Clinical trial NCT03028350
Conditions: Asthma, Aspirin-Induced
Sponsor: Cumberland Pharmaceuticals
Start date: 2017-07-17; Completion date: 2023-04-25
Enrollment: 54 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this phase 2 study is to assess the safety and efficacy of oral ifetroban for the treatment of aspirin-exacerbated respiratory disease (AERD). AERD is a disease that involves asthma, recurring nasal polyps, and respiratory reactions to aspirin and other nonsteroidal anti-inflammatory drugs.

Detailed description:
This is a randomized, placebo-controlled, double-blind phase 2 trial evaluating approximately 76 subjects with symptomatic AERD on the safety and efficacy of 8 weeks of oral ifetroban treatment. Eligible AERD subjects will be randomized to receive 8 weeks of either oral ifetroban daily or matching placebo followed by a 2-week post-treatment period.

Arms: arm 1: Oral ifetroban, 200 mg daily for 8 weeks arm 2: Oral placebo daily for 8 weeks
Interventions: intervention 1: Ifetroban Oral Capsule intervention 2: Placebo Oral Capsule
Intervention descriptions: intervention 1: Subjects will be treated with oral ifetroban daily for 8 weeks intervention 2: Subjects will be treated with oral placebo daily for 8 weeks

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
A Phase 2 Multicenter, Double-blind, Randomized, Placebo-Controlled Trial 
to Evaluate Oral Ifetroban in Subjects with Symptomatic Aspirin 
Exacerbated Respiratory Disease (AERD) 
 
Number: CPI-IFE-006 
 
 
Protocol Version 
 
Version Number:  
Original Protocol 
Final:  
 
22 December 2016 
 
Amendment:   
01 
Revised Final: 
02 May 2018 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable laws and regulations. 
In any event, persons to whom the information is disclosed must be informed that the information is 
privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will 
apply equally to all future information supplied to you which is indicated as privileged or confidential. 
 


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RESPONSIBLE PERSONNEL  
Sponsor - Medically Responsible Person 
 Sponsor’s Coordinating Office 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
Sponsor’s Clinical Operations  
 Coordinating Investigator 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 


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INVESTIGATOR’S STATEMENT 
I have read and agree to the Protocol CPI-IFE-006, “ A Phase 2 Multicenter, Double-blind, 
Randomized, Placebo-Controlled Trial to Evaluate Oral Ifetroban in Subjects with Symptomatic 
Aspirin Exacerbated Respiratory Disease (AERD), Amendment 01 dated 02 May 2018.”  I am 
aware of my responsibilities as an Investigator under the guidelines of Good Clinical Practice 
(GCP), local regulations (as applicable) and the study protocol.  I agree to conduct the study 
according to these guidelines and to appropriately direct and assist the staff under my control, who 
will be involved in the study. 
 
 
 
Principal Investigator 
Signature: 
 
 
 
 
 
 
Date of Signature 
 
 
 
 
 
 
Sponsor Signature 
Signature: 
 
 
 
 
 
 
Date of Signature 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
Date of Signature 
 
 


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SYNOPSIS 
Name of Sponsor: 
Cumberland Pharmaceuticals  
Name of Finished Product: 
Ifetroban Capsules 
Name of Active Ingredient: 
ifetroban 
Title of Study: 
A Phase 2 Multicenter, Double-blind, Randomized, Placebo-Controlled Trial to Evaluate Oral 
Ifetroban in Subjects with Symptomatic Aspirin Exacerbated Respiratory Disease (AERD) 
Study Centers (Planned):  Eight 
Phase of Development:  II 
Expected Study Duration (per subject): Screening period (3 weeks) + Treatment period (8 
weeks) + Post-treatment period (2 weeks) = 13 weeks 
Objectives: 
Primary Study Objective 
• Determine the efficacy of ifetroban compared to placebo to improve sino-nasal symptoms 
and quality of life (QoL) using the Sino-nasal Outcome Test (SNOT) - 22 score in 
symptomatic AERD subjects. 
Secondary Study Objectives 
• Evaluate the effect of ifetroban on asthma symptoms by forced expiratory volume 1 (FEV1) 
compared to baseline. 
• Assess nasal symptoms and QoL using the peak Nasal Inspiratory Flow Rate (PNIFR), 
University of Pennsylvania Smell Identification Test (UPSIT), fractional exhaled nitric oxide 
(FeNO), Asthma Control Questionnaire (ACQ) - 7 and Total Nasal Symptom Score (TNSS) 
• Determine whether ifetroban reduces the frequency and severity of asthma exacerbations and 
chronic sinusitis as well as the frequency of rescue medication and antibiotic use. 
• Evaluate the pharmacodynamic effects of TPr blockade on eicosanoids and eosinophil count 
Methodology: This is a multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the effect of 200 mg of oral ifetroban administered once daily for eight weeks. 
Number of subjects (planned):  A total of 76 AERD subjects will be randomized: 38 ifetroban, 
38 placebo 


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Name of Sponsor: 
Cumberland Pharmaceuticals  
Name of Finished Product: 
Ifetroban Capsules 
Name of Active Ingredient: 
ifetroban 
Study Population – Main Selection Criteria 
Inclusion criteria: 
1. History of physician-diagnosed asthma  
2. History of nasal polyposis 
3. History of at least two reactions to oral aspirin or other nonselective cyclooxygenase 
inhibitor with features of lower airway involvement (cough, chest tightness, wheezing, 
dyspnea) or one reaction that was life-threatening and required hospitalization, or a 
diagnosis of AERD by a physician-conducted challenge to aspirin in the last five years 
before starting treatment. 
4. Stable asthma (post-bronchodilator FEV1 of ≥ 60%, no glucocorticoid burst for at least 
two weeks prior to starting treatment, no hospitalizations or emergency room visits for 
asthma at least three months prior to starting treatment and not on a dose >1000 µg 
fluticasone or equivalent daily). 
5. ≥ 18 years of age 
6. Exhibit symptomatic AERD within three weeks of starting treatment by demonstrating a 
score of at least 20 on the Sino-nasal Outcome Test (SNOT) – 22. 
Exclusion criteria: 
1. Current smoking, defined as daily tobacco smoking in the last six months and at least one 
instance of tobacco smoking in the last three months. 
2. Current pregnancy or breastfeeding 
3. Use of oral or systemic steroids (e.g. prednisone or equivalent) > 20 mg daily in the last 
four weeks before starting treatment. 
4. Daily use of long-acting antihistamines in the last two weeks before starting treatment. 
5. Less than 12 months of allergy shots (maintenance dose of allergy shots are allowed if 
treatment duration exceeds 12 months).  
6. Any use of nonsteroidal anti-inflammatory drugs (NSAIDs) or any drug that inhibits the 
cyclooxygenase enzyme in the last two weeks before starting treatment. 
7. History of bleeding diathesis or use of anticoagulant or antiplatelet drugs in the last two 
weeks before starting treatment. 
8. Any immunosuppressive treatment including but not limited to methotrexate, 
cyclosporine, 
mycophenolate, 
tacrolimus, 
gold, 
penicillamine, 
sulfasalazine, 
hydroxychloroquine, azathioprine and cyclophosphamide in the last two weeks before 
starting treatment (maintenance dose of allergy shots are allowed if treatment duration 
exceeds 12 months). Biologics/immunotherapies such as Xolair or Nucala are permitted 
if duration exceeds three months. 
9. Endoscopic sinus surgery / polypectomy within the past three months 
10. Previously treated in a clinical trial with ifetroban within the past three months. 
11. Previously treated with other investigational drugs within eight weeks or five half-lives, 
whichever is longer, before screening 
12. Conditions/concomitant disease which make them unevaluable for the efficacy endpoints 
Investigational Medicinal Product (IMP), dose and mode of administration: 
Oral ifetroban capsules (200 mg)  
Duration of treatment: eight weeks 


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Name of Sponsor: 
Cumberland Pharmaceuticals  
Name of Finished Product: 
Ifetroban Capsules 
Name of Active Ingredient: 
ifetroban 
Reference therapy, dose and mode of administration: 
Matching oral placebo capsules 
Endpoints: 
Efficacy: SNOT-22, ACQ-7, FEV1, UPSIT, FeNO, PNIFR and TNSS  
Safety, tolerability and other exploratory endpoints: vital signs, adverse events (AE), physical 
examination, clinical laboratory tests and biomarkers. 
Sample Size: 
38 subjects per group will provide 90% power for the comparison of ifetroban and placebo with 
respect to the change from baseline in SNOT-22 scores at Week 8 (two-sided, level 0.05), 
assuming a common standard deviation of 16 and a true difference is 12. 
Randomization: 
Subjects will be randomized using a 1:1 randomization ratio for ifetroban 200 mg daily for eight 
weeks, or placebo daily for eight weeks.  
 
Analysis Population: 
All subjects who received at least one dose of study medication will be included in the Safety 
Population. All safety data, including AEs, laboratory parameter, vital signs, FEV1 and physical 
examinations, will be summarized for subjects in the Safety Population. 
 
The Intent-To-Treat (ITT) Population will consist of all treated subjects with at least one post-
baseline assessment of SNOT-22. The Per Protocol (PP) Population will consist of all subjects in 
the ITT population with no major protocol violations, including violation of inclusion or 
exclusion criteria or insufficient dosing. All efficacy analyses will be performed for both the ITT 
and PP Populations. Summary statistics will be presented for each corresponding analysis. 
 
Primary Analysis: 
The primary efficacy endpoint is the Change From Baseline (CFB) in SNOT-22 score and the 
primary analysis is the analysis of CFB in SNOT-22 at Week 8, using Analysis of Covariance 
(ANCOVA), with SNOT-22 at Baseline included as the only covariate. 
 
Secondary Analyses 
CFB in ACQ-7 and CFB in TNSS at Week 8 will be analyzed using ANCOVA, with the 
corresponding value at Baseline included as the only covariate. These variables, as well as CFB 
in SNOT-22, at Week 4 will also be analyzed as ancillary analyses. 
  
Analyses of CFB for other continuous efficacy variables at Weeks 4 and 8 will be performed as 
ancillary analyses using ANCOVA with the corresponding value at Baseline included as the only 
covariate. Responder analyses, defined as any improvement in SNOT-22, ACQ-7, and TNSS (Yes 
or No) at Weeks 4 and 8 will be performed as ancillary analyses using the normal approximation 
to the binomial distribution, assuming unequal variances. 
 


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TABLE OF CONTENTS 
1 
INVESTIGATOR’S STATEMENT ............................................................................. 3 
2 
SYNOPSIS .................................................................................................................. 4 
3 
TABLE OF CONTENTS ............................................................................................. 7 
4 
LIST OF ABBREVIATIONS .................................................................................... 10 
5 
INTRODUCTION ..................................................................................................... 12 
5.1 
Background Information ....................................................................................... 12 
5.2 
Stage of Development ........................................................................................... 14 
5.3 
Trial Rationale ....................................................................................................... 14 
5.4 
Dose Rationale ....................................................................................................... 14 
5.5 
Risk-Benefit Assessment ....................................................................................... 15 
6 
STUDY OBJECTIVES & ENDPOINTS .................................................................. 15 
6.1 
Primary Objective .................................................................................................. 15 
6.2 
Secondary Objectives ............................................................................................ 15 
6.3 
Primary Efficacy Endpoint .................................................................................... 16 
6.4 
Secondary Efficacy Endpoints and Other Exploratory Endpoints ........................ 16 
6.4.1 
Second and Exploratory Efficacy Endpoints ..................................................... 16 
6.4.2 
Safety Endpoints ................................................................................................ 16 
7 
STUDY DESCRIPTION ........................................................................................... 17 
7.1 
Study Design ......................................................................................................... 17 
7.2 
Randomization and Blinding Conditions and Methods ......................................... 18 
7.3 
Drugs and Dosages ................................................................................................ 18 
7.4 
Selection of Study Population ............................................................................... 19 
7.4.1 
Inclusion Criteria ............................................................................................... 19 
7.4.2 
Exclusion Criteria .............................................................................................. 20 
7.5 
Concomitant Medications ...................................................................................... 20 
7.6 
Prohibited Medications or Procedures ................................................................... 22 
7.7 
Dietary Requirements ............................................................................................ 22 
8 
STUDY VISITS AND PROCEDURES .................................................................... 23 
8.1 
Overview – Schedule of Time and Events ............................................................ 23 
8.1.1 
Screening Period ................................................................................................ 23 
8.1.2 
Treatment Period ............................................................................................... 25 


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8.1.3 
Post-treatment Period ........................................................................................ 29 
9 
SUBJECT DISCONTINUATION AND STUDY OR SITE TERMINATION ......... 32 
9.1 
Subject Discontinuation ......................................................................................... 32 
9.2 
Study or Site Termination ...................................................................................... 33 
10 
ADVERSE EVENTS................................................................................................. 34 
10.1 
Definitions ............................................................................................................. 34 
10.1.1 
Adverse Event Definitions ................................................................................ 34 
10.1.2 
Adverse Event Assessment Definitions ............................................................. 35 
10.2 
Collection, Recording and Reporting of Adverse Events ...................................... 36 
10.3 
Follow-up of Adverse Events ................................................................................ 36 
11 
STATISTICAL METHODS AND DATA ANALYSIS .............................................. 37 
11.1 
Sample Size Determination ................................................................................... 37 
11.2 
Subject Populations for Analysis ........................................................................... 37 
11.2.1 
Safety Population ............................................................................................... 37 
11.2.2 
Intent-to-Treat Population ................................................................................. 37 
11.2.3 
Per Protocol Population ..................................................................................... 37 
11.3 
Subgroup analysis .................................................................................................. 37 
11.4 
Randomization ....................................................................................................... 38 
11.5 
Methods for Handling Missing Data ..................................................................... 38 
11.6 
Data Analysis Plan ................................................................................................. 38 
11.6.1 
Demographic and Baseline Parameters ............................................................. 38 
11.6.2 
Exposure and Compliance ................................................................................. 38 
11.6.3 
Efficacy Analyses .............................................................................................. 38 
11.6.3.1 
Primary Analysis ............................................................................................ 39 
11.6.3.2 
Analysis of secondary endpoints ................................................................... 39 
11.6.4 
Safety Parameters .............................................................................................. 39 
12 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 40 
12.1 
Confidentiality ....................................................................................................... 40 
12.2 
Source Documents ................................................................................................. 40 
12.3 
Case Report Forms ................................................................................................ 40 
12.4 
Records Retention ................................................................................................. 41 
13 
STUDY MONITORING, AUDITING, AND INSPECTING ................................... 41 
13.1 
Study Monitoring Plan .......................................................................................... 41 


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ETHICAL CONSIDERATIONS ............................................................................... 41 
14.1 
Informed Consent .................................................................................................. 41 
14.2 
Protocol Compliance ............................................................................................. 42 
14.3 
Study Files ............................................................................................................. 42 
15 
REFERENCES .......................................................................................................... 43 
16 
APPENDICES ........................................................................................................... 45 
16.1 
Protection of Human Subjects ............................................................................... 45 
16.1.1 
Basic Elements Of Informed Consent ............................................................... 45 
16.2 
Requisite Documents for Approval of Study Site ................................................. 47 
16.3 
Responsibilities and Obligations of Investigators and Sponsors ........................... 48 
16.3.1 
Sponsor/Study Monitor ..................................................................................... 48 
16.3.2 
Investigator ........................................................................................................ 49 
16.4 
22-item Sino-nasal Outcome Test (SNOT-22)....................................................... 51 
16.5 
PNIFR Methodology ............................................................................................. 53 
16.6 
Total Nasal Symptom Score (TNSS) ..................................................................... 54 
16.7 
Asthma Control Questionnaire – 7 (ACQ-7) ......................................................... 55 
16.8 
Adult Equipotent Daily Doses of Inhaled Glucocorticosteroids ........................... 57 
16.9 
Self-assessment of Treatment (Optional) .............................................................. 58 
 
 


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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
5-LO 
ACQ 
5-Lipoxygenase 
Asthma Control Questionnaire 
AE 
Adverse Event/Experience 
AERD 
Aspirin Exacerbated Respiratory Disease 
ANCOVA 
Analysis of Covariance 
AUC 
Area Under the Curve 
C 
Celsius 
CFB 
Change From Baseline 
CFR 
Code of Federal Regulations 
cm 
Centimeter 
Cmax 
Maximum Plasma Concentration 
COX 
Cyclooxygenase 
CRF 
Case Report Form 
CPI 
Cumberland Pharmaceuticals Inc. 
cysLT 
Cysteinyl Leukotriene 
CysLT1R 
Cysteinyl Leukotriene 1 Receptor 
ER 
Emergency Room 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FeNO 
Fractional exhaled Nitric Oxide 
FEV1 
Forced Expiratory Volume in 1 Second 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product; synonymous with “study drug” 
INR 
International normalized ratio 
IRB 
ITT 
kg 
L 
Institutional Review Board 
Intent-To-Treat 
Kilogram 
Liter 
LTC4 
Leukotriene C4 
LTE4 
Leukotriene E4 
MCID 
Minimal Clinically Important Difference 
MedDRA 
Medical Dictionary for Regulatory Activities  


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Abbreviation 
Definition 
mg 
Milligram 
mL 
Milliliter 
NSAID 
Nonsteroidal Anti-inflammatory Drug 
PD 
Pharmacodynamic 
PG 
Prostaglandin 
PGD2 
Prostaglandin D2 
PNIFR 
PP 
PRN 
Peak Nasal Inspiratory Flow Rate 
Per Protocol 
pro re nata (use when necessary) 
PT 
Prothrombin time 
Ptges 
PGE2 synthase 
QoL 
Quality of Life 
SAE 
Serious Adverse Event/Experience 
SNOT-22 
Sino-nasal Outcome Test-22 
SOC 
System Organ Class 
TBXAS 
Thromboxane A2 synthase 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time of maximum plasma concentration 
TNSS 
Total Nasal Symptom Score 
TPr 
Thromboxane Prostanoid Receptor 
TXA2 
Thromboxane A2 
UPSIT 
University of Pennsylvania Smell Identification Test 


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5 
INTRODUCTION 
This study is to be performed in accordance with the International Conference on Harmonization’s 
(ICH) E6 guideline for Good Clinical Practice (GCP), the ethical principles that have their origin 
in the Declaration of Helsinki, Title 21 of the Code of Federal Regulations (CFR) Parts 50, 56 and 
312. 
5.1 
Background Information 
Ifetroban is a new chemical entity under development by Cumberland Pharmaceuticals Inc. (CPI) 
for aspirin exacerbated respiratory disease (AERD) and other diseases. The current formulation of 
oral ifetroban is a 50 mg capsule. Ifetroban is a well characterized pharmacological antagonist of 
the thromboxane prostanoid receptor (TPr), and has been studied previously in healthy volunteers 
and subjects with cardiovascular diseases. A large safety database exists from this work.  CPI is 
currently studying an intravenous formulation of ifetroban in subjects with hepatorenal syndrome 
and portal hypertension, and the oral formulation in systemic sclerosis. 
AERD affects 7-10% of all asthmatics and ~15% of severe asthmatics (Rajan 2015). AERD is 
characterized clinically by asthma, severe rhinosinusitis with nasal polyposis, tissue eosinophilia, 
and characteristic respiratory reactions to ingestion of aspirin and other nonselective inhibitors of 
cyclooxygenase-1 (COX-1) (White 2012). Biochemically, AERD is marked by over-activity of the 
5-lipoxygenase (5-LO) pathway and high levels of leukotriene E4 (LTE4), the stable end-product 
of cysteinyl leukotriene (cysLT) metabolism (Laidlaw 2012). There is no known cure for AERD, 
but chronic high-dose aspirin therapy is sometimes effective at controlling inflammation as 
measured by improvement in smell scores, decrease in nasal polyp formation, decrease in sinus 
infections/sinus surgery, improvement in asthma outcomes, and decreased need for nasal or 
systemic corticosteroids (Berges-Gimeno 2003). High-dose aspirin therapy does not however 
prevent cysLT production (Nasser 1995), although it has been shown to reduce end-organ reactivity 
to LTE4 (Arm 1989) and nasal mucosal expression of CysLT1R (Sousa 2002). Moreover, 30% of 
subjects find no benefit from high-dose aspirin treatment (Berges-Gimeno 2003).  
Preclinical studies revealed that a murine model of AERD generated by dust mite priming of mice 
lacking PGE2 synthase (Ptges-/- mice) display bronchoconstriction, intrapulmonary platelet and 
mast cell activation, and release prostaglandin D2 (PGD2) and cysLTs from their lungs in response 
to aspirin challenge (Liu 2013). These processes are dramatically attenuated by short-term 
blockade of TPr, or by depletion of platelets. Moreover, longer-term TPr blockade in this model 
significantly suppresses eosinophilic inflammation by modifying endothelial-driven leukocyte 
adhesion (Liu 2012) and lung IL-33 expression. Oral administration of ifetroban is capable of both 
preempting and reversing TPr-induced bronchospasm in rat and guinea pig studies (Schumacher 


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1990a; Schumacher 1990b). These studies suggest that TPr signaling is essential both upstream 
and downstream of the cysLTs, and is involved at multiple steps in AERD pathophysiology. TPr, 
its ligands and cysLTs are critical to a feed-forward network of mediators and cells that perpetuate 
respiratory inflammation, tissue remodeling, end-organ dysfunction, and clinical reactions to 
COX-1 inhibitors that define AERD (Figure 5.1). 
Figure 5.1  
Overview of role of TPr and ligands in AERD Pathogenesis 
 
AERD = Aspirin Exacerbated Respiratory Disease; CysLT = cysteinyl leukotriene 1 receptor; Eos = eosinophil; LTC4 
= leukotriene C4; MC = mast cell; PGD2 = prostaglandin D2; PMN = polymorphonuclear leukocytes; TPr = 
thromboxane prostanoid receptor; TXA2 = thromboxane A2 
In a small placebo-controlled safety study designed to investigate ifetroban 200 mg once daily in 
subjects with a history of AERD prior to and during an aspirin challenge, there were several 
noteworthy trends in favor of the ifetroban group: greater improvements to PNIFR and TNSS, half 
of all initial aspirin-provoked reactions occurred at a higher dose of aspirin, and fewer rescue 
medications were required in response to the aspirin-provoked reaction. The safety results 
demonstrated ifetroban did not cause a respiratory reaction nor did ifetroban worsen symptoms 
during the aspirin challenge compared to placebo. There were no treatment-related adverse events 
reported in the ifetroban group prior to the aspirin challenge. Collectively, these observations in 
both mice and humans suggest the TPr plays a major role in AERD and that blockade of this 
pathway may improve baseline disease control in AERD and blunt the feed-forward loop that 
drives the disease.  


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5.2 
Stage of Development  
CPI-IFE-006 is a randomized, double-blind, placebo-controlled, Phase 2 study to evaluate oral 
ifetroban administered daily for eight weeks in subjects with symptomatic AERD.  
Approximately 76 subjects will be randomized into two treatment groups of 38 subjects per group. 
5.3 
Trial Rationale 
The proposed trial of ifetroban is based on preliminary data from both preclinical models and 
clinical studies supporting the role of TPr as a central mediator and potential therapeutic target in 
AERD. Preclinically, ifetroban blocks all features of the reactions to aspirin in AERD-like Ptges-
/- mice including preventing cysLT and PGD2 generation. PGD2, along with the classical TPr 
agonist, thromboxane A2 (TXA2), may be acting in concert to cause bronchoconstriction and sino-
nasal symptoms in AERD subjects. Clinical studies identified subjects with AERD as having 
elevated levels of TPr-active metabolites in their urine (Bochenek 2003) and these levels increase 
further during an aspirin challenge and correlate with both a decrease in FEV1 and TNSS (Cahill 
2015). Further, expression of both thromboxane A2 synthase (TBXAS) and TPr are markedly 
elevated in nasal polyps from subjects with AERD thus potentially driving the effects of TXA2 
and TPr within the feed-forward loop (unpublished). 
Ifetroban is under development as a potential novel treatment for AERD. CPI-IFE-006 is a proof-
of-concept Phase 2 study designed to investigate the effect of eight weeks of 200 mg daily, oral 
ifetroban-mediated TPr inhibition in symptomatic AERD subjects.  
5.4 
Dose Rationale 
Oral ifetroban doses ≥ 100 mg have been shown to inhibit TPr induced platelet aggregation, with 
corresponding plasma Cmax levels of > 500 ng/mL. The bioavailability of oral ifetroban capsules 
has previously been found to be ≈ 42%. Our recent safety study in subjects with a history of AERD 
found oral ifetroban at 200 mg daily to be safe and well tolerated. There were no respiratory 
reactions or symptoms caused by ifetroban alone and no worsening of symptoms seen in the 
ifetroban group compared to the placebo group during the aspirin challenge. These data, taken 
together with the safety data of doses up to 500 mg, support a 200 mg oral ifetroban dose for use 
in this study. A placebo treatment arm will be included in this study to help provide data on the 
spontaneous response rate in symptomatic AERD. 


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5.5 
Risk-Benefit Assessment 
Ifetroban prevents TPr ligand binding and activation which plays a key role in the pathophysiology 
of AERD. Phase 2a data in AERD demonstrated a signal of efficacy for ifetroban compared to 
placebo with improvements seen in PNIFR and TNSS both before and during the aspirin challenge, 
higher provoking doses of aspirin and fewer rescue medications. While the aim of the Phase 2a 
study was safety, these encouraging trends provide a compelling case to further evaluate whether 
ifetroban will provide a benefit to subjects with AERD. This subsequent Phase 2 study aims to 
explore this signal in symptomatic AERD subjects in the absence of an aspirin challenge. The 
anticipated risks associated with the administration of oral ifetroban are well understood given the 
mechanism of action and its current safety database comprised of over 1,300 subjects. Based upon 
the current available data for ifetroban and the review of the data by an independent data 
monitoring committee, no important identified risks have been established. There is a potential 
risk based on the mechanism of action that treatment with a TPr antagonist may inhibit platelet 
function and thereby increase the risk of bleeding in AERD subjects. Although our Phase 2a study 
in subjects with a history of AERD did not demonstrate any abnormal laboratory findings or 
bleeding events, clinical laboratory results will be monitored for possible abnormalities related to 
clotting or bleeding in all study subjects.  
Given the preclinical and clinical data, there is a potential benefit to study subjects randomized to 
the ifetroban arm to experience a reduction in the incidence and severity of respiratory reactions. 
If TPr antagonism does indeed provide symptom control and improve the quality of life (QoL) for 
subjects with AERD, it would support the use of ifetroban as a therapeutic agent. As such, the 
potential risk to subjects seems reasonable compared to the potential benefit. 
6 
STUDY OBJECTIVES & ENDPOINTS 
6.1 
Primary Objective 
To determine the therapeutic efficacy of ifetroban to improve sino-nasal symptoms and QoL in the 
treatment of AERD. 
6.2 
Secondary Objectives 
To evaluate ifetroban in symptomatic AERD subjects with regards to: pulmonary function, subject-
reported outcomes and QoL scales, pharmacodynamics responses based on TPr blockade, 
frequency and severity of exacerbations, sinus infections and the use of rescue medications and 
antibiotics. 


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6.3 
Primary Efficacy Endpoint 
The primary endpoint of the study is the Change From Baseline (CFB) at Week 8 in SNOT-22 
score (see Section 16.4). The primary analysis will compare this outcome for each study subject 
after treatment with ifetroban compared to placebo. The SNOT-22 is a validated questionnaire to 
assess the impact of chronic rhinosinusitis (CRS) on QoL. This 22-item outcome measure on a 5-
category scale is applicable to sino-nasal conditions and surgical treatments. The score ranges from 
0 to 110. Higher total scores on the SNOT-22 imply a greater impact of CRS on QoL. The 
questionnaire was found easy to use with a time to completion of seven minutes and provided good 
discriminant validity (Hopkins 2009). The SNOT-22 was validated and recommended for routine 
clinical practice. The Minimal Clinically Important Difference (MCID) is ≥ 8.90. 
6.4 
Secondary Efficacy Endpoints and Other Exploratory Endpoints 
6.4.1 
Second and Exploratory Efficacy Endpoints 
• Subject reported symptoms: 
− Asthma Control Questionnaire (ACQ-7) 
− Total Nasal Symptom Score (TNSS) 
• FEV1 and peak Nasal Inspiratory Flow Rate (PNIFR) 
• University of Pennsylvania Smell Identification test (UPSIT) 
• Frequency and severity of asthma exacerbations and chronic sinusitis 
• Use of rescue medication and antibiotic use 
• Urinary leukotriene E4 and PG metabolite levels 
• Serum leukotriene B4 levels 
• Blood eosinophil count 
• Fractional exhaled Nitric oxide (FeNO) 
• Nasal epithelial, urinary and plasma eicosanoid levels 
6.4.2 
Safety Endpoints 
The same safety endpoints will be applied across all study subjects. These include adverse 
events, vital signs, physical exams and clinical laboratory tests. 


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7 
STUDY DESCRIPTION 
7.1 
Study Design 
CPI-IFE-006 is a randomized, double-blind, placebo-controlled Phase 2 study to evaluate oral 
ifetroban administered daily for eight weeks in symptomatic AERD subjects.  
Approximately 76 subjects will be randomized into two treatment groups of 38 subjects per group. 
The clinical study will be conducted with 3 periods: 
• Screening period of up to three weeks 
• Randomized ifetroban/placebo treatment period of eight weeks 
• Post-treatment period for safety and efficacy of two weeks 
Figure 7-1 
Study Design 
 
ACQ = Asthma Control Questionnaire; FeNO = Fractional exhaled nitric oxide; FEV1 = forced expiratory volume in 
one second; PBO = placebo; PD = pharmacodynamic; PNIFR = peak Nasal Inspiratory Flow Rate; SNOT = Sino-
nasal Outcome Test; TNSS = Total Nasal Symptom Score; UPSIT = Smell Identification Test 


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The total duration of the study participation for each subject is up to 13 weeks. Recruitment is 
planned to stop when approximately 76 subjects are randomized. The end of the study is defined 
as the last subject’s last visit/contact. 
7.2 
Randomization and Blinding Conditions and Methods 
Subjects who meet all the inclusion and no exclusion criteria during the Screening/Baseline Period 
will be randomized using a 1:1 randomization ratio to receive either ifetroban 200 mg daily or 
placebo. A central randomization will be utilized. Approximately 76 subjects shall be randomized 
to ensure at least 38 subjects per group will be analyzed for efficacy.  
The study will be double blind with respect to the treatment assignment. To maintain the study 
blind, the appearance of packaging and capsules will be identical in both study arms. Site and CPI 
clinical staff will be blinded to the treatment assignment until the completion of the study. 
Individual treatment assignment will remain blinded throughout the study. In the event a treatment 
assignment needs to be unblinded for safety reasons, the site principal investigator will notify the 
study project manager, who will consult with the medical monitor. The medical monitor will 
review the circumstances and grant approval as indicated. Any intentional or unintentional 
breaking of the blind should be reported to the Sponsor immediately and fully documented in the 
subject’s case report form.  
7.3 
Drugs and Dosages 
Oral ifetroban is available as the sodium salt of the free acid and is for investigational use only. 
The drug is supplied as a capsule dosage form (size # 1, white opaque) for oral administration. 
Ifetroban capsules are formulated as a dry powder blend and filled into hard gelatin capsules.  The 
formulation consists of ifetroban, mannitol, microcrystalline cellulose, crospovidone, magnesium 
oxide, colloidal silicon dioxide, and magnesium stearate.  Capsules are filled into high density 
polyethylene bottles and sealed with screw-cap closures.  Capsules are only available at one 
strength of the sodium salt, i.e., 52.5 mg corresponding to a free-acid dose of 50 mg.  
Matching placebo capsules are formulated as a dry powder blend filled into capsules.  The 
formulation consists of microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and 
magnesium stearate. Capsules are filled into high density polyethylene bottles and sealed with 
screw-cap closures. 
The bottles of oral Ifetroban or placebo will contain the following information on the label:  


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Additionally, each individual bottle will be labelled with a unique numeric code that identifies the 
contents to the unblinded sponsor representative.  Four (4) capsules each of IMP (oral ifetroban or 
matching placebo) will be taken by mouth per daily dose during the Treatment Period. 
7.4 
Selection of Study Population 
Study eligibility will be determined by the Investigator based on the inclusion and exclusion 
criteria below. 
7.4.1 
Inclusion Criteria 
Individuals who meet all of the following criteria are eligible for enrollment as study subjects: 
1. History of physician-diagnosed asthma 
2. History of nasal polyposis 
3. History of at least two reactions to oral aspirin or other nonselective cyclooxygenase 
inhibitor with features of lower airway involvement (cough, chest tightness, wheezing, 
dyspnea) or one reaction that was life-threatening and required hospitalization, or diagnosis 
of AERD via a physician-conducted challenge to aspirin in the last five years before 
starting treatment 
4. Stable asthma (post-bronchodilator FEV1 of ≥ 60%, no glucocorticoid burst for at least 
two weeks prior to starting treatment, no hospitalizations or emergency room visits for 
asthma at least three months prior to starting treatment and not on a dose >1000 µg 
fluticasone or equivalent daily). 
5. ≥ 18 years of age 
6. Exhibit symptomatic AERD within three weeks of starting treatment by demonstrating a 
score of at least 20 on the SNOT - 22 
PLACEBO OR IFETROBAN CAPSULES 50MG 
Quantity: 75 Capsules 
Instruction: Take capsules by mouth as directed. 
Store at controlled room temperature, 20oC – 25oC (68oF – 77oF) 
Caution: New Drug-Limited by Federal law to investigational use 
Cumberland Pharmaceuticals Inc. 


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7.4.2 
Exclusion Criteria 
Individuals who meet any of these criteria are not eligible for enrollment as study subjects: 
1. Current smoking, defined as daily tobacco smoking in the last six months and at least one 
instance of tobacco smoking in the last three months 
2. Current pregnancy or breastfeeding 
3. Use of oral or systemic steroids (e.g. prednisone or equivalent) > 20 mg daily in the last 
four weeks before starting treatment 
4. Daily use of long-acting antihistamines in the last two weeks before starting treatment 
5. Less than 12 months of allergy shots (maintenance dose of allergy shots are allowed if 
treatment duration exceeds 12 months). Less than 1 month of 5-lipoxygenase inhibitors 
(e.g. zileuton) and/or leukotriene receptor antagonists (e.g. montelukast). 
6. Any use of nonsteroidal anti-inflammatory drugs (NSAIDs) or any drug that inhibits the 
cyclooxygenase enzyme in the last two weeks before starting treatment 
7. History of bleeding diathesis or use of anticoagulant or antiplatelet drugs in the last 2 weeks 
before starting treatment 
8. Any immunosuppressive treatment including but not limited to methotrexate, cyclosporine, 
mycophenolate, tacrolimus, gold, penicillamine, sulfasalazine, hydroxychloroquine, 
azathioprine and cyclophosphamide in the last two weeks before starting treatment 
(maintenance dose of allergy shots are allowed if treatment duration exceeds 12 months). 
Biologics/immunotherapies such as Xolair or Nucala are permitted if duration exceeds 
three months. 
9. Endoscopic sinus surgery / polypectomy within the past three months 
10. Previously treated in any clinical trial with ifetroban 
11. Previously treated with other investigational drugs within eight weeks or five half-lives, 
whichever is longer, before screening 
12. Conditions/concomitant disease which make the participant unevaluable for the efficacy 
endpoints 
7.5 
Concomitant Medications 
A concomitant medication is any treatment received by the subject concomitantly to the IMP. All 
concomitant medication use will be tracked in the subject diary and recorded in the 


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appropriate Case Report Form (CRF).  All subjects must be protected by one of the following 
acceptable forms of effective contraception during the study: 
- Established use of oral, injected or implanted hormonal contraceptive 
- "Double barrier" methods (i.e., Double Intrauterine device with copper or intrauterine 
system with progestogen and barrier contraceptive [condom, diaphragm or cervical/vault 
caps] used with spermicide [foam, gel, film, cream or suppository]) 
- Female sterilization (e.g., tubal occlusion, hysterectomy or bilateral salpingectomy) 
- Male sterilization with post-vasectomy documentation of the absence of sperm in the 
ejaculate; for female subjects enrolled in the study, the vasectomized male partner should be 
the sole partner for that subject 
The following concomitant medications are allowed.  
a. Inhaled, oral or nasal corticosteroids: subjects on a stable dose ≥ 30 day prior to starting 
IMP.  Use of oral or systemic steroids (e.g. prednisone or equivalent) must be at a stable 
dose ≤ 20 mg daily. Modifications are allowed if symptoms require a change in dose or 
frequency. All use must be tracked in the subject diary and recorded in the appropriate CRF. 
b. Inhaled long-acting beta-adrenergic agonists and anti-muscarinic receptor antagonists: 
subjects may enter the trial on such medications based on the underlying condition. 
Modifications are allowed if symptoms require a change in dose or frequency. All use must 
be tracked in the subject diary and recorded in the appropriate CRF. 
c. Inhaled short-acting beta-adrenergic agonists (PRN use): subjects may enter the trial on 
such medications based on the underlying condition.  All use must be tracked in the subject 
diary and recorded in the appropriate CRF. 
d. Nasal budesonide rinses 
e. Short-term use of antibiotics (< 2 weeks) 
f. Daily use of long-acting antihistamines are prohibited two weeks before starting treatment 
however subjects may administer such medications on an as-needed basis only based on 
the underlying condition. All use must be tracked in the subject diary and recorded in the 
appropriate CRF.  
g. Maintenance dose of allergy shots if treatment duration exceeds 12 months 


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h. Use of 5-lipoxygenase inhibitors (e.g. zileuton) and leukotriene receptor antagonists (e.g. 
montelukast) if subjects are on a stable dose for ≥ 30 days. 
i. Use of biologics/immunotherapies such as Xolair or Nucala if subjects are on a stable dose 
for ≥ three months. 
7.6 
Prohibited Medications or Procedures 
Before randomization, a medication history will be collected for each subject to ensure that no 
prohibited medications and procedures will be taken during the study. The following medications 
and procedures are prohibited during the screening, treatment and post-treatment periods: 
• Use of oral or systemic steroids (e.g. prednisone or equivalent)  > 20 mg daily in the last 
four weeks before starting treatment 
• Daily use of long-acting antihistaminesin the last two weeks before starting treatment. 
Please note: daily use of long-acting antihistamines is prohibited however subjects may 
administer such medications on an as-needed basis only based on the underlying 
condition. All use must be tracked in the subject diary and recorded in the appropriate CRF.  
• Any use of nonsteroidal anti-inflammatory drugs (NSAIDs) or any drug that inhibits the 
cyclooxygenase enzyme in the last two weeks before starting treatment 
• Use of warfarin or any other antiplatelet or anticoagulant medications in the last two weeks 
before starting treatment 
• Long-term use of systemic antibiotics (> 2 weeks) 
• Any immunosuppressive treatment including but not limited to methotrexate, cyclosporine, 
mycophenolate, tacrolimus, gold, penicillamine, sulfasalazine, hydroxychloroquine, 
azathioprine and cyclophosphamide (maintenance dose of allergy shots are allowed if  
treatment duration exceeds 12 months). Biologics/immunotherapies such as Xolair or 
Nucala are permitted if duration exceeds three months. 
• Endoscopic sinus surgery / polypectomy within the past three months prior to starting 
treatment 
7.7 
Dietary Requirements 
Multiple food effect studies have demonstrated that high fat, protein or carbohydrate meals all had 
a similar effect of decreasing the maximum serum concentration (Cmax) (average of 80-90%), 


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prolonging the time of maximum plasma concentration (Tmax) (8-12 fold), and decreasing the area 
under the concentration time-curves from time zero to infinity (AUC0-∞) of ifetroban (average of 
25-35%) compared to the fasting state.  
For this reason, ifetroban and placebo should be taken at least 30 minutes before a meal or six 
hours after a meal.   
8 
STUDY VISITS AND PROCEDURES 
8.1 
Overview – Schedule of Time and Events 
This 13-Week study will consist of a three-week Screening Period (Week -3 to Week 0), an 8-week 
Treatment Period (Week 0 to Week 8) and a two-week Post-treatment Period (Week 8 to Week 10). 
The study visits occur on the planned dates relative to the first dose of IMP as scheduled. The visit 
schedule should be adhered to within the ± 5 day visit window. 
If a subject 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 one site visit if necessary, as long as the 
three-week screening period relative to the first dose of IMP is respected. Subjects 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 one additional time. 
8.1.1 
Screening Period 
The Screening Period is defined as the three-week period prior to Week 0 (IMP administration). 
Before the initiation of study-specific screening assessments, the subject must be given a complete 
explanation of the purpose of the study and evaluations that will be made as part of the study. 
Subsequently, the subject must sign and receive a copy of an Informed Consent Form that was 
approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC). Once 
informed consent has been obtained, the eligibility of the subject to participate in this study will 
be determined by the Investigator on the basis of the inclusion and exclusion criteria in Section 
7.4. Screening Period assessments will also be performed to determine eligibility. Only eligible 
subjects will be randomized to receive IMP at Week 0. 


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Following a discussion of participation in the clinical study and signed informed consent obtained, 
the following procedures will be performed to determine the subject’s eligibility for this study 
(Table 8–1) during the Screening Period (Week -3 to Week 0): 
• Informed Consent 
• Interview to collect subject medical history, including but not limited to, disease history 
(including asthma history, number of asthma exacerbations in the previous year, 
hypersensitivity to aspirin or other NSAIDs), surgical history (including the number and 
dates of previous nasal polypectomies), recently discontinued and concomitant 
medications (include all background therapy for AERD). 
• Demographic data 
• Administer SNOT-22. 
• Perform spirometry to ensure the subject has stable asthma (FEV1 ≥ 60% of predicted 
normal and has not experienced any exacerbation requiring treatment with ≥ 1 systemic 
(oral or parenteral) steroid bursts for worsening asthma and/or hospitalization or an 
emergency/urgent medical care visit for worsening asthma in the previous three months or 
are on a dose of inhaled corticosteroids > 1000 µg fluticasone or equivalent daily). 
• Obtain fasting blood samples for screening clinical laboratory determinations: 
o Hematology: To include hemoglobin, hematocrit, platelet count, total white blood 
cell count with five-part differential count, and total red blood cell count. 
o Serum chemistry: To include creatinine, blood urea nitrogen, glucose, uric acid, 
total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, 
chloride), bicarbonate, and creatine phosphokinase. 
o Prothrombin time (PT) and international normalized ratio (INR) 
• Review entry criteria to assess eligibility with special attention to verify the following: 
o History of at least two reactions to oral aspirin or other nonselective 
cyclooxygenase inhibitor with features of lower airway involvement (cough, chest 
tightness, wheezing, dyspnea) or one reaction that was life-threatening and required 


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hospitalization, or diagnosis of AERD via a physician-conducted challenge to 
aspirin in the last five years before starting treatment 
o Use of oral or systemic steroids (e.g. prednisone or equivalent) > 20 mg daily in the 
last four weeks before starting treatment, daily use of long-acting antihistamines in 
the last two weeks before starting treatment. Subjects on 5-lipoxygenase inhibitors 
(e.g. zileuton) and/or leukotriene receptor antagonists (e.g. montelukast) must be 
on a stable dose for ≥ 30 days before starting treatment. No NSAID, anticoagulants 
and immunosuppressive medication use is allowed. 
o Presence of a score of at least 20 on the SNOT - 22 
• Perform physical examination including vital signs [blood pressure, heart rate, respiration 
rate, body temperature, weight (kg), height (cm)] 
• Obtain pregnancy test if female of child-bearing potential (pre-menopausal female 
biologically capable of becoming pregnant). Confirm subject is protected by one of the 
following acceptable forms of effective contraception during the study: 
- Established use of oral, injected or implanted hormonal contraceptive 
- "Double barrier" methods (i.e., Double Intrauterine device with copper or intrauterine 
system with progestogen and barrier contraceptive [condom, diaphragm or cervical/vault 
caps] used with spermicide [foam, gel, film, cream or suppository]) 
- Female sterilization (e.g., tubal occlusion, hysterectomy or bilateral salpingectomy) 
- Male sterilization with post-vasectomy documentation of the absence of sperm in the 
ejaculate; for female subjects enrolled in the study, the vasectomized male partner should 
be the sole partner for that subject 
• Dispense subject diary, provide instructions for daily use and remind subject to bring it to 
the next visit. 
• Schedule appointment for next visit 
8.1.2 
Treatment Period 
Week 0 Start of Treatment Visit – Randomization 
After the three-week Screening Period, subjects will come into the site for Week 0 Visit. 
• Interval history, record baseline signs and symptoms, record all medication use with start 
date and dose and check for prohibited medications. 


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• Perform a limited physical exam with vital signs (blood pressure, heart rate, respiration 
rate, body temperature, weight) 
• Administer TNSS, ACQ-7, and SNOT-22 
• Obtain spirometry result and record in the electronic CRF (eCRF) 
• Reconfirm eligibility based on review of Inclusion/Exclusion criteria 
A subject will be considered to have failed screening if entry criteria are not met and should be 
discontinued. 
If the subject meets all inclusion and does not meet any exclusion criteria: 
• Subject will be randomized 
• PNIFR and FeNO will be recorded 
• Perform serum/urine pregnancy test (for women of childbearing potential). Confirm 
subject is protected by one of the following acceptable forms of effective contraception 
during the study: 
- Established use of oral, injected or implanted hormonal contraceptive 
- "Double barrier" methods (i.e., Double Intrauterine device with copper or intrauterine 
system with progestogen and barrier contraceptive [condom, diaphragm or cervical/vault 
caps] used with spermicide [foam, gel, film, cream or suppository]) 
- Female sterilization (e.g., tubal occlusion, hysterectomy or bilateral salpingectomy) 
- Male sterilization with post-vasectomy documentation of the absence of sperm in the 
ejaculate; for female subjects enrolled in the study, the vasectomized male partner should 
be the sole partner for that subject 
• Perform blood sampling (prior to administration of IMP) for clinical laboratories: 
hematology, chemistry, PT, and INR. 
Note: Clinical laboratory testing at Week 0 Visit is limited to biomarkers in serum and plasma if 
screening labs were performed within three weeks of starting IMP treatment. 
• Collect urine and blood samples for eicosanoid metabolites.  
• Collect nasoabsorptive matrix for eicosanoid measurements. 


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• Conduct a smell test (UPSIT) 
• Collect data from subject diary and remind subject to record daily medication usage 
including IMP, exacerbations, rescue medication or antibiotic usage, if applicable, twice 
daily TNSS (AM and PM) and to bring their diary to the next visit 
• Pre-IMP Dietary Assessment 
• Dispense IMP and administer IMP 
• Commence AE reporting 
• Schedule appointment for next visit 
Treatment Period (Week 0 to Week 8):   Subjects will take ifetroban or placebo daily for eight 
weeks. There will be a telephone encounter one week into this Treatment Period to ensure safety 
and confirm that baseline asthma symptoms have not worsened. 
Week 4 Treatment Visit  
After four weeks of treatment, subjects will return to the site for Week 4 Treatment Visit. 
• Record all medication use with start date and dose and check for prohibited medications. 
• Inquire about AEs/Serious Adverse Events (SAEs) and IMP tolerability 
• Perform a limited physical exam with vital signs (blood pressure, heart rate, respiration 
rate, body temperature, weight) 
• Administer TNSS, ACQ-7, and SNOT-22 
• Obtain spirometry, PNIFR and FeNO  
• Perform serum/urine pregnancy test (for women of childbearing potential) Confirm subject 
is protected by one of the following acceptable forms of effective contraception during the 
study: 
- Established use of oral, injected or implanted hormonal contraceptive 
- "Double barrier" methods (i.e., Double Intrauterine device with copper or intrauterine 
system with progestogen and barrier contraceptive [condom, diaphragm or cervical/vault 
caps] used with spermicide [foam, gel, film, cream or suppository]) 


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- Female sterilization (e.g., tubal occlusion, hysterectomy or bilateral salpingectomy) 
- Male sterilization with post-vasectomy documentation of the absence of sperm in the 
ejaculate; for female subjects enrolled in the study, the vasectomized male partner should 
be the sole partner for that subject 
• Collect urine and blood samples for eicosanoid metabolites.  
• Collect nasoabsorptive matrix for eicosanoid measurements. 
• Conduct a smell test (UPSIT) 
• Review subject diary for IMP compliance, content and completeness; collect data from 
subject diary and remind subject to continue recording daily medication usage including 
IMP, time of meals and doses, exacerbations, rescue medication or antibiotic usage (if 
applicable), twice daily TNSS (AM and PM) and to bring their diary to the next visit 
• Dispense IMP and administer IMP 
• Schedule appointment for next visit 
Week 8 End of Treatment Visit  
After four additional weeks of treatment, subjects will return to the site for Week 8 End of 
Treatment Visit. 
• Record all medication use with start date and dose and check for prohibited medications. 
• Inquire about AEs/SAEs and IMP tolerability 
• Perform a limited physical exam with vital signs (blood pressure, heart rate, respiration 
rate, body temperature, weight) 
• Administer TNSS, ACQ-7, and SNOT-22 
• Obtain spirometry, PNIFR and FeNO  
• Perform serum/urine pregnancy test (for women of childbearing potential). Confirm 
subject is protected by one of the following acceptable forms of effective contraception 
during the study: 
- Established use of oral, injected or implanted hormonal contraceptive 


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- "Double barrier" methods (i.e., Double Intrauterine device with copper or intrauterine 
system with progestogen and barrier contraceptive [condom, diaphragm or cervical/vault 
caps] used with spermicide [foam, gel, film, cream or suppository]) 
- Female sterilization (e.g., tubal occlusion, hysterectomy or bilateral salpingectomy) 
- Male sterilization with post-vasectomy documentation of the absence of sperm in the 
ejaculate; for female subjects enrolled in the study, the vasectomized male partner should 
be the sole partner for that subject 
• Perform blood sampling for clinical laboratories: hematology, chemistry, PT, and INR. 
• Collect urine and blood samples for eicosanoid metabolites.  
• Collect nasoabsorptive matrix for eicosanoid measurements. 
• Conduct a smell test (UPSIT) 
• Review subject diary for IMP compliance, content and completeness; collect data from 
subject diary and remind subject to continue recording daily medication usage, time of 
meals and doses, exacerbations, rescue medication or antibiotic usage (if applicable), twice 
daily TNSS (AM and PM) and to bring their diary to the next visit 
• Schedule appointment for next visit 
8.1.3 
Post-treatment Period 
After two weeks post-treatment, subjects will return to the site for Week 10 Post-treatment Visit. 
• Record all medication use with start date and dose and check for prohibited medications. 
• Inquire about AEs/SAEs  
• Perform a limited physical exam with vital signs (blood pressure, heart rate, respiration 
rate, body temperature, weight) 
• Administer TNSS, ACQ-7, and SNOT-22 
• Obtain spirometry, PNIFR and FeNO  
• Perform blood sampling for clinical laboratories if abnormal at Week 8 only: 
hematology, chemistry, PT, and INR. 


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• Collect urine and blood samples for eicosanoid metabolites.  
• Collect nasoabsorptive matrix for eicosanoid measurements. 
• Conduct a smell test (UPSIT) 
• Review subject diary for content and completeness; collect data from subject diary  
• 
Propose the optional qualitative self-assessment of the treatment to the subject 


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Table 8–1 
Schedule of Treatment & Events 
  
Screening Period 
Treatment Period 
Post-treatment 
Period 
  
Visit(s)  
Visit 
Phone 
Call 
Visit  
Visit 
Visit  
  
Week -3 to Week 0 
Week 0 
Week 1 
Week 4 
(± 5 days) 
Week 8 
(± 5 days) 
Week 10 
(± 5 days) 
Informed Consent 
X 
  
 
  
  
  
Inclusion/Exclusion Criteria 
X 
  
 
  
  
  
Medical & Surgical History 
X 
  
 
  
  
  
Subject Demography 
X 
  
 
  
  
  
Physical Exam with vital signs 
X 
 
 
 
 
 
Limited Physical Exam with vital signs 
 
X 
 
X 
X 
 X 
Spirometry (FEV1) 
 X 
X 
 
X  
X 
 X 
PNIFR and FeNO 
  
X 
 
X 
X 
 X 
Pregnancy Test (Serum/Urine)a  
 X 
X 
 
 X 
X 
 X 
Hematologyb 
 X 
Xd 
 
 
X 
  Xe 
PT, INR, Chemistryc 
 X 
Xd 
 
 
X 
 Xe 
SNOT-22, TNSS, ACQ-7 
 Xf 
X 
 
X 
X 
X 
Smell test (UPSIT) 
  
X 
 
X 
X 
X 
Collect urine & blood for eicosanoid levels 
 
X 
 
X 
X 
X 
Collect nasoabsorptive matrix for eicosanoid 
levels 
  
X 
 
X 
X 
X 
Self-assessment of the treatment (optional) 
  
 
 
 
X 
  
Dispense IMP 
  
X 
 
X 
 
  
IMP Dosing 
  
I------------Continual Once Daily Dosing (200 mg/day)---------I 
  
Record Concomitant Medications 
I-----------------------------------------------------------------Continual---------------------------------------------------------I 
AE/SAE Recording (if any) 
  
I-------------------------------------------Continual--------------------------------------------------I 
Dispense, review and/or collect subject diary 
 
X 
 
X 
X 
 X 
a) For women of childbearing potential; b) Hemoglobin, hematocrit, platelet count, total white blood cell count with five-part differential count, and total red blood cell count; c) Creatinine, 
blood urea nitrogen, glucose, uric acid, total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes 
(sodium, potassium, chloride), bicarbonate, and creatine phosphokinase; d) Week 0 hematology, chemistry, PT and INR do not have to be repeated if Screening labs were performed within 
3 weeks of starting IMP; e) Week 10 hematology, chemistry, PT and INR only performed for abnormal labs at Week 8; f) SNOT-22 only at Screening; All 3 questionnaires are required at 
subsequent visits. 
ACQ-7 = Asthma Control Questionnaire; AE = adverse event; FEV1 = Forced Expiratory Volume in 1 Second; FeNO = Fractional exhaled Nitric oxide; IMP = Investigational Medicinal 
Product; INR = international normalized ratio; PNIFR = Peak Nasal Inspiratory Flow Rate; PT = prothrombin time; SAE = serious adverse event; SNOT = Sino-nasal Outcome Test; TNSS 
= Total Nasal Symptom Score; UPSIT = Smell Identification Test 
 
 


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9 
SUBJECT 
DISCONTINUATION 
AND 
STUDY 
OR 
SITE 
TERMINATION 
9.1 
Subject Discontinuation 
Subjects will be encouraged to complete the study; however, they may voluntarily withdraw at any 
time.  The Investigator will provide a report in the CRF describing the reason for discontinuation.  
If a subject withdraws before completion, every effort should be made to complete the assessments 
scheduled during the final scheduled assessment.     
A subject may be terminated early from the study for the following reasons: 
• The subject elects to withdraw consent from all future study activities, including follow-
up. 
• The subject is “lost to follow-up” (i.e., no further follow-up is possible because attempts to 
reestablish contact with the participant have failed). 
• The subject dies. 
• The subject develops a medical condition or is started on new medication(s) prohibited by 
the study or 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 subject’s ability to comply with study requirements or that may impact 
the quality of the data obtained from the study. 
• If, in the course of an asthma exacerbation, a study investigator decides to discontinue 
study medication (ifetroban/placebo), the subject will be withdrawn from the study. 
• In addition, subjects must be withdrawn from the study if any of the following occur:  
o Any serious adverse event related to study medication (ifetroban/placebo or aspirin) 
or to a study procedure  
o Serious arrhythmia requiring therapy  
o Thrombocytopenia < 50 x 109/L 
o Anemia (a fall in baseline hemoglobin of 10% or more) 
o Gastrointestinal bleeding 


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o Pregnancy 
Subjects 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 
Independent Safety Monitor, the CPI Director of Medical Affairs and the Principal Investigator 
determine that the follow-up is complete. 
Subjects with early termination from this study will not be replaced. 
9.2 
Study or Site Termination 
If the Sponsor, Investigator, Independent Safety Monitor, Study Monitor, or appropriate regulatory 
officials discover conditions arising during the study that indicate that the study should be halted 
or that the study center should be terminated, this action may be taken after appropriate 
consultation among the Sponsor, Investigator, Independent Safety Monitor, and Study Monitor.   
Conditions that may warrant termination of the study include, but are not limited to, the following: 
• The discovery of an unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study 
• A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product 
• A study conducted at a single study site or a single study site in a multicenter study may 
also warrant termination under the following conditions: 
o Failure of the Investigator to enroll subjects into the study at an acceptable rate 
o Failure of the Investigator to comply with pertinent regulations of appropriate 
regulatory authorities 
o Submission of knowingly false information from the research facility to the 
Sponsor, Study Monitor, or appropriate regulatory authority 
o Insufficient adherence to protocol requirements 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
the International Conference on Harmonization (ICH) sixth efficacy publication (E6) on Good 
Clinical Practice, section 4.12, ICH E6 4.13, ICH E6 5.20, and ICH E6 5.21. 


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10 
ADVERSE EVENTS 
Adverse events will be captured in the CRF for this study.   
10.1 
Definitions 
10.1.1 
Adverse Event Definitions 
Adverse events are defined according to ICH Harmonized Tripartite Guideline E2A and 21 CFR 
312.32. 
Adverse event (AE) – is any untoward medical occurrence in a subject or clinical trial subject 
administered a trial product and which does not necessarily have a causal relationship with this 
treatment.  
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
The following is not considered or documented as an AE in study records: 
• Pre-planned procedure (documented as concomitant illness on the CRF at screening) unless 
the condition for which the procedure was planned has worsened from the first trial-related 
activity after the subject has signed the informed consent form. 
• Pre-existing conditions found as a result of screening procedures unless the condition 
worsens during treatment. 
• Events which are pre-defined as part of the efficacy analysis. However, if events are serious 
as defined below, events must be reported as such. 
Serious adverse event (SAE) – is any untoward medical occurrence or effect that at any dose: 
results in death; is life-threatening (this refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have caused death 
if it was more severe); requires in-subject hospitalization or prolongation of existing 
hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly 
or birth defect; is judged medically important (this refers to an event that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed). 


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10.1.2 
Adverse Event Assessment Definitions 
Severity 
The maximum severity of an adverse event is assessed by the investigator using the following 
definitions:  
• Mild: Transient symptoms, no interference with the subject’s daily activities. 
• Moderate: Marked symptoms, moderate interference with the subject’s daily activities. 
• Severe: Considerable interference with the subject’s daily activities, unacceptable. 
Relationship 
The causal relationship between an adverse event and the trial product is assessed by the 
investigator using the following definitions: 
• Probable: Good reasons and sufficient documentation to assume a causal relationship. 
• Possible: A causal relationship is conceivable and cannot be dismissed  
• Unlikely: The event is most likely related to an etiology other than the trial product. 
An adverse event is considered causally related to the use of the trial product when the relationship 
assessment is probable or possible. Events assessed as unlikely related to the use of trial product 
will generally be considered as having no relationship to treatment. 
Outcome 
The outcome of an adverse event is assessed by the investigator using the following definitions: 
• Recovered: Fully recovered, or by medical or surgical treatment the condition has returned 
to the level observed at the first trial-related activity. 
• Recovering: The condition is improving and the subject is expected to recover from the 
event. This term should only be used when the subject has completed the trial. 
• Recovered with sequelae: As a result of the AE the subject suffered persistent and 
significant disability/incapacity (e.g. became blind, deaf, paralyzed). Any AE recovered 
with sequelae should be classified as SAE.   
• Not recovered: The subject’s condition has not improved and the symptoms are unchanged 


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• Fatal 
• Unknown: The subject’s condition is unknown. This term should only be used when no 
other definition is possible (e.g. the subject is lost to follow-up). 
10.2 
Collection, Recording and Reporting of Adverse Events 
For this study, all events meeting the definition of an adverse event must be collected and reported 
from the first trial-related activity after the subject signs the informed consent and until end of 
post-treatment period.  
The investigator should record the diagnosis, if available. If no diagnosis is available the 
investigator should record each sign and symptom as individual adverse events. 
The investigator must report initial information on all serious adverse events within 24 hours of 
obtaining knowledge of the event. Furthermore, the investigator must complete the SAE forms 
within five days of obtaining knowledge of the SAE. The monitor must be informed accordingly. 
The investigator must inform the IRB in accordance with local requirements in force and the ICH 
guidelines for GCP and the Food and Drug Administration (FDA) Title 21 Code of Federal 
Regulations, Part 312.32. 
10.3 
Follow-up of Adverse Events 
All adverse events classified as non-serious adverse events that are both classified as severe and 
possibly or probably related to the investigational medicinal product must be followed until the 
subject has recovered and all queries have been resolved. 
For cases of chronic conditions, follow-up until “recovered” is not required. After the subject has 
completed the trial, these cases can be closed with the outcome “recovering” or “not recovered”. 
All other non-serious adverse events must be followed until the outcome of the event is 
“recovering” (for chronic conditions), “recovered” or until the last subject contact/visit/end of 
post-treatment follow-up period, whichever comes first, and until all queries related to the adverse 
event have been resolved. 
Follow-up of Serious Adverse Events 
All adverse events classified as serious should be followed until the outcome of the event is 
“recovered”, “recovered with sequelae”,  or “death” and until all queries have been resolved. For 
cases of chronic conditions and cancer, follow-up until “recovered”, “recovered with sequelae” or 


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“death” is not required. After the subject has completed the trial, these cases can be closed with 
the outcome “recovering” or “not recovered”. 
11 
STATISTICAL METHODS AND DATA ANALYSIS 
The following text provides general description of the statistical methodology for the assessment 
of efficacy, safety, and tolerability of 200 mg/day of oral ifetroban in this double-blind placebo-
controlled study in subjects with symptomatic AERD. Details of the statistical analyses will be 
provided in the Statistical Analysis Plan, which will be finalized prior to database lock and 
unblinding.  All recorded data will be listed. 
11.1 
Sample Size Determination 
Thirty-eight subjects per group will provide 90% power for the comparison of ifetroban and 
placebo with respect to the change from baseline in SNOT-22 scores at Week 8 (two-sided, level 
0.05), assuming a common standard deviation of 16 and a true difference is 12. 
11.2 
Subject Populations for Analysis 
11.2.1  
Safety Population 
All subjects who received at least one dose of study medication will be included in the Safety 
Population.  
Treatment emergent period for Safety Population is defined as the time from the first 
administration of study medication to the end of the post-treatment Period. 
11.2.2  
Intent-to-Treat Population 
The Intent-To-Treat (ITT) Population will consist of all treated subjects with at least one post-
baseline assessment of SNOT-22. 
11.2.3  
Per Protocol Population 
The Per Protocol (PP) Population will consist of all subjects in the ITT population with no major 
protocol violations, including violation of inclusion or exclusion criteria or insufficient dosing. 
Inclusion of subjects in the PP Population will be determined prior to unblinding.  
11.3 
Subgroup analysis 
To assess the consistency of treatment effects across the subgroup levels, and to examine baseline 
biomarkers for their potential value to predict treatment response, exploratory subgroup analyses 
will be conducted for the change from baseline in SNOT-22 with respect to age group, gender, 


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region, race, baseline SNOT-22, baseline TNSS, baseline ACQ-7 and selected biomarkers prior to 
the study. The details will be provided in the Statistical Analysis Plan. 
11.4 
Randomization 
Subjects will be randomized using a 1:1 randomization ratio for ifetroban 200 mg daily for eight 
weeks, or placebo daily for eight weeks.  
11.5 
Methods for Handling Missing Data 
All missing data will be queried. Missing efficacy data which are not retrievable through queries 
will be imputed. Binary response variables will be imputed by treating the missing data as a non-
response, i.e., non-responder imputation. Missing data for continuous variables will be imputed 
using Last Observation Carried Forward. Sensitivity analyses may be performed to assess the 
impact of the imputation technique(s). 
11.6 
Data Analysis Plan  
11.6.1 
 Demographic and Baseline Parameters 
Demographic and baseline characteristics will be summarized using descriptive statistics or 
frequency tables, by treatment group and overall. 
11.6.2 
  Exposure and Compliance 
Exposure and compliance will be summarized for the Safety Population by treatment group and 
overall. Comments recorded on the Study Drug Accountability CRF page will not be applied in 
the computation of compliance.   
Exposure is the duration (days) of treatment, computed as: 
Exposure = Date of Final Dose- Date of Baseline Visit + 1.  
Treatment compliance will be calculated as: 
Compliance (%) = 100*(Total Number of Capsules Dispensed-Total Number of Capsules 
Returned)/(4*Exposure). 
 
11.6.3 
Efficacy Analyses 
All hypothesis tests will be performed at the 0.05 level. Analyses of the primary and secondary 
efficacy variables will be performed using both the ITT and PP Populations. Corresponding 
summary statistics will be presented for all efficacy analyses. 


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11.6.3.1 
Primary Analysis 
The primary efficacy endpoint is the CFB in SNOT-22 score and the primary analysis is the 
analysis  of CFB in SNOT-22 at Week 8, using Analysis of Covariance (ANCOVA), with SNOT-
22 at Baseline included as the only covariate. 
11.6.3.2 
Analysis of secondary endpoints 
CFB in ACQ-7 and CFB in TNSS at Week 8 will be analyzed using ANCOVA, with the 
corresponding value at Baseline included as the only covariate. These variables, as well as CFB in 
SNOT-22, at Week 4 will also be analyzed as ancillary analyses.  
Analyses of CFB for other continuous efficacy variables will be performed at Weeks 4 and 8 in the 
same manner using ANCOVA with the corresponding value at Baseline included as the only 
covariate. 
Any improvement in SNOT-22, ACQ-7, and TNSS (Yes or No) at Weeks 4 and 8 will be analyzed 
using the normal approximation to the binomial distribution, assuming unequal variances. 
11.6.4   
Safety Parameters 
All safety data will be summarized. AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) (Version 9.0 or later). All Treatment Emergent Adverse Events (TEAEs) 
will be summarized by treatment group. Counts and percents will be presented by treatment group 
for each observed system organ class (SOC) and preferred term as defined in MedDRA.   
The preferred terms and SOCs will be summarized in the following set of tables: 
• 
All AEs; 
• 
All AEs by maximum level of intensity; 
• 
All AEs by closest relationship to the study medication. 
The frequencies and percentages of AEs will be tabulated. Incidence, relation to study medication, 
and severity will be summarized. 
Physical examination findings, laboratory parameters, vital signs, FEV1, weight, and 
corresponding changes from Baseline, as appropriate, will be summarized using descriptive 
statistics at each visit. 


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12 
STUDY MANAGEMENT AND DATA COLLECTION 
12.1 
Confidentiality 
All information regarding the nature of the proposed investigation provided by the Sponsor or 
Study Monitor to the Investigator (with the exception of information required by law or regulations 
to be disclosed to the IRB, the subject, or the appropriate regulatory authority) must be kept in 
confidence by the Investigator. 
The anonymity of participating subjects must be maintained. Subjects will be identified by an 
assigned subject number on CRFs and other study documents submitted to the Study Monitor. 
Documents that will not be submitted to the Study Monitor and that identify the subject (e.g., the 
signed informed consent document) must be maintained in strict confidence by the Investigator, 
except to the extent necessary to allow auditing by the appropriate regulatory authority, the Study 
Monitor, or Sponsor representatives. 
12.2 
Source Documents 
Source data are contained in source documents.  Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical trial. 
12.3 
Case Report Forms 
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs designed by 
the Sponsor to record (according to Sponsor instructions) all observations and other data pertinent 
to the clinical investigation in a timely manner. All CRFs should be completed in their entirety in 
a neat, legible manner to ensure accurate interpretation of data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows for identifying the modification. 
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
 
The computerized handling of the data by the Sponsor when available in the eCRF may generate 
additional requests to which the Investigator is obliged to respond by confirming or modifying the 
data questioned. The requests with their responses will be managed through the eCRF.   


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12.4 
Records Retention 
According to CFR21 312.62 (c) and ICH E6 4.9.5, all CRFs, as well as supporting documentation 
and administrative records, must be retained by the Investigator for a minimum of two years 
following notification that the appropriate regulatory authority has approved the product for the 
indication under study, if no application is to be filed or if the application is not approved for such 
indication, until two years after the investigation is discontinued and FDA is notified. It is the 
sponsor’s responsibility to inform the investigator as to when these documents no longer need to 
be retained. No study documents will be destroyed or moved to a new location without prior 
written approval from the Sponsor.  If the Investigator relocates, retires, or withdraws from the 
clinical study for any reason, all records required to be maintained for the study should be 
transferred to an agreed upon designee, such as the Study Monitor, another Investigator, or the 
institution where the study was conducted. 
13 
STUDY MONITORING, AUDITING, AND INSPECTING 
13.1 
Study Monitoring Plan 
The progress of the study will be monitored by using the following methods: 
• Periodic on-site visit(s) 
• Telephone communications, as needed, among the Investigator, Clinical Monitor and 
Medical Monitor 
• Review of CRFs and clinical records 
14 
ETHICAL CONSIDERATIONS 
This study will be conducted according to the standards of FDA, ICH, GCP Guidelines, IRB 
regulations, any applicable government regulations and procedures. This protocol and any 
amendments will be submitted to a properly constituted IRB for approval of the study conduct. 
14.1 
Informed Consent 
Written informed consent must be obtained from each subject (or the subject’s legal 
guardian/representative) before performing any Screening Period evaluations.  The signed 
informed consent document will be retained by the Investigator, and a copy will be given to the 
subject or subject’s legal guardian/representative.  The informed consent document, which is 
prepared by the Investigator, must have been reviewed and approved by the Sponsor and the 
Investigator’s IRB before the initiation of the study.  The document must contain the 20 elements 


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of informed consent described in ICH E6 4.8 (Appendix 16.1).  Appendix 16.1 provides further 
details regarding the specific requirements for informed consent.  In addition, subjects of 
appropriate intellectual maturity should provide written informed assent, as determined by the 
institution’s IRB or local legal requirement. 
14.2 
Protocol Compliance  
Substantive changes in the protocol include changes that affect the safety of subjects or changes 
that alter the scope of the investigation, the scientific quality of the study, the experimental design, 
dosages, assessment variable(s), the number of subjects treated, or the subject selection criteria.  
Such changes must be prepared as a protocol amendment by the Study Monitor and implemented 
only upon joint approval of the Sponsor, Investigator, and the Study Monitor.  A protocol 
amendment must receive IRB approval before implementation.  In parallel with the IRB approval 
process, the protocol amendment will be submitted to the appropriate regulatory authority as an 
amendment to the regulatory submission under which the study is being conducted.  If a protocol 
amendment requires changes in the informed consent document, the revised informed consent 
document prepared by the Investigator must be approved by the Sponsor, Study Monitor, and the 
IRB. 
Emergency departures from the protocol that eliminate an apparent immediate hazard to a 
particular subject and that are deemed crucial for the safety and well-being of that subject may be 
instituted for that subject only.  The Investigator or other attending physician also will contact the 
Medical Monitor as soon as possible in the case of such a departure.  These departures do not 
require pre-approval by the IRB; however, the IRB and Medical Monitor must be notified in 
writing as soon as possible after the departure has been made.  In addition, the Investigator will 
document in the subject’s CRF the reasons for the protocol deviation and the ensuing events. 
14.3 
Study Files 
Documentation concerning Investigator data, IRB data, and clinical laboratory data is required 
before shipment of oral ifetroban to the study site (Appendix 16.2).  Copies of these documents as 
well as supplemental information, such as the Investigator’s Brochure and Responsibilities and 
Obligations of Investigators and Sponsors (Appendix 16.3.2), will be kept on-site in a special study 
file. 
This 
file 
also 
will 
contain 
drug 
accountability 
(receipt/dispensing) 
records, 
Sponsor/Investigator correspondence, IRB correspondence, changes to the protocol, information 
regarding monitoring activities, subject exclusion records, biological samples records, and CRFs.  
Investigator data, including FDA Form 1572 and statement of qualifications for each Investigator, 
are provided in Appendix 16.3.2. 


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15 
REFERENCES 
Arm JP, O'Hickey SP, Spur BW, et al. Airway responsiveness to histamine and leukotriene E4 in 
subjects with aspirin-induced asthma. Am. Rev. Respir. Dis. 1989 Jul;140(1):148-53. 
Bachert C, Mannent L, Naclerio RM, et al. Effect of subcutaneous dupilumab on nasal polyp 
burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA. 
2016 Feb 2; 315(5): 469-79. 
Berges-Gimeno MP, Simon RA, Stevenson DD. Long-term treatment with aspirin desensitization 
in asthmatic subjects with aspirin-exacerbated respiratory disease. J. Allergy Clin. Immunol. 2003 
Jan;111(1):180-6. 
Bochenek G, Nagraba K, Nizankowska E, et al. A controlled study of 9 alpha, 11 beta-PGF2 (a 
prostaglandin D2 metabolite) in plasma and urine of subjects with bronchial asthma and healthy 
controls after aspirin challenge. J Allergy Clin Immunol 2003 Apr; 111(4):743-9. 
Cahill KN, Bensko JC, Boyce JA, Laidlaw TM. Prostaglandin D2: A dominant mediator of aspirin-
exacerbated 
respiratory 
disease. 
J.Allergy 
Clin. 
Immunol. 
2015 
Jan;135(1):245-52. 
PMCID:PMC4289104. 
Celikel S, Stevenson D, Erkorkmaz U, et al. Use of nasal inspiratory flow rates in the measurement 
of aspirin-induced respiratory reactions. Ann Allergy Asthma Immunol 2013 111:252-55. 
Hopkins C, Gillett S, Slack R, et al. Psychometric validity of the 22- item sinonasal outcome test. 
Clin Otolaryngology. 2009; 34: 447-454. 
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a 
questionnaire to measure asthma control. Eur Respir J. 1999 
Laidlaw T, Kidder M, Bhattacharyya N, et al. Cysteinyl leukotriene overproduction in aspirin-
exacerbated respiratory disease is driven by platelet-adherent leukocytes. Blood 2012 Apr 19; 
119(16):3790-8. 
Liu T, Laidlaw T, Feng C, et al. Prostaglandin E2 deficiency uncovers a dominant role for 
thromboxane A2 in house dust mite-induced allergic pulmonary inflammation. Proc Natl Acad Sci 
USA 2012 Jul 31; 109(31):12692-7. 
Liu T, Laidlaw T, Katz H, et al. Prostaglandin E2 deficiency causes a phenotype of aspirin 
sensitivity that depends on platelets and cysteinyl leukotrienes. Proc Natl Acad Sci USA 2013 Oct 
15; 110(42):16987-92. 


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Nasser SM, Patel M, Bell GS, et al. The effect of aspirin desensitization on urinary leukotriene E4 
concentrations in aspirin-sensitive asthma. Am. J. Respir. Crit Care Med. 1995 May;151(5):1326-
30. 
Rajan, J. P., N. E. Wineinger, D. D. Stevenson, et al. 2015. Prevalence of aspirin-exacerbated 
respiratory disease among asthmatic subjects: a meta-analysis of the literature. J. Allergy Clin. 
Immunol. 135: 676–681.e1. 
Schumacher W, Heran C. Inhibition and Reversal of U-46,619-lnduced Myospastic Responses in 
Anesthetized Rats by SQ 34,451 and Other Thromboxane Antagonists. Internal Report 1990 Dec 
26. 
Schumacher W, Steinbacher T. Inhibition of Bronchospasm and Arterial Hypertension in Guinea 
Pigs by Oral and Intravenous Administration of SQ 34,451 and SQ 34,943. Internal Report 1990 
Dec 29. 
Sousa AR, Parikh A, Scadding G, Corrigan CJ, et al. Leukotriene-receptor expression on nasal 
mucosal inflammatory cells in aspirin-sensitive rhinosinusitis. N. Engl. J. Med. 2002 Nov 
7;347(19):1493-9. 
White A, Stevenson D. Aspirin-Exacerbated Respiratory Disease: Update on pathogenesis and 
desensitization. Semin Respir Crit Care Med 2012 Dec; 33:588-94. 
 
 


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16 
APPENDICES 
16.1 
Protection of Human Subjects  
Informed consent must be obtained from every subject before he enters a study.  It must be given 
freely and not under duress.  Consent must be documented by the subject or the subject’s legally 
authorized representative signing an IRB/IEC-approved consent form.  Subjects who do not speak 
English must be presented with a consent form written in a language that they understand.  A copy 
of the signed consent form must be given to the subject signing it.  The original must be kept in 
the Investigator’s files and made available to Sponsor and representatives of the appropriate 
regulatory authority upon request.  If, for any reason, subject risk is increased as the study 
progresses, a revised, IRB/IEC-approved consent form must be signed by the subject.  Before the 
study begins, a sample of the consent form must be provided to the Sponsor.  The appropriate 
regulatory authority may reject otherwise scientifically valid studies if proper informed consent 
has not been obtained from all subjects. 
16.1.1 
 Basic Elements Of Informed Consent 
Every consent form must include explanations of each of the following 20 elements: 
• That the trial involves research 
• The purpose of the trial 
• The trial treatment(s) and the probability for random assignment to each treatment 
• The trial procedures to be followed, including all invasive procedures 
• The subject’s responsibilities 
• Those aspects of the trial that are experimental 
• The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to 
an embryo, fetus, or nursing infant 
• The reasonably expected benefits; and when there is no intended clinical benefit to the 
subject, the subject should be made aware of this 
• The alternative procedure(s) or course(s) of treatment that may be available to the subject, 
and their important potential benefits and risks 


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• The compensation and/or treatment available to the subject in the event of a trial-related 
injury 
• The anticipated prorated payment, if any, to the subject for participating in the trial 
• The anticipated expenses, if any, to the subject for participating in the trial 
• That the subject’s participation in the trial is voluntary and that the subject may refuse to 
participate or withdraw from the trial, at any time, without penalty or loss of benefits to 
which the subject is otherwise entitled 
• That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be 
granted direct access to the subject’s original medical records for verification of clinical 
trial procedures and/or data, without violating the confidentiality of the subject, to the 
extent permitted by applicable laws and regulations and that, by signing a written informed 
consent form, the subject or the subject’s legally acceptable representative is authorizing 
such access 
• 
That the records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly available; 
and if the results of the trial are published, the subject’s identity will remain confidential 
• 
That the subject or the subject’s legally acceptable representative will be informed in a 
timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial 
• 
The person(s) to contact for further information regarding the trial and the rights of trial 
subjects, and whom to contact in the event of a trial-related injury 
• 
The foreseeable circumstances and/or reasons under which the subject’s participation in 
the trial may be terminated 
• 
The expected duration of the subject’s participation in the trial 
• 
The approximate number of subjects involved in the trial 
Nothing in these regulations is intended to limit the authority of a physician to provide emergency 
medical care to the extent the physician is permitted to do so under applicable federal, state, or 
local laws. 


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Informed consent allows the subject to fully understand his participation and serves to protect the 
Investigator and Sponsor from potential negligence claims.  A fully informed subject is the best 
protection against such claims. 
The informed consent requirements in these regulations are not intended to preempt any applicable 
federal, state, or local laws that require additional information to be disclosed in order that 
informed consent be legally effective.  Some states require further action on the Investigator’s part 
concerning subject consent. 
16.2 
Requisite Documents for Approval of Study Site 
Oral ifetroban sodium will be provided to the Investigators after they have submitted the following 
documents to the Study Monitor: 
• Signed protocol 
• Signed Statement of Investigator or FDA Form 1572 (if required by the regulatory agency) 
• Document indicating IRB/IEC approval of the final protocol, the informed consent and/or 
assent and recruitment advertisement documents (to include name, address, and 
chairperson of the IRB/IEC) 
• Blank copy of the IRB/IEC-approved informed consent document 
• Signed Investigator’s Agreement and Letter of Confidentiality 
• Clinical Laboratory Certification and normal ranges for tests that are performed in the 
laboratory for study assessments   
• Curricula vitae for the Investigator and Sub-Investigator(s) (i.e. individuals who, as part of 
an investigative team, will assist the investigator and make a direct and significant contribution 
to the data. In general, if an individual is directly involved in the performance of procedures 
required by the protocol, and the collection of data, that person should be listed on the 1572). 
• Financial disclosure Form FDA 3454 (any study FDA relies on to establish that the product 
is effective or any study in which a single investigator makes a significant contribution to 
the demonstration of safety). 
 


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16.3 
Responsibilities and Obligations of Investigators and Sponsors 
16.3.1 
Sponsor/Study Monitor 
The CPI Study Monitor will: 
Conduct a pre-investigation Site Selection Visit and/or Study Initiation Visit to: 
• Establish the acceptability of the facility and record the visit in a written report 
(i.e., memorandum or form). 
• Discuss with the Investigator the proposed clinical trial and supply draft CRFs, the 
Investigator’s Brochure, and the draft protocol for review and approval. 
• Discuss with the Investigator the regulatory requirements with respect to informed consent, 
IRB/IEC approval of the trial, the protocol, protocol amendments, and changes to the 
informed consent document. 
• Discuss with the Investigator the timing of interim and final reports to the Study Monitor 
and obligation to supply the Study Monitor with copies of all study-related documents 
(including IRB/IEC approval, IRB/IEC charter or equivalent, membership and 
qualifications, protocol amendments, informed consent documents, and consent changes), 
CRFs, CRF changes, and all pertinent correspondence to and from the IRB/IEC. 
Conduct periodic on-site visit(s) to: 
• Assure adherence to the protocol. 
• Review CRFs and hospital records for accuracy and completeness of information. 
• Examine pharmacy or other IMP storage and dispensing records for documentation of 
quantity and date of receipt of investigational drug, dispensation and accountability data 
for product administration to each subject, loss of materials, contamination, and unused 
supplies. 
• Record and report (summarize) observations on the progress of the trial and continued 
acceptability of the facilities, and prepare an on-site visit report. 
• Review Investigator files for required documents, (e.g., protocols; protocol amendments; 
Investigator’s Brochure; Study Procedures Manual; IRB/IEC approval of protocols, 
amendments, and informed consent documents; IRB/IEC charter and membership; and 
communications to and from the IRB/IEC and the Study Monitor. 


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16.3.2 
Investigator 
Institutional Review Board/Independent Ethics Committee 
The Investigator must assure the Study Monitor in writing that the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC): 
• Meets FDA 21CFR 56 and/or ICH regulations as defined in ICH E 63: Institutional Review 
Board/Independent Ethics Committee (as applicable). 
• Has the authority delegated by the parent Institution and found in the IRB/IEC by-laws, 
operation guidelines, or charter to approve or disapprove clinical trials and protocols, 
including informed consent and other documents (e.g., protocol amendments and 
information to be supplied to subjects concerning informed consent). 
• Complies with proper personnel make-up of the Board. 
• Convenes meetings using acceptable rules of order for making decisions, recording such 
decisions, and implementing them. 
• Maintains files that contain (a) documentation of its decisions, such as are found in 
IRB/IEC minutes and correspondence, (b) written guidelines or by-laws governing 
IRB/IEC functions, (c) protocol, (d) protocol amendments, (e) approved informed consent 
document and information to be supplied to the subject, and (f) correspondence between 
the IRB/IEC and Investigator (e.g., consent changes, protocol amendments). 
Informed Consent of Human Subjects 
The Investigator must assure the Study Monitor in writing that the informed consent document for 
a subject: 
• Meets FDA 21CFR part 50 and/or ICH regulations as defined in ICH E6 4.8: Informed 
Consent of Trial Subjects (as applicable). 
• Has been approved by the IRB/IEC, including (when required) information to be given to 
the subject regarding the trial in which he is enrolled. 
• Includes the basic elements and any additional elements of informed consent that are 
appropriate. 


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• Has been signed by both the subject and the Investigator or designee, and a copy has been 
given to the subject. 
• May be provided to the subject in the "short form" informed consent document with written 
information as an alternative. 
Storage and Dispensing of Product Supplies 
The Investigator (or Pharmacist) must assure the Study Monitor in writing that: 
• Adequate and accurate written records show receipt and disposition of all product supplies, 
including dates, serial or lot numbers, quantities received, and each quantity dispensed, 
administered, or used, with identification of each subject. 
• Purpose and reasons are given in written records for product disposal (e.g., the amount 
contaminated, broken, or lost) and the quantity that was returned to the Sponsor. 
Case Report Forms 
The Investigator must assure the Study Monitor in writing that: 
• The completed CRF accurately reflects the hospital records for each subject. 
• The CRFs and hospital records will be accessible to the Clinical Monitor during on-site 
visits. 
Files and Records 
The Investigator must assure the quality, integrity, and content of his files, which will be subject 
to audit by the Study Monitor and the appropriate regulatory authority inspectors.  The files must 
contain, as minimum: 
• Correspondence to and from the IRB/IEC and to and from the Clinical Monitor. 
• Documents including the following: 
o IRB/IEC-approved protocols. 
o IRB/IEC-approved protocol amendments. 
o IRB/IEC-approved informed consent/assent documents and information to be supplied 
to the subject. 


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o IRB/IEC-approved recruitment advertisement(s) 
o IRB/IEC charter, membership, and qualifications of each member. 
• Clinical supplies records including the following: 
o Receipt, date and quantity, and batch or lot number. 
o Disposition dates and quantity administered to each subject. 
o Inventory records. 
Documents and records must be retained by the Investigator for a period of two years following 
the date a marketing application is approved for the product for the indication for which it is being 
investigated, OR If no application is to be filed or if the application is not approved for such 
indication, until two years after the investigation is discontinued and the appropriate regulatory 
authority is notified. 
16.4 
22-item Sino-nasal Outcome Test (SNOT-22) 
Below you will find a list of symptoms and social/emotional consequences of your rhinosinusitis. 
We would like to know more about these problems and would appreciate you answering the 
following questions to the best of your ability.  There are no right or wrong answers, and only you 
can provide us with this information. Please rate your problems as they have been over the past 
two weeks. Thank you for your participation.  Do not hesitate to ask for assistance if necessary. 
 
 


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1. Considering how severe the problem 
is when you experience it and how 
often it happens, please rate each item 
below on how "bad" it is by circling 
the number that corresponds with how 
you feel using this scale: → 
No Problem 
Very Mild Problem 
Mild or slight Problem 
Moderate Problem 
Severe Problem 
Problem as bad as it can be 
5 Most Important Items 
1. Need to blow nose 
0 
1 
2 
3 
4 
5 
 
2. Nasal Blockage 
0 
1 
2 
3 
4 
5 
 
3. Sneezing 
0 
1 
2 
3 
4 
5 
 
4. Runny nose 
0 
1 
2 
3 
4 
5 
 
5. Cough 
0 
1 
2 
3 
4 
5 
 
6. Post-nasal discharge 
0 
1 
2 
3 
4 
5 
 
7. Thick nasal discharge 
0 
1 
2 
3 
4 
5 
 
8. Ear fullness 
0 
1 
2 
3 
4 
5 
 
9. Dizziness 
0 
1 
2 
3 
4 
5 
 
10. Ear pain 
0 
1 
2 
3 
4 
5 
 
11. Facial pain/pressure 
0 
1 
2 
3 
4 
5 
 
12.  Decreased Sense of Smell/Taste 
0 
1 
2 
3 
4 
5 
 
13. Difficulty falling asleep 
0 
1 
2 
3 
4 
5 
 
14. Wake up at night 
0 
1 
2 
3 
4 
5 
 
15. Lack of a good night’s sleep 
0 
1 
2 
3 
4 
5 
 
16. Wake up tired 
0 
1 
2 
3 
4 
5 
 
17. Fatigue 
0 
1 
2 
3 
4 
5 
 
18. Reduced productivity 
0 
1 
2 
3 
4 
5 
 
19. Reduced concentration 
0 
1 
2 
3 
4 
5 
 
20. Frustrated/restless/irritable 
0 
1 
2 
3 
4 
5 
 
21. Sad 
0 
1 
2 
3 
4 
5 
 
22. Embarrassed 
0 
1 
2 
3 
4 
5 
 
2. Please mark the most important items affecting your health (maximum of 5 items)_________ 


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SNOT-20 Copyright 1996 by Jay F. Piccirillo, M.D., Washington University School of Medicine, St. Louis, MO 
SNOT-22 Developed from modification of SNOT-20 by National Comparative Audit of Surgery for Nasal Polyposis 
and Rhinosinusitis Royal College of Surgeons of England. 
16.5 
PNIFR Methodology 
Per Celikel 2013: 
Traditional NIFR measurements can yield highly variable results. However, assessment of the rate 
of peak nasal inspiratory flow (PNIF) has recently been shown to be an inexpensive, simple and 
fast method with good reproducibility. 
The PNIF meter is simply an inverted mini-Wright flow meter attached to an airtight face mask. 
The PNIF is then measured using a Youlten meter (or similar) in liters per minute. 
All subjects should be instructed on how to use the Youlten meter properly. All subjects should be 
seated during testing and encouraged to inhale as hard and fast as they can through the mask while 
keeping the mouth closed and starting from the end of a full expiration. Two individual NIFR 
measurements will be taken at all study time points.  The two measurements within 5% of each 
will be recorded.  If the measurements are not within 5% of each other, a third measurement will 
be made and recorded.   
 
 


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16.6 
Total Nasal Symptom Score (TNSS)  
Please answer all the questions to the best of your ability twice daily, once in the morning after 
waking up and a second time before bedtime.  
                              0 = NONE     1 = MILD    2 = MODERATE    3 = SEVERE    
Date: 
Date: 
Date: 
Date: 
 
AM 
PM 
AM 
PM 
AM 
PM 
AM 
PM 
Please rate how your nasal congestion 
has been over the past 12 hours: 
  
  
  
  
  
  
  
  
Please rate how your runny nose has 
been over the past 12 hours: 
  
  
  
  
  
  
  
  
Please rate how your nasal itching 
has been over the past 12 hours 
  
  
  
  
  
  
  
  
Please rate how your sneezing has 
been over the past 12 hours: 
  
  
  
  
  
  
  
  
Please rate how difficult has it been 
with nasal symptoms to sleep or go 
about your day's activities: 
  
  
  
  
  
  
  
  
 


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16.7 
Asthma Control Questionnaire –7 (ACQ-7) 
Please answer questions 1-6. Circle the number of the response that best describes how you have 
been during the past week. 
1. On average, during the past week, how often were you woken by your asthma during the 
night? 
0    Never 
1    Hardly ever 
2    A few times 
3    Several times 
4    Many times 
5    A great many times 
6 Unable to sleep because of asthma 
 
2. On average, during the past week, how bad are your asthma symptoms when you wake 
up in the morning? 
0 No symptoms 
1 Very mild symptoms 
2 Mild symptoms 
3 Moderate symptoms 
4 Quite severe symptoms 
5 Severe symptoms 
6 Very severe symptoms 
 
3. In general, during the past week, how limited were you in your activities because of your 
asthma? 
0 Not limited at all 
1 Very slightly limited 
2 Slightly limited 
3 Moderately limited 
4 Very limited 
5 Extremely limited 
6 Totally limited 
 
4. In general, during the past week, how much shortness of breath did you experience 
because of your asthma? 
0 None 
1 A very little 
2 A little 
3 A moderate amount 
4 Quite a lot 
5 A great deal 
6 A very great deal 
 


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5. In general, during the past week, how much time did you wheeze? 
0 Not at all 
1 Hardly any of the time 
2 A little of the time 
3 A moderate amount of the time 
4 A lot of the time 
5 Most of the time 
6 All the time 
 
6. On average, during the past week, how many puffs/inhalations of short-acting 
bronchodilator (eg. Ventolin) have you used each day? 
0 None 
1 1-2 puffs/inhalations most days 
2 3-4 puffs/inhalations most days 
3 5-8 puffs/inhalations most days 
4 9-12 puffs/inhalations most days 
5 13-16 puffs/inhalations most days 
6 More than 16 puffs/inhalations most days 
 
7. (To be completed by staff) 
FEV, % predicted: 
Points 
 
0 >95% predicted 
1 90-95% predicted 
2 80-89% predicted 
3 70-79% predicted 
4 60-69 predicted 
5 50-59% predicted 
6 <50% predicted 
Points assigned = ____________ 
Scoring: Sum points from all questions 1-7. Divide this sum by 7.  
If question 7 is not available, divide by 6. 
ACQ score = ___________ 
Juniper 1999 


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16.8 
Adult Equipotent Daily Doses of Inhaled Glucocorticosteroids 
     Bachert 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 


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16.9 
Self-assessment of Treatment (Optional) 
We would like to better understand your opinion on the treatment you received during the trial. 
Please, answer the following question. Thank you for your cooperation. 
Could you tell us about your opinion regarding the treatment you had during the trial? What 
did you like or dislike about the treatment? 
 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________ 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________ 

SAP_001.pdf: 
 
 
IFE006_Statistical Analysis Plan V1.9_REDACTED 
Page 1 of 21 
 
APPROVAL PAGE  
DOCUMENT: 
 Statistical Analysis Plan 
 
Number: 
 CPI-IFE-006 
Title: 
 A Phase 2 Multicenter, Double-blind, Randomized, Placebo-Controlled 
Trial to Evaluate Oral Ifetroban in Subjects with Symptomatic Aspirin 
Exacerbated Respiratory Disease (AERD) 
SAP DATE: 
 V1.9/ 21 Sept 2017 
SPONSOR: 
 Cumberland Pharmaceuticals Inc. 
PREPARED BY: 
  
 
 
APPROVERS: 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
IFE006_Statistical Analysis Plan V1.9_REDACTED 
Page 2 of 21 
 
 
TABLE OF CONTENTS 
1. INTRODUCTION .................................................................................................... 4 
2. LIST OF ABBREVIATIONS ................................................................................... 4 
3. STUDY OBJECTIVES ........................................................................................... 6 
3.1  
Primary Objective ...................................................................................................... 6 
3.2  
Secondary Objectives................................................................................................ 6 
4. STUDY DESIGN .................................................................................................... 7 
4.1  
General Study Design and Plan ................................................................................ 7 
4.2 
Study Population ....................................................................................................... 8 
4.3  
Randomization and Blinding ...................................................................................... 9 
4.4  
Study Assessments ................................................................................................. 10 
4.5 
Sample Size Determination ..................................................................................... 11 
4.6 
Study Variables ....................................................................................................... 11 
4.7  
ANALYSIS POPULATIONS .......................................................................... 13 
5.  
GENERAL STATISTICAL CONSIDERATIONS ............................................ 13 
5.1  
Handling of Dropouts or Missing Data ..................................................................... 14 
5.2 
Interim Analyses and Data Monitoring ..................................................................... 15 
5.3 
Multicenter Studies .................................................................................................. 15 
5.4 
Multiple Comparisons / Multiplicity ........................................................................... 15 
6.  
SUMMARY OF STUDY POPULATION DATA .............................................. 15 
6.1 
Subject Disposition .................................................................................................. 15 
6.2 
Demographics and Baseline Characteristics ........................................................... 15 
6.3  
Dosing and Extent of Exposure ............................................................................... 15 
6.4 
Concomitant Medications ........................................................................................ 16 
7 EFFICACY ANALYSES ........................................................................................ 16 
7.1 
Primary Efficacy Analysis ........................................................................................ 16 
7.2  
Secondary Efficacy Analyses .................................................................................. 17 
7.3  
Subgroup Analyses ................................................................................................. 19 
8 
SAFETY ANALYSES ........................................................................................ 20 
8.1  
Adverse Events ....................................................................................................... 20 
8.2  
Clinical Laboratory Evaluation ................................................................................. 20 
8.3 
Vital Signs ............................................................................................................... 20 
8.4 
Physical Exam ......................................................................................................... 20 
8.5 
Safety Labs ............................................................................................................. 20 


 
 
IFE006_Statistical Analysis Plan V1.9_REDACTED 
Page 3 of 21 
 
9.  
CHANGES IN THE STATISTICAL METHODS FROM THOSE STATED IN 
THE PROTOCOL ..................................................................................................... 20 
10  
APPENDIX ..................................................................................................... 21 
Appendix A ............................................................................................................................ 21 
Normal Approximation to the Binomial Distribution Test ........................................................ 21 


 
 
IFE006_Statistical Analysis Plan V1.9_REDACTED 
Page 4 of 21 
 
1.   INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on study procedures and analyses described in the protocol 
(dated 24 January 2017). Table shells and mock listings corresponding to the contents of this document will 
be included with the final version. This document, with table shells and mock listings, will be reviewed prior to 
any unblinded analyses, and revised if necessary. 
2.   LIST OF ABBREVIATIONS 
Term 
Definition 
ACQ 
Asthma Control Questionnaire 
AE 
Adverse Event 
AERD 
Aspirin Exacerbated Respiratory Disease 
ANCOVA 
Analysis of Covariance 
BMI 
Body Mass Index 
CFB 
Change From Baseline 
CPI 
Cumberland Pharmaceuticals Inc. 
CRF 
Case Report Form 
FeNO 
Fractional Exhaled Nitric Oxide 
FEV1 
Forced Expiratory Volume in 1 second 
INR 
International Normalized Ratio 
ITT 
Intent-to-Treat 
kg 
Kilogram 
LOCF 
Last Observation Carried Forward 
LS 
Least Squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation  
mL 
Milliliter 
NRI 
Non-Responder Imputation 
PCFB 
Percent Change From Baseline 
PP 
Per Protocol 
PNIFR 
Peak Nasal Inspiratory Flow Rate 
PT 
MedDRA Preferred Term 
PT 
Prothrombin Time 


 
 
IFE006_Statistical Analysis Plan V1.9_REDACTED 
Page 5 of 21 
 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SNOT 
Sino-Nasal Outcome Test 
SOC 
MedDRA System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TNSS 
Total Nasal Symptom Score 
TPr 
Thromboxane Prostanoid Receptor 
UPSIT 
University of Pennsylvania Smell Identification Test 


 
 
IFE006_Statistical Analysis Plan V1.9_REDACTED 
Page 6 of 21 
 
3. STUDY OBJECTIVES 
3.1  
Primary Objective 
Determine the efficacy of ifetroban compared to placebo to improve sino-nasal symptoms and quality of life 
(QoL) using the Sino-Nasal Outcome Test (SNOT) - 22 score in symptomatic AERD subjects. 
3.2  
Secondary Objectives 
• 
Evaluate the effect of ifetroban on asthma symptoms by forced expiratory volume 1 (FEV1) compared 
to baseline. 
• 
Assess nasal symptoms and QoL using the peak Nasal Inspiratory Flow Rate (PNIFR), University of 
Pennsylvania Smell Identification Test (UPSIT), fractional exhaled nitric oxide (FeNO), Asthma 
Control Questionnaire (ACQ) - 7 and Total Nasal Symptom Score (TNSS) 
• 
Determine whether ifetroban reduces the frequency and severity of asthma exacerbations and 
chronic sinusitis as well as the frequency of rescue medication and antibiotic use. 
• 
Evaluate the pharmacodynamic effects of TPr blockade on eicosanoids and eosinophil count. 
 
 


 
 
IFE006_Statistical Analysis Plan V1.9_REDACTED 
Page 7 of 21 
 
4.   STUDY DESIGN 
4.1  General Study Design and Plan 
This is a multicenter randomized, double-blind, placebo-controlled Phase 2 study to evaluate oral ifetroban 
administered daily for eight weeks in symptomatic AERD subjects. The clinical study will be conducted with 3 
periods: 
• 
Screening period of up to two weeks 
• 
Randomized ifetroban/placebo treatment period of eight weeks 
• 
Post-treatment period for safety and efficacy of two weeks 
 
 
 


 
 
IFE006_Statistical Analysis Plan V1.9_REDACTED 
Page 8 of 21 
 
4.2   
Study Population 
Approximately 76 subjects are to be randomized into two treatment groups with 38 subjects per group. 
 
Individuals who meet all of the following criteria are eligible for enrollment as study subjects: 
 
1. History of physician-diagnosed asthma 
 
2. History of nasal polyposis 
 
3. History of at least two reactions to oral aspirin or other nonselective cyclooxygenase inhibitor with 
features of lower airway involvement (cough, chest tightness, wheezing, dyspnea), or diagnosis of 
AERD via a physician-conducted challenge to aspirin in the last five years before starting treatment 
 
4. Stable asthma (post-bronchodilator FEV1 of ≥ 60%, no glucocorticoid burst for at least two weeks 
prior to starting treatment, no hospitalizations or emergency room visits for asthma at least three 
months prior to starting treatment and not on a dose >1000 µg fluticasone or equivalent daily). 
 
5. ≥ 18 years of age 
 
6. Exhibit symptomatic AERD within two weeks of starting treatment by demonstrating a score of at 
least 20 on the SNOT – 22 
 
Individuals who meet any of these criteria are not eligible for enrollment as study subjects: 
 
1. Current smoking, defined as daily tobacco smoking in the last six months and at least one instance 
of tobacco smoking in the last three months 
 
2. Current pregnancy or breastfeeding 
 
3. Use of oral or systemic steroids (e.g. prednisone or equivalent) > 20 mg daily in the last four weeks 
before starting treatment 
 
4. Daily use of long-acting antihistamines, 5-lipoxygenase inhibitors (e.g. zileuton) and leukotriene 
receptor antagonists (e.g. montelukast) in the last two weeks before starting treatment 
 
5. Less than 12 months of allergy shots (maintenance dose of allergy shots are allowed if treatment 
duration exceeds 12 months) 
 
6. Any use of nonsteroidal anti-inflammatory drugs (NSAIDs) or any drug that inhibits the 
cyclooxygenase enzyme in the last two weeks before starting treatment 
 
7. History of bleeding diathesis or use of anticoagulant or antiplatelet drugs in the last 2 weeks before 
starting treatment 
 
8. Any immunosuppressive treatment including but not limited to methotrexate, cyclosporine, 
mycophenolate, tacrolimus, gold, penicillamine, sulfasalazine, hydroxychloroquine, azathioprine, 
cyclophosphamide, and immunotherapy in the last two weeks before starting treatment (maintenance 
dose of allergy shots are allowed if treatment duration exceeds 12 months) 
 
9. Endoscopic sinus surgery / polypectomy within the past three months 
 
10. Previously treated in any clinical trial with ifetroban 
 
11. Previously treated with other investigational drugs within eight weeks or five half-lives, whichever 
is longer, before screening 


 
 
IFE006_Statistical Analysis Plan V1.9_REDACTED 
Page 9 of 21 
 
 
12. Conditions/concomitant disease which make the participant unevaluable for the efficacy 
endpoints 
4.3  
Randomization and Blinding 
 
Subjects who meet all the inclusion and no exclusion criteria during the Screening/Baseline Period will be 
randomized using a 1:1 randomization ratio to receive either ifetroban 200 mg once daily or matching 
placebo. A central randomization will be utilized. Approximately 76 subjects shall be randomized to ensure at 
least 38 subjects per group will be analyzed for efficacy 
 
The study will be double blind with respect to the treatment assignment. To maintain the study blind, the 
appearance of packaging and capsules will be identical in both study arms. Site and CPI clinical staff will be 
blinded to the treatment assignment until the completion of the study. Individual treatment assignment will 
remain blinded throughout the study. In the event a treatment assignment needs to be unblinded for safety 
reasons, the site principal investigator will notify the study project manager, who will consult with the medical 
monitor. The medical monitor will review the circumstances and grant approval as indicated. Any intentional 
or unintentional breaking of the blind will be reported to the Sponsor immediately and fully documented in the 
subject’s case report form. 
 
 


 
 
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4.4  
Study Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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 4.5 
Sample Size Determination 
Thirty-eight subjects per group will provide 90% power for the comparison of ifetroban and 
placebo with respect to the change from baseline in SNOT-22 scores at Week 8 (two-sided, 
level 0.05), assuming a common standard deviation of 16 and a true difference is 12. 
 4.6 
Study Variables 
Efficacy Variables 
• 
SNOT-22 score (Sino-Nasal Outcome Test)  
o Total Score = Sum of the values collected in the 22 questions collected in the 
database. 
o CFB (change from baseline) total score = post-treatment measurement - baseline 
o PCFB (percent change from baseline) = (post-treatment measurement – 
baseline)/baseline 
o Improvement in SNOT-22 (Yes or No): if CFB (SNOT-22) <0,  then improvement 
= ‘Yes’; otherwise improvement = ‘No’ 
o Nasal Related Subscale = sum of the following questions to calculate the 
subscale: “need to blow nose”, “sneezing”, “runny nose”, “nasal obstruction”, “loss 
of smell/taste”, and “post-nasal drip”,  
o Ear and Facial Related Subscale = sum of the following questions to calculate the 
subscale: “ear fullness”, “dizziness”, “ear pain”, “facial pain and pressure”  
o Quality of Life Related Subscale = sum of the following questions to calculate the 
subscale: “difficulty falling asleep”, “wake up at night”, “wake up tired”, “fatigue”, 
“reduced productivity”, “reduced concentration” 
o Psychologically Related Subscale = sum of the following questions to calculate 
the subscale: “frustrated/restless/irritable”, “sad”, “embarrassed” 
o CFB Nasal Related Subscale = post-treatment measurement visit - baseline 
o CFB Ear and Facial Related Subscale = post-treatment measurement visit – 
baseline 
o CFB Quality of Life Related Subscale = post-treatment measurement visit - 
baseline 
o CFB Psychologically Related Subscale = post-treatment measurement visit - 
baseline 
 
• 
 Forced Expiratory Volume 1 (FEV1)  
o FEV1 Value = Collected on the CRF. Measured as the “best effort” of the 3 
collected measurements at each time point where “best effort”= Max (fev1_1, 
fev1_2, fev1_3) 
o CFB FEV1 = post-treatment measurement – baseline 
 
 
 
 


 
 
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• 
Peak Nasal Inspiratory Flow Rate (PNIFR)  
o PNIFR value= Measured as the “best effort” of the 3 collected measurements at 
each time point where “best effort”= Max(pnfr1, pnfr2, pnfr3) 
o CFB PNIFR = post-treatment measurement - baseline 
 
• 
University of Pennsylvania Smell Identification Test (UPSIT)  
o UPSIT value - Calculated by staff. Found in the database.  
o CFB UBSIT= post-treatment measurement – baseline 
 
• 
Fractional exhaled Nitric Oxide (FeNO) 
o FeNO value – Collected on the CRF. 
o CFB FeNO  = post-treatment measurement - baseline 
 
• 
 Asthma Control Questionnaire (ACQ) – average of non-missing values 
o ACQ score. Calculated in database (ACQ_Score) 
o CFB ACQ = post-treatment measurement – baseline 
o Any improvement in ACQ-7 (Yes or No): If CFB ACQ<0, then improvement 
=’Yes’; otherwise improvement = ‘No’ 
 
• 
Total Nasal Symptom Score (TNSS) AM and PM measurements   
o TNSS Daily Score = sum of the 4 symptom scores (congestion, runny_nose, 
nasal_itching, sneezing) for both AM and PM, separately. (listed only) 
o TNSS Visit Score: The daily score for AM and PM are averaged over time 
between the visits separately. Baseline Visit Score for AM and PM is obtained by 
averaging over the screening period and the day of the baseline visit. Week 4 
Visit Score is obtained by averaging over the day after the baseline visit to the 
day of the Week 4 visit. Week 8 Visit Score is obtained by averaging over the day 
after Week 4 visit to the day of the Week 8 visit. Week 10 Visit Score is obtained 
by averaging over the day after Week 8 visit to the day of Week 10 visit. 
o CFB TNSS Visit Score = post-treatment measurement – baseline 
 
• 
Frequency and Severity of Asthma Exacerbations (Respiratory Reaction Questionnaire)  
o Subject Frequency =count the number of reports since the previous visit for each 
visit  
o CFB Frequency = post-treatment measurement – baseline 
o Max Severity= define the maximum severity for each subject (none, mild, 
moderate, or severe) over the period since the previous visit. 
o Inhaler or rescue med (number of reports) count=  count the number of reports 
where resp_rxn_inhaler >0 OR  resp_rxn_add_tx_yn=Yes 
o CFB Inhaler or rescue= post-treatment measurement – baseline 
 
 


 
 
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• 
Frequency and Severity of Chronic Sinusitis (Sinus Infection Questionnaire) 
o Antibiotic use Frequency (number of reports) count=  count the number of reports 
over the period since the previous visit where sinus_inf_antibio=yes 
o CFB Antibiotic use= post-treatment measurement – baseline 
 
Pharmacodynamic Variables and biomarkers 
 
• 
Plasma - Data from third party vendor 
o ScD10L (pg/mL)  
o Sp_selection (ng/mL) 
• 
Biomarkers - Data from third party vendor. 
o Urine LTE4 (ng/mg Creatinine) 
o Urine PGD-M (ng/mg Creatinine) 
o Urine TX-M (ng/mg Creatinine) 
o Plasma F2 Isoprostanes (ng/mL) 
o Serum LTB4 (ng/mL) 
o SAM-Eicosanoids PGD2 (ng/mL) 
o SAM-Eicosanoids PXA2 (ng/mL) 
o SAM-Eicosanoids F2 Isoprostanes (ng/mL) 
4.7  
ANALYSIS POPULATIONS 
Safety Population All subjects who received at least one dose of study medication will be 
included in the Safety Population.  
 
Intent-to-Treat Population The Intent-To-Treat (ITT) Population will consist of all treated 
subjects with at least one post-baseline assessment of SNOT-22. 
 
Per Protocol Population The Per Protocol (PP) Population will consist of all subjects in the ITT 
population with no major protocol violations, including violation of inclusion or exclusion criteria 
or insufficient dosing. Inclusion of subjects in the PP Population will be determined prior to 
unblinding. 
5.  
GENERAL STATISTICAL CONSIDERATIONS 
The following text provides general description of the statistical methodology for the assessment 
of efficacy, safety, and tolerability of 200 mg/day of oral ifetroban in this double-blind placebo- 
controlled study in subjects with symptomatic AERD. 
 
Appropriate summary statistics will be provided for categorical data (n, %) and for continuous 
data (n, mean, standard deviation, minimum, median, maximum). All recorded data will be listed 
by subject and by visit unless otherwise specified. 
 
 
 


 
 
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5.1  
Handling of Dropouts or Missing Data   
Missing efficacy data which are not retrievable through queries will be imputed.  
NRI 
Binary response efficacy variables will be imputed by treating the missing data as a failure, ie, 
non-responder imputation (NRI).  A response variable that is calculated from a continuous 
variable will only be imputed using NRI, not from the imputed continuous variable. 
LOCF 
Missing data for continuous efficacy variables with at least one post-baseline measurement will 
be imputed using Last Observation Carried Forward (LOCF). Any calculated continuous variable 
will be imputed after its creation.  
If the baseline value is missing for any variable, then the last screening value will be used. 
MI 
Multiple imputation (MI) will be provided as a sensitivity analysis for the primary efficacy variable 
(SNOT-22 Score CFB) only. Six imputations will be calculated from PROC MI. Week 8 will be 
imputed using week 0 and week 4 by treatment by treatment. The analysis will be performed on 
the 6 imputed sets which will provide 6 estimates of LS means from separate analyses of 
ANCOVAs (see Section 7.1).  
proc mi data=thedata out=outds nimpute=6 seed=310  
min=(-110 -110 -110 -110 -110 -110) 
max=(110 110 110 110 110 110) 
round=(1 1 1 1 1 1)  
minmaxiter=100 
noprint; 
by trt; 
var  SNOT22BASE  SNOT22CFB4 SNOT22CFB8; 
run; 
 
where SNOT22BASE is the baseline SNOT22 score and, SNOT22CFB4 and SNOT22CFB8 are 
the SNOT-22 Score values at Weeks 4 and 8, respectively. 
The seed specified above will be used for development, but may be changed prior to unblinding; 
any such change will be documented. If convergence is not achieved with minmaxiter=100, then 
increase the number of iterations to 500. The properties of this approach, including convergence 
and collinearity, will be assessed prior to unblinding and may be adjusted to improve the 
operating characteristics. 
 
After calculating the LS means of the two treatments and the estimated treatment difference and 
associated standard error from the ANCOVA, the 6 estimates can be placed in PROC MI 
analyze. 


 
 
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Code to obtain a single estimate of the treatment LS means and standard error. 
proc mianalyze=thedata ; **Data output from proc mixed; 
by trt; 
modeleffects estimate; ***estimate of lsmeans for 6 sets; 
stderr stderr; *** estimate of standard error for 6 sets; 
run; 
 
Code to obtain a single estimate p-value for the treatment difference. 
proc mianalyze=thedata ; **Data output from proc mixed with /diff option 
modeleffects diffestimate; ***estimate of the treatment difference for 6 sets; 
stderr diffstderr; *** estimate of treatment difference standard error for 6 sets; 
run; 
 
 5.2 
Interim Analyses and Data Monitoring 
There will be no interim analysis. Data will be monitored and queried throughout the study.  
 5.3 
Multicenter Studies  
The centers will be pooled for analysis. 
5.4    Multiple Comparisons / Multiplicity   
There are 2 treatment arms and 1 primary endpoint. There will be no adjustments for multiple 
comparisons or multiplicity.  
6.  
SUMMARY OF STUDY POPULATION DATA 
 6.1 
Subject Disposition 
The number and percentage of subjects completing the study and terminating early, with the 
reason for termination, will be summarized for each treatment group and overall for the Safety 
Population. Summary statistics for subjects randomized, and in each study population and 
reasons for exclusion from the ITT and PP Populations will be provided for each treatment group 
and overall for all screened subjects. The percentages for the summaries of the number of 
subjects in each study population will be based on the number of subjects in the Safety 
Population. Protocol deviations will be listed. 
 6.2 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics (for 
continuous variables) or frequency/percentage (for categorical variables), by treatment group 
and overall. Medical and surgical history will be listed for the Safety Population. Adverse events 
that are not treatment emergent (occur before treatment) will be listed by Safety Population. 
6.3  
Dosing and Extent of Exposure 
Exposure and compliance will be summarized for the Safety Population by treatment group and 
overall. Comments recorded on the Compliance CRF page regarding dosing will not be applied 
in the computation of compliance. Exposure is the duration (days) of treatment, computed as:  


 
 
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Exposure= Date of Final Dose- Date of Baseline Visit + 1.  
 
Treatment compliance will be calculated as:  
 
Compliance (%) = 100*(Total Number of Capsules Dispensed-Total Number of Capsules 
Returned)/Exposure. 
 
Summary statistics for exposure and compliance will be presented in a table with the 
corresponding listing for the Safety Population.  
 6.4 
Concomitant Medications 
A listing of concomitant medications will be provided for the Safety Population. Rescue 
medication for asthma exacerbation and antibiotic use for sinus infections will be summarized as 
noted above. 
7 EFFICACY ANALYSES 
All hypothesis tests will be performed at the 0.05 level. Analyses of the primary efficacy 
variables will be performed using both the ITT and PP Populations; analyses of secondary 
efficacy variables will be performed using the ITT population only. Summary statistics will be 
presented for all analyses of efficacy variables. 
 7.1 
Primary Efficacy Analysis 
The primary analysis of interest is the CFB in SNOT-22 at week 8 on the ITT population, 
imputed with LOCF. Between-treatment comparison will be performed using Analysis of 
Covariance (ANCOVA) with SNOT- 22 at baseline and treatment in the model. The p-value 
associated with the difference between the treatments in least squares will determine 
significance. Least squares (LS) means, differences in LS means and the associated p-value, 
corresponding standard errors, and corresponding confidence intervals will be presented in a 
table.  To assess sensitivity, this analysis will also be performed on the CFB SNOT-22 imputed 
using MI (Section 5.1). 
The chart below outlines the analyses to be performed on each variable. It identifies the weeks 
for which the analysis will be performed for the corresponding variable, population, and type of 
imputation.  
Variable 
Name 
Value 
Type 
Pop 
Weeks for Analysis 
Sensitivity (1) 
Summary 
ANCOVA 
SNOT-
22 
Score Value 
ITT/PP 
0,4,8,10 
 
LOCF 
Score CFB 
ITT/PP 
0,4,8,10 
4,8,10 
LOCF/MI 
(1) Imputation analysis outlined in Section 5.1. LOCF=Last observation carried forward, 
MI=Multiple Imputation 
 
 
 


 
 
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7.2  
Secondary Efficacy Analyses 
The analyses performed for the secondary efficacy variables will be combinations of summary 
statistics and ANCOVAs, using the normal approximation to the binomial (see Appendix A for 
details.) as appropriate, at specified visits presented in the table below.  
The ANCOVA will include the corresponding value at Baseline as the only covariate with 
treatment. The LS means, standard error and p-values will be presented with corresponding the 
summary statistics. 
Categorical variables will be analyzed using the normal approximation to the binomial 
distribution, assuming unequal variances. The p-value will be presented along with summary 
statistics. 
The chart below outlines the analyses to be performed on each variable. It identifies the weeks 
in which the analysis will be performed for the variable of interest, the population, and the type of 
imputation. 
Variable 
Name 
Value 
Type 
Pop 
Weeks for Analysis 
Imputation 
(2) 
Summary 
ANCOVA 
 
Binomial
(1) 
SNOT-22 
Score PCFB 
ITT 
0,4,8,10 
 
 
LOCF 
Improvement(y/n) 
ITT 
0,4,8,10 
 
4,8,10 
NRI 
SNOT-22 
Subscale 
Nasal Related 
ITT 
0,4,8,10 
 
 
LOCF 
Ear and Facial 
ITT 
0,4,8,10 
 
 
LOCF 
Quality of Life 
ITT 
0,4,8,10 
 
 
LOCF 
Psychological 
ITT 
0,4,8,10 
 
 
LOCF 
CFB Nasal Related 
ITT 
0,4,8,10 
 
 
LOCF 
CFB Ear and Facial 
ITT 
0,4,8,10 
4,8,10 
 
LOCF 
CFB Quality of Life 
ITT 
0,4,8,10 
4,8,10 
 
LOCF 
CFB Psychological 
ITT 
0,4,8,10 
4,8,10 
 
LOCF 
22 Questions 
ITT 
0,4,8,10 
 
 
LOCF 
FEV1 
Value 
ITT 
0,4,8,10 
 
 
LOCF 
CFB 
ITT 
0,4,8,10 
4,8,10 
 
LOCF 
PNIFR 
Value 
ITT 
0,4,8,10 
 
 
LOCF 
CFB 
ITT 
0,4,8,10 
4,8,10 
 
LOCF 
UPSIT 
Value 
ITT 
0,4,8,10 
 
 
LOCF 
CFB 
ITT 
0,4,8,10 
4,8,10 
 
LOCF 
FeNO 
Value 
ITT 
0,4,8,10 
 
 
LOCF 
CFB 
ITT 
0,4,8,10 
4,8,10 
 
LOCF 
ACQ 
Value 
ITT 
0,4,8,10 
 
 
LOCF 
CFB 
ITT 
0,4,8,10 
4,8,10 
 
LOCF 
Improvement (y/n) 
ITT 
0,4,8,10 
 
4,8,10 
NRI 
(1) Normal approximation to the Binomial 
(2) Imputation analysis outlined in Section 5.1. NRI=Non responder imputation, LOCF=Last 
observation carried forward  
 


 
 
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Variable 
Name 
Value 
Type 
Pop 
Analysis 
Summary 
ANCOVA 
 
Binomial 
(1) 
Imputation 
(2) 
TNSS 
AM/PM 
Visit Score 
ITT 
4,8,10 
 
 
LOCF 
CFB Visit score 
ITT 
4,8,10 
4,8,10 
 
LOCF 
Asthma 
 
Reports 
ITT 
0,4,8,10 
 
 
 
LOCF 
CFB Reports 
ITT 
0,4,8,10 
4,8,10 
 
LOCF 
Max Severity 
ITT 
0,4,8,10 
 
 
LOCF 
Rescue report 
ITT 
0,4,8,10 
 
 
LOCF 
CFB rescue report 
ITT 
0,4,8,10 
4,8,10 
 
LOCF 
 
Sinusitis 
Reports 
ITT 
0,4,8,10 
 
 
LOCF 
CFB Reports 
ITT 
0,4,8,10 
4,8,10 
 
LOCF 
Max Severity 
ITT 
0,4,8,10 
 
 
LOCF 
Antibiotic report 
ITT 
0,4,8,10 
4,8,10 
 
LOCF 
CFB  Antibiotic 
report 
ITT 
0,4,8,10 
 
 
 
LOCF 
 
Plasma 
 
ScD10L  
ITT 
0,4,8,10 
 
 
 
LOCF 
Sp_selection  
ITT 
0,4,8,10 
 
 
LOCF 
 
Bio- 
Markers 
 
LTE4 
ITT 
0,4,8,10 
 
 
 
LOCF 
PGD-M 
ITT 
0,4,8,10 
 
 
LOCF 
TX-M 
ITT 
0,4,8,10 
 
 
LOCF 
F2 Isoprostanes 
ITT 
0,4,8,10 
 
 
LOCF 
LTb4 
ITT 
0,4,8,10 
 
 
LOCF 
SAM-Eicosanoids 
PGD2 
ITT 
0,4,8,10 
 
 
LOCF 
SAM-Eicosanoids 
PXA2 
ITT 
0,4,8,10 
 
 
LOCF 
SAM-Eicosanoids 
F2 Isoprostanes 
ITT 
0,4,8,10 
 
 
LOCF 
(1) Normal approximation to the Binomial 
(2) Imputation analysis outlined in Section 5.1. NRI=Non responder imputation, LOCF=Last 
observation  carried forward  


 
 
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7.3  
Subgroup Analyses 
To assess the consistency of treatment effects across the subgroup levels, and to examine 
baseline biomarkers for their potential value to predict treatment response, exploratory analyses 
will be conducted for CFB SNOT-22 (imputed using LOCF) for the variables below. 
Each covariate will be used in separate regression models for CFB SNOT-22, along with the 
treatment and interaction. The p-value for treatment and the interaction will be presented. 
Additional ad-hoc exploratory analyses may be provided based on the results of these analyses; 
any additional analyses will be presented in a separate report. 
Covariate 
Pop 
Analysis 
Summary 
ANCOVA 
ANOVA 
Age 
ITT 
 
4,8,10 
 
Gender 
ITT 
 
 
4,8,10 
Site 
ITT 
 
 
4,8,10 
Race 
ITT 
 
 
4,8,10 
Baseline SNOT-22 
ITT 
 
4,8,10 
 
Baseline TNSS 
ITT 
 
4,8,10 
 
Baseline ACQ-7 
ITT 
 
4,8,10 
 
LTE4 
ITT 
8 
8 
 
PGD-M 
ITT 
8 
8 
 
TX-M 
ITT 
8 
8 
 
F2 Isoprostanes 
ITT 
8 
8 
 
LtBct 
ITT 
8 
8 
 
SAM-Eicosanoids PGD2 
ITT 
8 
8 
 
SAM-Eicosanoids PXA2 
ITT 
8 
8 
 
SAM-Eicosanoids F2 
Isoprostanes 
ITT 
8 
8 
 
 
 
 
 


 
 
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8 
SAFETY ANALYSES 
8.1  
Adverse Events 
Adverse Events (AEs) will be summarized by frequency and percentage. AEs will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) (Version 20.0 or later). An AE 
occurring between the first administration of study medication to the end of the study is 
considered a Treatment-Emergent Adverse Event (TEAE). All TEAEs will be summarized by 
treatment group. Counts and percents will be presented by treatment group for each observed 
system organ class (SOC) and preferred term (PT) as defined in MedDRA. The SOCs and PTs 
will be summarized in the following set of tables for the Safety Population:   
 
• 
All AEs 
• 
All AEs by maximum level of severity 
• 
All AEs by closest attribution to the study medication.  
 
 
Adverse events that occur during the screening period will be listed. 
8.2  
Clinical Laboratory Evaluation 
Clinical laboratory assessments taken from blood sampling such as hematology, chemistry, PT 
and INR will be summarized and listed for the Safety Population. 
 
Pregnancy test results and clinical laboratory values from urine samples will be listed for the 
Safety Population. 
 8.3 
Vital Signs 
Vital signs (heart rate, respiratory rate, systolic blood pressure, diastolic blood pressure and 
weight, and BMI) will be presented in a table with summary statistics by visit for the Safety 
Population. Height will be summarized for the Screening visit, 
8.4 
Physical Exam 
Physical examination assessments will be listed by subject, visit and exam type.  All exams will 
be listed for the baseline observation; Only abnormal results will be presented in the listings for 
the post baseline visits. 
 
8.5 
Safety Labs 
Safety labs, Prothrombin Time (PT) and International Normalized Ratio (INR) and their 
associated CFB values will be summarized and listed. 
 
9.  
CHANGES IN THE STATISTICAL METHODS FROM THOSE STATED IN THE 
PROTOCOL 
The secondary variables will be analyzed with the ITT population only. 
 
 


 
 
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10  
APPENDIX 
Appendix A 
Normal Approximation to the Binomial Distribution Test 
Let n1 and np  denote the sample sizes and let m1 and mp denote the number of responses for 
Ifetroban (200mg/day), and Placebo, respectively. Furthermore, let r1= m1/ n1, and rP =mP/ nP, 
denote the sample proportions for Ifetroban (200mg/day) and Placebo, respectively.  Note that 
‘r’ is used to denote proportions instead of the standard ‘p’ because p is being used to denote 
the p-value. 
 
 let 
Z1P= (r1- rP)/s1P 
where 
 
 
s1p={r1(1-r1)/n1 + rp(1- rp)/np}1/2.  
 
The corresponding p-value is p=1-Φ(Z1P) where Φ is the standard normal distribution function 
and is calculated using the PROBNORM SAS function in the data step.