 
2 x 300 mg ADX-629 tablet taken PO bid for minimum 1 week (+3 days)  
Placebo (Treatment B) 
2 x 300 mg Placebo tablet taken PO bid for minimum 1 week (+3 days)  
Dosing Instructions: 
• 
 
• 
The subjects should take each dose at least 60 mins before food. 
• 
There should be a gap of at least 4 hours between the two doses per day. 
• 
The subjects should not take broken tablets; however minor tablet defects like chipping or 
scratching are acceptable. 
• 
In case of an overdose, the subjects should hold the next dose and inform clinic 
immediately. 
• 
In case of a missed dose, the subjects should take the dose when they remember only if 
their next scheduled dose is not within time frame of 4 hours. If the next scheduled dose is 
within time frame of 4 hours then subject should not take their missed dose and take the 
next dose at scheduled time.  
• 
A minimum of two days of BID dosing during each treatment period are required before 
BAC/MCT. 
• 
During Post-Treatment Periods 1 and 2 (Visits 4a, 4b, 5a, and 5b), in lieu of the morning 
dose, 600 mg of the treatments will be administered approximately one hour prior to MCT 
or BAC testing. 
 
Randomization Sequence 
At Visit 3, eligible subjects will be randomized to one of the two sequences shown below. The 
randomization will be generated in blocks of two with each sequence occurring once in each 
block.  
The randomization schedule will be generated by using SAS® statistical software (Version: 9.4 
or higher; SAS Institute Inc., USA). The randomization schedule will be generated by a 
biostatistician of 
 Limited. 
The randomization schedule will be maintained under controlled access. The personnel involved 
in the dispensing of investigational products will be accountable for ensuring compliance to the 


 
  
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randomization schedule. The analytical staff concerned will not have access to the 
randomization schedule during the course of analysis. 
Treatments will be administered according to a two-treatment, two-period, and two-sequence 
design. 
 
Period 1 
Period 2 
Sequence 1 
A 
B 
Sequence 2 
B 
A 
Number of subjects per sequence = 6 
 
 
Masking and Unmasking  
10.3.1 Masking 
This is a double-masked clinical trial. Investigators, qualified site personnel (except pharmacy 
staff), and subjects will be masked to the investigational product administered. The Sponsor will 
also be masked to the IP administered until database lock. Only the pharmacy staff and 
Scientific Affairs staff involved with preparing the randomization will have access to the 
treatment under evaluation. 
10.3.2 Emergency Unmasking 
Emergency unmasking should only be performed when necessary to treat the subject. Most 
often, knowledge of the possible treatment assignments is sufficient to treat a clinical trial 
subject who presents with an emergency condition. 
The investigator should make every effort to contact the Medical Monitor to discuss the subject’s 
emergency and the need to unmask, prior to unmasking any subject. 
In situations in which the investigator has tried but is unable to reach the Medical Monitor, best 
judgement on the part of the investigator should be used, based on the nature and urgency of 
the clinical situation, and may proceed with unmasking without having successfully reached and 
discussed the situation with the Medical Monitor. Once a subject's treatment assignment has 
been unmasked, the Medical Monitor should be notified within 24 hours of unmasking of the 
treatment, without revealing the treatment.  
The emergency unmasking should be performed by the designated site personnel. The 
investigator must also indicate in source documents and in the CRF that the mask was broken 
and provide the date, time, and reason for breaking the mask.  
Any AE or SAE associated with breaking the mask must be recorded and reported as specified 
in the protocol. The investigator has the responsibility to contact the Sponsor or designee within 
24 hours of unmasking. In the event of a drug-related, serious, unexpected AE, the Sponsor’s 
Pharmacovigilance Department or designee will be provided with the treatment assignment for 
the subject for regulatory reporting. 


 
  
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If treatment assignment is unmasked, the treatment will be discontinued immediately, and the 
subject will be discontinued from the clinical trial.  
The mask may be broken in the case of a pregnancy should the subject desire this information.  
 
11. 
STUDY CONDUCT 
 
COVID-19 Screening 
The following procedures will be performed as part of COVID-19 screening: 
• 
Subjects will be pre-screened based upon a COVID-19 questionnaire at each clinic 
visit; 
• 
Body temperature will be measured at each visit.  This measurement may be in 
addition to other vitals taken at the visit; 
• 
A nasal/nasopharyngeal/oropharyngeal swab will be collected for COVID-19 testing 
within 5 days prior to Visits 2a, 4a and 5a.  
• 
Most recent COVID-19 test result (performed at Cliantha) will be reviewed prior to 
Visit 2a, 4a and 5a.  Subject will be allowed to continue only if COVID-19 test result 
is negative. 
Subject’s further participation in the study will be based on the results of the COVID-19 test 
results and procedures. 
 
 
Medical Screening: Visit 1 (Day - 28 to Day - 2) 
The following activities will be completed at Visit 1: 
• 
Verification of subject Identification (ID). 
• 
Subjects will be asked to sign the Informed Consent Form. 
• 
Demographic data including date of birth, age, race and ethnicity will be recorded.  
• 
Medical, surgical, and social history and prior/concomitant medication use will be 
completed for each subject (see Section 12.2.2). 
• 
An asthma control questionnaire will be completed. 
• 
Vital signs (blood pressure, heart rate, respiratory rate, and oral temperature) will be 
measured (see Vital Signs Section 12.2.4). 
• 
Height and weight will be measured and BMI will be calculated. 
• 
A physical examination will be performed (see Physical Examination Section 12.2.3). 
• 
Electrocardiogram (ECG) will be performed. 
• 
A urine sample will be collected for urinalysis (see Clinical Laboratory Tests 
Section 12.2.1). 
• 
Blood samples will be collected for clinical chemistry and complete blood count 
(CBC) with differential analysis (see Clinical Laboratory Tests Section 12.2.1). 


 
  
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• 
A urine pregnancy test will be performed (for all WOCBP). Subjects with a positive 
result will be excluded (see Clinical Laboratory Tests Section 12.2.1).  
• 
The subjects will be evaluated for study inclusion, exclusion, and restriction criteria.  
• 
A skin prick test (SPT) will be performed to show positivity to cat or HDM allergen 
(≥ 3 mm wheal compared to negative control) (see Skin Prick Test Section 12.1.1).  
• 
Subjects will undergo spirometry to demonstrate baseline (pre-bronchodilator) FEV1 
of ≥ 80% of the predicted value Post-bronchodilator FEV1 will be measured within 
15±5 minutes following 400 µg (4 puffs) of salbutamol inhalation and 
post-bronchodilator reversibility will be recorded (see Spirometry Section 12.1.2). 
• 
Adverse events and concomitants medications will be recorded before subject leaves 
the site (see Adverse Event Query/Concomitant Medication Query Section 12.2.5). 
 
 
Pre-Treatment Period (3 consecutive days): Visit 2a, 2b and 2c (Day 1, 2 
and 3) 
• 
Subjects will return to the clinic for the pre-treatment period within approximately 
4 weeks of Screening Visit. 
• 
At all visits, the following procedures will be performed: 
o Verification of Subject ID. 
o The subjects will be evaluated for study inclusion, exclusion and restriction 
criteria. 
o Vital signs (blood pressure, heart rate, oral temperature and respiratory rate) will 
be measured (see Vital Signs Section 12.2.4). 
o Adverse Event Query/Concomitant Medication Query: All subjects will be 
evaluated regarding their health status (see Adverse Event Query/Concomitant 
Medication Query Section 12.2.5). 
Visit 2a (Day 1): 
• 
Asthma control questionnaire will be completed. 
• 
Spirometry will be performed to ensure FEV1 ≥ 80% of the predicted value.  
• 
Subjects will have a pre-BAC MCT performed as per the site standard procedures.  
• 
Subjects will inhale normal saline and have a baseline FEV1 established. 
• 
Subjects will then be given subsequent doubling concentrations of Mch as per the 
site standard procedures (see Section 12.1.3). 
• 
FEV1 will be measured at approximately 30 and 90 seconds following nebulization. If 
the FEV1 drops < 20%, the subject will be given the next highest concentration and 
spirometry repeated. 
• 
Mch doses will continue to be administered sequentially (max concentration 
4 mg/mL) until FEV1 falls ≥ 20% of the baseline. At such time, the test will be 


 
  
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terminated and subjects will be given 400 µg (4 puffs) of salbutamol, followed by a 15 
±5 minute waiting period prior to FEV1 measurement. 
• 
Subjects whose FEV1 levels are not within 10% of their baseline will be given another 
dose of salbutamol as per Investigator’s discretion and spirometry measurement 
repeated after 15±5 minutes. Mch PC20 will then be calculated. 
• 
All MCT will be performed at the same time of the day within a timeframe of 
±1.5 hours throughout the entire study. 
• 
Those who qualify will undergo a multi-skin prick sensitivity test with doubling 
concentrations of cat/ HDM allergen extracts. A positive control and a negative 
control will also be administered. The wheal diameter will be measured as per the 
site standard procedures (see Multi-skin prick sensitivity test Section 12.1.4).  
• 
At Visit 2a, the subjects will be issued a diary (including Asthma Action Plan) to keep 
a daily log of any changes in their health or medication use (including rescue 
medication) in their diary while at home.  
• 
Salbutamol inhaler with spacer (rescue medication) will be provided to the subject to 
take home at Visit 2a and rechecked at every Clinic Visit to ensure that the subjects 
have enough medication.  
• 
The subjects will be given the option to be confined at the study site in order to 
facilitate early morning visit on the next day. 
 
Visit 2b (Day 2): 
• 
The next day after Visit 2a, subjects will undergo a BAC. 
• 
Before the test can be performed, qualified personnel will explain the procedure and 
expected symptoms to the subjects. 
• 
The allergen PC20 to be administered will be determined based on the results from 
the MCT and allergy SPT titrations performed at Visit 2a (see Section 12.1.5). 
• 
Following the calculation of the predicted allergen PC20, post-saline FEV1 i.e. 
baseline FEV1 will be recorded (see Section 12.1.5). 
• 
Subjects will then be given inhaled allergens as per the site’s procedure until a 20% 
drop in FEV1 is observed, or a maximum concentration of 5000 BAU/mL is given. 
• 
When a drop in FEV1 of 20% from baseline has finally been achieved the challenge 
will be terminated. 
• 
In order to assess an EAR, FEV1 will be measured at approximately 30, 60, 90, 120 
and 180 minutes post allergen exposure. To assess LAR, FEV1 will be measured 
every hour up to 7 hours post allergen challenge. 
• 
 At the end of the monitoring period, 4 puffs of bronchodilator will be administered to 
the subjects to restore FEV1 to 90% of pretest FEV1, if necessary. If FEV1 does not 
return to normal levels, the Investigator/medical designee will assess the subject. 


 
  
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Following the test, sputum will be induced, collected, and processed (approximately 
7 h post-BAC). 
• 
At Visit 2b, the subjects’ old diary (including Asthma Action Plan) will be collected and 
the subjects will be issued a new diary to keep a daily log of any changes in their 
health or medication use (including rescue medication) in their diary while at home. 
• 
The subjects will be given the option to be confined at the study site in order to 
facilitate early morning visit on the next day. 
 
Visit 2c (Day 3): 
• 
The next day after Visit 2b, sputum induction and collection (approximately 24 h post-
BAC) will be performed. Additionally, blood sample will be taken and sent to 
analytical lab for exploratory biomarkers (RASP and endotoxin-induced cytokine 
release). This will be considered as baseline value. 
• 
At Visit 2c, the subjects’ old diary will be collected and the subjects will be issued a 
new diary to keep a daily log of any changes in their health or medication use 
(including rescue medication) in their diary while at home. Subjects will also receive 
an asthma action plan to monitor asthma symptoms. 
• 
Subjects will be asked to return to the clinic after approximately 2 weeks. 
Note: Safety clinical laboratory tests will be repeated within 3 days prior to the first dose 
of study drug to ensure continued eligibility.   
 
Randomization Visit: Visit 3 (Day 17) 
Following at least 2 weeks wash-out period, eligible subjects will return to the clinic for 
Visit 3 to participate in the treatment periods.  
• 
Verification of Subject ID. 
• 
Clinic staff will update the subjects’ concomitant medication and collect AEs and vital 
signs (blood pressure, heart rate, oral temperature and respiratory rate).  
• 
Eligibility criteria will be reviewed. 
• 
Diary cards including asthma action plan will be collected and reviewed and subjects 
will be issued a new diary. 
• 
Asthma control questionnaire will be completed.  
• 
A urine pregnancy test will be performed (for all WOCBP). Subjects with a positive 
result will be excluded (see Clinical Laboratory Tests Section 12.2.1)  
• 
Subjects will be randomized to either Sequence treatment AB or Sequence 
Treatment BA. 
• 
Subjects will be dispensed ADX-629 or placebo for at-home treatment. Subjects will 
be instructed to take the treatment orally twice per day (refer Section 10.1 for detail 


 
  
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dosing instructions) and return to the Clinic for the Post-Treatment Period 1. Subjects 
will receive their first dose on-site. 
• 
Subjects will continue to keep a daily log of any changes in their health or medication 
use (including rescue medication) and time of dosing in their new diary while at 
home. They will also continue to refer to the asthma action plan, if there is any 
worsening of asthma control. 
• 
Blood sample will be collected for PK assessment at 1 hour (+5 minutes) post dose.  
• 
ECG will be performed at 1 hour (±15 minutes) post dose. 
 
 
Treatment Period 1 (Day 17 to Day 23 [+3]) 
• 
At home, subjects will take the treatment (Treatment A or Treatment B) orally twice 
per day i.e. PO bid dosing for minimum 1 week (+3 days) and return to the Clinic for 
the Post-Treatment Period 1. Subjects will take the morning and evening dose at the 
same time each day.  
• 
Subjects will continue to keep a daily log of any changes in their health or medication 
use (including rescue medication) and time of dosing in their diary while at home. 
They will also continue to refer to the asthma action plan, if there is any worsening of 
asthma control. 
11.5.1 Reminder Phone Calls - Treatment Period 1 
• 
There will be a phone call during the treatment period 1 to follow up on subject’s 
health and treatment compliance. 
• 
Additionally, subjects will receive a phone call on the last day of the treatment period 
to remind them that their morning dose (600 mg) of the treatment will be 
administered onsite next day. 
 
 
Post-Treatment Period 1 (2 consecutive days): Visits 4a and 4b (Day 24 
and 25) 
• 
Subjects will not stop treatment in order to maintain steady state concentration of the 
drug during the Visits 4a and 4b. Hence subjects will continue to receive their 
respective treatments with same schedule. However, on the days of visits 4a and 4b, 
subjects will receive their morning dose (600 mg) of the treatment on site 
approximately one hour prior to MCT or BAC. 
• 
Verification of Subject ID. 
• 
Eligibility criteria will be reviewed. 
• 
Diary cards including asthma action plan will be collected and reviewed and subjects 
will be issued a new diary. 
• 
Staff will update the subjects’ concomitant medication and collect AEs and vital signs 
(blood pressure, heart rate, oral temperature and respiratory rate).  


 
  
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• 
Staff will collect any remaining at home treatment (either at Visit 4a and/or 4b based 
on subject’s decision regarding confinement). At Visit 4a, subject will be dispensed at 
home treatment, if applicable based on their decision regarding confinement.  
• 
Asthma Control Questionnaire will be completed at Visit 4a.  
• 
Blood and urine sample will be collected for safety clinical laboratory tests (CBC with 
differential, electrolytes [Calcium, Sodium, Potassium, Chloride], eGFR, creatinine, 
BUN, ALT, AST, ALP, total bilirubin, albumin, total protein, glucose, total cholesterol, 
triglycerides, lipase and amylase and urinalysis including assessment of 
microalbuminuria). 
• 
At Visit 4a, pre-BAC FeNO (baseline) and baseline FEV1 will be performed. Pre-
BAC FeNO to be performed prior to baseline FEV1. At approximately 1 hour post-
dose blood samples will be taken and sent to analytical lab for exploratory 
biomarkers (RASP and endotoxin-induced cytokine release) prior to BAC. An 
additional blood sample will be collected for PK assessment at 1 hour (+5 minutes) 
post dose. An ECG will be performed at 1 hour (±15 minutes) post dose. 
• 
Subjects will undergo BAC with the target allergen titer dilution identified in the pre-
treatment allergen challenge visit (Visit 2b). Approximately 7 h post-BAC, FeNO will 
be measured (see Section 12.1.6) and then sputum will be induced, collected, and 
processed. FeNO to be performed prior to 7 h FEV1 measurements. Additionally, 
blood samples will be taken and sent to analytical lab for exploratory biomarkers 
(RASP and endotoxin-induced cytokine release), at approximately 7 h post-BAC. 
The subjects will be given the option to be confined at the study site in order to 
facilitate early morning visit on the next day.  
• 
Once all procedures are completed, subjects will be reminded to take their next day 
morning dose on site approximately one hour prior to MCT. 
• 
The following day (Visit 4b), subjects will undergo post-BAC, MCT, FeNO and 
sputum testing (approximately 24 h post-BAC). FeNO will be performed before any 
other procedure on Visit 4b. Procedures for MCT (including baseline FEV1) will be 
repeated as described in Visit 2a, except that the maximum concentration of Mch 
used in this visit will be up to 16 mg/mL. Following the MCT, sputum will be induced, 
collected, and processed (approximately 24 h post-BAC) (see Section 12.1.7). After 
completion of Visit 4b study procedures, subjects will be dispensed the second 
treatment according to their assigned sequence and at-home diaries and will be 
asked to follow the same instructions as previously directed.  
• 
Following Visit 4b, subjects will complete 2 weeks of washout period. Subjects will 
continue to keep a daily log any of any changes in their health or medication use 
(including rescue medication) and time of dosing in their new diary while at home. 
They will also continue to refer to the asthma action plan, if there is any worsening of 
asthma control. 
 


 
  
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Treatment Period 2 (2 weeks after Visit 4b) (Day 39 to Day 45) 
• 
At home, subjects will take the treatment (Treatment B or Treatment A) orally twice 
per day i.e. PO bid dosing for minimum 1 week (+3 days) and return to the Clinic for 
the Post-Treatment Period 2. Subjects will take the morning and evening dose at the 
same time each day.  
• 
Subjects will continue to keep a daily log of any changes in their health or medication 
use (including rescue medication) and time of dosing in their new diary while at 
home. They will also continue to refer to the asthma action plan, if there is any 
worsening of asthma control. 
 
11.7.1 Reminder Phone Calls - Treatment Period 2  
• 
Subjects will receive a phone call approximately 1 day prior to their scheduled 
initiation of at-home dosing as a reminder to start treatment. Staff will update the 
subjects’ concomitant medication and rescue medication use and collect AEs. 
• 
There will be a phone call during the Treatment Period 2 to follow up on subject’s 
health and treatment compliance. 
• 
Additionally, subjects will receive a phone call on the last day of the treatment period 
to remind them that their morning dose (600mg) of the treatment will be administered 
onsite next day. 
 
 
Post-Treatment Period 2 (2 consecutive days): Visits 5a and 5b (Day 46 & 
47) 
• 
Subjects will return to the Clinic for the Post-Treatment Period 2 following 
approximately 3 weeks (+3 days) later after having completed 2 weeks of washout 
and 1 week (+3 days) of at-home dosing. 
• 
At Visits 5a and 5b, subjects will follow same procedures as performed previously at 
Visits 4a and 4b, respectively. As with Visits 4a and 4b, on the days of visits 5a and 
5b, subjects will receive their morning dose (600 mg) of the treatment on site 
approximately one hour prior to MCT or BAC.  
• 
Additionally, at Visit 5b, paper diary cards including asthma action plan and any 
remaining at home treatment will be collected from the subjects and a urine 
pregnancy test will be administered to WOCBP. 
• 
Subjects will complete a health check prior to clinical trial exit. 
 
 
Early Termination Visit (ETV) 
The following procedures will be carried out following the premature withdrawal of any patient 
from the study, if possible:  
• 
Paper diaries will be collected and reviewed. 


 
  
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• 
Any unused at home treatments will be collected. 
• 
Patients will be queried for AEs and concomitant medication use. 
• 
Asthma control questionnaire will be completed. 
• 
Urine pregnancy test for WOCBP only, if not performed before on the same day. 
• 
Vital signs (blood pressure, heart rate, oral temperature and respiratory rate) will be 
measured. 
 
12. 
STUDY PROCEDURES AND SAFETY ASSESSMENTS 
 
Study Procedures 
12.1.1 Skin Prick Test (SPT) 
At Visit 1 (Medical Screening Visit), subjects will undergo SPT.  
In addition to the test allergens, positive controls and negative controls will be used during SPT 
challenge. A positive test is considered as ≥ 3 mm wheal compared to the negative control. 
Skin Prick Test will be performed with a panel of test allergens (HDM [Dermatophagoides 
pteronyssinus, Dermatophagoides fariniae] or cat [Felis domesticus], mold, dog). 
Skin Prick Test will be performed with a single prick device. 
For detailed SPT procedure, refer to the site standard procedures.  
 
12.1.2 Spirometry 
FEV1 measurement will be performed as described in the Study Schematic (see Section 5) and 
as per the site standard procedures. Spirometry training including instructions and 
demonstration of use will be provided to subjects at all study visits. 
FEV1 measurement is reported in litres. Normal values for FEV1 vary according to age, sex, 
height, weight and ethnicity. To account for such variations, FEV1 % predicted will be calculated. 
FEV1 % predicted is defined as subject’s FEV1 value expressed as a percentage of the 
reference average FEV1 for a person of similar age, sex and body composition.  
At Screening Visit, baseline (pre-bronchodilator) FEV1 will be recorded. Baseline FEV1 should 
be ≥ 80% of the predicted normal after withholding SABA for > 6 hours. Post-bronchodilator 
FEV1 will be measured within 15±5 minutes following 400 µg (4 puffs) of salbutamol inhalation 
and post- bronchodilator reversibility will be recorded.  
At Visit 2a, 4b and 5b spirometry procedures will be performed pre saline, post saline and after 
the administration of methacholine and will be repeated until PC20 is found.  
At Visit 2b, 4a and 5a spirometry procedures will be performed pre saline, post saline and 
during allergen challenge as per the allergen challenge procedures and will be repeated until 
FEV1 drops ≥20% of the baseline value.  


 
  
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At Visit 2a, 4a and 5a, the pre-saline FEV1 will be considered as Baseline (within visit). 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
  
 
  
 
  
  
 
12.1.4 Multi-skin Prick Sensitivity Test 
At Visit 2a, those subjects who complete MCT and continue to be eligible to participate in the 
study will undergo a multi-skin prick sensitivity test. This test will employ similar procedures as 
SPT (see Section 12.1.1). However, multi-skin prick sensitivity test will be done using doubling 
concentrations of cat/HDM allergen extracts as shown in table below.  


 
  
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Preparation of serial dilutions using a single allergen solution 
 
 
 
 
 
 
 
 
 
The wheal diameter will be measured as per the site standard procedures. Skin sensitivity will 
be defined as the lowest allergen concentration that produces a wheal of ≥ 3 mm in diameter 
relative to the negative control. 
12.1.5 Bronchial Allergen Challenge (BAC) 
Subjects will undergo BAC at Visit 2b, 4a, and 5a. Before the BAC can be performed, qualified 
personnel will explain the procedure and the expected symptoms to the subjects. The allergen 
concentration to be administered will be determined based on the results from the MCT and 
allergy SPT titrations performed at Visit 2a.  
 
  
  
 
  
 
 
 
  
12.1.6 Fractional Exhaled Nitric Oxide (FeNO) 
FeNO will be measured at Visit 4a, 4b, 5a and 5b at following timepoints: 
- Pre-BAC at Visit 4a and Visit 5a 
- Approximately 7 hour post-BAC at Visit 4a and Visit 5a 
- Approximately 24 hour post BAC at Visit 4b and Visit 5b.  


 
  
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FeNO to be performed before FEV1 measurements and sputum induction. The detailed 
technique for measurement of FeNO will be covered in site standard procedures. 
 
12.1.7 Sputum Analysis  
Sputum will be analysed for absolute count, percentage differential count of sputum eosinophils 
and neutrophils. Sputum will be induced, collected, and processed  
- Approximately 7 hour post-BAC at Visit 2b, Visit 4a and Visit 5a, 
- Approximately 24 hour post BAC at Visit 2c, Visit 4b and Visit 5b.  
The detailed technique of sputum collection and analysis will be covered in site standard 
procedures. 
12.1.8 Biomarkers  
Blood sample will be taken and sent to analytical lab for exploratory biomarkers (RASP and 
endotoxin-induced cytokine release) to be performed at an independent laboratory. Additional 
details regarding sample processing will be provided in separate lab manual. 
Blood samples for biomarkers will be collected at following timepoints: 
- Baseline at Visit 2c, 
- Per-BAC at Visit 4a and Visit 5a (approximately 1 hour post dose) and  
- Approximately 7 hour post-BAC at Visit 4a and Visit 5a. 
 
 
Safety Assessments 
Safety measurements may be obtained at the discretion of the Investigator in addition to the 
safety assessments described in this section. 
12.2.1 Clinical Laboratory Tests  
List of clinical laboratory tests that will be performed at Medical Screening Visit and within 
3 days prior to the first dose of study drug is provided below. Additional tests performed at Visit 
4a and 5a are also mentioned in the table with asterisk.  
CBC with Differential* 
Clinical Chemistry 
Urinalysis* 
• Hemoglobin 
• Hematocrit 
• White blood cell count with 
differential 
• Red blood cell count 
• Platelet count 
• Blood Urea Nitrogen* 
• Creatinine * 
• eGFR to be reported* 
• Total bilirubin* 
• Alkaline phosphatase* 
• AST (also known as SGOT)* 
• ALT (also known as SGPT)* 
• Glucose* 
• Albumin* 
• pH 
• Specific gravity 
• Protein 
• Glucose 
• Ketones 
• Bilirubin 
• Blood 
• Nitrites 
• Leukocyte esterase 


 
  
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CBC with Differential* 
Clinical Chemistry 
Urinalysis* 
• Total protein* 
• Electrolytes (Sodium, 
Potassium, Chloride, 
Calcium)* 
• Lipase* 
• Amylase* 
• GGT 
• CPK 
• Total cholesterol* 
• Triglyceride*  
• TSH 
• Microalbuminuria assessment*  
• Microscopic urine analysis will be 
done if blood, nitrite and/or 
leukocyte esterase are present in 
the chemical urinalysis.  
* Will be repeated at Visit 4a and Visit 5a 
Urine sample for a pregnancy test will also be collected for WOCBP at Medical Screening Visit, 
within 3 days prior to the first dose of study drug, at Visit 3, Visit 5b, and ETV. 
12.2.1.1 COVID-19 Test (SARS-CoV-2) 
Within 5 days of study Visits 2a, 4a and 5a a nasal/nasopharyngeal/oropharyngeal swab will be 
collected at the clinical site for SARS-CoV-2 testing. Subjects with a positive test result will be 
excluded/withdrawn from the study. 
12.2.2 Demographics and Medical, Surgical and Social History 
The demographic data and a complete medical, surgical, and social history will be recorded at 
the Medical Screening Visit. The following demographic information will be recorded: date of 
birth, gender, race, ethnicity, height, and weight. 
12.2.3 Physical Examination 
Physical examinations will be performed as per the Study Schematic (see Section 5). 
Investigator will report whether findings are normal or abnormal. Additional examinations may 
be obtained at the discretion of the Investigator(s) and/or designee. 
The physical examination at the Medical Screening Visit will consist of assessments of general 
appearance, skin, head and neck, lymph nodes, thyroid, musculoskeletal/extremities, 
cardiovascular, lungs, abdomen, and neurological system.  
 
12.2.4 Vital Signs  
All vital signs throughout the clinical trial will be measured in a rested (5 minutes) and seated 
position. Blood pressure, heart rate, respiratory rate and oral temperature will be measured at 
the Medical Screening Visit, Pre-Treatment Period (Visits 2a, 2b, and 2c), Randomization Visit 
(Visit 3), Post-Treatment Period 1 and 2 (Visits 4a, 4b, 5a, and 5b) and at the ETV. 
 


 
  
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12.2.5 Adverse Event Query/Concomitant Medication Query 
The staff will record all adverse events observed, queried, or spontaneously volunteered by the 
subjects. An adverse event/concomitant medication query will be performed as scheduled as 
per Investigator’s direction throughout the study. Subjects will be asked non-leading questions 
such as “How do you feel now?”, “How have you felt since last asked?”, or “Have you taken any 
medication since last asked?” If the presence of any symptom(s), adverse event(s), and/or 
concomitant medication is recorded, the clinical staff may advise the subjects to remain at the 
clinic site for safety reasons until the Investigator decides it is safe for the subjects to leave. If 
the subject decides to leave despite the advice of the Investigator/medical designee, he/she will 
be asked to sign a waiver. 
12.2.6 Paper Diaries  
During the study, each subject enrolled will be issued a paper diary including asthma action plan 
at Visits 2a, 2b, 2c, 3, 4a, 4b, and 5a, to collect the following at-home information as per 
Schedule of Assessments (see Section 5): 
• 
AEs (pre-treatment and post-treatment) 
• 
Disease symptoms  
• 
Concomitant medication use 
Paper diaries will be collected and reviewed at Visits 2b, 2c, 3, 4a, 4b, 5a, 5b, and ETV. 
 
12.2.6.1 
Asthma Action Plan 
During the study, each patient enrolled will be issued an asthma action plan to monitor asthma 
symptoms and instruction on when to call the study site if there is any worsening of asthma 
control. (Refer Appendix 2 for Asthma Action plan). Patients will be instructed to refer to the 
asthma action plan.  
 
12.2.7 Pharmacokinetic assessment  
PK assessments to confirm ADX-629 drug levels in blood will be performed as part of the safety 
assessment. Blood sample will be collected for PK assessment at 1 hour (+5 min) post dose at 
Visit 3, Visit 4a and Visit 5a. Details about sample collection, processing, handling, shipment 
and details regarding laboratory will be mentioned in a separate lab manual.    
 
12.2.8 Electrocardiogram 
 
A 12 lead ECG will be recorded at Screening Visit and at 1 hour (±15 min) post dose on Visit 3, 
Visit 4a, and Visit 5a. Additional ECGs may be obtained at the discretion of the Investigator(s) or 
designee. 
 
 


 
  
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13. 
ANALYSES AND REPORTS 
 
Handling of Dropouts or Missing Data 
The rules for handling of dropouts or missing data will be detailed in statistical analysis plan 
(SAP).   
 
 
Final Integrated Report 
A final integrated report will be issued to the Sponsor by 
 which will be 
reviewed and released by Cliantha Quality Assurance (QA). It will contain a narrative description 
of the clinical and statistical procedures used during the conduct of the clinical trial. Appropriate 
tables and graphs will be created to summarize the data. 
The regulatory agency for submission will be Health Canada. The final integrated report may 
also be included in submissions to other international regulatory agencies. 
14. 
STATISTICAL CONSIDERATIONS 
 
Statistical Plan 
A SAP, detailing the intended statistical analysis of the study data, will be prepared as a 
separate document and finalized before database lock. Any deviation from the original statistical 
plan will be described and justified in the final report, as appropriate. The procedure for 
accounting for missing, unused and spurious data will be included in the statistical analysis plan. 
All statistical analysis will be conducted using SAS®, Version 9.4 or higher. Datasets will be 
prepared using headings from Clinical Data Standards Interchange Consortium (CDISC) Study 
Data Tabulation Model (SDTM) implementation for human clinical trials and Analysis Dataset 
Model (ADaM). 
 
 
Sample Size Calculation 
Based on repeatability analyses24 in allergen-induced airway inflammation responses, a sample 
size of 12 subjects yields more than 80% power to detect a difference of 0.1 with standard 
deviation of 0.1 in change from baseline FEV1 across treatment groups.  
 
 
Analysis Populations 
Statistical analysis and data tabulation will be performed using the following analysis 
populations unless specified otherwise. 
• 
Safety population include all subjects who receive at least one dose of any of the study 
products will be included in the safety analysis.  
• 
Per-protocol (PP) population include subjects who are randomized and complete both 
treatments with at least one post-treatment efficacy assessments and who are without 
any major protocol deviations.  


 
  
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The safety population will be used for safety analyses while PP population will be used for 
efficacy analyses. 
 
 
Statistical Analyses 
 
14.4.1 General Descriptive Statistics  
The descriptive statistics for continuous variables will be the mean, median, standard deviation 
(SD), minimum, maximum, and number of patients. For the log normal data, geometric mean 
and geometric standard error of the mean (GSEM) will be added. 
 
Frequency distributions for all categorical variables will be presented using counts and 
percentages. 
14.4.2 Efficacy Variables  
The following efficacy variables will be summarized by treatment and timepoint using descriptive 
statistics; 
• 
Change from baseline (within visit*) in forced expiratory volume in one second (FEV1) to 
post-BAC (during 0-3 h post-BAC (Key Efficacy Endpoint) and 3-7 h post BAC); 
• 
Absolute count and percentage differential count of sputum eosinophils and neutrophils 
at approximately 7 h and 24 h post-BAC. 
• 
Allergen-induced shift in airway hyper responsiveness (AHR) as assessed by 
Methacholine PC20 (Mch PC20) post-BAC.  
• 
Change from baseline in fractional exhaled Nitric Oxide (FeNO) at approximately 7 h and 
24 h post-BAC. 
*Note: At Visit 2a, 4a and 5a, the pre-saline FEV1 will be considered as Baseline 
(within-visit) and for efficacy analysis, 7 hour and 24 hour FEV1 will be compared to the 
respective visit Baseline FEV1 value. For example, FEV1 at 7 hour (Visit 4a) will be 
compared to Baseline value at Visit 4a. 
 
14.4.3 Exploratory Variables  
The following exploratory variables will be summarized by treatment and timepoint using 
descriptive statistics:  
• 
Biomarkers (RASP and endotoxin-induced cytokine release) pre-BAC (at approximately 
1 hour post-dose) and 7 h post-BAC.  
• 
Area under curve (AUC) of FEV1 during 0-3 h post-BAC and/or 3-7 h post BAC 
 
14.4.4 Statistical Analysis of Efficacy Data 
Generally, the key efficacy variable may be analyzed using a mixed effect model for repeated 
measures. The following terms may be included in the model: 


 
  
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• 
sequence, visit (i.e., period), treatment group, post-BAC assessment time as 
independent factors, interaction of treatment by post-BAC assessment time 
• 
subject as random effect 
• 
Baseline within each visit as covariate 
• 
If deemed appropriate, additional covariates for FEV1: baseline sputum eosinophil count  
 
AUCs may be analyzed using a mixed effect model with following terms: 
• 
sequence, visit (i.e., period), treatment group  
• 
subject as random effect 
 
Baseline assessment for each period (within visit) will be defined in the SAP.   
 
The other efficacy endpoints may be compared between treatments using appropriate statistical 
models. 
 
Safety Analysis 
Safety analysis will include adverse events, laboratory assessments, vital signs, and physical 
examinations are available. They will be tabulated by treatment using appropriate descriptive 
statistics specified in Section 14.4.1. 
Adverse events will be classified using standard Medical Dictionary for Regulatory Activities 
(MedDRA) terminology Version 22 or higher and presented by treatment group. Summary 
tables listing the type, date of onset, date and time of resolution, incidence, severity, outcome, 
action taken, and Investigator’s opinion of relationship to the study product will be presented by 
treatment group for AEs reported after the first dose of study drug.  
Concomitant medication used during the study will be tabulated by treatment as well.  
 
 
Interim Analyses  
No interim analysis is planned at this point.  
 
Sub-group Analyses 
No sub-group analysis is planned at this point. 
 
Exploratory Analyses 
For the exploratory endpoints specified in Section 7.2 of the protocol, they will be tabulated 
using descriptive statistics specified in Section 14.4.1 as appropriate. 
Additional exploratory endpoints may be compared between treatments using appropriate 
statistical models. 
 
15. 
ADMINISTRATIVE STUDY RECORDS 
 
Subject Enrollment and Identification  
Patients will be enrolled into the clinical trial prior to any screening procedures being performed. 
All patients will be assigned a unique subject identification number. This number will be used to 


 
  
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identify their records until they are randomized into treatment groups. Patients who are 
randomized into the study will be assigned a unique randomization number which will be used 
to identify their records post-randomization. 
 
Study Charts/Records and Source Documents 
A study chart/record will be maintained on site for each subject to file records such as general 
observations, medical and medication use history, physical examination, and clinical laboratory 
data source documents and related documentation. The original record will be considered the 
data ‘source document’. The source documents will be available for inspection (direct/remote) 
by the study monitors and/or representatives before, during, or upon completion of the clinical 
trial. Good documentation practices will be followed for source documentation. The Investigator 
will retain the originals unless otherwise specified in writing by the Sponsor. 
All clinical trial data not available via electronic source will be collected by the Investigator and 
staff and recorded on source documents. The Investigator will assume responsibility for 
ensuring the completeness and accuracy of all clinical documents. 
This clinical trial will be conducted; and the data will be generated, documented (recorded), and 
reported in compliance to the protocol, GCP standards, ICH, and other applicable local laws and 
regulations. 
All 
 staff will be appropriately trained to ensure the collection of accurate, 
consistent, complete, and reliable data are entered onto an electronic case report form (eCRF) 
unique for each subject. 
This clinical trial will utilize a secure and validated electronic data capture (EDC) system. 
 staff will enter the data for each subject into an eCRF with the exception of 
the data collected in an electronic or paper source (e.g., lab data, biomarker data, etc.). Data 
source will be described in the Data Management Plan (DMP). 
The eCRF will contain edit checks and/or controls to ensure the quality, integrity, accuracy and 
completeness of the data entered. The Medical Monitor (medical representative) may examine 
eCRF for preliminary medical review (direct/remote). 
The eCRF data will be maintained in a validated study database with an audit trail of all changes 
that are made to the database, including the reason for the data change. AEs will be coded 
using a standard dictionary, Medical Dictionary for Regulatory Activities (MedDRA version 22.0 
or higher), while concomitant medications will be categorized using the World Health 
Organization Drug dictionary (the most updated version of the dictionary) at the start of the 
clinical trial. 
Creation and validation of the EDC system and management of the data will be conducted in 
accordance with Title 21 of the Code of Federal Regulations (CFR) Part 11 and the FDA 
Guidance for Industry on Computerized Systems used in Clinical Investigations. Methods used 
to ensure the quality and integrity of the data will be documented in the DMP, which will be 
approved by Data Management provider and the Sponsor. 


 
  
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Retention and Availability of Investigational Records 
All drug accountability records, case report forms (CRFs), source data and related regulatory 
documents must be retained for at least 25 years following completion of the clinical trial. 
16. 
DRUG ACCOUNTABILITY 
All study product receipt, inventory, dispensing, dosing, and reconciliation records will be 
maintained in compliance with federal regulations. The study product will be dispensed to 
qualified study subjects according to established procedures. At the end of the clinical trial (after 
the database has been locked) all used and unused study product, other than that which has 
been randomly selected for retention samples (if applicable), will be returned to Sponsor or 
designee. 
 
 
Product Shipment 
The drug supplies for this study will be shipped to: 
 
  
 
 
  
 
  
 
 
 
Product Receipt 
Upon receipt of drug supplies, the Investigator or designee will conduct an inventory and record 
the date received and the amount of drug received. If multiple containers of the test and/or 
reference products are received, the products will be randomized to dispensing inventory and 
retention inventory (if applicable). 
Any remaining and unused investigational products (excluding reserve samples, where 
applicable) will be returned to the Sponsor for disposal or otherwise stored or disposed of as 
determined and agreed upon by the Sponsor and 
 
 
 
Product Storage 
 
 The 
Investigator will be responsible for maintaining accurate records of drug receipt, dispensing, and 
return. At the end of the clinical trial, all partially used and unused study product will be returned 
to Sponsor. 
 


 
  
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Drug Dose Package Labeling 
The study medication will be packed in individual subject’s kits and labeled with study specific 
labels. Labels will reflect appropriate dosing and storage information, the use for the 
investigational purpose only, plus a unique number that will be used to assign the medication to 
the subject according to their randomized treatment assignment. 
 
 
Reserve Samples (if applicable) 
It is the responsibility of the Sponsor to ship a sufficient number of dosage units to allow the 
clinical research facility to maintain an appropriate sampling on-site as per applicable regulatory 
requirements. 
Reserve samples will be handled according to the applicable regulations.  
 
17. 
SUBJECT SAFETY MONITORING AND ADVERSE EVENTS 
 
Subject Safety Monitoring  
Study staff will monitor the subjects throughout the clinical trial. Between the time interval of the 
study periods, staff will be available for subject queries. The Investigator will be on-call 
throughout duration of the clinical trial. Either an Investigator or a suitably medically qualified 
designee must be onsite during methacholine and bronchial allergen challenges. All required 
medications to manage anaphylaxis, severe asthma and other potentially life threatening 
emergencies are available at site.  
 
The Sponsor will designate qualified individuals to maintain a close liaison with the Investigator 
and study staff to ensure the clinical investigation follows the approved protocol and the 
research intent of GCP. Internal Standard Operating Procedures (SOPs) for compliance with 
applicable government regulations will also be applied. This liaison will be documented by 
personal and/or telephone visits prior to study initiation and during the clinical trial to enable 
periodic reviews as well as clarify any questions, which may arise during the clinical trial. During 
on-site visits, Sponsor study monitors will be provided access to all study source documents to 
ensure the integrity of the data. Direct/remote access to such data during the inspection or 
audits/monitoring of the study will be provided to IRB, Sponsor/ its representatives and 
regulatory authorities, but they must agree to respect the confidentiality of the data. 
 
17.1.1 Pregnancy 
Any female with a confirmed positive pregnancy result during study participation (from the time 
of signing the informed consent form until the end of the clinical trial) will be excluded from the 
clinical trial or immediately withdrawn from the clinical trial. Because of the possibility that the 
fetus/embryo could have been exposed to the study drug through the parent and for the subject 
safety, the subject will be followed until the end of the pregnancy (including spontaneous or 
voluntary termination). 
If a subject becomes pregnant or suspects that they became pregnant during the clinical trial, or 
within 30 days after the study is complete, they must notify clinical site. 


 
  
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The pregnancy will be recorded on a Pregnancy form (provided by the clinical site or the 
Sponsor) and reported to the Sponsor and IRB. In the absence of a pregnancy form, an adverse 
event form can be used. 
Attempts to contact the subject to inquire about the status and progression of the pregnancy will 
be made at intervals deemed appropriate (e.g., at least every three months) until an outcome of 
the pregnancy is known. This contact will be documented. 
 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related. AEs may include any changes in 
physical examination or laboratory parameters that are, in the Investigator's opinion, clinically 
significant changes.   
An SAE is defined as any AE that, in the view of either the Investigator or Sponsor, results in 
any of the following outcomes: 
• 
Death 
• 
A life-threatening AE 
• 
In-patient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• 
A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition.   
Life threatening AE: 
Any AE that places the subject, in the view of either the 
Investigator or Sponsor, at immediate risk of death. It does not 
include an AE that, had it occurred in a more severe form, might 
have caused death. 
Unexpected AE: 
Any AE not listed in the applicable product information (e.g., 
drug product label or investigator’s brochure) or that is not listed 
at the specificity or severity that has been observed.  
"Unexpected," as used in this definition, also refers to AEs that are mentioned in the applicable 
product information as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. If such an unexpected AE is suspected to be related to the 
drug then it is known as “Suspected Unexpected Serious Adverse Reactions (SUSARs)”. 
 
17.2.1 Recording Adverse Events 
The staff will record all AEs observed, queried, or spontaneously volunteered by the subjects 
(regardless of seriousness or relationship to study treatment) in the appropriate section of the 
subject’s case report form or source documents. Subjects experiencing AEs (including those 


 
  
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withdrawn from the study due to an AE) will be followed until recovery to a satisfactory state, or 
stabilization, or appropriate outcome is established as judged by the Investigator.  
The following details will be recorded for AEs: 
• 
Description of event/symptom 
• 
Onset date and time of event 
• 
End date and time of event 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Action taken with study treatment noted as follows: 
▪ 
Dose not changed 
▪ 
Dose reduced 
▪ 
Drug interrupted 
▪ 
Drug withdrawn 
▪ 
Not applicable 
▪ 
Unknown 
• 
Any other action taken (such as concomitant medication, non-drug therapy, hospitalization 
or none) 
• 
Outcome of AE noted as follows:  
▪ 
Fatal 
▪ 
Not recovered/not resolved 
▪ 
Recovered/resolved 
▪ 
Recovered/Resolved with sequelae 
▪ 
Unknown 
• 
Causality noted as follows: 


 
  
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Related: 
A causal relationship between the study treatment and the 
AE is a reasonable possibility. 
Not Related: 
A causal relationship between the study treatment and the 
AE is not a reasonable possibility. 
 
17.2.2 Reporting Serious Adverse Events 
AEs and medical history will be coded and classified according to the MedDRA and AEs will be 
reported with respect to severity, duration, relationship to study drug(s) and action taken. 
Concomitant medications will be categorized using the World Health Organization Drug 
dictionary (the most updated version of the dictionary) at the start of the study. 
All serious adverse experiences, whether deemed drug-related or not, will be reported to the 
sponsor preferable by email (or by telephone if email is not possible) immediately after the 
awareness by Investigator and in no case later than 24 hours, followed by a written report within 
2 working days. The investigator is responsible for following all local regulations for the reporting 
of safety information, including the reporting of SAEs to their local IRB/REB/IEC. 
The investigator must promptly report to his or her local IRB/REB/IEC all unanticipated problems 
involving risks to subjects. This includes death from any cause and all serious adverse events 
reasonably or possibly associated with the use of investigational product.  
The Sponsor or their designee is responsible for appropriate reporting of relevant AEs, 
suspected unexpected serious adverse reactions (SUSARs) involving investigational product, to 
all regulatory authorities as per the below timeline:  
• 
When neither fatal nor life-threatening, within 15 days after becoming aware of the 
information 
• 
When fatal or life-threatening, immediately when possible and, in any event, within seven 
(7) days after becoming aware of the information 
• 
Within eight (8) days after having informed HC of the ADR, submit a report that includes 
an assessment of the importance and implication of any findings 
In addition, the Sponsor or designee will be responsible for the submission of safety letters 
(e.g., SUSARs) to the central IRB/REB/IEC and to participating investigators of all SUSARs 
involving IP according to applicable regulations.  
After termination of the clinical trial (determined as last subject, last visit), any unexpected safety 
issue that changes the risk-benefit analysis and is likely to have an impact on the subjects who 
have participated in it, will be reported by the Sponsor as soon as possible to the competent 
authority(ies) concerned together with proposed actions. 
The following sponsor representative is to be contacted immediately following the occurrence of 
a SAE: 
 


 
  
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17.2.3 Removal of Subjects from Clinical Trial 
Subjects will be advised that they are free to withdraw from the clinical trial at any time for any 
reason or, if necessary, the Investigator may withdraw a subject from the clinical trial to protect 
the health of that subject. A subject may also be withdrawn for not complying with study 
procedures. The clinical report will include all reasons for early withdrawals. 
All subjects who receive at least one dose of any of the study products will be included in the 
safety analysis. If a subject terminates from the clinical trial early, all efforts will be made to 
complete the ETV. In case of early termination the Investigator will fully document the reason for 
early termination. Reasons for early termination may include the following: 
• 
Voluntary withdrawal by subject. 
• 
Significant AE that led the Investigator or subject to withdraw for safety reasons. 
• 
Non-compliance with protocol requirements (e.g., use of restricted medication, 
not following dosing procedures, failure to make scheduled study visits in a timely 
fashion). 
• 
Pregnancy 
• 
Significant worsening of asthma (require corticosteroids including inhaled, oral or 
parenteral to treat an asthma exacerbation, any subject that meets the criteria for 
the Red Zone as per Asthma Action Plan [Refer Appendix 2]) such that the 
Investigator and/or subject believes it is in the best interest of the subject to 
withdraw from the study and be provided alternative treatment. 
• 
Participant enrolls in another clinical trial, or is found to have previously enrolled 
in this clinical trial. 
• 
Positive COVID-19 test result. 
 
17.2.4 Termination of Study Due to Adverse Events 
If, in the opinion of the Investigator, Sponsor, Regulatory authorities or the IRB, the incidence 
and severity of AE(s) outweighs the benefit of continuing the clinical trial, the clinical trial may be 
terminated. In the event this course of action is to be pursued, the Investigator will make every 
attempt to communicate with the Sponsor prior to the decision to develop a complete plan of 
action and to assess outcomes. 
 
18. 
ETHICS OF CONDUCT 
This clinical trial will be conducted in compliance with the protocol and in accordance with the 
appropriate guidelines and all applicable federal government codes, acts and regulations, the 


 
  
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ethical pricinples that have their origins in the Declaration of Helsinki and all amendments, Good 
Clinical Practice (GCP) requirements, The International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guidance E6 (R2) on Good Clinical 
Practice, and Tri-Council Policy Statement (Canada). 
 
19. 
QUALITY CONTROL AND QUALITY ASSURANCE 
 will implement and maintain quality control procedures to ensure that the 
study is conducted, and that the data are generated, documented, and reported in compliance 
with the protocol, GCP and applicable regulatory documents. 
• 
All participant data relating to the clinical trial will be recorded on electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator 
is responsible for verifying that data entries are accurate and correct by electronically signing 
the CRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/REB/IEC review, and 
regulatory agency inspections and provide direct/remote access to source data documents. 
• 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study 
is being conducted in accordance with the currently approved protocol, written SOPs, study 
specific plans and any other study agreements, ICH GCP, and all applicable regulatory 
requirements. 
• 
Separate risk management plan will be developed prior to start of the study in accordance 
with ICH E6 (R2). 
The Sponsor may conduct audit visits at clinical study site to verify adherence to the study 
protocol, the protection of the rights and well-being of the subjects and the accuracy and 
completeness of reported study data recorded on the source documentation. 
 
 
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 clinical research situation and has put subject’s safety, protocol 
compliance and data validity at high risk. 
Due to the COVID-19 pandemic, challenges may arise for clinical study conduct, for example, 
quarantines of site personnel/study participants, travel limitations, interruptions to the supply 
chain for the investigational product(s), or other considerations if site personnel or study 
participants become infected with COVID-19. These challenges may lead to difficulties in 


 
  
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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 the approved protocol which include (but are not limited to) 
conducting the clinical trial in multiple groups, change in study procedures timing, change in 
subject’s housing duration; ambulatory visits, 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 filed 
and notified to IRB and/or local regulatory (as applicable). 
All participants will be pre-screened prior to enrolment into the clinical trial and evaluated for risk 
factors and symptoms of COVID-19 according to the most recent regional Public Health 
guidelines25 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 clinical trial at the discretion of Investigator/designee, even if not specified 
in the protocol. Subject who has tested positive to COVID-19 during the study will be withdrawn 
from the clinical trial. 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 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 the COVID-19 pandemic. 
 
 
20. 
REGULATORY 
 
Institutional Review Board/Health Canada 
The Investigator agrees to provide the IRB with all appropriate material, including a copy of the 
protocol, consent document, and advertising text (if study-specific advertising is used). The 
clinical trial will not be initiated without written IRB approval of the research plan and consent 
document. Copies of the IRB approval will be forwarded to the Sponsor. The Investigator will 
provide appropriate reports on the progress of this study to the IRB and Sponsor in accordance 
with applicable government and/or Institute regulations and in agreement with Sponsor policy. 
The IRB will be informed of any modifications of the protocol or consent document. Approval in 
writing will be obtained from the IRB prior to implementation of any changes which may increase 
subject risk or which may alter the validity or objectives of the data collected. A copy of the IRB 
approval letter covering such alterations will be furnished by the Investigator to the Sponsor. For 
modifications to the protocol which are administrative in nature, or do not affect subject risk, the 
IRB will be notified in writing by the Investigator with a copy provided to the Sponsor. 


 
  
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The Investigator must promptly report to the IRB all unanticipated problems involving risks to 
subjects. This includes AEs and other types of problems (i.e., AEs are a subset of unanticipated 
problems) that the investigator is required to report to IRB.  
Sponsor should submit a notification to Health Canada indicating that the clinical trial is 
complete. 
 
 
Consent Document 
A properly executed, written consent in compliance with current federal codes, GCP, acts and 
regulations and in accordance with ICH Guidance E6 (R2) on GCP shall be obtained from each 
subject prior to entering the trial or prior to performing any unusual or non-routine procedure 
involving risk to the subject. A copy of the consent document(s) to be used may be reviewed 
and approved by the Sponsor. It will be submitted by the Investigator to the IRB for review and 
written approval prior to the start of the study. The Investigator shall provide a copy of the 
consent to the subject and a signed copy shall also be maintained in the study records. 
Attention is directed to the basic elements required in the consent document under current 
federal regulations for Protection of Human Subjects: 
1. A statement verifying the study involves research, an explanation of the purposes 
of the research, the expected duration of the subject's participation, a description 
of the procedures to be followed, and identification of any procedures which are 
experimental. 
2. A description of any reasonably foreseeable risks or discomforts to the subject.  
3. A description of any benefits to the subject or to others which may reasonably be 
expected from the research. 
4. A disclosure of appropriate alternative procedures or courses of treatment, if any, 
that might be advantageous to the subject. 
5. A statement describing the extent, if any, to which confidentiality of records 
identifying the subject will be maintained and noting the possibility the applicable 
regulatory agencies and the study Sponsor may inspect the records. 
6. For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are 
available if injury occurs and, if so, what they consist of, or where further 
information may be obtained. 
7. An explanation of whom to contact for answers to pertinent questions about the 
research and research subject's rights and whom to contact in the event of a 
research-related injury to the subject. 
8. A statement that participation is voluntary and refusal to participate will involve no 
penalty or loss of benefits to which the subject is otherwise entitled; and the 
subject may discontinue participation at any time without penalty or loss of 
benefits to which the subject is otherwise entitled. 
Additional elements of consent, if appropriate, must be provided to the subject: 


 
  
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1. A statement that the particular treatment or procedure may involve risks to the 
subject (or to the embryo or fetus, if the subject is or may become pregnant) 
which are currently unforeseeable. 
2. Anticipated circumstances under which the subject's participation may be 
terminated by the Investigator without regard to the subject's consent. 
3. Any additional costs to the subject that may result from participation in the study. 
4. The consequences of a subject's decision to withdraw from the research and 
procedures for orderly termination of participation by the subject. 
5. A statement that significant new findings developed during the course of the 
research that may relate to the subject's willingness to continue participation will 
be provided to the subject. 
6. The approximate number of subjects involved in the study. 
When seeking informed consent for applicable clinical trials, a statement may be provided to the 
subject that clinical trial information has been or will be submitted for inclusion in the clinical trial 
registry databank, if applicable. 
 
 
Confidentiality 
All information disclosed to the Investigator by the Sponsor, or Sponsor designees, shall be 
treated by the Investigators as strictly confidential. The Investigator will only use this information 
for the purpose of conducting the clinical trial described within this protocol. The Investigator 
must agree not to disclose any information contained within this protocol to any third party, 
except to those involved in the conduct of this clinical study and who are bound by the 
obligations of confidentiality. 
Information concerning the study treatment, patent applications, processes, unpublished 
scientific data, and other pertinent information is confidential and remains the property of the 
Sponsor. Details should be disclosed only to those involved in the approval or conduct of the 
study. It is understood that the Investigator will use the information obtained during the clinical 
study in connection with the development of the treatment and therefore may disclose it as 
required to regulatory agencies. The Investigator understands that he has an obligation to 
provide the Sponsor with all data obtained during the study. 
 
Investigator's Statement 
The Investigator agrees to conduct the trial as outlined in the approved protocol and in 
accordance with the Sponsor's guidelines and all applicable federal government codes, acts 
and regulations, GCP requirements, and ICH guidance E6 (R2) on Good Clinical Practice. 
These GCP guidelines include, but are not limited to: 
1. Permission to allow the Sponsor or applicable regulatory agencies to inspect study 
facilities and pertinent records at reasonable times and in a reasonable manner that 
ensures subject confidentiality. If this study is to be inspected by a regulatory agency, 
the Sponsor will be notified as soon as possible. 


 
  
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2. Submission of the proposed clinical investigation, including the protocol, consent 
document, and advertising text (if study-specific advertising is used) to a duly 
constituted IRB for approval and acquisition of written approval for each, prior to study 
initiation. 
3. Use of a written consent document obtained prior to entry into the study or prior to the 
performance of any non-routine procedures that involve subject risk. The consent 
document(s) must contain all the elements as specified in the federal regulations and 
which has been previously approved by the Sponsor and the IRB. 
4. Submission of any proposed change in or deviation from the protocol to the IRB, using 
a signed formal amendment document prepared by the Sponsor and/or Investigator. If 
the change or deviation increases risk to the study population, or adversely affects the 
validity of the clinical investigation or the subject’s rights, IRB approval must be 
obtained prior to implementation. IRB will be notified regarding changes that do not 
involve risk or affect the validity of the investigation or the subject’s rights. 
5. Documentation and explanation of protocol deviations will be made on the appropriate 
case report form page, source document or by written documentation to the Sponsor. 
6. The Investigator shall promptly report to the Sponsor any severe adverse event that 
may reasonably be regarded as caused by, or probably caused by, the study 
treatments. 
7. The Investigator shall submit timely progress reports to the IRB and Sponsor at 
appropriate intervals, but not to exceed one year. The final report will be submitted to 
the IRB within 4 months after study completion, termination, or discontinuation. 
8. The Investigator and study staff shall maintain accurate source documents from which 
case report form data or source documents are based and accountability records which 
show the receipt and disposition of all test article(s) shipped to the Investigator by the 
Sponsor. 
9. When new information is relevant to participants’ welfare, Investigator must promptly 
inform all participants to whom the information applies that requires to be reported to 
Health Canada as well.  
The Investigator agrees that all information provided by the Sponsor (including pre-clinical 
data) protocols, case report form data or source documents, and verbal and written 
information, will be kept strictly confidential and confined to the personnel involved in 
conducting the trial. It is recognized this information may be given in confidence to the IRB. 
 
 


 
  
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21. 
REFERENCES  
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23. Global Strategy for Asthma Management and Prevention, 2020 update available at 
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22. 
APPENDICES  
 
 


 
  
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Appendix 2: Asthma Action Plan 
 

SAP_001.pdf: