Clinical trial NCT02874144
Conditions: Nasal Polyps
Sponsor: Northwestern University
Start date: 2016-06-20; Completion date: 2020-08-10
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy of an anti-inflammatory agent compared with placebo in relieving signs and symptoms of disease in patients with sinusitis.

Detailed description:
This is a Phase 2a, single-center, randomized, placebo-controlled, double-blind study that includes 12 weeks of treatment with experimental drug anti-inflammatory agent or placebo TID administered orally.

All subjects will be ≥18 years, have sinusitis with persistent symptoms despite standard of care treatment, and have failed a course of steroids in the past.

Arms: arm 1: 40 mg 12 weeks TID po arm 2: 40 mg 12 weeks TID po
Interventions: intervention 1: AZ compound intervention 2: Collection of Biological Specimens intervention 3: Intranasal corticosteroid intervention 4: Placebo
Intervention descriptions: intervention 1: 40 mg three times daily po for 12 weeks intervention 2: collection of biomarkers for analysis of nasal disease intervention 3: QD Nasal Spray intervention 4: looks like AZ compound, made by same company, double blind. 40 mg three times daily po for 12 weeks

Protocol documents:
Prot_SAP_000.pdf: 
 
Anti-Inflammatory Agent in Sinusitis     
 
A Phase IIa, single-center, randomized, placebo-controlled, double-blind study to assess the efficacy of 
CRTh2 Antagonist AZD1981 in patients with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP). 
 
 
 
 
ID: E1416 Sinus 
 
NCT02874144 
 
 
April 8, 2021 
 
 
Anju Peters, MD  
Northwestern University 
Department of Medicine 
Division of Allergy-Immunology 
211 East Ontario St., Suite 1000 
Chicago, IL 60611   
 
 


 
 
AZD1981 in CRSwNP 
 
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PROTOCOL SYNOPSIS 
 
Version  
 
 
Version 6.0 dated April 5, 2018 
Title 
A Phase IIa, single-center, randomized, placebo-controlled, double-
blind study to assess the efficacy of CRTh2 Antagonist AZD1981 in 
patients with Chronic Rhinosinusitis with Nasal Polyps (CRSwNP). 
Short Title 
AZD1981 in CRSwNP 
Protocol Number 
AP20151107  
Study Drug 
AZD1981 
Clinical Phase 
Phase IIa 
Principal Investigator 
Anju Peters, MD  
Northwestern University 
Department of Medicine 
Division of Allergy-Immunology 
211 East Ontario St., Suite 1000 
Chicago, IL 60611   
Primary Objective 
To evaluate the efficacy of AZD1981 compared with placebo in 
relieving signs and symptoms of disease in patients with Chronic 
Rhinosinusitis with Nasal Polyps (CRSwNP) poorly controlled on 
intranasal steroid therapy. 
Study Design 
This is a Phase IIa, single-center, randomized, placebo-controlled, 
double-blind study that includes 12 weeks of treatment with AZD1981 
(40 mg TID) or placebo TID administered orally as an add-on therapy 
to intranasal corticosteroids (INS). All subjects will be ≥18 years, have 
chronic rhinosinusitis with nasal polyps (CRSwNP) with persistent 
symptoms despite daily treatment over ≥ 6 weeks with intranasal 
corticosteroid, and have failed one or more courses of oral steroids 
(typically 0.5mg/kg for one to two weeks). All subjects will have a total 
nasal polyp score by nasal endoscopy (summation of both nasal 
cavities) > 4 with at least a score of 2 in each nasal cavity. All subjects 
will have the presence of at least two of the following symptoms prior 
to screening: nasal blockade/obstruction/congestion; nasal discharge 
(anterior/posterior nasal drip), facial pain/pressure; reduction or loss 
of sense of smell.  


 
 
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The study will enroll approximately 60 patients (30 per arm placebo 
and AZD1981) and will consist of three phases:  
1. Screening and Run-in (-3 weeks to Day 0) 
2. Double-Blinded, Randomized Treatment Period (Day 0 – 
Week 12) 
3. Washout (Week 13-16) 
During the screening period, each patient’s eligibility for the trial will 
be established. To be eligible at the screening visit (Week 0), patients: 
1. Must be ≥18-70 years of age 
2. Must have a diagnosis of CRSwNP based on a prior 
standard of care sinus CT scan and/or endoscopy 
3. Must have the presence of at least two of the following 
symptoms 
prior 
to 
screening: 
nasal 
blockade/obstruction/congestion; nasal discharge (anterior/ 
posterior nasal drip); facial pain/pressure; reduction or loss 
of sense of smell 
4. Must have CRSwNP with persistent symptoms despite daily 
treatment over ≥ 6 weeks with intranasal corticosteroid spray 
(fluticasone propionate, fluticasone furoate, mometasone 
furoate, 
ciclesonide, 
budesonide, 
triamcinolone, 
or 
beclomethasone), and have failed one or more courses of 
oral steroids (typically 0.5mg/kg for one to two weeks) 
5. Must have a total nasal polyp score by nasal endoscopy 
(summation of both nasal cavities) > 4 with at least a score 
of 2 in each nasal cavity during a prior standard of care visit 
in the 1 month prior to screening. 
During the 3 week run-in period (Week-3 to Day 0), patients must 
remain on a stable dose of INS (fluticasone propionate, fluticasone 
furoate, mometasone furoate, ciclesonide, budesonide, triamcinolone, 
or beclomethasone) of 2 actuations in each nostril once a day. 
Randomized double blind placebo controlled treatment 
At Day 0 of treatment, eligible patients will be randomly allocated (in 
a 1:1 ratio) to receive one of the two treatments: AZD1981 at a dose 
of 40 mg TID or matched placebo for a total of 12 weeks. Efficacy data 
will be collected. The primary endpoint will be measured at Weeks 4, 
8, 12, and 16.  
For the duration of the 12 week treatment period, patients must remain 
on 2 actuations of their prior standard of care INS (fluticasone 


 
 
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propionate, fluticasone furoate, mometasone furoate, ciclesonide, 
budesonide, triamcinolone, or beclomethasone) QD.  
After completion of the 12 week treatment period, all patients will be 
followed for an additional 4 weeks during a wash-out (Week 13-16) 
to collect additional efficacy (persistence of cellular and clinical 
phenotype) data.  They will continue their INS during the wash-out 
phase. 
Patients with a clinical diagnosis of co-morbid asthma at screening will 
be asked to maintain their usual asthma medications, including but 
not limited to long-acting beta agonists and inhaled corticosteroids. 
Starting a leukotriene modifier treatment will not be permitted during 
the randomized period. The treating physicians will manage asthma 
exacerbations as necessary. 
Patients who require oral steroids to treat persistent/worsening 
disease will be discontinued from the study. 
Study Duration 
5 months (including recruitment) 
Primary Endpoints 
1. Change in Total Polyp Score (TPS) from baseline. TPS is the sum 
of both nostrils as evaluated by nasal endoscopy. Polyp size will 
be scored for each nasal cavity from 0 to 4 (Total score 0-8) (Table 
1).   
 
Secondary Endpoints  
1. Change in total nasal symptom (TNSS) score from baseline. 
Subjective nasal symptoms will be recorded by using visual 
analog scores (VAS). Scores range from 0 to 10 cm with lower 
scores indicating milder symptoms (Table 2, page 23). 
2. Change in sinus CT score from baseline as assessed by the Lund-
Mackay scoring system (Table 3, page 23). 
3. Change in Peak Nasal Inspiratory Flow (PNIF) from baseline. 
4. Change in sinonasal outcome test (SNOT)-22 from baseline 
(Appendix 2). SNOT-22 contains 22 questions on sinonasal 
quality of life related items.  Scores range from 0 to 110, with 
higher scores indicating poorer outcomes and with 8.9 as the 
minimally clinically important difference between scores. 
5. Change in Brief Smell Identification Test (B-SIT) from baseline 
(Appendix 3). B-SIT will objectively assess olfaction, as smell loss 
is common and a bothersome in patients with CRSwNP.  The B-
SIT is a validated 12-item, standardized, quantitative test of 
olfaction. Higher scores indicate better olfactory function while 
lower scores represent olfactory dysfunction. 


 
 
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Exploratory Endpoints 
1. Change from baseline in soluble inflammatory mediators. Nasal 
lavage fluid (NLF) will be collected and tested for type 2 
inflammatory mediators (eotaxin 3 and periostin), products of T cell 
activation (e.g. IL-5 and IL-13) and well as products of eosinophil 
activation and degranulation (e.g. ECP and EPX). Urine will be 
collected for measurement of LTE4. 
2. Change in Forced Expiratory Volume in 1 second (FEV1) from 
baseline. 
3. Change in Asthma Control Questionnaire (ACQ5) from baseline 
(Appendix 4). The questionnaire is comprised of 5 questions that 
are assessed on a scale from 0-6, where 0 represents good 
asthma control and 6 represents poor astma control.  The overall 
score is the mean of the responses and the minimal important 
difference is defined as a change in score of 0.5.   
Safety Outcome Measures The safety of AZD1981 will be assessed using the following outcome 
measures: incidence and severity of treatment-emergent adverse 
events and serious adverse events, clinical laboratory measures, and 
vital signs. In particular we will measure CBC with differential at Week 
4, 8, 12, and 16 and liver and renal function tests at Week -3, 2, 4, 8, 
12 and 16 based on past trial experience of dose-related toxicity. 
Pharmacokinetic 
Outcome Measures 
Plasma samples will be collected for total AZD1981 plasma 
concentrations and transported to Astra Zeneca at week 8, 12, and 
16. 
Inclusion Criteria 
1. Male or female, age 18-70. 
2. Females must be surgically sterile or postmenopausal or using a 
highly effective form of birth control such as an estrogen containing 
combined 
oral 
contraceptive, 
progesterone-containing 
contraception, or double barrier method contraception condom 
with spermicide or copper banded intrauterine device. Females in 
certain categories (not sexually active, vasectomized partner, 
tubal occlusion) will be admitted at the discretion of the investigator 
on a case-by-case basis. 
3. Females must have a negative urine pregnancy test at screening 
unless 
documented 
to 
have 
a 
hysterectomy 
or 
be 
postmenopausal. 
4. History of moderate to severe CRSwNP (diagnosed at prior 
standard of care visit by endoscopy and/or a sinus CT scan) with 
presence of at least two of the following symptoms: nasal 
blockade/obstruction/congestion; 
nasal 
discharge 
(anterior/posterior nasal drip), facial pain/pressure; reduction or 
loss of sense of smell. 


 
 
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5. Poorly controlled by steroidal standard of care at the time of 
screening, as defined by persistent symptoms despite daily 
treatment over ≥ 6 weeks with intranasal corticosteroid (fluticasone 
propionate, fluticasone furoate, mometasone furoate, ciclesonide, 
budesonide, triamcinolone, or beclomethasone) and having failed 
one or more courses of oral steroids. 
6. Must have a total nasal polyp score by nasal endoscopy 
(summation of both nasal cavities) > 4 with at least a score of 2 in 
each nasal cavity in the month prior to V0 (Table 1, page 22). 
7. The ability to give informed consent and comply with all study 
procedures. 
Exclusion Criteria 
1. Pregnant females or females with plans to become pregnant or 
breastfeed during the duration of the study. 
2. Inability or unwillingness of a participant to give written informed 
consent or comply with study protocol. 
3. Use of any investigational drugs within 30 days of screening. 
4. Oral or systemic steroids within 2 weeks of screening or at any 
time during the screening or run-in. One single course of oral 
steroids (< 0.5mg/kg/day) for up to 5 days will be permitted for 
asthma exacerbation during the randomization period and the 
following scheduled visit will be pushed out by 2 weeks.   
5. Inability to comply with informed study protocol.  
6. Any clinically relevant abnormal findings in clinical chemistry, 
hematology, urinalysis, physical examination, pulse, blood 
pressure, at screening which, in the opinion of the investigator, 
could put the patient at risk because of his/her participation in the 
study. 
7. Past or current medical problems or findings from physical 
examination or laboratory testing that are not listed above which, 
in the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s ability 
to comply with the study requirements or may compromise the 
quality of the data obtained from the study. 
8. Previous anaphylaxis to AZD1981. 
9. Acute infection needing antibiotic treatment at screening. 
10. Nasal-sinus surgery within the previous 6 months. 
11. Use of new leukotriene antagonists/modifier within 2 weeks of 
screening.  


 
 
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12. SNOT-22 <7 (appendix 2).  
13. Patients with asthma are excluded if an exacerbation requiring 
systemic 
(oral 
and/or 
parenteral) 
steroid 
treatment 
or 
hospitalization for treatment of asthma has occurred within 2 
weeks prior to screening, or are on maintenance doses of oral 
corticosteroids, or FEV1<50% of predicted or less. 
14. Omalizumab within 3 months of visit 1. 
15. History of Churg-Strauss syndrome (eosinophilic granulomatosis 
with polyangiitis), cystic fibrosis or primary ciliary dyskinesia 
disorder. 
16. On aspirin (>325mg) for Aspirin Exacerbated Respiratory 
Disease. 
17. Initiation of allergen immunotherapy within 3 months prior to Visit 
1 or a plan to begin therapy during the study. 
 
18. Recent history of drug or alcohol abuse (within 3 years prior to 
Visit 1). 
19. Contraindications to INS. 
Safety Plan  
1. Patient will be instructed to recognize the signs and symptoms of 
any severe hypersensitivity reaction, and to contact a healthcare 
provider in case of any such symptoms. 
2. Individual patient unblinding may be conducted if safety 
considerations warrant.  During the course of the study, a 
treatment assignment should be unblinded only in the case of a 
life-threatening medical emergency, or in the event of an 
unexpected serious event judged by the investigator as related to 
the study drug. Unblinding will be implemented following 
agreement by both the investigator and Medical Monitor. 
3. Safety data including laboratory tests will be reviewed internally on 
a periodic basis during the study.   
4. Patients with co-morbid asthma may experience serious 
exacerbations as part of their symptoms and emergent use of 
systemic corticosteroids maybe indicated. Patients who require 
treatment with systemic corticosteroids greater than one single 
course of oral steroids (< 0.5mg/kg/day for up to 5 days) will be 
discontinued from the study and followed for safety assessment 
for the remainder of the study. Patients will be provided emergency 
contact information and advised to contact a physician during the 
entire trial, in case of severe asthma exacerbation. 


 
 
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Investigational 
Product(s)/Intervention(s), 
Dosage and Mode of 
Administration 
Patients will receive the study drug (AZD1981 or placebo, supplied by 
Astra Zeneca), which is administered orally. AZD1981 is a white pill. 
The placebo contains the same ingredients as the AZD1981 with the 
exception of the active compound. Study drug will be supplied in a 
blinded fashion. Three doses will be given daily (40 mg). 
Study Procedures 
1.  Phlebotomy 
2.  Nasal Endoscopy 
3.  Sinus CT  
4.  Peak Nasal Inspiratory Flow 
5.  Brief Smell Identification Test 
6.  Spirometry 
7.  Allergy skin testing 
Statistical Considerations 
The trial design is a continuous outcome superiority trial with primary 
efficacy outcome measure of change in Total Polyp Score (TPS) from 
baseline (V1) to the completion of the treatment phase 1 (V5).  
Total polyp score is a standardized method for assessing nasal polyp 
size by endoscopy, based on a scale of 1-4 per side.  Inclusion 
criterion for this study is a TPS of ≥4 with a maximum of 8 and a 
standard deviation ± 2.  A clinically meaningful effect is considered to 
be a decrease in total polyp score of 1.5 (Table 1, page 22).  
The analysis of the primary outcome measure will consist of treatment 
comparisons made using analysis of covariance (ANCOVA); pairwise 
comparisons for assessing differences between treatment arms will 
be performed using two treatment groups at a time.  


 
 
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Table of Contents 
PROTOCOL SYNOPSIS ........................................................................................................... 0 
1.  BACKGROUND AND RATIONALE.....................................................................................13 
1.1 Background .....................................................................................................................13 
1.2 Rationale for Selection of Study Population .....................................................................14 
1.3 Investigational Product(s) (IP) /Intervention(s) .................................................................14 
1.4 Rationale for Selection of Investigational Product(s)/Intervention(s) and Regimen ..........14 
1.4.1  Preclinical Studies ..................................................................................................15 
1.4.2  Clinical Studies .......................................................................................................16 
1.5 Risks .................................................................................................................................16 
1.5.1 
Risks of Investigational Product(s)/Intervention(s) ..................................................16 
1.5.2  Study Procedures and Risks ..................................................................................16 
1.5.3  Risk of Concomitant Medications, Prophylactic Medications and Rescue 
Medications .......................................................................................................................18 
1.6 Benefits ...........................................................................................................................18 
1.6.1  
Benefits of Investigational Product(s)/Intervention(s) ..............................................18 
1.6.2  Benefits of Study Procedure(s) ...............................................................................18 
2. OBJECTIVES .......................................................................................................................19 
2.1 Primary Objective ............................................................................................................19 
2.2 Secondary Objectives .....................................................................................................19 
2.3 Exploratory Objectives .....................................................................................................19 
3. STUDY DESIGN ...................................................................................................................20 
3.1 Study Endpoints ..............................................................................................................21 
3.1.1  Primary Endpoint ....................................................................................................21 
3.1.2 
Secondary Endpoints .............................................................................................21 
3.1.3  Exploratory Endpoints ............................................................................................22 
3.2 Study Completion ............................................................................................................23 
4. SELECTION AND WITHDRAWAL OF PARTICIPANTS ......................................................24 
4.1 Inclusion Criteria ..............................................................................................................24 
4.2 Exclusion Criteria .............................................................................................................24 
4.3 Participant Withdrawal Criteria .........................................................................................25 
4.4 Management of Participant Withdrawal ...........................................................................26 
4.5 Recruitment Methods.......................................................................................................26 
5. INVESTIGATIONAL PRODUCT ...........................................................................................28 
5.1 INVESTIGATIONAL PRODUCT(S) / INTERVENTION(S) ...............................................28 
5.2 Packaging and Labeling ..................................................................................................28 


 
 
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5.3 Preparation, Administration, and Dosage.........................................................................28 
5.4 Accountability of Investigational Products(s) / Intervention(s) ..........................................28 
5.5 Assessment of Compliance with Investigational Product(s)/Intervention Materials ...........29 
5.6 Discontinuation of Investigational Product(s)/Intervention Material(s) ..............................29 
6. OTHER MEDICATIONS........................................................................................................30 
6.1 Concomitant Medications ................................................................................................30 
6.2 Prophylactic Medications .................................................................................................30 
6.3 Rescue Medications .....................................................................................................30 
6.4 Prohibited Medications ....................................................................................................30 
7. STUDY VISITS AND PROCEDURES ...................................................................................31 
7.1 Enrollment and Randomization ........................................................................................31 
7.2 Screening ........................................................................................................................31 
7.3 Main Study Visits .............................................................................................................32 
7.4 Follow-up Visit(s) .............................................................................................................36 
7.5 Visit Windows ..................................................................................................................37 
7.6 Study Procedures ............................................................................................................37 
7.7 Study Arm Assignment Procedures .................................................................................38 
7.7.1  Blinding and Randomization ...................................................................................38 
7.7.2  Securing Blinding and Randomization Information .................................................38 
7.7.3  Requirements for Unblinding ..................................................................................38 
7.7.4  Documenting an Unblinding ...................................................................................38 
8. SAFETY PROCEDURES ......................................................................................................39 
8.1 Stopping Rules ................................................................................................................39 
8.1.1 
Study stopping Rules .............................................................................................39 
8.1.2 
Individual Stopping Rules .......................................................................................39 
8.1.3 
Additional Study Procedures ..................................................................................39 
8.1.4 
Premature Discontinuation of Investigational Product(s)/Intervention(s) with 
continued study participation/follow-up ..............................................................................40 
8.1.5 
Premature Termination Follow-up ..........................................................................40 
8.1.6 
Participant Replacement ........................................................................................40 
8.2 Adverse Events ...............................................................................................................40 
8.2.1 
Adverse Event Definition ........................................................................................40 
8.2.2 
Serious Adverse Event (SAE) Definitions ...............................................................41 
8.2.3 
“Expected” verses “Unexpected” Adverse Event Definition.....................................41 
8.3 Management of Adverse Events ......................................................................................41 
8.3.1 
Collecting Procedure ..............................................................................................41 
8.3.2 
Recording and Reporting Procedure ......................................................................42 


 
 
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8.3.3  Grading and Attribution ..........................................................................................42 
8.4 Management of Serious Adverse Events .........................................................................44 
8.4.1 
 SAE Collecting Procedure .....................................................................................44 
8.4.2 
 SAE Recording and Reporting Procedure .............................................................44 
8.5 Protocol Deviations ..........................................................................................................46 
8.5.1 
Protocol Deviation Definition ..................................................................................46 
8.5.2 
Management of Protocol Deviations .......................................................................47 
9. SAMPLE SIZE CALCULATIONS AND STATISTICAL PLAN ..............................................48 
9.1 Sample Size and Power Calculations ..............................................................................48 
9.2 Data Analysis ..................................................................................................................48 
9.2.1 
Study Participant Baseline Characteristics and Demographics ...............................48 
9.2.2 
Primary Endpoint Analyses ....................................................................................48 
9.2.3   Secondary Endpoint Analyses ................................................................................49 
9.2.4 
Exploratory Endpoint Analyses ...............................................................................49 
9.2.5    Safety Analysis ......................................................................................................49 
9.2.6 
Pharmacokinetic and Pharmacodynamic Data Analyses ........................................49 
9.2.7 
Medical History .......................................................................................................49 
9.2.8 
Medication Use ......................................................................................................49 
9.2.9 
Study Completion ...................................................................................................49 
9.3 Interim Analyses ..............................................................................................................49 
9.4 Deviations from Statistical Plan .......................................................................................49 
10. IDENTIFICATION AND ACCESS TO SOURCE DATA ......................................................50 
10.1 Identifying Source Data .................................................................................................50 
10.2 Updating Source Documentation ...................................................................................50 
10.3 Permitting Access to Source Data .................................................................................50 
11. QUALITY CONTROL AND QUALITY ASSURANCE .........................................................51 
12. ETHICAL CONSIDERATONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE .52 
12.1 Statement of Compliance ..............................................................................................52 
12.2 Informed Consent and Assent .......................................................................................52 
12.3 Privacy and Confidentiality.............................................................................................52 
13. References .........................................................................................................................53 
14. Appendices ........................................................................................................................56 
Appendix 1. Study Design .....................................................................................................56 
Appendix 2. Sino-Nasal Outcome Test-22 Questionnaire ......................................................57 
Appendix 3. B-SIT .................................................................................................................58 
Appendix 4. ACQ5 .................................................................................................................66 


 
 
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Glossary of Abbreviations 
ACQ 
 
Asthma control Questionnaire 
AE 
 
Adverse Event 
ALP 
 
Alkaline Phosphatase 
ALT 
 
Alanine Amino Transferase 
ANCOVA 
Analysis of Covariance 
AST 
 
Aspartate Amino Transferase 
ALP 
 
Alkaline Phosphatase 
BUN 
 
Blood Urea Nitrogen 
B-SIT  
Brief smell identification test 
CBC 
 
Complete Blood Count 
 
CFR 
 
Code of Federal Regulations  
CMV  
Cytomegalovirus 
COPD  
Chronic Obstructive Pulmonary Disease 
CRF 
 
Case Report Form 
CRSwNP 
Chronic rhinosinusitis with nasal polyp 
CRTh2  
Chemoattractant receptor-homologous molecule on TH2 
CTCAE 
Common Terminology for Adverse Events 
EBV 
 
Epstein Barr Virus 
ECP 
 
Eosinophil cationic protein 
EPX 
 
Eosinophil peroxidase 
FEV1  
Forced expiratory volume in 1second 
GMP   
Good Manufacturing Practice 
ICH  
 
International Conference on Harmonization 
ICS 
 
Inhaled Corticosteroid 
IDE 
 
Investigation al Device Exemption 
IL-5 
 
Interleukin 5 
IL-13  
Interleukin 13 
IND 
 
Investigational New Drug 
INR 
 
International Normalized Ratio 
INS 
 
Intranasal steroid 
IP 
 
Investigational product 
IRB 
 
Institutional Review Board 
Kg 
 
Kilogram 
 


 
 
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LABA  
Long acting Beta 2 Agonist 
LTE4 
 
Leukotriene E4 
MOP  
Manual of Operations 
NP 
 
Nasal polyp 
NSAID  
Nonsteroidal anti-inflammatory drug 
PD 
 
Pharmacodynamics 
PK 
 
Pharmacokinetic 
QD 
 
Once a Day 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SGOT  
Serum Glutamic Oxaloacetic Transaminase 
SGPT  
Serum Glutamic Pyruvate Transaminase 
Th2 cells 
Type 2 helper T cells 
SNOT-22 
Sinonasal outcome test-22 
TID 
 
Three Times a Day 
TPS 
 
Total polyp score 
ULN 
 
Upper limit of Normal 
VAS 
 
Visual analog score 
 
 


 
 
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1.  BACKGROUND AND RATIONALE 
1.1 Background 
Overview of CRSwNP 
Chronic rhinosinusitis (CRS) is an inflammatory disease of the sinuses that affects over 12% of 
the U.S. population and accounts for almost $10 billion in annual direct healthcare costs (1, 2).   
In addition, CRS is associated with a significant negative impact on quality of life.  Patients with 
CRS have symptoms including sinus pressure or pain, post nasal drainage, nasal blockage, 
anosmia or hyposmia and fatigue lasting more than 12 weeks in association with objective 
evidence of sinus inflammation on computed tomography (CT) scan and/or endoscopy (3). The 
initial treatment of CRS includes corticosteroids and antibiotics.  If medical therapy fails, sinus 
surgery is recommended.  CRS can be further divided into two subgroups based on the presence 
or absence of nasal polyps, CRS with nasal polyps (CRSwNP) or CRS without nasal polyps 
(CRSsNP), respectively. CRSwNP has a prevalence of 2-4% in US and Europe and has a greater 
disease burden as this subgroup of CRS is often refractory to conventional medical treatment with 
corticosteroids and antibiotics and disease persists despite sinus surgery (4) (5). Interestingly, 
patients with CRSwNP are more likely to undergo revision sinus surgeries for disease 
management when compared to patients with CRSsNP.  Finally, as many as 40-60% of CRSwNP 
patients are diagnosed with asthma and, conversely, patients with moderate to severe asthma 
have a higher prevalence of CRSwNP compared to those with mild asthma (6).  Worsening of 
severe asthma is often related to CRS exacerbations, which adds to the morbidity and costs 
associated with CRS (7) (8).  Taken together, CRSwNP is an aggressive form of CRS with 
substantial impact on QOL that is often resistant to medical and surgical treatment and, as such, 
there is an unmet need for novel therapies aimed at improving care of patients with CRSwNP. 
 
Mechanism active in CRSwNP 
Nasal polyps (NPs) are characterized by a pronounced tissue eosinophilia and a predominant 
type 2 inflammatory infiltrate comprised of mast cells, type 2 innate lymphoid cells (ILC2s), T 
helper type 2 (Th2) cells and basophils (9) (10) (11) (12) (13) (14) (15). These immune cells are 
capable of producing a variety of type 2 pro-inflammatory mediators that can perpetuate the 
ongoing inflammatory response observed in NPs. Of note, studies from our lab and others have 
shown elevations in levels of the classic type 2 cytokines, IL-5 and IL-13, as well as the 
eosinophilic chemotactic proteins, eotaxin-1, 2, and 3 in the nasal polyps and lavage fluid of 
patients with CRSwNP compared to sinonasal tissue and nasal lavage fluid from patients with 
CRSsNP and controls (15) (9). Prostaglandin D2 (PGD2) is another important inflammatory 
mediator elevated in nasal polyps (16).  This arachidonic acid metabolite is produced mostly by 
mast cells and induces chemotaxis of inflammatory cells including TH2 cells, eosinophils, ILC2s, 
and basophils (16) (17, 18).  PGD2 acts via 2 different receptors, one of which is chemoattractant 
receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2). This receptor is 
expressed on Th2 cells, ILC2 cells, eosinophils, and basophils, many of the inflammatory cells 
implicated in the pathogenesis of nasal polyps (18, 19).  Signaling via CRTH2 mediates 
chemotaxis of the type 2 inflammatory cells, release of type 2 cyokines by ILC2s, and activation 
of eosinophils and Th2 cells (18) (20) (21). The biological actions of CRTh2 can be reduced via 
blocking the PGD2 binding site on the CRTh2 (22).  Past studies have shown that sinus disease 
severity and a poor overall disease prognosis are associated with increased eosinophils in the 
sinonasal tissue (23) (24) (25) (26).  Since PGD2, a known inducer of eosinophil chemotaxis and 
type 2 inflammation, is elevated in nasal polyps, we hypothesize that blocking PGD2 signaling 
with a CRTh2 antagonist will decrease the type 2 eosinophilic inflammation observed in nasal 
polyps and result in improved sinonasal symptoms in patients with CRSwNP.  
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The current medical management of CRSwNP remains a challenge and there is a serious gap of 
new and effective medical treatment options for CRSwNP.  Intranasal and oral corticosteroids are 
currently utilized to treat nasal polyps.  At present, only one INS, Nasonex™ (mometasone 
furoate), is approved by the FDA for the treatment of nasal polyps, but its efficacy is modest (27).  
This is due to the fact that it is difficult for INS sprays to penetrate into the polyp mucosa to reduce 
inflammation, so polyps rarely regress with this treatment alone.  Oral corticosteroids, although 
more effective than INS, offer only transient relief and are associated with serious side effects 
such as adrenal insufficiency and osteoporosis, limiting their use.  Surgery is recommended for 
patients with CRSwNP who fail medical therapy however, up to 50% of CRSwNP patients with 
eosinophilia have disease recurrence and almost 12% need revision surgery by 36 months (28). 
Given that patients are poorly responsive to INS, systemic corticosteroids provide short term 
benefit with a potential for long term adverse effects, and because surgery is not uniformly 
effective, there remains an unmet need for a new treatment for CRSwNP. Mucosal-based 
eosinophilia has been shown to directly correlate with sinus disease severity as observed by sinus 
CT and endoscopy, and is associated with a poor prognosis after surgery including a significant 
negative impact on QOL outcomes and higher rates of polyp recurrence (24-26).  The lack of a 
drug that effectively treats the type 2 eosinophilic inflammation in nasal polyps is a critical 
shortcoming in the treatment of CRSwNP.  Understanding the inflammatory pattern of CRSwNP 
and biomarkers that characterize an effective treatment approach against the type 2 inflammation 
that includes ILC2s, eosinophils, basophils, and mast cells will represent a substantial 
development in the targeted pharmacologic management of patients with CRSwNP.   
 
1.2 Rationale for Selection of Study Population 
 
We aim to examine the added effects of a CRTh2 antagonist in CRSwNP subjects with moderate 
to severe disease not controlled on treatment with steroid-based standard of care due to an unmet 
medical need in this population. 
 
1.3 Investigational Product(s) (IP) /Intervention(s) 
 
AZD1981 is an oral, potent, selective, reversible antagonist of CRTh2 that has been evaluated 
by Astra Zeneca in 18 clinical studies, including Phase II trials in asthma. 
 
1.4 Rationale for Selection of Investigational Product(s)/Intervention(s) and 
Regimen 
 
CRTh2 is expressed on many of the inflammatory cells implicated in allergic airway inflammation 
such as asthma, including Th2 lymphocytes, eosinophils, and basophils (18, 19). The biological 
consequences of CRTh2 activation include eosinophil shape change, basophil degranulation, Th2 
cytokine production, upregulation of adhesion molecules, and chemotaxis of eosinophils, basophil 
and Th2 lymphocytes(19) (18). Stimulation of CRTh2 is expected to induce the recruitment of 
these cells into the site of PGD2 accumulation as well as to induce eosinophil and Th2 cell 
activation and to inhibit apoptosis of Th2 cells (21) (20). 
We propose to use AZD1981 in subjects with CRSwNP who are otherwise uncontrolled on first-
line intranasal corticosteroid therapy and have failed at least one course of oral steroids. The 
nasal polyp pathology of CRSwNP shows elevations in not only the number of mast cells but also 
the levels of PGD2 in nasal polyp tissue when compared to healthy controls (12, 16). The 


 
 
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chemotactic effects of PGD2 are mediated through engagement with its receptor CRTh2.  This 
G-protein coupled receptor is expressed on the surface of eosinophils, basophils, ILC2s, and Th2 
cells. Through this interaction, studies have shown that PGD2 can promote eosinophil and Th2 
cell accumulation in areas of inflammation.  Th2 cells can then become activated and secrete pro-
inflammatory cytokines including IL-5 and IL-13. Additionally, recruited eosinophils can activate 
and degranulate releasing their granular proteins including eosinophil cationic protein (ECP) and 
eosinophil peroxidase (EPX). Recent studies have also demonstrated that CRTh2 interaction with 
PGD2 leads to ILC2 chemotaxis and type 2 cytokine release from ILC2 cells (20).  The 
inflammatory environment in CRSwNP is characterized by a type 2 inflammatory response 
consisting of elevated eosinophilic chemokines, eosinophils, and eosinophilic degranulation 
products (ECP and EPX), Th2 lymphocytes and type 2 cytokines such as IL-5, basophils and 
mast cells (9, 10, 12).  In addition, ILC2 cells, the key component in innate immunity that release 
type 2 cytokines are elevated in NP as well. Furthermore, CRTh2 expression has been observed 
on eosinophils, Th2 lymphocytes and ILC2s in NP tissue (14, 19). We have recently confirmed 
the presence of CRTH2 gene expression on NP tissue (unpublished data by A. Kato et al.). These 
findings suggest that the PGD2/CRTh2 pathway may contribute to the known type 2 inflammatory 
environment observed in CRSwNP.  Functionality of the PGD2/CRTh2 pathway has been 
demonstrated in a small study using a nasal polyp explant system (17). In this study, incubation 
of nasal polyp tissue with IgE/anti-IgE led to increased production of PGD2 and enhanced 
expression of its receptors. The study also showed that the CRTh2 pathway was involved in the 
chemotaxis of human Th2 cells in the supernatants from nasal polyp tissue. 
Our proposed hypothesis is that AZD1981 in CRSwNP will reduce CRTh2-expressing leukocyte 
recruitment to the nasal polyp and nasal mucosa and will reduce leukocyte activation through 
CRTh2, thus reducing the signs and symptoms of CRSwNP refractory to control with steroids. 
A CRTh2 antagonist has the potential to impact CRSwNP patients in the following ways: 
1. The quality of life impairment in CRSwNP is pronounced with higher bodily pain and 
decreased social function compared to chronic diseases that are considered more serious 
than CRS such as congestive heart failure, chronic obstructive pulmonary disease 
(COPD), and angina (27); 
2. CRS has significant negative economic impact. With almost 12% of the US population 
suffering from CRS, it is estimated that the overall annual economic burden of CRS in the 
United States is about $22 billion (1).  A significant portion of this cost is related to 
medication usage without clear evidence of effective symptom control, leading to the need 
for sinus surgery, each costing about $8,000 US dollars. It is estimated that over 500,000 
sinus surgeries are done annually for refractory CRS, contributed to by the high rate of 
recurrence in patients after surgery who return to steroid-based medical management that 
is ineffectual. 
3. Current therapy options in uncontrolled patients are off-label and include the use of 
corticosteroids with greater risks to patients and potential for significant toxicity (diabetes, 
osteoporosis, cataracts, glaucoma, avascular necrosis of hips). 
1.4.1  Preclinical Studies 
Relevant preclinical studies of AZD1981 have provided evidence that AZD1981 blocks CRTh2-
mediated shape change in human eosinophils and basophils in blood, blocks CRTh2 mediated 
chemotaxis of human Th2 cells and eosinophils.  


 
 
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1.4.2  Clinical Studies 
AZD1981 has undergone extensive clinical trials in subjects with allergic asthma but is not 
currently FDA approved for this indication.  In the 17 clinical studies completed to date, AZD1981 
was generally well tolerated (AZ Investigator’s Brochure, version 10).  The clinical efficacy of 
AZD1981 in asthma has been evaluated in 3 randomized, double-blind, placebo-controlled 
studies.  Two of the studies were 4-week studies; the third was a 12-week study.  The first 4-week 
study in asthma patients withdrawn from their ordinary low-dose inhaled corticosteroid (ICS) 
treatment, indicated a positive effect on morning peak expiratory flow (PEF) (primary variable).  
Differences between treatment groups for secondary variables (lung function, reliever use and 
asthma symptoms) were small, but generally in favor of AZD1981.  The second 4-week dose-
finding study, in asthma patients not adequately controlled on their current ICS treatment, found 
no statistically significant effect of AZD1981 on morning PEF (primary variable).  However, 
secondary efficacy variables measured in the clinic (forced expiratory flow in 1 second [FEV1] 
and Asthma Control Questionnaire [ACQ] results) showed clinically relevant improvements over 
placebo.  The positive clinical effects of AZD1981 on both lung function and asthma control were 
almost exclusively seen in the atopic (allergic) subgroup.  The 12-week dose-finding study of 
AZD1981 as add-on therapy in atopic asthma patients uncontrolled on low-dose inhaled 
corticosteroids (ICS) and long –acting-b2-agonists (LABA) did not significantly change pre-dose, 
pre-bronchodilator FEV1 (primary variable) or any other efficacy outcome compared t placebo in 
atopic asthma patients treated with ICS/LABA.  AZD1981 has also been tested in COPD.  
However, neither of the 2 completed 4-week studies in COPD patients showed any indication of 
clinical efficacy and the current focus in clinical development of AZD1981 at Astra Zeneca has 
been allergic diseases such as asthma and urticaria.  
 
1.5 Risks 
1.5.1 Risks of Investigational Product(s)/Intervention(s) 
AZD1981:  In studies in healthy volunteers as well as in studies in patients with asthma and 
COPD, a small number of subjects had transient elevations of hepatic enzymes (alanine 
aminotransferase, aspartate aminotransferase, and/or alkaline phosphatase), abnormal renal 
function (elevated creatinine and BUN, decreased GFR), abnormal urine routine (presence of 
blood, elevated WBC, urine protein), raised WBC count, decreased blood albumin, skin eruptions 
(over back, abdomen and skin folds), fever, dizziness and headache. All the events subsided with 
stoppage of IMP.  There were no other identified safety concerns based on adverse event (AE) 
reporting, and no consistent clinically relevant changes in safety laboratory variables, vital signs, 
electrocardiogram (ECG) results, or physical examination findings were observed in the 17 clinical 
studies completed to date using AZD1981 (AZ investigator’s Brochure, version 10).  The thorough 
QT study has confirmed that there are no effects on cardiac repolarization. 
 
1.5.2  Study Procedures and Risks 
Phlebotomy:  May cause pain, bruising, infection, light-headedness and fainting. The maximum 
blood that would be drawn in a 2-month period in the primary outcome study is 66 mL (less than 
5 tablespoons total) over six blood draws. Liver and renal function tests will be drawn at baseline 
for safety monitoring and at the end of week 2, 4, 8, 12, and 16.   CBC with differential, 
comprehensive chemistry (renal and liver function) will checked at screening and at V2 (week 2), 
V3 (week 4), V4 (week 8), V5 (week 12), and V6 (week 16).  Plasma will also be sent to Astra 
Zeneca for PK studies at Week 8, 12, and 16. 
 


 
 
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Allergy Skin Testing: May experience swelling, itching and redness at the site where the skin is 
pricked by the needle. There is also a remote possibility of a generalized reaction to the allergy skin 
tests. Reactions could include hives, hay-fever symptoms, difficulty breathing, and rarely feeling faint 
or dizzy.   Participants will be evaluated for environmental allergies using skin prick tests.  The 
skin prick test consists of putting a drop of the allergen (e.g. pollen, animal dander) on the skin 
(forearm) and pricking the skin lightly with a needle.  If the subject is allergic, they will develop a 
small welt similar to a mosquito bite. For prick skin tests, we use 24 standard allergens. We also 
include 2 control tests, histamine and saline, which serve as positive and negative controls 
respectively.  
 
Nasal Endoscopy: May cause sense of pressure or tickling in the nose. In rare instances, subjects 
may have an allergic reaction to the sprays used before the nasal endoscopy. These reactions 
usually occur in patients who have had exposure to the spray multiple times in the past. If a 
reaction occurs, subjects may develop a rash, itching, or have some swelling.  This is a routine 
procedure that allows physicians to evaluate nasal passages and tissues around the sinus 
openings. An anesthetic spray (tetracine hydrochloride) will be applied to the inside of the 
subject’s nose before the subject is examined. The maximum dose will be no more than 20 mg.  
This procedure will take approximately 30 minutes to complete. 
 
Sinus CT scan: The radiation dose received from this protocol (2 CT scans), is approximately 
equal to 50 days of background radiation. A CT scan will be performed at Day 0 and at 12 weeks 
to evaluate how a participant’s sinus disease improves over the course of treatment with 
AZD1981. This will be performed in the Otolaryngology Clinic using a cone-beam CT scan.  The 
CT scans are important objective measure for assessing disease burden as it is unaffected by 
subjective symptom reporting. The scanner utilized is a Xoran X-cat open frame scanner and is 
not an enclosed ring like the traditional CT scan.  For research related CT scans, the CT scan will 
only be interpreted by the investigators (and not a radiologist).  We will utilize a protocol, which 
exposes subjects to the lowest possible dose of radiation in order to obtain a CT scan suitable for 
assessment of CRS status.  Using this protocol, participants will be subjected to radiation 
exposure of 0.04mSv, which is comparable to a chest X-ray. The cone-beam CT scan enables 
sinus CT scans to be obtained at a significantly lower radiation dose than a conventional CT 
scanner.  The subject may need further imaging if any unexpected findings are found on the CT 
scan.  
 
Nasal lavage:  This procedure is routinely used as treatment for some patients with chronic 
rhinosinusitis. Other than the sometimes unpleasant sensation of water in the nose, there are no 
significant risks to this procedure. Participants will be asked to provide nasal lavage fluid. For this, 
5mL of pre-warmed lactated Ringer solution (Kendall McGaw Laboratories, Irvine, CA) will be 
instilled into each nostrils with a syringe while the head is extended. Then, after approximately 10 
seconds, the subject will tilt their head downward expelling the solution into a plastic collecting 
basin.   The specimens will be stored in the Allergy-Immunology Research Laboratories on the 
McGaw Mezzanine at -80°C for assays per manufacturer’s instructions (IL-5, IL-13, eosinophil 
cationic protein [ECP], eosinophil peroxidase [EPX], periostin, eotaxin 3). 
 
Spirometry:  This test may cause a cough or temporary feeling of lightheadedness. These 
symptoms typically resolve shortly after the test is finished.  Participants will be asked to have 
their pulmonary function measured by spirometry. For this breathing test, subjects will be asked 
to breathe hard and quickly into a machine, called a spirometer. This machine measures how fast 
and how much air moves out of the lungs over a period of time. Subjects may be asked to blow 
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Peak Nasal Inspiratory Flow: May cause temporary feeling of lightheadedness which typically 
resolves shortly after the test is finished. Participants will be asked to have their nasal inspiratory 
flow measured. For this upper airway breathing test, subjects will place a mask over their nose 
and mouth that forms a seal with their face. This mask is connected to a special meter such that 
when they sniff hard and quickly, the meter will determine their nasal inspiratory flow. Subjects 
may be asked to sniff into the mask several times for an accurate reading. This test can take up 
to 10 minutes to complete. 
 
Questionnaires:  Questionnaires may be perceived as intrusive and/or tedious. Participants will 
complete sinusitis, asthma, and allergy questionnaires including the Sino-Nasal Outcome Test 
(SNOT-22) and Asthma Control Questionnaire (ACQ5). These are a series of questions about 
whether subjects have sinus symptoms, if they have had any previous evaluations or treatments, 
and how well they feel their asthma is controlled. The questionnaires also include questions on 
quality of life. Overall, completing a questionnaire usually takes 15 minutes. 
 
Smell tests: Some odors used in the B-SIT may be perceived as unpleasant. Participants will 
undergo evaluation with a clinically validated. Brief Smell Identification Test (B-SIT). The B-SIT is 
a validated 12-item, standardized, quantitative test of olfaction with high test-retest reliability and 
is highly correlated with more sophisticated measures of olfactory dysfunction. Each smell test 
will take approximately 20 minutes to complete.   
 
1.5.3  Risk of Concomitant Medications, Prophylactic Medications and Rescue 
Medications 
Intranasal steroid (concomitant medication allowed during study) may cause nasal irritation. 
 
1.6 Benefits 
1.6.1  
Benefits of Investigational Product(s)/Intervention(s) 
The patients treated with AZD1981 may experience decreased polyp size and nasal symptoms 
associated with nasal polyps.   The patients may also notice improvement in asthma if they also 
have asthma in addition to the CRSwNP.   It is not known if these benefits will be maintained after 
treatment.  The placebo group has no potential clinical benefits.   
 
1.6.2  Benefits of Study Procedure(s) 
There are no known benefits of the study procedures (phlebotomy, nasal endoscopy, nasal 
lavage, smell test, and spirometry) in the general population or in participants with CRSwNP. The 
participant may gain knowledge about their disease.  
 
 


 
 
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2. OBJECTIVES 
2.1 Primary Objective 
 
To evaluate the efficacy of AZD1981 compared with placebo in decreasing polyp size as 
measured by the TPS in patients with intranasal corticosteroid refractory chronic rhinosinusitis 
with nasal polyps. 
 
2.2 Secondary Objectives  
 
1. To evaluate the clinical efficacy of AZD1981 by measuring improvement in nasal symptoms 
by visual analog scores (VAS), radiographic improvement in CRSwNP by Sinus CT scan and 
nasal patency by quantifying nasal peak inspiratory flow. 
 
2. To evaluate the improvement in sinonasal quality of life benefit provided by treatment of 
refractory CRSwNP with AZD1981 by measuring SNOT-22 (appendix 2).  In addition, we will 
objectively assess olfaction via B-SIT (appendix 3). 
2.3 Exploratory Objectives 
 
1. To evaluate the efficacy of AZD1981 in asthma in patients with coexistent CRSwNP and 
asthma by assessing lung function and asthma control based on ACQ5 (Appendix 4). 
 
2. Measure markers of eosinophilic type 2 inflammation that are targeted by CRTH2 inhibition.  
We will measure ECP, EPX, IL-5, IL-13, eotaxin 3, and periostin in the nasal lavage fluid. In 
addition, we will measure urinary LTE4 to assess change in the PGD2 pathway. 
 
 
 


 
 
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3. STUDY DESIGN 
 
This study is a Phase IIa, single-center, randomized, double-blind, placebo-controlled, parallel-
group study of the efficacy and safety of an orally administered AZD1981 as add-on therapy for 
the treatment of adult patients (18-70 years old) who have been diagnosed with CRSwNP either 
by endoscopy and/or sinus CT scan and remain symptomatic despite treatment with therapeutic 
doses of INS.  All participants will have CRSwNP and will have been on INS (fluticasone 
propionate, fluticasone furoate, mometasone furoate, ciclesonide, budesonide, triamcinolone, or 
beclomethasone) for at least 6 weeks and failed one or more courses of oral steroids.  All 
participants will have a baseline TPS of 4 or greater with at least a score of 2 in each nasal cavity 
despite treatment with standard doses of INS during a prior standard care of visit.  The TPS 
measures size of nasal polyps by endoscopy and is the summation of both nasal cavities.   In 
addition, the participants must have at least two of the following symptoms prior to screening:  
nasal congestion/blockage/obstruction; nasal discharge (anterior/posterior nasal drip); facial 
pain/pressure or reduction/loss of smell.  
 
This study will enroll 60 patients (30 per arm placebo and AZD1981) and will consist of 3 phases. 
 
1. Screening and run-in (week -3 to Day 0) 
 
During the screening, each patient’s eligibility for the trial will be established.  To be 
eligible, patients: 
 
 
 
A. Must have an endoscopy total polyp score (TPS) > 4 with at least a score of 2 
in each nasal cavity during a prior standard care of visit within the month prior 
to screening. The TPS measures size of nasal polyps by endoscopy and is the 
summation of both nasal cavities (Table 1, page 22).      
 
B. Must have presence of at least two of the following symptoms prior to screening: 
1. 
Nasal 
congestion/blockage/obstruction; 
2. 
Nasal 
discharge 
(anterior/posterior nasal drip); 3. Facial pain/pressure; or 4. Reduction or loss 
of smell. 
 
C. Must have been on 2 actuations of INS in each nostril daily for at least 6 weeks 
prior to the screening visit. Approved agents include: fluticasone furoate, 
fluticasone propionate, triamcinolone acetonide, mometasone furoate, 
budesonide, ciclesonide, or beclomethasone.   
 
D. Must be willing to fill out questionnaires  
 
E. During the 3 week run-in period (Week-3 to Day 0), patients must remain on 
their prior standard of care INS (fluticasone furoate, fluticasone propionate, 
triamcinolone acetonide, mometasone furoate, budesonide, ciclesonide, or 
beclomethasone) of 2 actuations in each nostril once a day. 
 
 
2. Double-Blinded, Randomized Treatment Period (Day 0 to Week 12) 
 
At Day 0 of treatment, eligible patients will be randomly allocated (in a 1:1 ratio) to receive 
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of 12 weeks.  Efficacy, safety, pharmacokinetic (PK), and pharmacodynamics (PD) data 
will be collected.  The primary end points will be measured at Weeks 4, 8, 12 and 16.  For 
the duration of the 12-week treatment period, patients must continue their prior standard 
of care INS (fluticasone furoate, fluticasone propionate, triamcinolone acetonide, 
mometasone furoate, budesonide, ciclesonide, or beclomethasone), 2 actuations each 
nostril QD and those with asthma will continue their pre-determined asthma treatment.    
 
 
 
3. 4 Week Washout  
 
 
 
After completion of the 12 week treatment period, all patients will be followed for an 
additional 4 weeks during a placebo wash-out to characterize the PK and PD properties 
of AZD1981 and to collect additional efficacy and safety data.  The participants will remain 
on their INS 2 actuations each nostril QD. 
 
Patients who require treatment for persistent or worsening sinus disease or oral steroids 
for asthma exacerbation will be discontinued from the study. 
 
3.1 Study Endpoints 
3.1.1  Primary Endpoint 
The primary endpoint will be change in endoscopic polyp size as measured by the TPS from 
baseline (Day 0) size to week 12 in the treatment period.  The TPS obtained at randomization 
(V1) will be used as the baseline.   
 
 
Table 1. Endoscopic Total Polyp Score (TPS) 
Polyp score 
Polyp size 
0 
No polyps 
1 
Small polyps in the middle meatus not 
reaching below the inferior border of the middle 
turbinate 
2 
Polyps reaching the lower border of the middle 
turbinate or polyp medial to the middle 
turbinate 
3 
Large polyps reaching the lower border of the 
inferior turbinate 
4 
Large polyps causing complete obstruction of 
the inferior  nasal cavity 
3.1.2 Secondary Endpoints 
Change from baseline at Week 12 in:  
1. Nasal symptoms as measured by visual analog scores (VAS) from baseline to week 12 
in the treatment period.  The score obtained at randomization will be used as the 
baseline.  
 
 
 
 
 
 


 
 
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Table 2. Visual analog scores (VAS) for nasal symptoms 
VAS score 
Severity of symptoms 
0-3 cm 
Mild 
>3-7 cm 
Moderate 
>7-10 cm 
Severe 
 
Visual Analog Scale: How troublesome are your symptoms of rhinosinusitis currently? 
(Mark on line) 
 
 
 
 
 
2. 
Sinus CT scan assessment by Lund-Mackay scoring system. 
 
 
Table 3. Lund Mackay Sinus CT Staging System (29) 
 
Right 
Left 
Maxillary 
 
 
Anterior ethmoid 
 
 
Posterior ethmoid 
 
 
Sphenoid 
 
 
Frontal 
 
 
Osteomeatal complex 
 
 
Total (0-24) 
 
 
Scores each sinus: 0-2, osteomeatal complex: 0 or 2 
0=Normal, 1=partial opacification, 2=total opacification 
Interpretation of total score 
1) Normal (score = 0) 
2) Equivocal (score = 1 to 4) 
3) Abnormal (score = ≥ 5) 
 
3. Nasal patency as measured by PNIF (peak nasal inspiratory flow). 
 
4. Patient reported symptoms as assessed by the 22-item Sinonasal Outcome Test 
(SNOT-22) (Appendix 2). 
 
5. Smell test (B-SIT) (Appendix 3). 
3.1.3  Exploratory Endpoints 
1. Change from baseline at 12 weeks in asthma outcomes (lung function as measured by 
FEV1 and control [ACQ5; Appendix 4] in patients with coexistent CRSwNP and asthma. 
 
2. Measure markers of eosinophilic type 2 inflammation that are targeted by CRTH2 
inhibition. We will measure ECP, EPX, IL-5, IL-13, eotaxin 3, and periostin in the nasal 


 
 
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lavage fluid. In addition, we will measure urinary LTE4 to assess change in the PGD2 
pathway. 
 
3.2 Study Completion 
 
This study will be considered “complete” when the primary, secondary and/or exploratory 
objectives have been met.  This includes analysis of all the data required to meet the chosen 
objectives. 
 


 
 
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4. SELECTION AND WITHDRAWAL OF PARTICIPANTS 
4.1 Inclusion Criteria 
 
1. Male or female, ages 18-70 years old with CRSwNP diagnosed by a sinus CT scan and/or 
endoscopy during a prior standard of care visit. 
 
2. Females must be surgically sterile or post-menopausal or using a specified acceptable 
form of birth control throughout the duration of the study, oral contraceptive, (i.e., double 
barrier method contraception (condom with spermatocide or copper banded intrauterine 
device)).  Females in certain categories (non-sexually active, vasectomized partner, 
postmenopausal) will be admitted at the discretion of the investigator on a case-by-case 
basis. 
 
3. Females must have a negative urine pregnancy test at screening unless documented to 
have a hysterectomy or postmenopausal. 
 
4. A minimal endoscopy total nasal polyp score of 4 out of a maximum score of 8 for both 
nostrils (with at least a score of 2 for each nostril) during a prior standard care of visit within 
1 month of screening despite completion of a prior INS treatment for at least 6 weeks 
before screening. 
 
5. Presence of at least two of the following symptoms prior to screening: nasal 
obstruction/congestion; nasal discharge [anterior or posterior]; facial pressure/pain; or 
reduction or loss of smell. 
 
6. Signed written informed consent. 
 
4.2 Exclusion Criteria 
 
1. Pregnant females or females with plans to become pregnant or breastfeed during the 
duration of the study. 
 
2. Recent history of drug or alcohol abuse (within 3 years prior to Visit 1). 
 
3. Inability or unwillingness of a participant to give written informed consent or comply with 
study protocol. 
 
4. Use of any investigational drugs within 30 days of screening. 
 
5. Use of oral corticosteroids (OCS) within 2 weeks before screening or are scheduled to 
receive OCS during the study period for another condition. One single course of oral 
steroids (< 0.5mg/kg/day) for up to 5 days during the randomization will be permitted for 
asthma exacerbation and the following scheduled visit will be pushed out by 2 weeks. 
 
6. Monoclonal antibody or immunosuppressive treatment within 3 months of screening. 
 
7. Use of new leukotriene antagonists/modifier within 2 weeks of screening. 
 


 
 
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8. Initiation of allergen immunotherapy within 3 months prior to Visit 1 or a plan to begin 
therapy during the Screening Run-in Period or the Randomized Treatment Period.  
 
9. Patients who have undergone any nasal surgery within 6 months before screening. 
 
10. Patients who are on aspirin for desensitization (> 325 mg daily).  
 
11. Acute infection needing antibiotic at the time of screening. 
 
12. Ongoing rhinitis medicamentosa. 
 
13. Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis), Young’s 
syndrome, Kartagener’s syndrome or dyskinetic ciliary syndromes, cystic fibrosis. 
 
14. Patients with comorbid asthma are excluded if: 
A. Forced expiratory volume (FEV1) is 50% (of predicted normal) or less. 
B. An exacerbation requiring systemic (oral and/or parenteral) steroid treatment or 
hospitalization (>24 hour) for treatment of asthma has occurred within 2 weeks prior 
to screening. 
C. Are on maintenance doses of oral corticosteroids. 
 
15. Uncooperative or any condition that could make the patient potentially non-compliant to 
the study procedures. 
 
16. Any clinically relevant abnormal findings in clinical chemistry, hematology, urinalysis, 
physical examination, pulse, blood pressure at screening, which, in the opinion of the 
investigator, could put the patient at risk because of his/her participation in the study. 
 
17. Contraindications to INS (refer to National Product labeling for all contraindications or 
warning/precaution of use related to INS). 
 
18. Past or current medical problems or findings from physical examination or laboratory 
testing that are not listed above, which, in the opinion of the investigator, may pose 
additional risks from participation in the study, may interfere with the participant’s ability to 
comply with study requirements or may compromise the quality of the data obtained from 
the study.   
 
19. Previous anaphylaxis to AZD1981 
 
20. Initiation of allergen immunotherapy within 3 months prior to Visit 1 or a plan to begin 
therapy during the study. 
 
4.3 Participant Withdrawal Criteria 
 
Participants may be prematurely terminated from the study for the following reasons: 
 
1. The participant elects to withdraw consent from all future study activities, including follow-
up. 
 
 


 
 
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2. Patient decision. The patient is at any time free to discontinue treatment, without prejudice 
to further treatment.  
 
3. The participant is “lost to follow-up” (i.e., no further follow-up is possible because attempts 
to reestablish contact with the participant have failed). 
 
4. The participant dies. 
 
5. The participant develops a medical condition or is initiated on new medication (s) not 
previously mentioned in the list of prohibited medications that, in the opinion of the 
investigator, may pose additional risks from participation in the study, may interfere with 
the participant’s ability to comply with study requirements or may compromise the quality 
of the data obtained from the study. 
 
6. The participant meets any of the individual stopping rules as delineated in Section 8. 
 
7. Patient is non-compliant with study protocol in the judgment of the PI. 
 
4.4 Management of Participant Withdrawal 
 
Patients are at any time free to withdraw from study without prejudice to further treatment 
(withdrawal of consent).  Such patients will always be asked about the reason(s) and the presence 
of any adverse events.  Adverse events will be followed up (See Sections 8.1.4 and 8.1.5); the 
patient should return all study drugs.  If possible, they will be seen and assessed by an 
investigator. 
 
For patients withdrawn due to incorrect inclusion and for patients for whom the treatment code 
has been prematurely broken by the investigator, no further assessments will be performed 
except for the completion of the Follow-up Visit.  This is done out of concern for the patients’ 
safety. 
 
If a patient prematurely discontinues the study after randomization, the patient will be asked to 
complete Visit 6 at the time of discontinuation.  For patient withdrawn due to study specific 
discontinuation criteria, see Section 4.3. 
 
Withdrawn subjects will not be replaced. 
 
4.5 Recruitment Methods 
 
Potential subjects will be recruited through print advertising (e.g., flyers, posters at Northwestern 
Memorial Hospital and other affiliates, ads on transit lines), registries (e.g., Research Match, 
Illinois Women’s Health Registry), online advertising (e.g., social media) and referrals from 
physicians. Recruitment will continue throughout the trial until 60 patients are randomized into the 
trial. 
Flyers and posters will be placed in the Allergy and Otolaryngology clinics at Northwestern 
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EPAM is a company which advertises through social media (i.e. Facebook, Twitter, and Reddit) 
and targets individuals with chronic rhinosinutis or nasal polyps using the iSwarm system. 
Potential research subjects are sought out as pre-qualified clinical candidates in the iSwarm 
system by pooling user demographics, locations, and identified on line communities.  Digital 
engagement strategies such Northwestern IRB-approved as banner ads, side panel ads and 
promoted messaging allows the potential subjects to contact the research team directly by taking 
a secure, confidential online pre-screening survey. 
Research Match is a secure online, national recruitment tool that is maintained by Vanderbilt 
University. ResearchMatch.org allows researchers to conduct feasibility or recruit potential study 
participants. Participants who are interested and released their contact information to the study 
team will be contacted via telephone or email. If participants cannot be reached via telephone, 
the Research Match follow-up email will be sent to them.  
The Illinois Women's Health Registry was established and overseen by Northwestern University's 
Women's Health Research Institute at the Feinberg School of Medicine to encourage investigator-
initiated research targeting women's health. The role of the Registry is to facilitate the recruitment 
and identification of women who may be eligible to participate in IRB approved research being 
conducted at Northwestern University and other research institutions across the state of Illinois.  
 
 


 
 
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5. INVESTIGATIONAL PRODUCT 
5.1 INVESTIGATIONAL PRODUCT(S) / INTERVENTION(S) 
 
AZD1981 (Astra Zeneca) is a sterile, white pill. 
 
AZD1981: Refer to Section 1.5, Section 1.6, and applicable product labeling for product 
description and for known and potential risks to human participants associated with the 
investigational product(s)/intervention(s).  
 
Placebo: contains the same ingredients as the AZD1981 with the exception of the active 
compound. 
 
5.2 Packaging and Labeling 
 
Astra Zeneca will supply AZD1981 and matched placebo for this study in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines.  The tablets will be packaged in 
child-resistant bottles. The patients will receive a four-week supply of the investigational product 
(IP) or placebo at dispensing visits.  The labels will fulfill GMP Annex 13 requirements for labeling.  
Booklet labels will be used where applicable and label text will be translated into local languages. 
 
5.3 Preparation, Administration, and Dosage 
 
AZD1981 for oral administration will be available in tablet form. A pharmacist at the research 
pharmacy (Investigational Pharmacy, Northwestern Memorial Hospital, 251 E. Huron Street, 
LC700, Chicago, IL 60611) will dispense the study drug or placebo to subjects. Subjects and 
study team will be blinded to treatment assignment during trial.  The drug will be self-administered 
by the subject.  
 
AZD1981 tablets will be provided in 20mg strengths.  All patients will take 2 tablets in the morning, 
2 tablets in the afternoon, and 2 tablets in the evening of AZD1981 and/or placebo.  The tablets 
should be swallowed whole with a glass of water.  
 
5.4 Accountability of Investigational Products(s) / Intervention(s) 
 
Under Title 21 of the Code 21 of the Code of Federal Regulations (21CFR§312.62) the 
investigator will maintain adequate records of the disposition of the investigational 
product(s)/intervention material(s), including the date and quantity of the drug received, to whom 
the drug was dispensed (participant-by-participant accounting, and a detailed accounting of any 
investigational products(s)/intervention material(s) accidentally or deliberately destroyed.   
 
The study site will maintain records for records for receipt, storage, use, and disposition.  A 
dispensing log will be kept current for each participant.  This log will contain the identification of 
each participant and the date and quantity of investigational product(s)/intervention material(s) 
dispensed.  
 


 
 
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All records regarding the disposition of the investigational product(s)/intervention material(s) will 
be available for inspection by the FDA.  All residual product(s) will be destroyed or retained for 
future in vitro studies. 
 
5.5 Assessment of Compliance with Investigational Product(s)/Intervention 
Materials 
All study drug supplies will be supplied at treatment facility.  The pharmacy will keep records of 
doses dispensed.  
 
5.6 Discontinuation of Investigational Product(s)/Intervention Material(s) 
Refer to Section 4.3 and Section 8. 
 
 


 
 
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6. OTHER MEDICATIONS 
6.1 Concomitant Medications 
 
Concomitant medications may be used as follows: Leukotriene antagonists/modifier will be 
permitted during the study, as long as they were started at least 2 weeks prior to screening. Oral 
and topical antihistamines without decongestants at the current FDA-approved doses. Low dose 
estrogen containing oral contraception is permitted.  Patients taking  
H2 
blockers 
and 
proton pump inhibitors for gastroesophageal reflux disease will be permitted to continue their use 
during the study.  Inhaled asthma controllers, including corticosteroids and quick relief inhalers 
such as albuterol or levoalbuterol are permitted during the study.  Antihypertensives  
and 
cholesterol agents will be permitted as long as the doses and type of medication were stable for 
at least 6 weeks prior to screening. These  diseases must be recorded as part of the medical 
history collected during the screening period. All concomitant medication and changes in 
treatment will be recorded in appropriate section. Normal nasal saline will be allowed during the 
study. Topical decongestants, e.g. Oxymetazoline hydrochloride (to reduce the swelling and 
widen the path for the endoscope), as well as a topical anesthetic e.g. Lidocaine are allowed 
before endoscopy.  
 
6.2 Prophylactic Medications 
 
None 
 
6.3 Rescue Medications 
 
None 
 
6.4 Prohibited Medications 
Oral corticosteroids will be prohibited at screening and run-in but may be allowed as a rescue 
medication.  One single course of oral steroids (0.5mg/kg) for up to 5 days will be permitted for 
asthma exacerbation and the following scheduled visit will be pushed out by 2 weeks. 
 
Starting a new leukotriene antagonists/modifier (e.g. montelukast) will not be allowed within 2 
weeks of screening or during the treatment phases.   
 
 


 
 
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7. STUDY VISITS AND PROCEDURES 
 
7.1 Enrollment and Randomization 
 
A dedicated clinical study coordinator will be responsible for advertising, screening and 
consenting the study subjects.  This research study will be explained in lay terms to each potential 
research participant.  The potential participant will sign an informed consent form before 
undergoing any screening study procedures.  Participants who are deemed eligible (See Section 
4.1, 4.2, and 4.3) will be enrolled and assigned a unique participant number.  The study will take 
place in the Department of Otolaryngology (675 North St. Clair, Galter 15, Chicago, IL 60611) 
and/or Division of Allergy-Immunology (675 North St. Clair, Galter 18-250, Chicago, IL 60611) 
 
The clinical trial consists of three periods, using an add-on therapy approach to INS: 
 
1. Screening and Run in period (3 weeks) 
2. Randomized treatment period (12 weeks; Visits 1-5) 
3. Post-treatment period (4 weeks; Visit 6) 
 
The study visits occur on the planned dates (relative to the first dose), as scheduled.  The visit 
schedule should be adhered to within the + 4 day visit window. 
 
If a patient is prematurely discontinued from treatment, all assessments planned at the End of 
Treatment visit should be performed.  
 
Prior to all screening assessments, after discussion of participation in the study, the written 
consent form must be signed and dated. 
 
Although the screening assessments for this study are grouped under the heading of a single visit 
in this protocol, it is possible for them to be performed over more than 1 site visit if necessary, as 
long as the screening visit window prior to Day 0 (V1) is respected.  Patients that fail screening 
for exclusion criteria, for example concomitant medications, acute illness (upper respiratory tract 
infection), required drug-specific discontinuation periods or laboratory tests may be rescreened 
for study eligibility 1 additional time. 
 
7.2 Screening 
 
Visit 0 (D-21); Screening Run-in 
 
1. Obtain informed consent document signed by participant and assign number.  
 
 
2. Review inclusion and exclusion checklist. 
 
3. Interview to collect patient demographic information, nasal polyposis information, other 
medical history (including asthma history, number of asthma exacerbations in the previous 
year, hypersensitivity to aspirin or NSAID), surgical history (including number and dates 
of previous surgery for nasal polyps), and prior and concomitant medications (including 
background therapy for NP and asthma).  
 


 
 
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4. Measure vital signs [blood pressure, heart rate, respiration rate, body temperature, weight 
(kg), height (cm)]. 
 
5. Perform physical examination (nose, heart, and lung). 
 
6. Perform spirometry, within the time period between V0 and V1, for all patients and ensure 
that patients with co-morbid asthma are stable (with a FEV1>50% (of predicted normal) 
and has not experienced any exacerbation requiring treatment with > 1 systemic (oral or 
parenteral) steroids bursts for worsening asthma and/or hospitalization or an 
emergency/urgent medical care visit for worsening asthma in the previous 2 weeks. 
 
7. Obtain safety labs:  Complete blood count (including platelet count) with differential, IgE, 
comprehensive chemistry [glucose, BUN, sodium, potassium, bicarbonate, creatinine, 
total and direct bilirubin, alkaline phosphatase (ALP), total protein, albumin, SGOT (AST), 
SGPT (ALT)] and calcium (8 mL blood total). 
 
8. Obtain urine for urinalysis (dipstick). 
 
9. Urine pregnancy test for all females unless surgically sterile or postmenopausal. 
 
10. Remind participant to continue their standard of care INS (fluticasone furoate, fluticasone 
propionate, triamcinolone acetonide, mometasone furoate, budesonide, ciclesonide, or 
beclomethasone), 2 actuations each nostril as mandatory background therapy throughout 
the study.   
 
11. Assessment of adverse events during study visit. 
 
12. Schedule appointment for the next visit. 
 
 
7.3 Main Study Visits 
 
Visit 1, (DAY 0): Randomization 
 
1. Record all medication use with start date and dose in CRF; inquire about AEs/SAEs and 
background therapy tolerability. 
 
 
2. Perform nasal endoscopy. 
 
3. Record physical.  
 
4. Reconfirm eligibility based on review of Inclusion/Exclusion Criteria and the V1 endoscopy 
local reading. 
 
5. Obtain spirometry and record result in the CRF. 
 
6. Check compliance with background use of the mandatory background INS therapy as 
defined as: 
 
 
>80% of total number of prescribed “stable dose” sprays taken during the 
 
screening period. 


 
 
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7. Check for use of prohibited medications. 
 
8. Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, 
weight). 
 
9. Perform allergy skin testing. The participant will not have to be skin tested if testing was 
done in the Division of Allergy-Immunology at Northwestern Medical Group during a prior 
standard care of visit. 
 
10. Administer SNOT-22. 
 
11. Perform sinus CT scan (within the time period between V0 and V1) if one was not done 
within a 4 month window of V0. 
 
12. Nasal lavage with 10 cc of normal saline for mechanistic studies (as described in Section 
1.5.2): ECP, EPX, eotaxin 3, IL-5, IL-13, periostin. 
 
13. Urine for LTE4. 
 
14. Administer VAS for nasal symptoms. 
 
15. Administer the smell test (B-SIT) 
 
16. Administer the ACQ5 in patients with asthma.  
 
17. Check PNIF. 
 
18. Randomize subjects (1:1) to receive either study drug or placebo per research pharmacist. 
 
19. Dispense study drug or placebo from pharmacy to patient (4 week supply). 
 
20. Remind participant to continue their standard of care INS (fluticasone furoate, fluticasone 
propionate, triamcinolone acetonide, mometasone furoate, budesonide, ciclesonide, or 
beclomethasone), 2 actuations each nostril as mandatory background therapy throughout 
the study.    
 
21. Schedule appointment for next visit. 
 
Visit 2, (Week 2) 
 
 
1. Obtain blood for liver and renal function test: AST, ALT, ALP, total bilirubin, BUN and 
creatinine (5 mL total). 
 
Visit 3, (Week 4) 
 
1. Record all medication use with start date and dose in CRF; inquire about AEs/SAEs and 
background therapy tolerability. 
 
2. Check compliance with background use of the mandatory background INS therapy as 
defined as: 


 
 
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>80% of total number of prescribed “stable dose” sprays taken during the 
 
screening period. 
 
3. Obtain spirometry and record result in the CRF. 
 
4. Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, 
weight). 
5. Perform extended physical examination. 
 
 
6. Perform nasal endoscopy. 
 
7. Administer VAS for nasal symptoms 
 
8. Nasal lavage with 10 cc of normal saline for mechanistic studies (as described in Section 
1.5.2): ECP, EPX, eotaxin 3, IL-5, IL-13, periostin. 
 
9. Urine for LTE4. 
 
10. Check PNIF. 
 
11. Perform SNOT-22. 
 
12. Perform ACQ5 in those with asthma.  
 
13. Obtain safety labs:  Complete blood count (including platelet count) with differential, 
sodium, potassium, glucose, BUN, bicarbonate, phosphorus, creatinine, total and direct 
bilirubin, alkaline phosphatase, total protein, albumin, SGOT (AST), SGPT (ALT) and 
calcium (8 mL total).  
 
14. Urine for urinalysis. 
 
15. Dispense study drug or placebo from pharmacy to patient (4 weeks).  
 
16. Remind participant to continue their standard of care INS (fluticasone furoate, 
fluticasone propionate, triamcinolone acetonide, mometasone furoate, budesonide, 
ciclesonide, or beclomethasone), 2 actuations each nostril as mandatory background 
therapy throughout the study.   
 
17. Schedule appointment for next visit. 
 
Visit 4, (Week 8) 
 
1. Record all medication use with start date and dose in CRF; inquire about AEs/SAEs and 
background therapy tolerability. 
 
2. Check compliance with background use of the mandatory background INS therapy, as 
defined as: 
 
 
>80% of total number of prescribed “stable dose” sprays taken during the 
 
screening period. 
 


 
 
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3. Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, 
weight). 
 
4. Perform focused physical examination of nose, heart, skin and lungs. 
 
5. Administer VAS for nasal symptoms. 
 
6. Nasal lavage with 10 cc of normal saline for mechanistic studies (as described in 
Section1.5.2): ECP, EPX, eotaxin 3, IL-5, IL-13, periostin. 
 
7. Check PNIF. 
 
8. Perform nasal endoscopy.  
 
9. Administer SNOT-22. 
 
10. Obtain urine for LTE4. 
 
11. Obtain safety labs:  Complete blood count (including platelet count) with differential, 
glucose, BUN, bicarbonate, phosphorus, creatinine, total and direct bilirubin, alkaline 
phosphatase, total protein, albumin, SGOT (AST), SGPT (ALT) and calcium. Also, obtain 
blood for PK studies that will be stored frozen and sent to Astra Zeneca (15 mL blood 
total). 
 
12. Urine for urinalysis. 
 
13. Dispense study drug or placebo from pharmacy to patient (4 weeks).  
 
14. Remind participant to continue their standard of care INS (fluticasone furoate, fluticasone 
propionate, triamcinolone acetonide, mometasone furoate, budesonide, ciclesonide, or 
beclomethasone), 2 actuations each nostril as mandatory background therapy throughout 
the study.   
 
15. Schedule appointment for next visit. 
 
 
Visit 5, (Week 12) 
 
1. Record all medication use with start date and dose in CRF; inquire about AEs/SAEs and 
background therapy tolerability. 
 
2. Check compliance with background use of the mandatory background INS therapy as 
defined as:  
 
>80% of total number of prescribed “stable dose” sprays taken during the 
 
screening period. 
 
3. Obtain spirometry and record result in the CRF. 
 
4. Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, 
weight). 
 


 
 
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5. Perform extended physical examination including head and neck, heart, lungs, 
abdomen, and skin exam. 
 
6. Administer VAS for nasal symptoms. 
 
7. Nasal lavage with 10 cc of normal saline for mechanistic studies (as described in Section 
1.5.2): ECP, EPX, eotaxin 3, IL-5, IL-13, periostin. 
 
8. Check PNIF. 
 
9. Perform nasal endoscopy.  
 
10. Administer SNOT-22. 
 
11. Perform ACQ5. 
 
12. Perform smell test (B-SIT).  
 
13. Obtain urine for LTE4. 
 
14. Obtain safety labs:  Complete blood count (including platelet count) with differential, 
glucose, BUN, bicarbonate, phosphorus, creatinine, total and direct bilirubin, alkaline 
phosphatase, total protein, albumin, SGOT (AST), SGPT (ALT) and calcium. Also, 
obtain blood for PK studies that will be stored frozen and sent to Astra Zeneca (15 mL 
blood total). 
 
15. Urine for urinalysis. 
 
16. Obtain a sinus CT scan. 
 
17. Remind participant to continue their standard of care INS (fluticasone furoate, 
fluticasone propionate, triamcinolone acetonide, mometasone furoate, budesonide, 
ciclesonide, or beclomethasone), 2 actuations each nostril as mandatory background 
therapy throughout the study. 
 
18. Schedule appointment for next visit. 
 
7.4 Follow-up Visit(s) 
 
Visit 6, (Washout) 
 
1. Record all medication use with start date and dose in CRF; inquire about AEs/SAEs and 
background therapy tolerability. 
 
2. Comprehensive physical exam of the head and neck, heart, lungs, abdomen, and skin 
including height, weight, and vital signs. 
 
3. Check compliance with background use of the mandatory background INS therapy as 
defined as: 


 
 
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>80% of total number of prescribed “stable dose” sprays taken during the 
 
screening period. 
 
4. Nasal lavage with 10 cc of normal saline for mechanistic studies (as described in Section 
1.5.2): ECP, EPX, eotaxin 3, IL-5, IL-13, periostin. 
 
 
5. Urine for urinalysis. 
 
6. Obtain Safety labs: CBC with differential, comprehensive chemistry [glucose, BUN, 
bicarbonate, phosphorus, creatinine, total and direct bilirubin, alkaline phosphatase, total 
protein, albumin, SGOT (AST), SGPT (ALT)].  Also, obtain blood for PK studies that will 
be stored frozen and sent to Astra Zeneca (15 mL blood total). 
 
 
If abnormal, the patient will be contacted and approached as outlined in Section 8.1.2. 
 
As needed visits 
 
1. Subjects may come in at any time at the discretion of the investigator or the subject for 
follow up. 
 
Early discontinued patients will be required to report for safety follow-up visit within a 
month of study discontinuation. 
 
7.5 Visit Windows 
 
Study visits should take place within the time limits below: 
 
1. As detailed above, most visits have + 4 day window for 4 week visits. 
 
7.6 Study Procedures 
 
1. Phlebotomy 
 
 
2. Nasal endoscopy 
 
3. Spirometry 
 
4. Peak nasal inspiratory flow 
 
5. Nasal lavage 
 
6. Smell test (B-SIT) 
 
7. Allergy skin testing 
 


 
 
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7.7 Study Arm Assignment Procedures 
7.7.1  Blinding and Randomization 
Individual investigational product(s)/intervention(s) assignments for this blinded study will be on 
occluded labels (provided by the site pharmacist) in 3 blocks of 4 weeks for the 12-week study. 
 
7.7.2  Securing Blinding and Randomization Information 
Randomization lists will be maintained in a secured area by the pharmacist(s) responsible for 
maintaining the blind.  During site visits, the pharmacist will check the occluded labels to ensure 
that they are intact and in a secure, yet accessible, location for study personnel. 
 
7.7.3  Requirements for Unblinding 
This study may be unblinded only for safety reasons or only if the study information is needed for 
an interim or final analysis as described below.  If a clinically significant event occurs and 
knowledge of treatment assignment is required, the blind may be broken.  Unblinding must be 
approved by the study Medical Monitor unless an immediate life threatening condition has 
developed and the Medical Monitor is not accessible. 
 
7.7.4  Documenting an Unblinding 
Any unblinding (opening of a label or disclosure envelope) will require a full written account of the 
event(s) that necessitated the unblinding of the treatment assignment for an individual participant.  
This account will be made in the participant study file and in the final study report and will include 
the reason(s) for the unblinding, the name of the Medical Monitor who was notified and approved 
the unblinding, the names of the individuals unblinded, and the date and time the unblinding 
occurred.  
 
 


 
 
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8. SAFETY PROCEDURES 
8.1 Stopping Rules 
 
8.1.1 Study stopping Rules 
Study enrollment and ongoing study procedures will be suspended pending expedited review of 
all pertinent data by the institutional review board (IRB), medical monitor and the FDA if any one 
of the following occurs: 
 
1. A serious adverse event (Section 8.2.2). 
 
8.1.2 Individual Stopping Rules 
A study participant will be discharged from the study if he/she suffers: 
 
 
1. A severe adverse event (Section 8.2.2) 
 
 
2. A severe, unanticipated, drug-related event (Section 8.3.3.1) 
 
3. Pregnancy (Section 8.4.2.1) 
 
4. Any of the following liver function test abnormalities 
 
A. ALT or AST > 8 x ULN 
 
B. ALT or AST > 5 x ULN for more than 2 weeks 
 
C. ALT or AST >3 x ULN and total bilirubin > 2 x ULN or prothrombin INR > 1.5 
 
D. ALT or AST > 3x ULN and with appearance of or worsening of fatigue, nausea, 
(eosinophils > 5% of leukocytes) 
 
E. If the above liver abnormalities occur, scheduled study visits should no longer be 
performed, but should be replaced with the assessments described below in “Additional 
Study Procedures,” before the patient is withdrawn from the study.  Patients should not be 
withdrawn from the study until liver enzymes are back to normal.  
 
8.1.3 Additional Study Procedures 
If a patient reach a limit of ALT or AST > 3 times ULN, the patient could continue with the study 
treatment and the scheduled study visits as planned.  In addition, additional assessments as 
described below should be performed. 
 
1. Repeat liver enzymes (AST, ALT and ALP), eosinophil count, prothrombin time, INR and 
total serum bilirubin every 48 hours until values begin to decrease.  The frequency of 
monitoring can then be reduced until the lab parameters return to the normal range.  
Samples will be analyzed locally to assure immediate access of laboratory results to the 
site. 
 


 
 
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2. Obtain full medical history including alcohol use, medicines, recreational drug use, 
surgery, blood transfusions, excessive physical exercise and special diets.  
3. Screen for acute viral hepatitis A, B, C, D and E, EBV, CMV, and autoimmune hepatitis 
(antinuclear antibodies).  Perform clinical examination looking for evidence for other acute 
or chronic liver diseases such as alcoholic hepatitis, nonalcoholic steatohepatitis, ischemic 
hepatitis and biliary tract disease. 
 
4. Request an ultrasound investigation of the liver and biliary tract and consider 
gastroenterology or hepatology consultation. 
 
8.1.4 Premature Discontinuation of Investigational Product(s)/Intervention(s) with 
continued study participation/follow-up 
Continued follow up if the investigation products were discontinued for safety reasons would be 
based on the visit number in the protocol at the time of drug discontinuation and the possibility of 
evaluating outcome. 
 
8.1.5 Premature Termination Follow-up 
Participants who are prematurely terminated from the study will be followed to monitor safety for 
a minimum of 30 days or until resolution of the disqualifying event whichever is longer or until the 
Medical Monitor and the Principal Investigator determine that the follow-up is complete. 
 
8.1.6 Participant Replacement 
Participants who prematurely terminate from this study will not be replaced. 
 
8.2 Adverse Events 
 
This section defines the types of adverse events and outlines the procedures for appropriately 
collecting, grading, recording, and reporting them.  Information in this section complies with ICH 
Guideline E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting and ICH E6: Guideline for Good Clinical Practice, and applies the standards set forth 
in the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events version 
3.0 (Aug. 9, 2006). The investigators conducting this trial have reviewed these criteria and 
consider them appropriate for this subject population.   
 
8.2.1 Adverse Event Definition 
An adverse event is any occurrence or worsening of an undesirable or unintended sign, 
symptom, abnormal laboratory finding, or disease that is temporally associated with participation 
in this study whether considered related to the study or not.  
 
Any adverse event that occurs from the moment the subject has signed the consent form will be 
recorded and is reportable.  An adverse event will be followed until any of the following takes 
place:  a) it is resolved, b) participant is stable, c) a minimal of 30 days after participant is 
terminated from the study or d) the Medical Monitor and the Principal Investigator determine that 
follow-up is complete. 
 


 
 
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8.2.2 Serious Adverse Event (SAE) Definitions 
An SAE is defined as “any adverse event occurring at any dose that suggest a significant hazard, 
contraindication, side effect, or precaution.”  This includes but is not limited to any of the following 
events:  
1. Death. A death that occurs during the study or that comes to the attention of the 
investigator during the protocol-defined follow-up after the completion of study will be 
reported whether it is considered to be study-related or not. 
 
2. A life-threatening event. A life-threatening event is any adverse experience that, in the 
view of the investigator, places the study participant at immediate risk of death from the 
reaction as it occurred. 
 
3. An inpatient hospitalization or prolongation of existing hospitalization. 
 
4. Persistent or significant disability. 
 
5. An event that required intervention to prevent permanent impairment or damage. 
 
6. An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, 
it may jeopardize the participant and may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
 
7. Congenital anomaly or birth defect. 
 
Regardless of the relationship of the adverse event to the study, the event will be reported as an 
SAE if it meets any of the above definitions.  
 
8.2.3 “Expected” verses “Unexpected” Adverse Event Definition 
A suspected adverse reaction is considered “expected” when it is listed in the investigator 
brochure, the package insert or the protocol.  An adverse event is considered “unexpected” when 
its nature or severity is not consistent with the information that is provided in the Package insert, 
and/or this protocol (Section 1.5). 
 
8.3 Management of Adverse Events 
8.3.1 Collecting Procedure 
Adverse events may be discovered through any of these methods: 
 
1. Observing the participant.   
 
2. Questioning the participant, with standardized questions at the beginning (except Visit 0) 
and the end of study visits. 
 
3. Receiving an unsolicited complaint from the participant. 
 
4. An abnormal value or result from a clinical or laboratory evaluation (e.g., a radiograph, an 
ultrasound, or an electrocardiogram) can also indicate an adverse event. 


 
 
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8.3.2 Recording and Reporting Procedure 
Throughout the study the Principal Investigator will record all adverse events on appropriate 
adverse event case report forms regardless of their severity or relation to the study. 
 
8.3.2.1  
NOTIFYING THE MEDICAL MONITOR 
The Principal Investigator will ensure the timely dissemination of AE information to the Medical 
Monitor. 
 
8.3.2.2  
NOTIFYING THE INSTITUTIONAL REVIEW BOARD 
The Principal Investigator will ensure the timely dissemination of AE information to the IRB in 
accordance with the applicable regulations and guidelines. 
 
8.3.2.3  
NOTIFYING THE FDA 
The IND Sponsor will file all adverse events in the IND Annual Report to the FDA. The Principal 
Investigator will be responsible for compiling the IND Annual Report. 
 
8.3.3  Grading and Attribution 
 
8.3.3.1  
GRADING CRITERIA 
 
In addition to determining whether an adverse event fulfills criteria for a serious adverse event 
or not, the severity of adverse events experienced by study participants will be graded according 
to the criteria set forth in the National Cancer Institute’s Common Terminology Criteria for 
Adverse Events Version 3.0 (published Aug. 9, 2006).  This document (referred to herein as the 
NCI-CTCAE manual) provides a common language to describe levels of severity, to analyze and 
interpret data, and to articulate the clinical significance of all adverse events. 
 
 
Adverse events listed in the NCI-CTCAE will be graded on a scale from 1 to 5 according to 
the following standards in the NCI-CTCAE manual: 
  
 
  
Grade 1 = Mild adverse event. 
 
  
Grade 2 = Moderate adverse event. 
 
  
Grade 3 = Severe and undesirable adverse event 
 
  
Grade 4 = Life-threatening or disabling adverse event. 
 
  
Grade 5 = Death. 
 
 
Adverse events not included in the NCI-CTCAE listing, which have relative specificity for 
the protocol will be recorded and graded 1 to 5 according to the grade definition provided 
below. 
 
  
For anaphylaxis:  
 
  
Grade 1 = Oral urticarial or erythema 


 
 
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Grade 2 = Flushing, urticarial, periorbital or facial angioedema; mild dyspnea, wheeze  
  
 
 
or upper respiratory symptoms; mild abdominal pain and /or emesis. 
 
  
Grade 3 = Marked dysphagia, hoarseness, and /or stridor; shortness of breath,    
  
 
 
wheezing & retractions; crampy abdominal pain, recurrent vomiting and /  
  
 
 
or diarrhea; and /or mild dizziness 
 
  
Grade 4 = Cyanosis or SpO2 < 92% at any stage, hypotension, confusion, collapse, loss 
  
 
 
of consciousness; or incontinence 
 
  
Grade 5 = Death. 
 
 
Other adverse events not included in the NCI-CTCAE listing, will be recorded and graded 
1 to 5 according to the General Grade Definition provided in the Table below: 
 
Grade 1 
Mild 
Transient or mild discomforts (< 48 
hours), no or minimal medical 
intervention/therapy required, 
hospitalization not necessary (non-
prescription or single-use 
prescription therapy may be 
employed to relieve symptoms, e.g., 
aspirin for simple headache, 
acetaminophen for post-surgical 
pain). 
Grade 2 
Moderate 
Mild to moderate limitation in 
activity some assistance may be 
needed; no or minimal 
intervention/therapy required, 
hospitalization possible. 
Grade 3 
Severe 
Marked limitation in activity, some 
assistance usually required; 
medical intervention/therapy 
required, hospitalization possible. 
Grade 4  
Life-threatening 
Extreme limitation in activity, 
significant assistance required; 
significant medical/therapy 
intervention required hospitalization 
or hospice care probable. 
Grade 5 
Death 
Death. 
 
 
8.3.3.2  
DEFINITION OF ATTRIBUTION  
The relationship, or attribution, of an adverse event to the study will be determined by the 
Principal Investigator or designee by using the descriptors provided in the following table. The 
Principal Investigator or designee by using the descriptors provided in the following table. The 
Principal Investigator or designee will record the determination of attribution on the appropriate 
adverse event or serious adverse event form.  The relationship of an adverse event to the 


 
 
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investigational drug(s)/intervention(s)/procedure(s) or other study drug will be furthered 
determined.   
 
NCI-CTCAE attribution of adverse events 
 
Code 
Descriptor 
Definition 
UNRELATED CATEGORY 
1 
Unrelated 
The adverse event is clearly not 
related to study 
RELATED CATEGORIES 
2 
Unlikely 
The adverse event is doubtfully 
related to study 
3 
Possible  
The adverse event may be related to 
study 
4 
Probable 
The adverse event is likely related to 
study 
5 
Definite 
The adverse event is clearly related to 
study 
 
(For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-
CTCAE website: http://ctep.cancer.gov/reporting/ctc.html) 
 
8.4 Management of Serious Adverse Events 
8.4.1  
SAE Collecting Procedure 
Serious adverse events will be collected described for adverse events in Section 8.3.1. 
 
8.4.2  
SAE Recording and Reporting Procedure 
Serious adverse events will be recorded on the serious adverse event case report form 
(Appendix 6) and will include a narrative of the event signed and dated by the Principal 
Investigator and the site Medical Monitor.  In addition, the FDA MedWatch 3500A form will be 
filled out. 
 
8.4.2.1  
REPORTING PREGNANCY 
The Principal Investigator or a physician designee will counsel the participant and discuss the 
risks of continuing with the pregnancy ad the possible effects of the fetus.  Monitoring of the 
participant will continue until the conclusion of the pregnancy, and follow-up adverse event case 
report form detailing the outcome of the pregnancy will be submitted.  Follow-up information 
detailing the outcome of the pregnancy should be reported to the Medical Monitor as it becomes 
available.   Any premature termination of the pregnancy will be reported.  Any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded as an 
AE. 
 
8.4.2.2  
UNEXPECTED, NON-SERIOUS ADVERSE EVENTS 
An unexpected, non-serious adverse event that is of Grade 2 severity or higher and study related 
will be recorded and reported to the site Medical Monitor under the serious adverse event 
reporting procedure outlined below in Sections 8.4.2.3, 8.4.2.4, and 8.4.2.6.  


 
 
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8.4.2.3  
SAE REPORTING CRITERIA AND PROCEDURES 
 
 
The Principal Investigator will be notified by the staff no later than 24 hours after a staff 
member becomes aware of a SAE. 
  
 
 
The site Medical Monitor will be notified by the Principal Investigator no later than 24 
hours after the Principal Investigator becomes aware of the SAE. 
 
 
Within another 24 hours, the site Medical Monitor will discuss with the Principal 
Investigator the impact of the SAE on the participant and on the study and will decide 
whether standard or expedited reporting will be applied.  A finalized, initial SAE case 
report form and a MedWatch 3500A form will be generated by the Principal 
Investigator. 
 
8.4.2.4  
NOTIFYING THE MEDICAL MONITOR 
The Principal Investigator will ensure the timely dissemination of SAE information, including 
expedited reports, to the Medical Monitor. 
 
8.4.2.5  
NOTIFYING THE INSTITUTIONAL REVIEW BOARD 
The Principal Investigator will ensure the timely dissemination of SAE information, including 
expedited reports, to the IRB in accordance with IRB regulations and guidelines. 
 
8.4.2.6  
NOTIFYING THE FDA 
The following process for reporting a serious adverse event ensures compliance with the ICH 
guidelines, 21 CFR 46 and 21 CFR §312.32.  After the SAE has been reported by the principal 
investigator and assessed by the IND sponsor, the IND sponsor must report the event to the 
appropriate health authorities using one of the two options: 
 
1. Standard reporting to the FDA (report in the context of an IND Annual Report) applies if 
the adverse event is classified as either: 
 
 
A. Serious, related to the study and expected (Section 8.2.1 and 8.2.2) or  
 
 
B. Serious and unrelated to the study (Section 8.2.3) 
 
For standard reporting, the IND Sponsor will file the finalized forms to the FDA together 
with all other SAE documents in the IND Annual Report.  The Principal Investigator will be 
responsible for compiling the IND Annual Report. 
 
2. Expedited reporting (IND safety report) to the FDA applies if the adverse event is 
considered serious, related to the study and unexpected.  SAEs that do not strictly fit the 
above criteria may be reported to the FDA in an expedited manner if the IND Sponsor 
chooses to do so.  This option applies if the AE is classified as one of the following: 
 
A. Serious and unexpected suspected adverse reaction 


 
 
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The sponsor must report any suspected adverse reaction that is both serious and 
 
 
unexpected.  The sponsor must report an adverse event as a suspected adverse  
 
 
reaction only if there is evidence to suggest a causal relationship between the  
 
 
study drug and the adverse event, such as:  
 
i. 
A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure (e.g., angioedema, hepatic injury, 
or Stevens-Johnson Syndrome); 
 
ii. 
One or more occurrences of an event that is not commonly associated 
with drug exposure, but is otherwise uncommon in the population exposed 
to the drug (e.g., tendon rupture); 
 
iii. 
An aggregate analysis of specific events observed in a clinical trial (such 
as known consequences of the underlying disease or condition under 
investigation or other events that commonly occur in the study population 
independent of drug therapy) that indicates those events occur more 
frequently in the drug treatment group than in a concurrent or historical 
control group. 
 
B. Findings from other studies 
 
The sponsor must report any findings from other epidemiological studies, pooled 
analysis of multiple studies, or clinical studies that suggest a significant risk in 
humans exposed to the drug that would result in a safety-related change in the 
protocol, informed consent, investigator brochure, or other aspects of the overall 
conduct of the study.   
 
These events will be reported by the IND Sponsor within 15 calendar days after 
the IND sponsor becomes aware of the SAE; fatal or life-threatening events will be 
reported within 7 calendar days.  All principal investigators must report SAEs to 
their respective IRBs as mandated by them. 
 
8.5 Protocol Deviations 
 
The practices below are consistent with Good Clinical Practice (GCP ICH E6) Sections: 
 
 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3. 
 
 
 
 
Quality Assurance and Quality Control, section 5.1.1. 
 
 
Noncompliance sections 5.20.1, and 5.20.2. 
 
8.5.1 Protocol Deviation Definition 
A protocol deviation is any noncompliance with the protocol, Good Clinical Practice (GCP), or 
the study’s Manual of Operations (MOP).  Noncompliance may be either on the part of the 
participant, the investigator, or the study staff. 
 


 
 
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8.5.2 Management of Protocol Deviations 
 
8.5.2.1  
DETECTING PROTOCOL DEVIATIONS 
Protocol deviations will be detected by direct questioning of participants and regular review of 
CRFs to determine if visits take place in appropriate windows.  
 
8.5.2.2 
REPORTING PROTOCOL DEVIATIONS 
Upon determination that a protocol deviation has occurred, the study staff will a) notify the 
Principal Investigator and b) and will begin completing the Protocol Deviation Form (Appendix 
7).  The Principal Investigator will complete and sign the Protocol Deviation form and submit to 
the site IRB, per IRB regulations.  The IND sponsor will be responsible for notifying the FDA. 
 
 


 
 
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9. SAMPLE SIZE CALCULATIONS AND STATISTICAL PLAN 
 
9.1 Sample Size and Power Calculations 
 
The sample size estimates were calculated according to the study and primary endpoint 
parameters for TPS described above powered to either 90% or 80%.  From these calculations, 
the more conservative number of study subjects was 24 per arm.  We plan to enroll 30 per arm 
to be cautious in anticipating a drop-out rate of 20%. 
 
 
9.2 Data Analysis 
9.2.1 Study Participant Baseline Characteristics and Demographics 
Summary descriptive statistics for baseline and demographic characteristics will be provided for 
all enrolled participants.  Demographic data will include age, race, sex, body weight, and height; 
these data will be presented in the following manner: 
 
 
Continuous data (i.e., age, body weight, and height) will be summarized descriptively by 
mean, standard deviation, median, and range. 
 
 
 
Categorical data (i.e., sex and race) will be presented as enumerations and percentages. 
 
Analyses of primary and secondary outcomes were conducted by intention-to-treat analysis with 
participants analyzed according to the randomly assigned treatment group irrespective of 
compliance. The Mann Whitney U test will be used to compare treatment groups if a non-
Gaussian distributed data are generated; otherwise, if data are normally distributed, an unpaired 
t test will be used.  Wilcoxon rank-sum tests will be used to compare continuous variables within 
groups and Fisher’s exact tests will be used to compare categorical variables.  The level of 
significance employed will be 0.05.  Relationships between the primary efficacy variable and 
various in vitro and in vivo variables will be explored using Pearson product-moment correlation 
coefficient or the Spearman rank correlation coefficient, as appropriate. 
 
Summary statistics will be reported for all secondary efficacy variables.  Continuous variables will 
be summarized by sample size, mean, median, standard deviation, minimum, and maximum.  
Discrete variables will be summarized by frequencies and percentages. 
9.2.2 Primary Endpoint Analyses 
The analysis of the primary outcome measures will consist of treatment comparisons made using 
analysis of covariance (ANCOVA); pairwise comparisons for assessing differences between 
treatment arms will be performed using two treatment groups at a time.  
 
 
1-Sided 
alpha 
Power 
Difference in mean 
Standard dev 
TOTAL sample size  
(inclusive of Treatment 
and Placebo) 
0.1 
0.90 
1.5 
2 
47 
0.1 
0.80 
1.5 
2 
33 


 
 
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9.2.3   Secondary Endpoint Analyses 
This study is not designed or powered to perform hypothesis testing on secondary endpoints.  All 
secondary analyses will be treated as supportive.  Treatment comparisons of change from 
baseline to Week 12 will be made using ANCOVA. 
9.2.4 Exploratory Endpoint Analyses  
Student t test will be used to analyze continuous variable differences.  Mann-Whitney U test will 
be used to analyze unpaired comparisons.   
9.2.5    Safety Analysis 
Safety analyses will include AEs SAEs, laboratory abnormalities, and physical examination 
abnormalities.  All participants in the safety sample will be included in all safety analyses.  
Frequency of AEs will be tabulated by system organ class and preferred term, as well as by 
seriousness, severity, and treatment relatedness.  Frequency of SAEs will be tabulated by system 
organ class and preferred term.  For pertinent laboratory measurements, mean and mean change 
from baseline values will be presented by treatment group and visit.  Frequency of physical 
examination abnormalities will be tabulated by treatment group. 
9.2.6 Pharmacokinetic and Pharmacodynamic Data Analyses 
Plasma sample will be collected and stored frozen at week 8, 12, and 16 and transported to Astra 
Zeneca with coded sample numbers to maintain confidentiality.   
9.2.7 Medical History 
Medical history within the past 12 months – including the existence of current signs and symptoms 
– will be collected for each body system. 
9.2.8 Medication Use 
All medications taken by or administered to study participants beginning 30 days before 
enrollment and continuing throughout the study will be collected.  All medications used will be 
coded according to the WHO drug dictionary.  The number and percentage of participants 
receiving prior and concomitant medications/therapies will be presented overall and by medication 
class. 
9.2.9 Study Completion 
The percent of participants who complete the study, losses to follow-up, times to lost to follow-up, 
and reasons for discontinuation (e.g., adverse events) will be presented. 
 
9.3 Interim Analyses 
 
Given the small study size, no interim data analysis is planned. 
 
9.4 Deviations from Statistical Plan 
 
The principal features of the study design and of the plan for statistical analysis of the data are 
outlined in this protocol.  Any changes in these principal features will require a protocol 
amendment.  
 
 
 


 
 
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10. IDENTIFICATION AND ACCESS TO SOURCE DATA 
 
10.1 Identifying Source Data 
 
The investigator will keep accurate records to ensure that the conduct of the study is fully 
documented.  Data derived from source documents will be transferred to protocol-specific CRFs.  
The results of all clinical and clinical laboratory evaluations will be maintained in the participant’s 
medical records and the data will be transferred to clinical CRFs, as applicable.  
 
10.2 Updating Source Documentation 
 
Documents describing the safety profile of an investigational product(s)/intervention material(s), 
such as eh investigator’s brochure and the package insert, will be amended as needed by the 
investigational product(s)/intervention material(s) manufacturer to ensure that the description of 
safety information adequately reflects any new clinical findings. 
 
The Principal Investigator will provide the site Medical Monitor, and the IRB with the most up-to-
date versions of the above documents as soon as the Principal Investigator becomes aware of 
any changes.  For purchased investigation product(s)/intervention material(s), the Principal 
Investigator will confirm that there are no changes to the package insert every 3 months.  In case 
of package insert changes, the Principal Investigator will notify the site Medical Monitor and the 
IRB. 
 
10.3 Permitting Access to Source Data 
 
The investigational site participating in this study will maintain the highest degree of confidentiality 
of the clinical and research information obtained from the participants in this clinical trial.  Medical 
and research records will be maintained at each site in the strictest confidence.  However, as a 
part of the quality assurance and legal responsibilities of an investigation, the investigational site 
will permit authorized representatives of the sponsor(s) and health authorities to examine (and 
when required by applicable law, to copy) clinical records for the purpose of quality assurance 
reviews, audits, and evaluations of the study safety and progress.  Unless required by the laws 
that permit copying of records, only the coded identity associated with documents or with other 
participant data may be copied (and all personally identifying information will be removed).  
Authorized representatives as noted above are bound to maintain the strict confidentiality of 
medical and research information that is linked to identified individuals. 
 
The records will be maintained in locked file cabinets in Allergy-Immunology offices in 211 E. 
Ontario or Department of Otolaryngology in 675 N. St. Clair and/or password protected 
computers.  
 
 


 
 
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11. QUALITY CONTROL AND QUALITY ASSURANCE 
 
The Principal Investigator will keep accurate records to ensure that the conduct of the study is 
fully documented.  The investigator will ensure that all CRFs are complete, they will be reviewed 
and signed by the Principal Investigator.  All discrepancies identified will be resolved with the 
Principal Investigator and the CRFs will be amended as needed. They will be stored by the 
investigator according to Northwestern University and GCP ICH guidelines.   
 
 
 


 
 
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12. ETHICAL CONSIDERATONS AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE 
 
12.1 Statement of Compliance 
 
This study was designed to ensure the protection of subjects according to the ethical principles 
of the Declaration of Helsinki and amendments concerning medical research in human subjects.  
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance 
for Industry: E6 Good Clinical Practice Consolidated Guidance, and according to the criteria 
specified in this study protocol. Before study initiation, the protocol, the informed consent 
documents will be reviewed and approved by IRB, as well as any other appropriate health 
authorities.  Any amendments to the protocol or to the consent materials will also be approved by 
the appropriate bodies listed above prior to implementation.  
 
12.2 Informed Consent and Assent 
 
The informed consent will provide information about the study to ta prospective participant to allow 
for an informed decision about participation in the study.  All participants (or their legally 
acceptable representative) must read, sign, and date a consent form prior to study participation. 
Consent materials for participants who do not speak or read English will be translated into the 
participants’ appropriate language. 
 
The informed consent form will be revised whenever important new safety information is available, 
whenever the protocol is amended, and/or whenever any new information becomes available that 
may affect participation in the trial. 
 
A copy of the informed consent will be given to a prospective participant for review.  The Principal 
Investigator or an approved designee will discuss the consent with the prospective participant and 
answer questions.  The prospective participant will be told that being in the trial is voluntary and 
that he or she may withdraw from the study at any time, for any reason. 
 
12.3 Privacy and Confidentiality  
 
A participant’s privacy and confidentiality will be respected throughout the study.  Each participant 
will be assigned a sequential identification number and these numbers rather than names will be 
used to collect, store, and report participant information. 
 
 


 
 
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28. Vlaminck S, Vauterin T, Hellings PW, Jorissen M, Acke F, Van Cauwenberge P, Bachert C, 
Gevaert P. The importance of local eosinophilia in the surgical outcome of chronic 
rhinosinusitis: a 3-year prospective observational study. American journal of rhinology & 
allergy 2014; 28: 260-264. 


 
 
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29. Lund VJ, Mackay IS. Staging in rhinosinusitus. Rhinology 1993; 31: 183-184. 
 
 
 


 
 
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14. Appendices 
Appendix 1. Study Design
 
V=Visit; SNOT-22: Sinonasal Outcome Test; B-SIT: Brief Smell Identification Test; VAS: Visual 
analog scores; ACQ5: Asthma Control Questionnaire 5-item 
 
#: randomization to placebo or drug daily 
¶: CBC with diff, comprehensive chemistry, Calcium, IgE 
§: AST, ALT, Alk Phos, T bili 
$: CBC with differential, Comprehensive chemistry (LFTs and renal function), Calcium 
¥: plasma for pharmacokinetic studies 
Nasal lavage fluid:  IL-5, Il-13, ECP, EPX: Eosinophil peroxidase, periostin, eotaxin 3 INS: 
Fluticasone propionate, 2 actuations each nostril QD 
 


 
 
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Appendix 2. Sino-Nasal Outcome Test-22 Questionnaire 
 


 
 
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Appendix 3. B-SIT 
 


 
 
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Appendix 4. ACQ5 
 
 
 
 
 
 
 


 
 
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