Clinical trial NCT03326063
Conditions: Nasal Polyps Asthma, Aspirin-Induced Aspirin-exacerbated Respiratory Disease Aspirin-Sensitive Asthma With Nasal Polyps
Sponsor: Brigham and Women's Hospital
Start date: 2018-04-26; Completion date: 2023-04-15
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The overall aim of the study is to determine the efficacy of oral ifetroban, a novel antagonist of T prostanoid (TP) receptors, as a treatment for patients with aspirin-exacerbated respiratory disease (AERD).

Detailed description:
The protocol involves a 4-week, double-blind, placebo-controlled parallel-design trial of oral ifetroban in patients with AERD. At the end of the 4-week treatment phase (ifetroban or placebo) each subject will undergo a graded oral aspirin desensitization procedure in order to initiate high-dose aspirin therapy, which is standard-of-care at our institution and is the only available therapy known to modify the course of AERD.

Arms: arm 1: Subjects will be randomized to receive ifetroban (200 mg dose per day) for 4 weeks. arm 2: Subjects will be randomized to receive placebo for 4 weeks.
Interventions: intervention 1: Ifetroban intervention 2: Placebo
Intervention descriptions: intervention 1: 4-week, double-blind, placebo-controlled parallel-design trial of oral ifetroban (a TP receptor antagonist) in patients with AERD intervention 2: 4-week, double-blind, placebo-controlled parallel-design trial of oral ifetroban (a TP receptor antagonist) in patients with AERD

Protocol documents:
Prot_SAP_000.pdf: 
DAIT Interventional (Clinical Trials) Protocol Template 
 
 
 
ASTHMA AND ALLERGIC DISEASES COOPERATIVE RESEARCH CENTER  
 
Therapeutic Control of Aspirin-Exacerbated Respiratory Disease  
VERSION 7.0/07/24/2020 
IND# 135837 
Study Sponsor(s): 
 
The National Institute of Allergy and Infectious Diseases (NIAID) 
NIAID Funding Mechanism: U19 Grant 
 
NCT#: 03326063 
 
 
IND Sponsor/Number: 
Elliot Israel, MD/IND#135837 
Study Drug Manufacturer/Provider: Cumberland Pharmaceuticals  
 
 
 
 
 
 
 
 
 
 
 
 


DAIT Interventional (Clinical Trials) Protocol Template 
 
PREFACE 
This document is the Division of Allergy, Immunology, and Transplantation (DAIT) protocol 
template, which is required for developing DAIT-sponsored interventional (clinical trials) 
protocols.  Note that instructions and explanatory text are indicated by italics and should be 
replaced in your protocol document with appropriate protocol-specific text.  Section headings 
and template text formatted in regular type should be included in your protocol document as 
provided in the template.  Text should be formatted using Body Text style.  Bulleted lists should 
be formatted using Bullet (listing) style. 
This template attempts to provide a general format applicable to all clinical trials evaluating an 
investigational product.  Where specific examples are provided, they are often from DAIT areas 
of investigation. 
Throughout this protocol template, there may be subject headings that do not apply to your 
particular study.  In such instances, please write “not applicable.” 
In places where the information is duplicative, it is acceptable to reference another section 
rather that repeating the information. 
Refer questions regarding use of this protocol template to your DAIT programmatic staff contact 
or the DAIT Clinical Research Operations Program,   NIAIDCROPPolicyGroup@niaid.nih.gov.


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ASTHMA AND ALLERGIC DISEASES COOPERATIVE RESEARCH CENTER  
AADCRC-BWH-02 
 
Therapeutic Control of Aspirin-Exacerbated Respiratory Disease  
VERSION 7.0/07/24/2020 
IND# 135837 
Study Sponsor(s): 
 
The National Institute of Allergy and Infectious Diseases (NIAID) 
NIAID Funding Mechanism: U19 Grant 
 
NCT#: 03326063 
 
 
IND Sponsor/Number: 
Elliot Israel, MD/IND#135837 
Study Drug Manufacturer/Provider: Cumberland Pharmaceuticals  
PRINCIPAL INVESTIGATOR-ELLIOT ISRAEL, 
MD 
Asthma Research Center Director 
Brigham and Women’s Hospital 
75 Francis St 
Clinics Bldg, 3rd Floor 
Boston/MA/02115 
Phone: 617-732-8110 
Fax: 617-732-2858 
Email: eisrael@partners.org  
NIAID MEDICAL MONITOR-PETER GERGEN, MD, 
MPH 
Division of Allergy, Immunology and  
Transplantation  
National Institute of Allergy  
and Infectious Diseases 
5601 Fishers Lane 6B58  
Rockville, MD 20892  
Phone: 240-627-3545 
E-mail: lisa.wheatley@nih.gov 
BIOSTATISTICIAN- JING CUI 
Chief Statistician 
BWH Section of Clinical Sciences  
Brigham and Women’s Hospital 
221 Longwood Ave, BLI-341-G 
Boston, MA  02115 
Tel: (617) 732-6384 
E-mail: jcui3@partners.org  
 
PROJECT MANAGER-SUSAN PERRY, RN 
Division of Allergy, Immunology, and 
Transplantation 
National Institute of Allergy  
and Infectious Diseases 
5601 Fishers Lane  6B55 
Bethesda, MD 20892-9828, USA 
Phone: 240-669-2865 
E-mail: susan.perry@nih.gov   
REGULATORY OFFICER-JULIAN GOLDSTEIN,  
MD 
Office of Regulatory Affairs 
Division of Allergy, Immunology, and 
Transplantation 
National Institute of Allergy and 
Infectious Diseases 
5601 Fishers Lane 
Bethesda, MD 20892-9828, USA 
Phone:   
E-mail:   
Confidentiality Statement 
The information contained within this document is not to be disclosed in any way without the prior permission of the Protocol Chair, or 
the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases of the National Institutes of 
Health. 
 
 
 


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INVESTIGATOR SIGNATURE PAGE 
Protocol #:  
  
Version/Date:  
7.0/07/24/2020 
Site Principal Investigator: Elliot Israel, MD  
  
Title:  Therapeutic Control of Aspirin-Exacerbated Respiratory Disease 
  
Study Sponsor:  The National Institute of Allergy and Infectious Diseases (NIAID) 
 
INSTRUCTIONS: The site Principal Investigator should print, sign, and date at the indicated location 
below.  A copy should be kept for your records and the original signature page sent. After signature, 
please return the original of this form by surface mail to:  
DAIT Regulatory Management Center 
Pharmaceutical Product Development 
3900 Paramount Parkway 
Morrisville, NC 27560 
 
I confirm that I have read the above protocol in the latest version.  I understand it, and I will work 
according to the principles of Good Clinical Practice (GCP) as described in the United States Code of 
Federal Regulations (CFR) – 45 CFR part 46 and 21 CFR parts 50, 56, and 312, and in the International 
Conference on Harmonization (ICH) document Guidance for Industry: E6 Good Clinical Practice: 
Consolidated Guidance dated April 1996.  Further, I will conduct the study in keeping with local legal 
and regulatory requirements. 
As the site Principal Investigator, I agree to carry out the study by the criteria written in the protocol 
and understand that no changes can be made to this protocol without the written permission of the 
IRB and NIAID. 
 
____________________________________     
Site Principal Investigator  (Print) 
 
____________________________________                                      _________________ 
Site Principal Investigator (Signature)                                                 Date 


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Protocol Synopsis 
Title 
Therapeutic Control of Aspirin-Exacerbated Respiratory Disease  
Short Title 
Aspirin-Exacerbated Respiratory Disease 
Clinical Phase 
Phase II 
Number of Sites 
N=1 
 
IND Sponsor/Number   
Elliot Israel, MD/IND#135837 
Study Objectives 
1. To determine the efficacy of ifetroban as a treatment for patients with 
AERD.  
2. To determine the relevance of TP receptor signaling, and the effect of TP 
receptor blockade, on platelet and mast cell activation, mediator generation, 
release of IL-33, and cell recruitment in subjects with AERD, in regard to their 
chronic respiratory symptoms and during clinical reactions to aspirin.  
Study Design 
The protocol involves a 4-week, double-blind, placebo-controlled parallel-
design trial of oral ifetroban in patients with AERD. At the end of the 4-week 
treatment phase (ifetroban or placebo) each subject will undergo a graded oral 
aspirin desensitization procedure in order to initiate high-dose aspirin therapy, 
which is standard-of-care at our institution and is the only available therapy 
known to modify the course of AERD. 
Primary Endpoint(s) 
The calculated dose of aspirin that induces an increase in the Total Nasal 
Symptom Score (TNSS) of 2 from the pre-aspirin challenge value,  “PD2” 
Secondary Endpoint(s)  
1. Severity of bronchoconstriction (as measured by maximum fall in FEV1 
during the aspirin-induced reaction) during the aspirin-induced reaction at Visit 
2, compared between patients on placebo vs ifetroban, with the changes also 
analyzed with provocative aspirin dose as a covariate. 
2. Increase of urinary, and nasal lavage levels of LTE4 during aspirin-induced 
reaction from Visit 2 pre-aspirin levels, compared between patients on placebo 
vs ifetroban,  with the changes also analyzed with provocative aspirin dose as a 
covariate. 
3. Change from Visit 1 in baseline FEV1, Asthma Control Questionnaire (ACQ), 
and Sino-Nasal Outcome Test (SNOT-22) at Visit 2, compared between patients 
on placebo vs ifetroban. 
4. Change in levels of other urinary, and nasal eicosanoids, and levels of 
plasma/serum and nasal tryptase, from Visit 1 to Visit 2  pre-aspirin challenge 
and Visit 2 pre-aspirin to during the aspirin-induced reaction at Visit 2, 
compared between patients on placebo vs ifetroban,  with the changes also 
analyzed with provocative aspirin dose as a covariate. 
5. Change from Visit 1 in baseline exhaled nitric oxide (FeNO) levels at Visit 2, 
compared between patients on placebo vs ifetroban. 


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6. Change in numbers/percentages of activated platelets and platelet-
leukocyte aggregates in the peripheral blood from Visit 1 to Visit 2  baseline 
(pre-aspirin administration) and during the aspirin-induced reaction at Visit 2 
from Visit 2 baseline, compared between patients on placebo vs ifetroban,  
with the changes also analyzed with provocative aspirin dose as a covariate. 
 
Accrual Objective 
50 subjects 
Study Duration 
36 months 
Treatment Description  
Ifetroban and aspirin 
Inclusion Criteria 
1. History of AERD, defined as meeting the diagnostic triad with: 
1. History of physician-diagnosed asthma and  
2. History of physician-diagnosed nasal polyposis and 
3. History of pathognomonic reactions aspirin or other nonselective COX 
inhibitors. 
2. Stable asthma (post-bronchodilator FEV1 of ≥70%, no glucocorticoid burst for 
at least 2 weeks prior to Visit 1, and no hospitalizations or ER visits for asthma 
for at least the prior 6 months) 
3. Age between 18 and 70 years 
4. No current smoking (not more than one instance of smoking in the last 3 
months) 
5. Non-pregnant 
Exclusion Criteria 
1. Hypersensitivity to montelukast 
2. Current use of zileuton 
3. History of bleeding diathesis or use of anticoagulant or antiplatelet drugs 
4. Current use of any NSAIDs aside from the aspirin provided during the study 
5. Current use of beta blockers 
6. Use of any biologics within the last 4 months prior to initiating the study 
7. Heart rate of <50bpm at Screening Visit or evidence of any type of heart 
block at Screening. 
8. Evidence of liver failure (AST or ALT levels >3x normal at Screening) 
9. Evidence of kidney failure (creatinine levels >1.5mg/dl in women and 
>1.7mg/dl in men) 
 
Study Stopping Rules 
The study PI or ISM may terminate this study at any time. Reasons for 
termination may include, but are not limited to the incidence or severity of AEs 
in this study indicating a potential health hazard to subjects or unsatisfactory 
subject enrolment. Any serious and/or persistent noncompliance by the 
investigator with the protocol, the clinical research agreement, the Form FDA 
1572, or other local applicable regulatory guidelines in conducting the study 
may also be grounds for termination of the study. The PI will promptly inform 
all other investigators conducting the study if the study is suspended or 
terminated for safety reasons, and will also inform the regulatory authorities of 
the suspension or termination of the study and the reason(s) for the action.  


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Study enrollment, investigational drug, and study procedures will be 
suspended pending expedited review of all pertinent data by the IRB and the 
NIAID, if any one of the following occurs: 
1. If any death occurs that is designated as related to ifetroban or to a study 
procedure.  
2. If 3 AERD enrolled trial participants experience serious non-fatal AEs related 
to aspirin desensitization, or if 2 AERD enrolled participants experience serious 
non-fatal AEs related to ifetroban/placebo, or to another study procedure. 


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Study Contacts: Participating Centers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SITE  PRINCIPAL INVESTIGATOR 
Elliot Israel, MD 
Asthma Research Center Director 
Brigham and Women’s Hospital 
75 Francis St 
Clinics Bldg, 3rd Floor 
Boston/MA/02115 
Phone: 617-732-8110 
Fax: 617-732-2858 
Email: eisrael@partners.org 
 
 
 
 


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Study Contacts: Core Laboratories [Options: Document in the Study Protocol or MOP] 
 
 
AADCRC PI 
Joshua A. Boyce, MD 
Division of Rheumatology, 
Immunology, and Allergy 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA 02115 
Phone: 617-525-1261 
Email: jboyce@partners.org 
 
CO-INVESTIGATOR 
Tanya M. Laidlaw, MD 
Division of Rheumatology, 
Immunology, and Allergy 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA 02115 
Phone: 617-525-1034 
Email: tlaidlaw@partners.org 
CO-INVESTIGATOR  
Kathleen M. Buchheit, MD 
Division of Rheumatology, Immunology, 
and Allergy 
Brigham and Women’s Hospital 
75 Francis Street 
Boston, MA 02115 
Phone: 617-525-1290 
Email: kbuchheit@partners.org 
BIOSTATISTICIAN 
Jing Cui 
BWH Section of Clinical Sciences  
Brigham and Women’s Hospital 
221 Longwood Ave, BLI-341-G 
Boston, MA  02115 
Tel: (617) 732-6384 
E-mail: jcui3@partners.org  
 
 
 


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Table of Contents 
Glossary of Abbreviations ...............................................................................................................................................14 
Study Definitions Page [Optional]....................................................................................................................................15 
1. 
Background and Rationale .......................................................................................................................................16 
1.1. 
Background and Scientific Rationale ................................................................................................................16 
1.2. 
Rationale for Selection of Investigational Product or Intervention ....................................................................17 
1.3. 
Preclinical Experience ......................................................................................................................................17 
1.4. 
Clinical Studies .................................................................................................................................................18 
2. 
Study Hypotheses/Objectives ..................................................................................................................................18 
2.1. 
Hypotheses ......................................................................................................................................................18 
2.2. 
Primary Objective(s) ........................................................................................................................................18 
2.3. 
Secondary Objective(s) ....................................................................................................................................19 
3. 
Study Design ...........................................................................................................................................................19 
3.1. 
Description of Study Design .............................................................................................................................19 
3.2. 
Primary Outcome ............................................................................................................................................22 
3.3. 
Secondary Outcomes .......................................................................................................................................22 
3.4. 
Exploratory Outcomes .....................................................................................................................................23 
3.5. 
Stratification, Randomization, and Blinding/Masking .......................................................................................23 
3.5.1. 
Procedure for Unblinding/Unmasking ..........................................................................................................23 
4. 
Selection of Participants and Clinical Sites/Laboratories ..........................................................................................24 
4.1. 
Rationale for Study Population ........................................................................................................................24 
4.2. 
Inclusion Criteria ..............................................................................................................................................24 
4.3. 
Exclusion Criteria .............................................................................................................................................24 
5. 
Known and Potential Risks and Benefits to Participants ...........................................................................................25 
5.1. 
Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert ................25 
5.1.1. 
Reproductive Risks and Toxicology for Ifetroban ..........................................................................................26 
5.2. 
Risks of Investigational Product or Intervention cited in Medical Literature .....................................................27 
5.3. 
Risks of Other Protocol Specified Medications .................................................................................................27 
5.4. 
Risks of Study Procedures ................................................................................................................................28 
5.5. 
Potential Benefits ............................................................................................................................................29 
6. 
Investigational Agent /Device/Intervention .............................................................................................................29 
6.1. 
Investigational Agents/Devices/Interventions ..................................................................................................29 


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6.1.1. 
Investigational Agent #1 ...........................................................................................................................29 
6.1.1.1. 
Formulation, Packaging, and Labeling...................................................................................................29 
6.1.1.2. 
Dosage, Preparation, and Administration .............................................................................................30 
6.1.2. 
Investigational Agent #2 ...........................................................................................................................30 
6.1.2.1. 
Formulation, Packaging, and Labeling...................................................................................................30 
6.1.2.2. 
Dosage, Preparation, and Administration .............................................................................................30 
6.1.3. 
Investigational Agent #3 ..............................................................................................................................30 
6.1.3.1. 
Formulation, Packaging, and Labeling...................................................................................................30 
6.1.3.2. 
Dosage, Preparation, and Administration .............................................................................................30 
6.2. 
Drug Accountability .........................................................................................................................................30 
6.3. 
Assessment of Participant Compliance with Investigational Agent ...................................................................31 
6.4. 
Toxicity Prevention and Management..............................................................................................................31 
6.5. 
Premature Discontinuation of Investigational Agent ........................................................................................31 
7. 
Other Medications ..................................................................................................................................................31 
7.1. 
Concomitant Medications ................................................................................................................................31 
7.2. 
Prophylactic Medications .................................................................................................................................32 
7.3. 
Prohibited Medications ...................................................................................................................................32 
7.4. 
Rescue Medications .........................................................................................................................................32 
8. 
Study Procedures ....................................................................................................................................................33 
8.1. 
Enrollment .......................................................................................................................................................33 
8.2. 
Screening/Baseline Visit ...................................................................................................................................33 
8.3. 
Study Visits ......................................................................................................................................................33 
8.4. 
Visit Windows ..................................................................................................................................................35 
9. 
Mechanistic Assays..................................................................................................................................................35 
10. 
Biospecimen Storage ...........................................................................................................................................36 
11. 
Criteria for Participant and Study Completion and Premature Study Termination ................................................36 
11.1. 
Participant Completion ................................................................................................................................36 
11.2. 
Participant Stopping Rules and Withdrawal Criteria .....................................................................................36 
11.3. 
Participant Replacement ..............................................................................................................................37 
11.4. 
Follow-up after Early Study Withdrawal .......................................................................................................37 
12. 
Safety Monitoring and Reporting .........................................................................................................................38 
12.1 Overview .............................................................................................................................................................38 
12.2 Definitions ...........................................................................................................................................................38 


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12.2.1 Adverse Event (AE) .......................................................................................................................................38 
12.2.2 Unexpected Adverse Event ...........................................................................................................................39 
12.2.3 Serious Adverse Event (SAE) .........................................................................................................................39 
12.3 Grading and Attribution of Adverse Events ..........................................................................................................39 
12.3.1 Grading Criteria ............................................................................................................................................39 
12.3.2 Attribution Definitions ..................................................................................................................................40 
12.4 Collection and Recording of Adverse Events ........................................................................................................41 
12.4.1 Collection Period ..........................................................................................................................................41 
12.4.2 Collecting Adverse Events .............................................................................................................................41 
12.4.3 Recording Adverse Events .............................................................................................................................41 
12.5 Reporting of Serious Adverse Events and Adverse Events ....................................................................................42 
12.5.1 Reporting of Serious Adverse Events to Sponsor (DAIT/NIAID) ......................................................................42 
12.5.2 Reporting to Health Authority .......................................................................................................................42 
12.5.3 Reporting of Adverse Events to IRBs/IECs .....................................................................................................43 
12.6   
Pregnancy Reporting ....................................................................................................................................43 
12.7 Reporting of Other Safety Information ................................................................................................................44 
12.8 Review of Safety Information ..............................................................................................................................44 
12.8.1 Medical Monitor Review ...............................................................................................................................44 
12.8.2 ISM Review ...................................................................................................................................................44 
12.8.3 DSMB Review ...............................................................................................................................................44 
13. Statistical Considerations and Analytical Plan ............................................................................................................45 
13.1 
Overview .........................................................................................................................................................45 
13.2 
Outcomes ........................................................................................................................................................45 
13.4 
Analysis Plan ....................................................................................................................................................46 
13.4.1 
Analysis Populations. ...............................................................................................................................46 
13.4.2 
Primary Analysis of Primary Outcome ......................................................................................................46 
13.4.3 
Supportive Analyses of the Primary Endpoint(s)/Outcome(s) ...................................................................46 
13.4.4 
Analyses of Secondary and Other Endpoint(s)/Outcome(s) ......................................................................46 
13.4.5 
Analyses of Exploratory Endpoint(s)/Outcome(s) .....................................................................................47 
13.4.6 
Descriptive Analyses ................................................................................................................................47 
13.5 
Interim Analyses ..............................................................................................................................................48 
13.5.1 
Interim Analysis of Efficacy Data ..................................................................................................................48 
13.5.2 
Interim Analysis of Safety Data ....................................................................................................................48 


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13.5.3 
Futility Analysis ............................................................................................................................................48 
13.6 
Statistical Hypotheses ......................................................................................................................................48 
13.7 
Sample Size Considerations .............................................................................................................................48 
13. 
Identification and Access to Source Data .............................................................................................................48 
13.1. 
Source Data .................................................................................................................................................48 
13.2. 
Access to Source Data ..................................................................................................................................48 
14. 
Protocol Deviations .............................................................................................................................................49 
14.1. 
Protocol Deviation Definitions .....................................................................................................................49 
14.2. 
Reporting and Managing Protocol Deviations...............................................................................................49 
15. 
Ethical Considerations and Compliance with Good Clinical Practice .....................................................................49 
15.1. 
Statement of Compliance.............................................................................................................................49 
15.2. 
Informed Consent Process ...........................................................................................................................49 
15.3. 
Privacy and Confidentiality...........................................................................................................................50 
16. 
Publication Policy ................................................................................................................................................50 
17. 
Appendix 1. Schedule of Events  ..........................................................................................................................50 
18. 
References ..........................................................................................................................................................55 
 
 


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Glossary of Abbreviations 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MOP 
Manual of Procedures 
NIAID 
National Institute of Allergy and Infectious Diseases 
PI 
[Site] Principal Investigator 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SOP 
Standard Operating Procedure 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
 


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Study Definitions Page [Optional] 
Lost to Follow-up 
 
Medical Monitor 
 
NIAID Project Manager 
 
Principal Investigator 
 
Program Officer 
 
Protocol Mandated 
Procedures 
 
Randomized 
 
Regulatory Affairs 
Officer 
 
Site Principal 
Investigator 
 
Site Study Coordinator 
 
Study Termination 
 
Study Therapy 
 
Withdrawal from 
Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. Background and Rationale  
1.1. Background and Scientific Rationale 
Aspirin-exacerbated respiratory disease (AERD) is highly overrepresented in populations with severe asthma, refractory 
sinusitis, and nasal polyposis.1,2 There are few available therapeutic options. AERD is typified by sinonasal dysfunction, 
asthma, eosinophilic respiratory tract inflammation, overproduction of cysteinyl leukotrienes (cysLTs), as determined by 
high levels of urinary leukotriene (LT)E4, and persistent release of  mast cell products (histamine, tryptase, and 
prostaglandin (PG)D2) in the absence of exposure to aspirin. The reactions to aspirin and other nonselective 
cyclooxygenase (COX) inhibitors are associated with bronchoconstriction and worsening congestion, rhinorrhea, 
sneezing, and ocular symptoms. These reactions are accompanied by further explosive tissue mast cell activation and 
cysLT generation. Although CysLT1R antagonists are widely used in AERD, they rarely improve basal symptoms, provide 
only partial protection from aspirin-induced bronchoconstriction,3 and do not prevent sinonasal and ocular features of 
reactions to aspirin.  
CysLT overproduction is a hallmark of AERD, and cysLTs are important mediators of the pathognomonic reactions to 
COX-1 inhibitors, as well as of some features of the chronic disease state. Overexpression of LTC4S by eosinophils,4 
increased conversion of granulocyte-derived LTA4 to LTC4 by adherent LTC4S-expressing platelets,5 and failure to 
maintain tissue levels of COX-2-derived PGE2 sufficient to suppress 5-lipoxygenase (LO) activity and mast cell activation6,7 
all likely contribute to dysregulated cysLT synthesis in AERD. As a result, further depletion of PGE2 by aspirin or other 
COX-1-active drugs results in a stereotypical respiratory reaction accompanied by dramatic increases in urinary LTE4 8 
However, while the 5-LO inhibitor zileuton and CysLT1R antagonists can attenuate physiologic responses to aspirin 
challenge in AERD, they are neither uniformly effective nor disease-modifying, and they frequently fail to control the 
severe sinus disease and asthma that are typical chronic features.3,9,10 Moreover, high-dose aspirin treatment after 
desensitization, the only modality that prevents recurrence of nasal polyps in AERD,11 does not suppress basal cysLT 
production,12,13 although it does reduce pulmonary reactivity to LTE4 14 and nasal mucosal expression of CysLT1R.15 
Additionally, 30% of subjects do not benefit from high-dose aspirin treatment.11 Additional insights into disease 
mechanism(s) are urgently needed in order to develop new therapies. 
Although AERD pathogenesis clearly involves mediators other than cysLTs and cysLT receptors other than CysLT1R, the 
limited availability of selective antagonists has precluded analyses of these mediators and receptors in humans. Both our 
preliminary studies and our recent publications12,16 implicate two T prostanoid (TP) receptor ligands, PGD2 and 
thromboxane (TX)A2, as central mediators and important potential therapeutic targets in AERD. TP receptors and cysLTs 
act as components of a hierarchical, feed-forward network of mediators and cells that drive the persistent respiratory 
inflammation, tissue remodeling, end-organ dysfunction, and clinical reactions to COX-1 inhibitors that define AERD. TP 
receptor ligands may also be responsible for some features of aspirin reactions that resist blockade of CysLT1R. We will 
validate our predictions in a carefully phenotyped cohort of subjects with AERD and will test the efficacy of a safe, novel 
potential treatment that is based on strong biological plausibility. Completion of these studies will substantially advance 
our knowledge of the mechanisms that drive the persistent baseline features of the disease (respiratory tract 
inflammation, disturbed lipid mediator metabolism) and the clinical reactions to aspirin (mast cell and platelet 
activation, incremental release of eicosanoids and IL-33). Additionally, since the implicated mechanisms apply to innate 
type 2 immunity and overlap substantially with severe asthma in general, the knowledge gained will have immeasurable 
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1.2. Rationale for Selection of Investigational Product or Intervention 
TP receptors are G protein-coupled receptors (GPCRs) that are expressed by platelets, endothelial cells, cholinergic 
nerves,17 naive T cells,18 and both bronchial and vascular smooth muscle cells. They bind TXA2 with high affinity, and also 
bind isoprostanes (PG-like arachidonic acid-derived products generated nonenzymatically by oxidative stress).19 Two TP 
receptor isoforms (TPα and TPβ) arise from alternative splicing of a single gene, producing receptors with different C-
terminal sequences.20 TP signaling induces/amplifies platelet aggregation in response to multiple stimuli, and 
upregulates adhesion receptor expression by lung vascular endothelial cells.21 TP signaling also constricts human and 
rodent bronchi by both neurally-mediated pathways17,22 and by direct smooth muscle stimulation.23 Interestingly, 
multiple PGs (PGD2, PGF2, high-dose PGE2) require TP receptors to contract human bronchi ex vivo.24 Thus, TP receptor 
antagonism may broadly alter physiologic responses in contexts where contractile prostaglandins are generated at high 
levels, such as AERD (Figure 1).12 
This proposal directly tests the central hypothesis 
using new tools and approaches we have 
developed during the current period of support. 
Combining mechanistic information from our 
mouse model with studies carried out on a cohort 
of subjects with AERD, we have identified several 
readouts that likely reflect, at least in part, the 
signatures of TP receptor actions in AERD in vivo. 
These include changes in the numbers of 
circulating effector cell populations during clinical 
reactions (a real-time measure of cell 
recruitment), changes in the levels of eicosanoid 
receptor expression by these cells (reflecting in 
vivo exposure to their ligands released during 
reactions), and intravascular platelet activation 
(potentially requiring TP signaling for amplification). With the aid of Core C, we will monitor urinary and nasal lavage 
levels of TP-active eicosanoids (PGD2, TXA2), as well as cysLTs, which will enable us to determine whether cysLTs act 
upstream or downstream of TP ligands. By combining a pivotal proof-of-concept trial with real-time monitoring of these 
surrogates, along with established physiological (changes in lung function, nasal symptoms) and biochemical (mast cell 
activation products) readouts, this project gains essential new knowledge of AERD pathophysiology. It also addresses a 
substantial unmet need by introducing a safe and potentially efficacious new treatment for AERD that is based on 
principles supported by our own studies. The  mechanistic studies proposed will verify whether TP blockade (as we 
suspect) will interrupt the feed-forward system that drives persistent activation of the innate immune system, mast cell 
mediator release, platelet activation, and cysLT overproduction that characterize AERD (Figure 1). 
1.3. Preclinical Experience 
Our preclinical studies in the previous AADCRC strongly suggest that TP receptors play an essential role in AERD. Mouse 
studies demonstrate that TP signaling acts upstream of cysLTs to initiate LTC4 formation during reactions to aspirin (likely 
through effects on platelet-adherent leukocytes), as well as downstream of the cysLTs (via CysLT2R), permitting effector 
functions of TP-active PGs at endothelial cells, smooth muscle, and perhaps other targets.25,26The latter effects include 
induction of lung IL-33 expression, which amplifies eosinophilia and drives mast cell activation with aspirin challenges.27 
In the mouse model, endogenous cysLTs signal through CysLT2R to drive TXA2 generation by platelets.26,28 TXA2 may then 
amplify IL-33 generation through TP receptors. This putative TP-mediated feed-forward loop may explain why long-term 
Figure 1. Overview of role of TP receptors and their ligands in AERD 
pathogenesis. 


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blockade of TP receptors (or their deletion) suppresses pulmonary eosinophilia and prevents aspirin sensitivity in Ptges-/- 
mice.25 We have found that ifetroban, the agent used in this proposal, blocks all features of reactions to aspirin in AERD-
like Ptges-/- mice when administered in drinking water overnight, including cysLT and PGD2 generation, release of mast 
cell and platelet products, and (most importantly), change in 
airway resistance (Figure 2). We had obtained similar results 
with SQ29,548, another TP antagonist, in our previous 
study.16 These exciting preclinical findings compel us to 
determine the role of TP and the efficacy of TP blockade in 
AERD in this Project. 
 
1.4. Clinical Studies 
Ifetroban is a potent, selective TP receptor antagonist. It was 
the subject of extensive preclinical and clinical development 
for cardiovascular patients in the 1990s and a large safety 
database exists from this work, but development for 
cardiovascular applications was discontinued due to business 
reasons.  In 2009, Cumberland Pharmaceuticals Inc. acquired 
ownership of the ifetroban program. A phase 2 trial to 
determine the safety of oral ifetroban in 16 subjects with 
AERD (NCT02216357) completed in December 2015 and 
showed no adverse effects.   
Ifetroban is rapidly and almost completely (91%) absorbed after oral administration of a 50 mg dose, and the absolute 
bioavailability of the capsule formulations is 42%. The half-life of ifetroban is similar after IV and oral administration (22 
hours). The volume of distribution, 4.4 L/kg, is much larger than total body water indicating that the drug distributes into 
tissues. Ifetroban is eliminated primarily by metabolism and biliary excretion with 30% of the dose excreted in the urine 
(< 4% as unchanged drug) and the remainder excreted in the feces.  
See Section Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert for further 
detailed Clinical Studies. 
2. Study Hypotheses/Objectives 
2.1. Hypotheses 
We will test the central hypothesis that TP receptor signaling on platelets, endothelial cells, and airway smooth muscle 
promotes persistent eosinophilic respiratory inflammation, drives cysLT overproduction, facilitates release of innate type 
2 cytokines downstream of cysLTs and platelets, and mediates bronchoconstriction in response to TXA2 and PGD2 
released by mast cells during reactions to aspirin in AERD. As such, we expect that TP receptor blockade will interfere 
with both the cysLT-dependent and -independent features of AERD pathophysiology and will interrupt a feed-forward 
loop that drives the disease. 
2.2. Primary Objective(s) 
 
  
Figure 2. Blockade TP 
receptors abrogates 
aspirin sensitivity in 
PGE2-deficient mice. 
Peak change in lung 
resistance (RL) (top) in 
response to challenges 
of Ptges−/− mice with 
aerosolized Lys-ASA or 
PBS 24h after the last of 
6 treatments with Df. 
Some mice received 
ifetroban in drinking 
water (25 mg/ml) for 2 d 
before challenge. Levels 
of the indicated 
mediators were 
measured in the BAL 
fluid (BALF) from the 
same mice. Results are 
from 5 mice per group.  
 


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The primary clinical objective is to determine whether blocking TP receptors with ifetroban attenuates the severity of 
aspirin-induced respiratory reactions. We will also determine the effect of ifetroban on baseline lung function and 
symptom control in AERD, as well as changes in urinary and respiratory eicosanoids.  
2.3. Secondary Objective(s) 
The secondary objective is to determine the relevance of TP receptor signaling, and the effect of TP receptor blockade, 
on platelet and mast cell activation, mediator generation, release of IL-33, and cell recruitment in subjects with AERD at 
baseline and during clinical reactions to aspirin. 
3. Study Design 
3.1. Description of Study Design  
The central hypothesis will be tested using a randomized, double-blinded, placebo-controlled trial of ifetroban, a potent, 
selective TP receptor antagonist,29,30 in subjects with AERD. We will monitor clinical symptoms and markers of 
respiratory inflammation to determine the extent to which TP receptor signaling contributes to the chronic pathobiology 
of the disease. We will also determine whether TP receptor blockade prevents the airflow obstruction and the surge in 
cysLT generation that accompany clinical reactions to aspirin, as predicted from the murine AERD model. We will 
monitor platelet and mast cell activation signatures in vivo and will monitor IL-33 release. We serve a large referral 
population (10-12 new referrals per month to our BWH AERD Center), have all of the tools to test our central 
hypothesis, and have extensive experience running clinical trials. This project introduces a new potential therapeutic 
strategy for patients with AERD, therefore addressing an unmet need. 


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The Study Population will consist of individuals with AERD referred to the BWH Asthma Center, BWH Allergy or 
Otolaryngology clinics, or the BWH AERD Center for evaluation and potential aspirin desensitization.  50 individuals with 
suspected AERD will be enrolled in this study with the anticipation that there will be a dropout rate of 10-20%. All 
subjects will have a clinical history consistent with AERD (asthma, nasal polyposis, and a history of a suspected reaction 
to a nonselective COX inhibitor). All subjects will be on standard therapy for persistent asthma, which may include some 
combination of inhaled glucocorticoids, oral glucocorticoids, long- and short-acting β-agonists, and CysLT1R antagonists. 
We will exclude individuals being treated with omalizumab (monoclonal anti-IgE) or mepolizumab (monoclonal anti-IL-
5), as the effects of these medications on the aspirin-induced reactions in AERD are not known. Detailed Inclusion and 
Exclusion criteria are listed in Section 4.2 and 4.3. We have found that all of the subjects who are currently enrolled in 
our trial of prasugrel and meet these strict inclusion criteria exhibited respiratory reactions to aspirin, confirming their 
diagnosis of AERD. The Study Schema overview is shown in Figure 3. 
At a Screening Visit for patients with AERD, the study will be explained, and the participant will sign informed consent 
before undergoing any procedures. A physical exam, baseline ECG, spirometry and lab work (CBC, urine pregnancy) will 
be performed. Assessments of asthma control (ACQ score, which evaluates asthma control over the preceding 1 week), 
and nasal symptoms (SNOT-22 score, which assesses symptoms over the preceding 2 weeks) will also be obtained.  
There will be a 2-week Run-In after the Screening Visit during which subjects will begin taking montelukast 10mg daily 
(if not already on montelukast as part of their regular asthma care) and will stop taking zileuton (if they are on 
 
Figure 3. Schematic of Intervention Study. After Run-in, subjects (n=50) will be randomized at Visit 1 to receive 
ifetroban or placebo for 4 wks. All subjects will be desensitized to aspirin at Visit 2, with detailed evaluations of the 


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zileuton as part of their regular asthma care). A telephone encounter (Phone Call 1) 1 week later will ensure safety and 
confirm stable asthma. 
After the 2-week Run-In Period on montelukast, subjects will come into the ARC for Visit 1. Interval history, physical 
exam, ACQ, SNOT-22, pre-challenge TNSS and spirometry will be recorded, along with FeNO. Blood will be drawn for 
CBC/differential, and cellular profiling and activation assays. A urine sample will be collected for pregnancy and eicosanoid 
metabolites. Nasal lavage for cytokine and eicosanoid measurements and a nasal epithelial scraping sample for RNA 
extraction will be taken. Subjects will be randomized to receive ifetroban (200 mg dose per day), or placebo for 4 weeks. 
Subjects will take ifetroban or placebo daily for 4 weeks and will continue taking daily montelukast. There will be a 
telephone encounter (Phone Call 2) 1 week into this Treatment Period to ensure safety and confirm that chronic asthma 
symptoms have not worsened. 
After the 4-week treatment period, subjects will come into the ARC for Visit 2. Before aspirin is given, interval history, 
physical exam, ACQ, SNOT-22, TNSS, and spirometry will be recorded, along with FeNO, and a  urine sample will be 
collected for pregnancy and eicosanoid metabolites. Nasal lavage and a nasal epithelial scraping sample will also be taken 
(prior to the TNSS questionnaire to ensure that the procedures do not affect the symptom assessment), along with a blood 
draw for CBC/differential and cellular assays.  After waiting at least 15 minutes following the nasal lavage and scraping so 
that any nasal irritation has subsided, subjects will then undergo an oral aspirin desensitization procedure. They will 
receive an initial 40.5 mg dose of aspirin, and then every 90 minutes will be given increasing doses of 81, 162, and 325 
mg aspirin.  Vital signs are obtained every 90 minutes during the aspirin challenge/desensitization. If at any point the 
subject develops symptoms of a reaction, we will examine them and record the time of onset of reaction. The dose of 
reaction that induces an increase in TNSS of 2 or more points will be recorded as the provocative dose. 
Following the onset of reaction, patients will be observed for a 3-hour period, during which time no more aspirin doses 
will be given. TNSS will be recorded at the onset of reaction and again every 30 minutes during this 3-hour period after 
reaction. Pulmonary function testing is repeated before each dose and at the onset of reaction and if it remains within 
85% of their pre-challenge FEV1, it will be repeated every 90 minutes during the 3-hour period after reaction. If the FEV1 
falls by 15% or more from their morning FEV1, they will be treated with albuterol, administered by metered dose inhaler 
(MDI), (up to 8 puffs per administration), and FEV1 will be repeated every 30 minutes until it has returned to within 85% 
of their morning pre-challenge FEV1. If after 3 rounds of albuterol administered by MDI (a total of 24 puffs), the subject’s 
FEV1 has not returned to within 85% of their morning pre-challenge FEV1, nebulized albuterol will be administered. No 
medications (except albuterol and ipratropium) will be used for relief of symptoms during the desensitization until the 3-
hour period of observation following onset of reaction is completed, unless required for a patient’s safety. A blood 
sample will be collected 1 hour after the onset of reaction for CBC/differential, platelet activation assays, and platelet-
leukocyte aggregate measurements. Urine and nasal samples will be collected at the onset of reaction, and again 90 
minutes and 3 hours after the onset of reaction, or if there is no clinical reaction at all, will be collected 90 minutes after 
the 325mg dose of aspirin is given. 
Upon completion of the 3-hour period of observation, further aspirin doses will be administered every 90 minutes until 
a state of clinical desensitization to and tolerance of 325 mg of aspirin is achieved. Patients will be discharged home 90 
minutes after ingestion of 325 mg of aspirin and will be instructed to begin taking daily aspirin, as is part of our standard-
of-care for these patients. If required due to time constraints, this visit could proceed onto the next day, during which 
the subject would begin by repeating the aspirin dose they ended with the day before.  However, 95% of our aspirin 
desensitization procedures done as part of clinical patient care are completed within the first day. 


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We anticipate it will take us 36 months to 
recruit 45-50 subjects with AERD into this 
study to complete the 4-week treatment 
phase and the aspirin desensitization, with a 
plan to enroll 1-2 subjects/month (15/year). 
Based on the monthly patient referral 
volume at our BWH AERD Center and our 
success in recruiting for our current study, 
our recruitment goal is readily achievable 
(Table 1).  
3.2. Primary Outcome 
The primary outcome is the calculated dose of aspirin that induces an increase in the Total Nasal Symptom Score (TNSS) 
of 2 from the baseline value, or “PD2”.  
The PD2 will be calculated during the aspirin desensitization at Visit 2 as follows: 
𝑖𝑛𝑣𝑒𝑟𝑠𝑒𝑙𝑜𝑔10 (
(2 −(𝑃𝑟𝑒𝑣𝑇𝑁𝑆𝑆−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒𝑇𝑁𝑆𝑆)) × (𝑙𝑜𝑔10𝑃𝑟𝑜𝑣𝑜𝑐𝐷𝑜𝑠𝑒−𝑙𝑜𝑔10𝑃𝑟𝑒𝑣𝐷𝑜𝑠𝑒)
(𝑀𝑎𝑥𝑇𝑁𝑆𝑆−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒𝑇𝑁𝑆𝑆) −(𝑃𝑟𝑒𝑣𝑇𝑁𝑆𝑆−𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒𝑇𝑁𝑆𝑆)
+ (𝑙𝑜𝑔10𝑃𝑟𝑒𝑣𝐷𝑜𝑠𝑒)) 
Where: 
Baseline TNSS =  TNSS score prior to administration of aspirin 
PrevTNSS =  TNSS score immediately previous to onset of aspirin reaction 
MaxTNSS =  Maximum TNSS score recorded during 3-hour observation period during aspirin reaction 
ProvocDose =  Dose of aspirin that provoked a reaction 
PrevDose =  Dose of aspirin that preceded the provocative dose 
We have used this outcome in our current nearly completed study of 40 patients with AERD and have found that it is an 
accurate reflection of reaction severity and aspirin sensitivity. As PD2 is based both on the provocative dose of aspirin 
that induced a reaction and on the severity of the reaction, it reflects each patient’s sensitivity to aspirin. Nasal and 
upper respiratory symptoms (congestion, rhinorrhea, sneezing, nasal and ocular itching) in response to the 
provocative dose of aspirin will be monitored based on a 0- to 5-point scale (0, none; 1, little; 2, moderate; 3, quite a 
bit; 4, severe; 5, very severe) as described.31 The maximum TNSS possible (indicating maximal symptoms) is 40. 
3.3. Secondary Outcomes 
The secondary outcomes include the following: 
• 
The severity of bronchoconstriction (measured by maximum percent fall in FEV1) during the aspirin-induced 
reaction at Visit 2, compared between patients on placebo vs ifetroban. 
• 
Increase in urinary and nasal levels of cysLTs during aspirin-induced reaction at Visit 2 from Visit 2 pre-aspirin 
levels, compared between patients on placebo vs ifetroban, as a proof-of-mechanism that TP receptor signaling 
in AERD drives cysLT overproduction.  
• 
Change in levels of other urinary and nasal eicosanoids, and levels of plasma/serum and nasal tryptase, both 
from Visit 1 to Visit 2 prior to aspirin administration and also from Visit 2 prior to aspirin administration to 
during aspirin-induced reactions at Visit 2, compared between patients on placebo vs ifetroban. 
• 
Change in numbers/percentages of activated platelets and platelet-leukocyte aggregates in the peripheral blood 
between Visit1 and Visit 2 baseline (pre-aspirin administration) and Visit 2 baseline and during the aspirin-
induced reaction at Visit 2, compared between patients on placebo vs ifetroban. 
 


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• 
Change in baseline (pre-aspirin administration) FEV1, Asthma Control Questionnaire (ACQ), and Sino-Nasal 
Outcome Test (SNOT-22) at Visit 2 from Visit 1, compared between patients on placebo vs ifetroban. 
• 
Change in Visit 2 baseline (pre-aspirin administration) levels of exhaled nitric oxide (FeNO) from Visit 1, 
compared between patients on placebo vs ifetroban. 
• 
For each secondary endpoint above, which compares the aspirin-induced changes during the aspirin-induced 
reaction at Visit 2 for patients on placebo vs ifetroban, we will also analyze these changes with provocative 
aspirin dose as a covariate. We will treat provocative aspirin dose as level variable: in log scale, if the aspirin 
doses are 40.5, 81, 162, and 325, we will code the dose variable as dose 1, 2, 3 and 4 assume each increase in 
dose is linear. 
 
 
3.4. Exploratory Outcomes 
The exploratory outcomes include the following: 
 
• 
Plasma and nasal lavage levels of IL-33 , and platelet products, as measured at baseline (pre-aspirin 
administration) and during aspirin-induced reactions at Visit 2, compared between patients on placebo vs 
ifetroban. 
• 
Other inflammatory mediator levels in plasma, nasal lavage, and urine, as measured at baseline (pre-aspirin 
administration) and during aspirin-induced reactions at Visit 2, compared between patients on placebo vs 
ifetroban. 
• 
Levels of surface expression of eicosanoid receptors by effector cells (eosinophils, basophils, and ILC2s) in the 
peripheral blood at baseline (pre-aspirin administration) and during the aspirin-induced reaction at Visit 2, 
compared between patients on placebo vs ifetroban. 
• 
For each exploratory endpoint above, which compares the aspirin-induced changes during the aspirin-induced 
reaction at Visit 2 for patients on placebo vs ifetroban, we will also analyze these changes with provocative 
aspirin dose as a covariate. We will treat provocative aspirin dose as level variable: in log scale, if the aspirin 
doses are 40.5, 81, 162, and 325, we will code the dose variable as dose 1, 2, 3 and 4 assume each increase in 
dose is linear. 
 
3.5. Stratification, Randomization, and Blinding/Masking 
We will use block randomization in groups of four, ensuring that equal numbers of subjects are randomized to each 
group.  For this two-arm balanced-design study, the randomization will consist of blocks of 4 patients randomly assigned 
(allocation ratio of 1:1) to ifetroban or placebo. Matching capsules of ifetroban and placebo will be supplied by 
Cumberland Pharmaceuticals and provided to the BWH Investigational Drugs Services pharmacy (IDS) for storage and 
distribution. The IDS will conduct the randomization and keep records to maintain study blinding.  
3.5.1. Procedure for Unblinding/Unmasking 
Unblinding must be approved by the study Medical Monitor unless an immediate life threatening condition has 
developed and the Medical Monitor is not accessible.  In case of an emergency where a subject needs to be 
unblinded, the PI or physician co-investigators may contact IDS to unblind the subject. The IDS pharmacist is on 
call 24 hours a day. The PI will notify the protocol chair of the unblinding event on the next business day.  
A full account of the event will be recorded, including the date and time of the unblinding, the reason for the 
decision to unblind, and the name of the individual who made the decision and the names of the Medical 
Monitor and others who were notified. The reasons for unblinding of a participant’s treatment will be included 
in the final study report. 
Unblinding of the entire study will require written approval from NIAID. 


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4. Selection of Participants and Clinical Sites/Laboratories 
4.1. Rationale for Study Population 
Since AERD is virtually always an adult-onset disease, adults will comprise all of the study subjects. AERD affects both 
sexes and all races; no exclusions will be made based on sex or ethnicity. 
4.2. Inclusion Criteria 
Individuals who meet all of the following criteria are eligible for enrollment as study participants:  
1. Subject must be able to understand and provide informed consent 
2. Age between 18 and 70 years  
3. History of AERD, defined as meeting the diagnostic triad with: 
a. History of physician-diagnosed asthma and  
b. History of physician-diagnosed nasal polyposis and 
c. History of pathognomonic reactions to aspirin or other nonselective COX inhibitors.  
To ensure all patients stringently meet this criteria and truly have AERD, we will require that patients either: 
1. Have a history of at least two pathognomonic clinical reactions to aspirin or other nonselective COX 
inhibitors with features of lower (cough, chest tightness, wheezing, dyspnea) and/or upper 
(rhinorrhea, sneezing, nasal obstruction, conjunctival itching and discharge) airway involvement. 
Or... 
2. Have had a confirmatory physician-administered challenge with aspirin or another nonselective COX 
inhibitor that induced a pathognomonic respiratory reaction as above.   
4. Stable asthma (post-bronchodilator FEV1 of ≥70%, no glucocorticoid burst (increase > 10mg per day or doubling daily 
dose, whichever is less) for at least 2 weeks prior to Visit 1, and no hospitalizations or ER visits for asthma for at least 
6 months prior to Visit 1), and for those patients on daily oral steroids, they must require no more than a daily dose 
of 10mg prednisone or equivalent for their standard daily therapy to be considered for inclusion. 
5. For females: Non-pregnant and practicing adequate birth control or abstinence  
6. For males: practicing adequate birth control or abstinence  
7. No current smoking (not more than one instance of smoking in the last 3 months) 
4.3. Exclusion Criteria 
Individuals who meet any of these criteria are not eligible for enrollment as study participants:  
1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol 
2. Hypersensitivity to montelukast  
3. Current use of zileuton (which blunts the peak levels of urinary LTE4 during reactions)  
4. Any history of bleeding diathesis or current use of anticoagulant/antiplatelet drugs 
5. Any history of gastrointestinal bleeding 
6. Current use of oral beta blockers, though opthalmic formulations are acceptable 


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7. The use of an additional non-steroidal anti-inflammatory drugs (NSAIDs), except the aspirin dosing as detailed for 
the study 
8. Use of any biologic therapy within the prior 4 months (120 days) of Visit 1. 
9. History of cardiac rhythm disturbances. 
10. Heart rate of <50 bpm at Screening Visit, or evidence of any type of heart block on ECG at Screening Visit. 
11. Pregnant, nursing, or planning to become pregnant. 
12. Past or current medical problems or findings from physical examination or laboratory testing that are not listed 
above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may 
interfere with the participant’s ability to comply with study requirements or that may impact the quality or 
interpretation of the data obtained from the study. 
13. Evidence of liver failure (AST or ALT levels >3x normal at Screening) 
14. Evidence of kidney failure (creatinine levels >1.5mg/dl in women and >1.7mg/dl in men) 
 
5. Known and Potential Risks and Benefits to Participants 
5.1. Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert 
Risks of Ifetroban:  
The pharmacodynamics of ifetroban were studied in single- and repeat-dose safety studies and in an ifetroban and 
aspirin interaction study in healthy volunteers. In the single-dose study, bleeding time was prolonged (2x baseline) in 
subjects receiving doses of ifetroban greater than 10 mg. Platelet aggregation induced by the TP receptor agonist 
U46619 was inhibited by all doses of ifetroban including 10 mg. This effect lasted for up to six days for the highest dose 
(1000 mg). Ifetroban also blocked arachidonic acid-induced platelet aggregation and partially inhibited collagen-induced 
aggregation. While epinephrine-induced primary aggregation was not affected by ifetroban, the secondary aggregation 
(degranulation) appeared to be inhibited. There was no drug effect on ADP-induced aggregation. Ifetroban alone or in 
combination with aspirin inhibited U46619-induced platelet aggregation. Treatment with aspirin alone did not prevent 
U46619-induced aggregation. Bleeding time was prolonged after all doses following the single dose and at steady state, 
although no dose-dependent increase in bleeding time was observed. No indication of accumulation effect was seen 
after nine days of dosing. No significant effect on urinary excretion of TXA2 and prostacyclin metabolites was observed. 
In the aspirin interaction study, urinary excretion of both 2,3-dinor-TXB2 and 2,3-dinor-6-keto-PGF1α was decreased after 
administration of 325 mg of aspirin alone and 325 mg of aspirin + 250 mg ifetroban. Administration of ifetroban alone 
had no effect on urinary excretion of either 2,3-dinor-TXB2 or 2,3-dinor-6-keto-PGF1α. Thus, TP receptor blockade has no 
effect on the synthesis of vasoprotective PGI2. Of specific importance to our proposed trial, no significant safety concerns 
emerged in the studies of ifetroban with aspirin. 


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Ifetroban was the subject of 24 controlled and uncontrolled human pharmacology and pharmacokinetic studies. It was 
also the subject of eight placebo-controlled clinical trials for various cardiovascular indications which are summarized in 
Table 2. The incidence rate of adverse events was generally comparable between the ifetroban-treated subjects and the 
placebo-treated subjects. Bradycardia was reported 
more often in the ifetroban group (N=32; 3.3%) than 
with placebo (N=7; 1.2%). Gastrointestinal events 
tended to occur more often in the ifetroban subjects 
than in the placebo subjects, although incidence 
rates were too small to suggest a trend or pattern. 
The most frequently reported adverse events (N; % 
ifetroban vs. N; % placebo) were headache (N=80; 
8.4 vs. N=47; 7.7), musculoskeletal pain (N=48; 5.0 vs. 
N=19; 3.1), angina pectoris (N=33; 3.5 vs. N=22; 3.6), 
bradycardia (N=32; 3.3 vs. N=7; 1.2), myocardial 
infarction (N=28; 2.9 vs. N=18; 3.0), nausea/vomiting 
(N=25; 2.6 vs. N=10; 1.6), dyspepsia (N=24; 2.5 vs. 
N=9; 1.5), upper respiratory infection (N=24; 2.5 vs. 
N=9; 1.5), hematoma (N=23; 2.4 vs. N=8; 1.3), 
coronary artery bypass (N=22; 2.3 vs. N=10; 1.6), 
coronary angioplasty (N=21; 2.2 vs. N=10; 1.6), abdominal pain (N=20; 2.1 vs. N=10; 1.6), and anxiety/nervousness 
(N=19; 2.0 vs. N=9; 1.5). All remaining events occurred at a rate less than 2.0% in both treatment groups except for 
dizziness which occurred in 2.1% (N=13) of placebo-treated subjects (ifetroban: N=13; 1.9%). 
5.1.1. Reproductive Risks and Toxicology for Ifetroban 
Reproductive Risks:  
Pregnant and nursing females will not be included in clinical trials of ifetroban. Furthermore, sexually active 
enrollees should be counselled against either becoming pregnant or fathering a child while participating in ifetroban 
clinical trials. Acceptable methods of male birth control include abstinence, 3-months post vasectomy, or condom 
use in combination with spermicide. Females of nonchildbearing potential may be allowed to participate provided 
that they are either 12-months post-menopausal prior to the first dose of study drug or have been surgically 
sterilized (e.g. tubal ligation or hysterectomy). Females of childbearing potential may be allowed to participate 
provided they use an acceptable method of contraception. Acceptable female methods of birth control include 
abstinence, condom used in combination with spermicide, oral contraceptives or contraceptive patch, contraceptive 
ring, or an implanted intrauterine device. Ifetroban appears to be teratogenic in rodents. Embryo-fetal toxicity was 
observed at doses of 100 and 1000 mg/kg administered orally by gavage once daily during gestation and 
maternotoxicity was seen at the 1000 mg/kg dose. No drug-related changes in the dams or fetuses were seen at the 
10 mg/kg level. While these levels are well in excess of those studied in clinical trials thus far, the effects of ifetroban 
on human fetal development are unknown.  
 
 
 
 


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Rat Model  
An initial teratology study in rats examined once daily doses (750 and 1500 mg/kg) of ifetroban administered by 
oral gavage to presumed pregnant rats on days 6 through 15 of gestation. There was a high incidence of 
resorptions at the doses studied (Lochry 1993, Internal Report 93012).  
A reproductive toxicity study conducted in rats investigated once daily doses of ifetroban administered by oral 
gavage (7, 70, and 700 mg/kg) to both male and female rats prior to mating (4 week in males and 2 week in 
females) and during gestation. No reproductive effects in terms of fertility or early embryonic development 
were detected (Lochry 1995, Internal Report 94020).  
In a second reproductive toxicity study, rats were given once daily doses (7.5, 75, 750 mg/kg) of ifetroban by oral 
gavage (gestation days 6-21) were well tolerated at doses up to 75 mg/kg. At 750 mg/kg, ifetroban was deemed 
toxic resulting in mortality, body weight loss, and enlarged adrenals and kidneys in the dams and an increased 
frequency of stillbirths and poor pup survival in the offspring (Gietl 1996, Internal Report 95201).  
In a study of embryo-fetal development in rats, ifetroban was administered orally by gavage to presumed-
pregnant rats once daily on days 6 through 15 of gestation at doses of 10, 100, or 1000 mg/kg. There were no 
drug-related changes in the dams or fetuses at 10 mg/kg. At 100 mg/kg, maternal liver weights were increased 
and the offspring demonstrated dilated lateral ventricles in the brain. At 1000 mg/kg, the dams again 
demonstrated increased liver weights as well as mortality associated with stomach lesions (concretions, ulcers, 
perforations, thickened mucosa, and/or multifocal discoloration of the stomach); body-weight loss; decreased 
food consumption; increased incidences of chromodacryorrhea, piloerection, and salivation or regurgitation of 
the dosing solutions; and increased kidney and spleen weights. Embryo-fetal toxicity at 1000 mg/kg included 
increased resorptions with an associated decrease in live-litter size, enlarged subarachnoid space of the brain, 
irregular ossification of the sternum, and decreased fetal weights with related developmental delays in 
ossification of the vertebrae, sternebrae, metacarpals, metatarsals, and phalanges. Ifetroban is therefore 
considered teratogenic in rats (Internal Report 94211, Feb 1996). 
Rabbit Model  
A reproductive toxicity study conducted in rabbits investigated once daily doses of ifetroban administered by 
oral gavage (4, 40, and 400 mg/kg) to presumed pregnant females on days 6 through 18 of gestation. No 
changes were seen in animals receiving either 4 or 40 mg/kg. At 400 mg/kg, maternal findings included body 
weight loss and decreased food consumption and the offspring demonstrated sternal defects (Jahn 1995, 
Internal Report 94207). 
5.2. Risks of Investigational Product or Intervention cited in Medical Literature 
5.3. Risks of Other Protocol Specified Medications 
Risks of montelukast.  Montelukast is a widely prescribed, once daily oral therapy approved for the treatment of asthma 
and allergic rhinitis. It is commonly prescribed as a treatment for AERD because of the established prominent role for 
the cysLTs in the disease. It is useful for reducing the severity of bronchoconstrictor responses to aspirin administration, 
likely due to its ability to competitively antagonize the effects of LTC4 and LTD4 acting at CysLT1R. Montelukast is 
generally safe and well tolerated. The most common adverse reactions to montelukast identified in placebo-controlled 
trials (incidence ≥ 5% and greater than placebo; listed in descending order of frequency) were upper respiratory 
infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, 


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and otitis. Additional reactions reported voluntarily during post-approval use of montelukast are of unknown frequency, 
and causality is not established. These include increased bleeding tendency, hypersensitivity reactions including 
anaphylaxis, hepatic eosinophilic infiltration, agitation including aggressive behavior or hostility, anxiousness, 
depression, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and 
behavior (including suicide), tremor, drowsiness, paresthesia/hypoesthesia, seizures, palpitations, epistaxis, diarrhea, 
dyspepsia, nausea, pancreatitis, vomiting, and hepatitis. Cases of eosinophilic granulomatosis with polyangiitis (Churg-
Strauss syndrome) have been reported as well. Most, but not all, of these cases have been associated with the reduction 
of oral glucocorticoid therapy.  
Risks of aspirin treatment.  Aspirin, or acetylsalicylic acid, is a nonsteroidal anti-inflammatory drug primarily 
used to temporarily relieve fever and minor aches and pains due to: headache, colds, muscle pain, toothache, 
menstrual pain, and arthritis pain. In this study we will be using the generic form of Bayer Aspirin Regimen (81 mg) and 
Ecotrin (325 mg). Aspirin is FDA approved and will be open label throughout the entire study. Visit 2 of the intervention 
study involves desensitization to aspirin followed by twice daily administration of aspirin at 650 mg, which the patients 
will then continue as part of their standard medical regimen. Aspirin is being used as both a provocative agent and a 
therapeutic. The risks of aspirin treatment after desensitization are described here, whereas the risks of the aspirin 
desensitization procedure appear below. Treatment of individuals with AERD with aspirin is an accepted approach and a 
standard of practice for individuals with AERD whose sinonasal disease cannot be adequately controlled with topical or 
systemic glucocorticoid therapy. The most common side effects of aspirin are bruising, gastrointestinal bleeding, 
cerebral hemorrhage, gastric irritation, and tinnitus. In a study of aspirin at 650 mg twice daily as a long-term (1 year) 
treatment for AERD, 14% of 172 patients discontinued aspirin due to side effects, and 70% had a clinical benefit.11  
Risks of corticosteroids.  Virtually all subjects will have been on inhaled corticosteroids prior to enrollment in the study, 
and some will have been maintained on chronic oral steroids. Corticosteroid dosing will not be changed for this study. 
Nonetheless, subjects will be informed that when taken at high doses for extended periods, inhaled corticosteroids can 
produce hoarseness, sore throat, and thrush, as well as cause adrenal gland suppression, weight gain, bruising of the 
skin, and diabetes. Inhaled corticosteroids have also been associated with reduced growth velocity in children, but 
subjects in our study will all be age 18 and over. 
5.4. Risks of Study Procedures  
Risks of aspirin desensitization procedure.  All individuals with AERD will experience a clinical reaction to aspirin, most 
often at a dose of 81 mg or below. By using the modified Scripps Institute protocol,32 limiting the study to individuals 
with stable asthma and no history of life-threatening reaction to COX inhibitors, and administering montelukast to all 
individuals undergoing the challenge, the procedure can safely be done in an ambulatory setting and is routinely 
performed in the Allergy Clinic at the BWH. To ensure safety of the challenge, vital signs will be obtained every 90 
minutes, and patients are instructed to report any of the following symptoms; cough, dyspnea, chest tightness, 
rhinorrhea, congestion, sneeze, ocular pruritus and discharge. Spirometry is repeated before each dose, or at the time 
symptoms are reported. A decrease in pre-challenge FEV1 of 15% or more is considered indicative of a positive lower 
respiratory tract reaction. In our experience, ~60% of individuals with AERD who are treated with montelukast develop 
airflow obstruction of this magnitude, while the remainder experience a reaction confined to the sinonasal tract. In 
addition to respiratory symptoms, occasionally extrapulmonary symptoms occur as well, which can include 
gastrointestinal manifestations (abdominal discomfort, nausea, vomiting, or diarrhea) and skin manifestations (flushing, 
itching, and rash). Systemic reactions that involve the cardiovascular system are very rare in this selected population. 


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Injectable adrenalin, oxygen, and resuscitation equipment are present in the ARC in the unlikely event of a systemic 
reaction, as are physicians skilled in resuscitation.  
Risks of ACQ, SNOT-22, and TNSS questionnaires.  There are no risks associated with questionnaires. 
Risk of blood draw.  Risks associated with drawing blood include some pain when the needle is inserted. There is a small 
risk of bruising and/or infection at the place where the needle enters the arm.  Some people may experience 
lightheadedness, nausea or fainting.  It is possible to develop an infection, but this is rare and can be treated. 
Risk of spirometry. Occasionally, individuals may develop a slight dizzy feeling and/or temporary cough and/or chest 
discomfort when performing breathing tests. These tests are used in hundreds of laboratories throughout the world on 
a daily basis without harmful effects. 
Risks of Exhaled Nitric Oxide (FeNO). There are no known risked for exhaled nitric oxide collection.   
Nasal fluid and cell collection.  The nasal procedures that we will use to collect fluid and cells from the nose may be 
uncomfortable. When using a nasal sponge, the absorbent cotton material will increase in size with absorption of nasal 
discharge and may result in transient blockage of the nostrils or sensation of fullness or pressure. Local irritation of the 
nostril is possible which could include blood-tinged discharge that is expected to resolve on its own. To minimize the 
possibility of inducing blood-tinged discharge, we will alternate which nostril is used for nasal sample collection. Risk for 
infection will be minimized by using sterile absorbent material for each collection. Rinsing the nose with saline solution 
may result in accidental swallowing of the saline solution and brushing the inside of the nose may cause minor local 
bleeding. 
5.5. Potential Benefits 
Most subjects are expected to benefit from the desensitization and aspirin treatment following Visit 2 of the study. 
There is a small potential benefit to individual subjects while taking ifetroban if it improves chronic symptoms or 
decrease the severity of response to aspirin challenge. If TP receptor antagonism does block features of the reaction to 
aspirin or improves symptomatic control of AERD, it would support the use of ifetroban or other TP receptor antagonists 
as potential therapeutic agents in AERD. Thus, the studies should shed light on how to improve therapy for AERD and 
better understand how these therapies work.  
The risks associated with the treatments in this study are identifiable and small. There is extensive experience with 
ifetroban, and the brief period during which individuals are being treated with both ifetroban and aspirin are not likely 
to substantially increase the risk of bleeding. Furthermore, the risk of severe reactions to aspirin challenges are low, and 
such reactions can be readily managed in the study setting.  
6. Investigational Agent /Device/Intervention  
6.1. Investigational Agents/Devices/Interventions 
6.1.1. Investigational Agent #1 
Ifetroban: Cumberland Pharmaceuticals  
6.1.1.1. Formulation, Packaging, and Labeling 
Description of the Formulation: Ifetroban capsules are formulated as a dry powder blend and filled into 
hard gelatin capsules.  The formulation consists of Ifetroban, mannitol, microcrystalline cellulose, 


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crospovidone, magnesium oxide, colloidal silicon dioxide, and magnesium stearate.  Capsules are filled 
into high density polyethylene bottles and sealed with screw-cap closures.   
Stability Characteristics of the Formulation: Ifetroban capsules are part of an ongoing stability study to 
support long term use in clinical studies.  Available data suggest the capsules will be stable for at least 24 
months.   
6.1.1.2. Dosage, Preparation, and Administration 
Oral Ifetroban is supplied as a 50mg capsule (4 capsules will be provided for each 200mg dose) for oral 
administration and is taken once daily. It is stored at controlled room temperature. 
6.1.2. Investigational Agent #2 
Placebo: Cumberland Pharmaceuticals  
6.1.2.1. Formulation, Packaging, and Labeling 
Description of the Formulation: Placebo for ifetroban 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. 
6.1.2.2. Dosage, Preparation, and Administration 
Placebo capsules will be supplied for oral administration and 4 capsules will be taken once daily. It is 
stored at controlled room temperature. 
6.1.3. Investigational Agent #3 
Aspirin 
6.1.3.1. Formulation, Packaging, and Labeling 
• 
Active ingredient: Aspirin 
• 
Doses will range from 40 mg- 650 mg.  
• 
Doses will be given in the form of yellow (81 mg) or orange (325 mg) tablets.  
• 
Store aspirin between 20 and 25 C (68 and 77 F). 
• 
Manufactured by Rugby Laboratories, Duluth, Georgia.  
 
6.1.3.2. Dosage, Preparation, and Administration 
Aspirin will be open label. We will increase the dose of aspirin from 40 mg to 325 mg during the course 
of a day.  All aspirin will be taken by mouth and should be taken with plenty of water.  We will obtain 
the aspirin for this study from the IDS pharmacy. They will count and dispense the correct amount of 
aspirin needed. For the 40 mg dose of aspirin, we will use ½ of a chewable 81 mg tablet of aspirin.  
 
6.2. Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) the investigator will maintain adequate records of the 
disposition of the investigational agent, including the date and quantity of the drug received, to whom the drug was 
dispensed (participant-by-participant accounting), and a detailed accounting of any drug accidentally or deliberately 
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Records for receipt, storage, use, and disposition will be maintained by the study site.  A drug-dispensing log will be kept 
current for each participant.  This log will contain the identification of each participant and the date and quantity of drug 
dispensed. 
All records regarding the disposition of the investigational product will be available for inspection by NIAID. 
Unused study drugs will be returned to the IDS pharmacy. Unused study drugs will only be re-used if they were never in 
the hands of the subject. Once the subject has received the drugs, any unused drugs will be destroyed on site.  
6.3. Assessment of Participant Compliance with Investigational Agent 
Subjects will be asked to bring back any remaining doses of montelukast at Visits 1 and 2, and ifetroban or placebo, at 
Visit 2. We will provide subjects with bottles for each medication. The number of pills in the bottles will be clearly 
labeled on the bottle at the time of dispensation.  We will also provide subjects with medication diary cards to fill out at 
home where they will write the number of study medication (ifetroban/placebo) and montelukast pills taken daily. 
6.4. Toxicity Prevention and Management 
No modifications are permitted. 
6.5. Premature Discontinuation of Investigational Agent 
Study therapy may be prematurely discontinued for any participant for any of the following reasons: 
• 
A subject has more than one protocol-defined asthma exacerbation (defined as the development of an increase 
in symptoms of cough, chest tightness, or wheezing [independently of the symptoms anticipated to occur as a 
result of the aspirin challenge] requiring treatment with oral glucocorticoids. For those subjects maintained with 
a stable oral glucocorticoid dose, the definition will be an increase of ≥10 mg or a doubling of dose, whichever is 
less) 
• 
The subject experiences gastrointestinal bleeding 
• 
The subject becomes pregnant 
Study therapy may also be prematurely discontinued for any participant if the investigator believes that the study 
treatment is no longer in the best interest of the participant. Subjects that must discontinue the investigational agent 
will come in for a final visit with a study physician.  
7. Other Medications 
7.1. Concomitant Medications 
7.1.1. Protocol-mandated 
Montelukast:  Montelukast protects the lower airways from severe reactions in patients undergoing aspirin 
desensitization and thus increases the safety of aspirin challenges and desensitizations.  It is the standard of care 
to use montelukast as a pre-treatment for patients with AERD undergoing a planned aspirin desensitization, and 
therefore all participants will be prescribed montelukast 10 mg daily for the duration of the study.   
7.1.2.  Other permitted concomitant medications 


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• 
Inhaled, oral or nasal corticosteroids:  Participants may enter the trial on such medications based on the 
underlying condition.  No modifications will be made with the exception of a temporary increase in the dose 
of oral corticosteroids if worsening asthma requires such an intervention. For those patients who require 
daily oral steroids for their standard maintenance regimen, they must be on no more than a daily dose of 
10mg prednisone or equivalent for their standard daily therapy to be considered for inclusion. 
• 
Inhaled long acting beta-adrenergic agonists and inhaled ipratropium: participants may enter the trial on 
such medications based on the underlying condition.  No modifications will be made in the course of the 
trial.  
• 
Inhaled short acting beta-adrenergic agonists (PRN use): participants may enter the trial on such 
medications based on the underlying condition.  No modifications will be made in the course of the trial.       
7.2. Prophylactic Medications 
N/A 
7.3. Prohibited Medications 
• Zileuton. Subjects who were previously taking zileuton will discontinue it at the Screening Visit so as not to 
interfere with cysLT production and the accurate assessment of clinical symptoms occurring during the aspirin 
desensitization. A telephone encounter (Phone Call 1) 1 week after the Screening Visit will ensure safety and 
confirm stable asthma for those patients who were asked to discontinue zileuton. Zileuton may be used as a 
rescue medication during the aspirin desensitization procedure, but the subject must be free of zileuton for at 
least 3 weeks preceding each Study Visit.  
• Anticoagulants. Use of warfarin or any other antiplatelet or anticoagulant medications will be prohibited. 
• Beta-blockers. Due to the risk of bronchospasm associated with beta blockers, current use of any oral beta 
blocker will be prohibited. 
• NSAIDs. The use of any additional non-steroidal anti-inflammatory drugs (NSAIDs), except the aspirin dosing as 
detailed for the study, will be prohibited throughout their participation in the study. 
• Biologics. The use of any biologics is prohibited in the 120 days prior to Visit 1, and throughout the study.  
 
7.4. Rescue Medications  
The following medications can be used during the aspirin desensitization at Visit 2, for patient safety and/or comfort. 
Only albuterol and ipratropium may be used during the designated 3-hour period of observation following the onset of 
reaction symptoms. The remaining medications may only be provided for patient comfort after the 3-hour period of 
observation has concluded. 
• 
Albuterol. 90 mcg/puff of MDI albuterol (up to 8 puffs per administration), a total of 3 administrations and 
2.5mg of nebulized albuterol may be used as rescue inhalation treatment during the aspirin 
challenge/desensitization procedures, if bronchospasm occurs. 
• 
Ipratropium. 0.5 mg/vial of ipratropium may be used during the aspirin challenge/desensitization procedures, if 
needed for patient comfort, to relieve any ongoing symptoms of reaction to aspirin if albuterol does not suffice. 
• 
Zileuton (Zyflo CR). 1200 mg PO x1-2 may be given for patient comfort due to upper or lower respiratory 
symptoms, swelling, skin changes, or gastrointestinal discomfort. 


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• 
Prednisone. 20-50mg PO x1 may be given for patient comfort due to upper or lower respiratory symptoms, 
swelling, skin changes, or gastrointestinal discomfort. 
• 
Ondansetron. 4-8 mg ODT tablet x1 may be given PO for patient comfort due to nausea, vomiting, or 
gastrointestinal discomfort. 
• 
Diphenhydramine. 25 mg PO x1 may be given for patient comfort due to skin changes, itching, congestion, or 
rhinorrhea. 
8. Study Procedures 
8.1. Enrollment 
Our study population will consist of individuals with suspected AERD referred to the Brigham and Women’s Hospital 
(BWH) Drug Desensitization Program for diagnostic evaluation and potential aspirin challenge/desensitization.  
Patients seen in evaluation for suspected AERD in either the Allergy or Pulmonary Clinics at BWH will be identified by 
their allergist or pulmonologist, and if interest is expressed in aspirin challenge/desensitization and participation in the 
study, will be offered the opportunity to take home the Consent Form and call back if they wish to participate.   
As several of the investigators conducting this study are recognized as specialists in the field of aspirin 
challenge/desensitization and management of patients with AERD, it is likely that a high proportion of patients with 
AERD will be identified from within their own clinical practice and referral base at BWH.  In order to minimize the 
possibility that these patients will feel obligated to participate because it is their own physician who is asking, those 
investigators will initially present the study and offer a Consent Form to take home, and then ask a physician colleague 
or study coordinator  to re-contact the potential study participant.  
The research study will be explained in lay terms to each potential research participant. The potential participant will 
sign an informed consent form before undergoing any study procedures. Once the participant consents to the study and 
signs the informed consent, the participant is considered enrolled in the study and will be assigned a unique participant 
number.   
8.2. Screening/Baseline Visit 
Screening Visit  The purpose of the screening visit is to confirm eligibility to continue in the study.  
The following procedures, assessments, and laboratory measures will be conducted to determine participant eligibility:  
1. A physical exam 
2. Spirometry to assess lung function 
3. Lab work (urine pregnancy, liver enzymes (AST and ALT), and creatinine level) 
4. Assessment of asthma control (ACQ score, which evaluates asthma control over the proceeding 1 week) 
5. Assessment of nasal symptoms (SNOT-22 score, which assesses nasal symptoms over the proceeding 2 
weeks) 
6. Baseline ECG 
The labwork is typically completed within 24 hours of the blood draw.  After the Screening Visit there is a 2-week Run-in 
Period in which subjects will begin taking montelukast 10mg daily (if not already on montelukast as part of their regular 
asthma care). A telephone encounter (Phone Call 1) 1 week later will ensure safety and confirm stable asthma.  
8.3.  Study Visits  


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Visit 1  After the 2-week Run-In period on montelukast, subjects will come into the ARC for their baseline visit (Visit 1). 
The following procedures, assessments, and laboratory measures will be conducted: 
1. Interval history, physical exam, ACQ, SNOT-22, TNSS and spirometry will be recorded, along with FeNO.  
2. Blood will be drawn for CBC/differential, and the cellular profiling and activation assays.  
3. A urine sample will be collected for pregnancy and eicosanoid metabolites. Nasal lavage for cytokine and 
eicosanoid measurements and a nasal epithelial scraping sample for RNA extraction will be taken. 
4. Subjects will be randomized to receive ifetroban (200 mg dose per day), or placebo for 4 weeks.  
Subjects will take ifetroban or placebo daily for 4 weeks and will continue taking daily montelukast. There will be a 
telephone encounter (Phone Call 2) 1 week into this Treatment Period to ensure safety and confirm that chronic asthma 
symptoms have not worsened (as assessed by an ACQ-6 score). 
 
Pharmacokinetic studies of ifebtroban have demonstrated that ifetroban absorption is lower, and maximum plasma 
concentration is lower, if the drug is taken following a meal.  To ensure that absorption of the oral ifetroban is 
consistent, it is recommended that it should be taken 30 minutes or more prior to a meal.  Therefore, we will request 
that patients take their daily ifetroban or placebo tablets first thing in the morning, at least 30 minutes before their 
breakfast. 
Until institutional guidelines change, all subjects must obtain a negative COVID-19 test result within 72 hours prior to 
Visit 2. This is to ensure the safety of study staff during the pandemic due to aerosol-generating procedures that may 
occur at Visit 2. If the COVID-19 test comes back positive, the subject will be informed of their positive results and will be 
withdrawn from the study. They will receive a safety phone call one week later as follow-up. 
Study staff will refer subjects to the current best PCR COVID test available advised by Infectious Disease. 
Visit 2   After the 4-week treatment period, subjects will come into the ARC for Visit 2. 
1. Interval history, physical exam, ACQ, SNOT-22, TNSS and spirometry will be recorded, along with FeNO.  
2. Before aspirin is given, a  urine sample will be collected for pregnancy and eicosanoid metabolites, and a  nasal 
fluid and nasal epithelial scraping sample will be taken, along with a blood draw for CBC/differential and 
cellular assays.   
3. Subjects will then undergo an oral aspirin desensitization procedure. They will receive an initial 40.5 mg dose 
of aspirin, and then every 90 minutes will be given increasing doses of 81, 162, and 325 mg aspirin.   
4. Vital signs are obtained every 90 minutes during the aspirin challenge/desensitization.  
5. If at any point the subject develops symptoms of a reaction, we will examine them and record the time of 
onset of reaction. The dose of reaction that induces an increase in TNSS of 2 or more points will be recorded 
as the provocative dose. 
6. Following the onset of reaction, patients will be observed for a 3-hour period, during which time no more 
aspirin doses will be given. TNSS will be recorded at the onset of reaction and again every 30 minutes during 
this 3-hour period after reaction. 
7. Pulmonary function testing is repeated before each dose and at the onset of reaction and if it remains within 
85% of their pre-challenge FEV1, it will be repeated every 90 minutes during the 3-hour period after 
reaction. If the FEV1 falls by 15% or more from their morning pre-challenge FEV1, they will be treated with 


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MDI albuterol (up to 8 puffs per administration), followed by nebulized albuterol if needed and FEV1 will be 
repeated every 30 minutes until it has returned to within 85% of their morning pre-challenge FEV1. 
8. No medications (except albuterol and ipratropium) will be used for relief of symptoms during the 
desensitization until the 3-hour period of observation following onset of reaction is completed, unless 
required for a patient’s safety. 
9. A blood sample will be collected 1 hour after the onset of reaction for CBC/differential, platelet activation 
assays, and platelet-leukocyte aggregate measurements. Urine and nasal fluid samples will be collected 90 
minutes after the onset of reaction, or if there is no clinical reaction at all, will be collected 90 minutes after 
the 325mg dose of aspirin is given. 
Upon completion of the 3-hour period of observation, the subject will receive the provocative dose for a second time 
followed by the next subsequent aspirin dose after 90 minute observation intervals. Once the subject has effectively 
tolerated, as determined by a study physician, the repeat provocative dose and one subsequent dose bringing the 
cumulative dose of aspirin ingested during the procedure to ≥325 mg, the subject will be discharged home 90 minutes 
after the last dose, and will be instructed to begin taking daily aspirin, 325mg twice daily for a week until the Phone Call 
3, as is part of our standard-of-care for these patients.  
Following the 3-hour period of observation, the rescue medications described in Section 7.4 may be used for patient 
comfort. A sufficient 2-week supply of aspirin will be provided for patients so that they have enough to have them 
continue daily aspirin through the 2-week follow-up phase. 
Follow-up Phase (2 weeks):  During the follow-up phase, safety will be assessed through a telephone interview (Phone 
Call 3) 1 week after Visit 2 to recommend the patient increases their daily aspirin dose from 325mg twice daily to 650mg 
twice daily, and again through a telephone interview (Phone Call 4) 1 week after that dose increase to ensure that the 
patient is tolerating the 650mg twice daily aspirin therapy and to ensure that the patient has an appropriate follow-up 
visit scheduled with their primary provider within 2 months of initiating the daily aspirin therapy. In order to ensure 
patient safety and consistency, patients will be prescribed sufficient montelukast at the Screening Visit to have them 
continue daily montelukast through this follow-up phase.  
8.4. Visit Windows 
Study visits should take place within the time limits specified below: the designated visit windows (i.e. +/- n days) for 
each scheduled visit are also indicated on the Table of Events. 
Table 3. Table of Events.  
Screening Visit 
Phone Call 1 
Visit 1** 
Phone Call 2 
Visit 2 
Follow-up: 
Phone Call 3 
Follow-up: 
Phone Call 4 
Week 0 
Week 1  
(±3 days) 
Week 2  
(±5 days)* 
Week 3  
(±3 days) 
Week 6 (+10 
days/- 5 days) 
Week 7  
(± 3 days) 
Week 8  
(±3 days) 
*The run in period after the Screening Visit can be skipped for Visit 1 if the subject is already taking montelukast at the 
time of the Screening Visit, so that for patients already taking montelukast for at least 2 weeks prior to Screening, Visit 1 
could occur as soon as 24 hours after Screening.  
**A 6-week supply of ifetroban will be provided at Visit 1. 
9. Mechanistic Assays 
Assess the effect of TP receptor blockade in vivo on platelet activation in vivo. 20 -40µL of blood or platelet-rich plasma 
will be stained with Abs against CD61 and P-selectin. The percentages of P-selectin+ events in the CD61+ platelet-sized 


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gate will be determined. The changes in P-selectin+ platelets will be correlated with the corresponding changes in urinary 
eicosanoids and nasal lavage eicosanoids. 
Assess the effect of TP receptor blockade on platelet activation in vitro. Platelet rich plasma obtained at visit 1 and before 
the challenge at Visit 2 will be stimulated with LTC4 or with U46619 for 30 min. Platelets will be monitored for activation, 
and platelet-free supernatants monitored for TXA2 generation. 
Determine the effect of TP receptor blockade on release of mediators derived from cell activation. Nasal lavage fluids will 
be collected once at Visit 1 and again prior to administration of aspirin at Visit 2 and then serially at Visit 2 during the 
reactions to aspirin, and will be monitored by ELISA for mediators derived from mast cell and platelet activation. 
Monitor innate Type 2 cytokine expression. RNA from nasal scrapings obtained at Visits 1 and 2 (before challenge) will 
be subjected to qPCR analysis for expressions of IL-33 and TSLP. Nasal fluid IL-33 levels will be measured at baseline and 
during reactions. 
Monitor activation of mast cells and their associated eicosanoids. Total tryptase concentrations in nasal fluid and 
plasma/serum will be measured by ELISA (performed at Virginia Commonwealth University on a fee-for service basis). 
Urinary PG metabolites will be measured by GC-MS and LTE4 by LC-MS as in our previous studies,12 and nasal eicosanoids 
will be measured by ELISA. 
10. Biospecimen Storage   
The following biospecimen types will be obtained with the intention to be analyzed within the context of this protocol, 
but in some cases, there may be excess sample volume left over after the specified analyses. In those cases, the excess 
volume would be stored in our long-term biorepository (Core C) as detailed in the AADCRC overall proposal. 
• 
Nasal fluid 
• 
Nasal cells 
• 
Urine 
• 
Plasma 
• 
Serum 
Sample storage data will be accessible only to members of the AADCRC projects at BWH, and the BWH Asthma Research 
Center via clinical sample management software. Before patient visits, anticipated samples will be entered into the 
database and associated with the patient ID and the date and number of the visit so that labels for sample containers 
can be printed and applied. When samples are received, the entries will be updated to reflect the actual type and 
number of samples obtained, any aliquots of samples to be made for storage purposes will be accounted for, labels will 
be printed for the aliquot tubes, and space in a dedicated -80°C freezer will be assigned. This process will permit tracking 
of the history of all samples, as well as multi-parameter searches to identify and locate samples with the characteristics 
and thus minimize temperature fluctuations in the freezer when samples are sought. 
11. Criteria for Participant and Study Completion and Premature Study Termination 
11.1. 
Participant Completion 
After completing Visit 2, the subjects will have completed the study.  
11.2. 
Participant Stopping Rules and Withdrawal Criteria 


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Participants may be prematurely terminated from the study for the following reasons: 
1. The participant elects to withdraw consent from all future study activities, including follow-up. 
2. The participant is “lost to follow-up” (i.e., no further follow-up is possible because attempts to reestablish 
contact with the participant have failed). 
3. The participant dies.  
4. The Investigator no longer believes participation is in the best interest of the participant. 
5. A subject has more than one protocol-defined asthma exacerbation (defined as the development of an increase 
in symptoms of cough, chest tightness, or wheezing [independently of the symptoms anticipated to occur as a 
result of the aspirin challenge] requiring treatment with oral glucocorticoids. For those subjects maintained with 
a stable oral glucocorticoid dose, the definition will be an increase of ≥10 mg or a doubling of dose, whichever is 
less) 
6. The subject experience gastrointestinal bleeding 
7. The subject becomes pregnant 
11.3. 
Participant Replacement 
Additional participants will be recruited if a participants withdraw or are withdrawn if the termination occurs prior to 
receiving the first dose of the study medication (ifetroban or placebo). 
11.4. 
Follow-up after Early Study Withdrawal 
If a subject needs to discontinue any of the investigational drugs prior to the end of the study, we will ask him/her to 
come in for one final visit. During this visit we will ask them to return all unused medication, have one final blood draw 
(to make sure their complete blood count (CBC) is normal), and one final pregnancy test (if applicable). If the subject 
does not return for this final visit, a study investigator will attempt to speak to the subject by telephone, and if 
unreachable at their preferred contact number, a clear message regarding the importance of follow-up and study 
investigator contact information will be left. If a subject experiences an adverse event that results in discontinuation 
from the study, we will follow the subject until the event is resolved or until the subject is discharged to alternate care. 
11.5.  Study Stopping Rules 
The study may be prematurely terminated for the following reasons: 
The Study PI or ISM may terminate this study at any time. Reasons for termination may include, but are not limited to 
the incidence or severity of AEs in this study indicating a potential health hazard to subjects or unsatisfactory subject 
enrollment. Any serious and/or persistent noncompliance by the investigator with the protocol, the clinical research 
agreement, the Form FDA 1572, or other local applicable regulatory guidelines in conducting the study may also be 
grounds for termination of the study. The PI will promptly inform all other investigators conducting the study if the study 
is suspended or terminated for safety reasons and will also inform the regulatory authorities of the suspension or 
termination of the study and the reason(s) for the action.  
Study enrollment, investigational drug, and study procedures will be suspended pending expedited review of all 
pertinent data by the IRB and the NIAID, if any one of the following occurs: 
1. If any death occurs that is designated as related to ifetroban or to a study procedure 


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2. If 3 AERD enrolled trial participants experience serious non-fatal AEs related to aspirin desensitization, or if 2 
AERD enrolled participants experience serious non-fatal AEs related to ifetroban/placebo, or to another study 
procedure. 
12. Safety Monitoring and Reporting 
12.1 Overview 
This section defines the types of safety data that will be collected under this protocol and outlines the procedures for 
appropriately collecting, grading, recording, and reporting those data. Adverse events that are classified as serious 
according to the definition of health authorities must be reported promptly (per Section 12.5, Reporting of Serious 
Adverse Events and Adverse Events) to the sponsor DAIT/NIAID.  Appropriate notifications will also be made to site 
principal investigators, Institutional Review Boards (IRBs), and health authorities.  
Information in this section complies with ICH Guideline E2A: Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting, ICH Guideline E-6: Guideline for Good Clinical Practice, 21CFR Parts 312 and 320, and applies the 
standards set forth in the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.0: http://ctep.cancer.gov/reporting/ctc.html. 
12.2 Definitions 
12.2.1 Adverse Event (AE) 
Any untoward or unfavorable medical occurrence associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research (modified from the definition of 
adverse events in the 1996 International Conference on Harmonization E-6 Guidelines for Good Clinical Practice) 
(from OHRP "Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or 
Others and Adverse Events (1/15/07)" http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2 )  
For this study, an adverse event will include any untoward or unfavorable medical occurrence associated with:   
• 
Study therapy regimen:  
o Ifetroban: any AEs occurring during the treatment period after randomization and for 14 days 
after completion or discontinuation from the study.  
o Aspirin desensitization: any AEs occurring during the aspirin desensitization and for 14 days after 
completion or discontinuation from the study.  
▪ 
The aspirin challenge/desensitization procedures are expected to produce a set of aspirin-
induced reaction symptoms, which can vary from patient-to-patient, and are listed in  Section 
5.4 Risks of aspirin desensitization procedure. These common and transient aspirin-induced 
reaction symptoms will not be reported as AEs. However, if any of the following events occur 
that are associated with the aspirin-induced reaction during the desensitization, they WILL be 
reported as AEs: 
1. Aspirin-induced bronchoconstriction with a fall in FEV1 of >50% from that morning’s 
baseline value. 
2. Aspirin-induced symptomatic hypotension (fall in SBP of 20% or more from that 
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3. Any aspirin-induced reaction that produces symptoms severe enough to warrant the 
use of injectable epinephrine (including, but not limited to, angioedema of the 
respiratory tract and prolonged hypotension), as deemed medically necessary by 
the treating study physician. 
4. Any aspirin-induced reaction that produces symptoms severe enough to warrant 
transfer of the patient to the Emergency Department for monitoring, as deemed 
medically necessary by the treating study physician. 
• 
Study mandated procedures: Blood draw: Any AE occurring 24 hours after blood collection. Nasal 
sample collection: Any AE occurring 24 hours after procedure.  
12.2.1.1 Suspected Adverse Reaction (SAR)  
Any adverse event for which there is a reasonable possibility that the investigational drug or 
investigational study therapy regimen caused the adverse event. For the purposes of safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and 
the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug (21 CFR 312.32(a)). 
12.2.2 Unexpected Adverse Event  
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the Investigator 
Brochure or package insert or is not listed at the specificity, severity or rate of occurrence that has been 
observed; or is not consistent with the risk information described in the general investigational plan or 
elsewhere in the IND. Any event not listed as a known risk for the aspirin challenge will be considered an 
unexpected adverse event. 
12.2.3 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator 
or Sponsor or DAIT/NIAID, it results in any of the following outcomes (21 CFR 312.32(a)): 
1. Death. 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of either the 
investigator or Sponsor or DAIT/NIAID, its occurrence places the subject at immediate risk of death. It does 
not include an AE or SAR that, had it occurred in a more severe form, might have caused death.  
3. Inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. 
5. Congenital anomaly or birth defect.  
6. Important medical events that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Elective hospitalizations or hospital admissions for the purpose of conduct of protocol mandated procedures are 
not to be reported as an SAE unless hospitalization is prolonged due to complications. 
12.3 Grading and Attribution of Adverse Events 
12.3.1 Grading Criteria 
The study site will grade the severity of adverse events experienced by the study subjects according to the 
criteria set forth in the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0. This document (referred to herein as the NCI-CTCAE manual) provides a common language to 


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describe levels of severity, to analyze and interpret data, and to articulate the clinical significance of all adverse 
events. The NCI-CTCAE has been reviewed by the, Principal Investigator, and has been deemed appropriate for 
the subject population to be studied in this protocol.  
Adverse events will be graded on a scale from 1 to 5 according to the following standards in the NCI-CTCAE 
manual: 
Grade 1 = mild adverse event. 
Grade 2 = moderate adverse event. 
Grade 3 = severe and undesirable adverse event. 
Grade 4 = life-threatening or disabling adverse event. 
Grade 5 = death. 
Events grade 2 or higher will be recorded on the appropriate AE case paper CRF report form for this study. 
For grading an abnormal value or result of a clinical or laboratory evaluation (including, but not limited to, a 
radiograph, an ultrasound, an electrocardiogram etc.), a treatment-emergent adverse event is defined as an 
increase in grade from baseline or from the last post-baseline value that doesn’t meet grading criteria. Changes 
in grade from screening to baseline will also be recorded as adverse events, but are not treatment-emergent. If 
a specific event or result from a given clinical or laboratory evaluation is not included in the NCI-CTCAE manual, 
then an abnormal result would be considered an adverse event if changes in therapy or monitoring are 
implemented as a result of the event/result. 
 
12.3.2 Attribution Definitions 
The relationship, or attribution, of an adverse event to the study therapy regimen or study procedure(s) will 
initially be determined by the site investigator and recorded on the appropriate AE paper case report form 
(AE/SAE paper CRF).  Final determination of attribution for safety reporting will be determined by DAIT/NIAID.  
The relationship of an adverse event to study therapy regimen or procedures will be determined using the 
descriptors and definitions provided in Table 12.3.2.  
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-CTCAE web site: 
http://ctep.cancer.gov/reporting/ctc.html. 
 
       
Table 12.3.2 Attribution of Adverse Events 
Code 
Descriptor 
Definition (guidelines) 
UNRELATED CATEGORY  
1 
Unrelated 
The adverse event is clearly not related to study.  The event is 
completely related to an etiology other than the study product or 
study intervention (the alternative etiology must be documented 
in the study subject’s medical record) 
2 
Unlikely 
The adverse event is doubtfully related to study and likely to be 
related to factors other than study product or study intervention. 
RELATED CATEGORIES 


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3 
Possible 
The adverse event may be related to study.  There is an 
association between the event and the administration of study 
product and there is a plausible mechanism for the event to be 
related to the study product; there may be also an alternative 
etiology, such as characteristics of the subject’s clinical status 
and/or underlying disease 
4 
Probable 
The adverse event is likely related to study.  There is (1) an 
association between the event and the administration of study 
product or study intervention, (2) a plausible mechanism for the 
event to be related to the study product,  and (3) the event could 
not be reasonably explained by known characteristics of the 
subject’s clinical status and  or an alternative etiology is not 
apparent 
5 
Definite 
The adverse event is clearly related to study.  There is (1) an 
association between the event and the administration of the 
study product or study intervention, (2) a plausible mechanism for 
the event to be related to the related to the study product, and 
(3) causes other than the study product have been ruled out 
and/or the event re-appeared on re-exposure to the study 
product 
 
12.4 Collection and Recording of Adverse Events 
12.4.1 Collection Period 
Adverse events will be collected from the time of enrollment, until a subject completes study participation or 
until 14 days after he/she prematurely withdraws (without withdrawing consent) or is withdrawn from the study 
if the subject has received study medication or has undergone aspirin challenge. 
12.4.2 Collecting Adverse Events 
Adverse events (including SAEs) may be discovered through any of these methods: 
• 
Observing the subject. 
• 
Interviewing the subject with specific questions about whether there has been any change in health status.  
• 
Receiving an unsolicited complaint from the subject. 
• 
Notification through the hospital medical record 
• 
In addition, an abnormal value or result from a clinical or laboratory evaluation can also indicate an adverse 
event, as defined in Section 12.3, Grading and Attribution of Adverse Events. 
12.4.3 Recording Adverse Events 


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Throughout the study, the investigator will record adverse events and serious adverse events as described 
previously on the appropriate paper case report form (AE/SAE paper CRF) regardless of the relationship to study 
therapy regimen or study procedure. 
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or until the end of study 
participation, or until 14 days after the subject prematurely withdraws (without withdrawing consent)/or is 
withdrawn from the study, whichever occurs first. 
12.5 Reporting of Serious Adverse Events and Adverse Events 
12.5.1 Reporting of Serious Adverse Events to Sponsor (DAIT/NIAID) 
This section describes the responsibilities of the site investigator to report serious adverse events to the sponsor 
via email.  Timely reporting of adverse events is required by 21 CFR and ICH E6 guidelines.  
Site investigators will report all serious adverse events to the sponsor in any of the “related” categories (see 
Section 12.2.3, Serious Adverse Event), regardless of expectedness within 24 hours of discovering the event. 
For serious adverse events, all requested information on the AE/SAE paper CRF will be provided.  However, 
unavailable details of the event will not delay submission of the known information.  As additional details 
become available, the AE/SAE paper CRF will be updated and submitted. 
12.5.2 Reporting to Health Authority 
After an adverse event requiring 24-hour reporting (per Section 12.5.1, Reporting of Serious Adverse Events to 
Sponsor) is submitted by the site investigator and assessed by DAIT/NIAID, there are two options for DAIT/NIAID 
to report the adverse event to the appropriate health authorities: 
12.5.2.1 Annual Reporting 
DAIT/NIAID will include in the annual study report to health authorities all adverse events classified as: 
o Serious, expected, suspected adverse reactions (see Section 12.2.1.1, Suspected Adverse Reaction, 
and Section 12.2.2, Unexpected Adverse Event). 
o Serious and not a suspected adverse reaction (see Section 12.2.2, Suspected Adverse Reaction). 
o Pregnancies. 
Note that all adverse events (not just those requiring 24-hour reporting) will be reported in the Annual 
DSMB Report. 
12.5.2.2 Expedited Safety Reporting  
This option, with 2 possible categories, applies if the adverse event is classified as one of the following: 
Category 1:  Serious and unexpected suspected adverse reaction [SUSAR] (see Section 12.2.1.1, 
Suspected Adverse Reaction and Section 12.2, Unexpected Adverse Event and 21 CFR 312.32(c)(1)i).  
The sponsor shall report any suspected adverse reaction that is both serious and unexpected.  
The sponsor shall report an adverse event as a suspected adverse reaction only if there is 
evidence to suggest a causal relationship between the study drug and the adverse event, such 
as: 
1. A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, or Stevens-Johnson Syndrome); 


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2. One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., 
tendon rupture); 
3. An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that 
indicates those events occur more frequently in the drug treatment group than in a 
concurrent or historical control group. 
 
Category 2: Any findings from studies that suggests a significant human risk  
 
The sponsor shall report any findings from other epidemiological studies, analyses of adverse 
events within the current study or pooled analysis across clinical studies or animal or in vitro 
testing (e.g. mutagenicity, teratogenicity, carcinogenicity) that suggest a significant risk in 
humans exposed to the drug that would result in a safety-related change in the protocol, 
informed consent, investigator brochure or package insert or other aspects of the overall 
conduct of the study.   
 
DAIT/NIAID shall notify the FDA and all participating investigators of expedited Safety within 15 calendar 
days; unexpected fatal or immediately life-threatening suspected adverse reaction(s) shall be reported as 
soon as possible or within 7 calendar days.  
12.5.3 Reporting of Adverse Events to IRBs/IECs 
All investigators shall report adverse events, including expedited reports, in a timely fashion to their 
respective IRBs/IECs in accordance with applicable regulations and guidelines. All Safety Reports to the FDA 
shall be distributed by DAIT/NIAID or designee to all participating institutions for site IRB/IEC submission. 
   12.6   Pregnancy Reporting 
 
The investigator shall be informed immediately of any pregnancy in a study subject or a partner of a study 
subject. A pregnant subject shall be instructed to stop taking study medication. The investigator shall counsel 
the subject and discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
Monitoring by phone call of the pregnant subject shall continue until one month after the conclusion of the 
pregnancy.    
The investigator shall report to the DAIT/NIAID all pregnancies within 1 business day of becoming aware of the 
event using the Pregnancy paper CRF.  All pregnancies identified during the study shall be followed to conclusion 
and the outcome of each must be reported.  The Pregnancy paper CRF shall be updated and submitted to the 
DAIT/NIAID when details about the outcome are available.  When possible, similar information shall be obtained 
for a pregnancy occurring in a partner of a study subject. 
Information requested about the delivery shall include: 
 
o 
Gestational age at delivery 
o 
Birth weight, length, and head circumference 
o 
Gender 
o 
Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5 minutes, and 24 hours 
after birth, if available 


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o 
Any abnormalities. 
All pregnancy complications that result in a congenital abnormality, birth defect, miscarriage, and medically 
indicated abortion - an SAE shall be submitted to the DAIT/NIAID using the SAE reporting procedures described 
above.  
12.7 Reporting of Other Safety Information 
An investigator shall promptly notify the site IRB as well as the DAIT/NIAID when an “unanticipated problem 
involving risks to subjects or others” is identified, which is not otherwise reportable as an adverse event. 
12.8 Review of Safety Information 
12.8.1 Medical Monitor Review 
The DAIT/NIAID Medical Monitor shall receive monthly reports from the Principal Investigator compiling new 
and accumulating information on AEs, SAEs, and pregnancies recorded by the study site on appropriate paper 
CRFs. 
In addition, the Medical Monitor shall review and make decisions on the disposition of the SAE and pregnancy 
reports received by the Principal Investigator (See Reporting of Serious Adverse Events to Sponsor, and 
Pregnancy Reporting).   
12.8.2 ISM Review  
12.8.2.1 Planned ISM Reviews  
The Independent Safety Monitor (ISM) is a physician who is independent from the study team and will, 
at minimum, review all SAEs to assess for possible changes to the overall risk of the study. This person 
will be expected to communicate with the PI and the NIAID Medical Officer regarding any safety issues 
and may be requested to review study safety documentation. 
The ISM shall review safety data at least yearly, which will include, at a minimum, a listing of all reported 
AEs and SAEs.   
12.8.2.2 Ad hoc ISM Reviews  
In addition to the pre-scheduled yearly data reviews and planned safety monitoring, the ISM may be 
called upon for ad hoc reviews. The ISM will review any event that potentially impacts safety at the 
request of the PI or DAIT/NIAID. In addition, the following events will trigger an ad hoc comprehensive 
safety review by the ISM:  
o 
Any death that occurs in the study, which is possibly or definitely related to study treatment 
regimen. 
o 
The occurrence of a Grade 3 or higher related and unexpected SAE in 3 or more of the study 
participants who have received a study treatment. 
After review of the data, the ISM will make recommendations regarding study conduct and/or 
continuation. 
12.8.3 DSMB Review 
12.8.3.1 Planned DSMB Reviews  


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The Data and Safety Monitoring Board (DSMB) shall review safety data at least yearly during planned 
DSMB Data Review Meetings. Data for the planned safety reviews will include, at a minimum, a listing of 
all reported AEs and SAEs.   
The DSMB will be informed of an Expedited Safety Report in a timely manner. DSMB notification will 
occur as soon as site personnel are aware of the event but no later than 72 hours, which aligns with the 
requirements set forth by institutional guidelines.   
12.8.3.2 Ad hoc DSMB Reviews  
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may be called 
upon for ad hoc reviews. The DSMB will  review any event that potentially impacts safety at the request 
of the protocol chair or DAIT/NIAID. In addition, the following events will trigger an ad hoc 
comprehensive DSMB Safety Review:  
o 
Any death that occurs in the study, which is possibly or definitely related to study treatment 
regimen. 
o 
The occurrence of a Grade 3 or higher related and unexpected SAE in 3 or more of the study 
participants who have received a study treatment. 
After review of the data, the DSMB will make recommendations regarding study conduct and/or 
continuation. 
12.8.3.2.1 Temporary Suspension of enrollment for ad hoc DSMB Safety Review  
A temporary halt in enrollment will be implemented if an ad hoc DSMB safety review is 
required. 
In the event that study enrollment temporarily halts, new participants will not be consented 
during the enrollment halt.  However, subjects already enrolled and on investigational 
drug/placebo will continue on therapy, and any subjects in the Screening phase of the study will 
continue to undergo minimal risk procedures.  
13. Statistical Considerations and Analytical Plan 
13.1 
Overview  
This Project will determine the role of TP receptors in the pathophysiology of AERD. Using a double blinded, 
placebo controlled crossover trial of ifetroban, a potent and selective TP receptor antagonist, we will test the 
central hypothesis that TP receptor signaling promotes persistent eosinophilic respiratory inflammation, drives 
cysLT overproduction, facilitates release of innate type 2 cytokines downstream of cysLTs and platelets, and 
mediates bronchoconstriction in response to TXA2 and PGD2 released by mast cells during reactions to aspirin in 
AERD. As such, TP receptor blockade will interfere with both the cysLT-dependent and -independent features of 
AERD pathophysiology and interrupt a feed-forward loop that drives the disease. 
13.2 
Outcomes  
The primary outcome is the calculated dose of aspirin that induces an increase in the Total Nasal Symptom Score 
(TNSS) of 2 from the baseline value, or “PD2”. The PD2 will be calculated during the aspirin desensitization at Visit 
2 as follows: 


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inverselog10 (
(2 −(PrevTNSS −BaselineTNSS)) × (log10ProvocDose −log10PrevDose)
(MaxTNSS −BaselineTNSS) −(PrevTNSS −BaselineTNSS)
+ (log10PrevDose)) 
Where: 
Baseline TNSS =  TNSS score prior to administration of aspirin 
PrevTNSS =  TNSS score immediately previous to onset of aspirin reaction 
MaxTNSS =  Maximum TNSS score recorded during 3-hour observation period during aspirin reaction 
ProvocDose =  Dose of aspirin that provoked a reaction 
PrevDose =  Dose of aspirin that preceded the provocative dose 
 
The secondary and exploratory outcomes are detailed in Sections 3.3 and 3.4 and involve the measurement of 
clinical outcomes and biologic levels as measured at Visit 1, Visit 2 baseline and Visit 2 during aspirin-induced 
reactions, compared between patients on placebo vs ifetroban. 
 
 
13.3 
Measures to Minimize Bias  
We will use block randomization, ensuring that equal numbers of subjects are randomized to each group.  For 
this two-arm balanced-design study, the randomization will consist of blocks of patients randomly assigned 
(allocation ratio of 1:1) to ifetroban or placebo. Matching capsules of ifetroban and placebo will be supplied by 
Cumberland Pharmaceuticals and provided to the BWH Investigational Drugs Services pharmacy (IDS) for 
storage and distribution. The IDS will conduct the randomization and keep records to maintain study blinding. 
Laboratory analyses (flow cytometry, cellular assays, eicosanoid measurement, etc.) as required for any 
secondary and exploratory outcomes will also be performed in a blinded fashion, as along with the clinical staff, 
laboratory staff will also be blinded during the study. 
13.4 
Analysis Plan 
13.4.1 Analysis Populations. 
N/A 
13.4.2 Primary Analysis of Primary Outcome 
To power for a change in the PD2, we will use a two-sided two-sample t-test for mean difference with 
unequal variance, comparing the difference between treatment with ifetroban and placebo. Based on 
our current internal clinical data, we estimate an average PD2 of 60, with a standard deviation of 42. 
Assuming this standard deviation to remain true, with a sample size of 20 patients per treatment arm, 
we will have 83% power to detect a 3-fold shift in PD2 (or an average an increase in PD2 to 180 for 
patients on ifetroban, with a standard deviation of 170), at a 0.05 level of significance.  
13.4.3 Supportive Analyses of the Primary Endpoint(s)/Outcome(s)  
N/A 
13.4.4 Analyses of Secondary and Other Endpoint(s)/Outcome(s) 
Using a two-sided two-sample t-test for mean difference with unequal variance we will compare each 
secondary outcome (aspirin-induced fall in FEV1, aspirin-induced peak urinary LTE4 and serum/nasal 
tryptase) separately on treatment with ifetroban or placebo. Based on our current internal clinical data: 


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i. We estimate an average maximum aspirin-induced fall in FEV1 of 14.6% with a standard 
deviation of 8.3. With 20 patients per treatment group, we will have 72% power to 
detect a 50% difference in the fall of FEV1 at a 0.05 level of significance. 
ii. We estimate an average aspirin-induced peak urinary LTE4 of 6.0 ng/mg Cr with a 
standard deviation of 3.9. With 20 patients per treatment group, we will have 74% 
power to detect a difference of 2.4 ng/mg Cr (or a 40% decrease in the rise in LTE4) at a 
0.05 level of significance. 
We will compare each outcome (ifetroban-induced changes in baseline FEV1, asthma control (ACQ), 
nasal symptoms (SNOT-22), FeNO and baseline LTE4) separately after 4 weeks of treatment with 
ifetroban or placebo using a two-sided two-sample t-test. Based on our current internal clinical baseline 
data of 25 patients with AERD: 
iii. We estimate an average baseline FEV1 of 92% predicted and a standard deviation of 9.8, 
we will have 78% power to detect a difference in FEV1 of 6%, at a 0.05 level of 
significance. 
iv. We estimate an average baseline ACQ of 0.64 and a standard deviation of 0.54, we will 
have 82% power to detect a difference of 0.35 points, at a 0.05 level of significance. A 
fall in ACQ of 0.5 points is consistent with clinically significant improvement.33 
v. We estimate an average baseline SNOT-22 score of 38 and a standard deviation of 14, 
we will have 86% power to detect a difference of 9 points, at a 0.05 level of significance. 
A fall in SNOT-22 score of 8.9 is consistent with clinically significant improvement.34 
We estimate an average baseline urinary LTE4 of 0.37 ng/mg Cr and a standard deviation of 0.22, we will 
have 80% power to detect a difference of 0.14 ng/mg Cr (or a decrease in urinary LTE4 of 30% from 
baseline, roughly half of the effect of zileuton,35,36 at a 0.05 level of significance. 
13.4.5 Analyses of Exploratory Endpoint(s)/Outcome(s) 
Nasal fluid IL-33 and tryptase levels are expected to increase during aspirin-induced reactions and those 
increases will be compared between patients on ifetroban vs. placebo to determine if ifetroban 
treatment blunts the aspirin-induced increases. The IL-33 and tryptase levels will also be correlated to 
clinical symptoms (TNSS and fall in FEV1). We will measure the incremental increase in platelet or mast 
cell-derived chemokines in the nasal fluid during aspirin-induced reactions for patients on ifetroban vs. 
placebo and determine if those increases are blunted by ifetroban or correlate with the increase in nasal 
eicosanoids during reaction.  
13.4.6 Descriptive Analyses  
Summary of descriptive statistics for baseline and demographic characteristics will be provided for all 
enrolled participants.  Demographic data will include age, race, sex, body weight, and height; these data 
will be presented in the following manner: Age, body weight, and height will be averaged per treatment 
group.  Race and sex will be summarized as the number and percent of subjects in each category.  
Baseline control and severity of asthma will be provided as tabular summaries of average baseline ACQ 
score, average baseline FEV1 as percent of predicted, and average baseline daily corticosteroid use.  
The percent of participants who complete the study, losses to follow-up, time to lost to follow-up, and 
reasons for discontinuation (e.g., adverse events) will be presented.   


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13.5 
Interim Analyses  
N/A 
13.5.1 Interim Analysis of Efficacy Data 
13.5.2 Interim Analysis of Safety Data 
13.5.3 Futility Analysis 
13.6 
Statistical Hypotheses  
See sections 13.4.2 through 13.4.5 above for detailed comparisons. 
13.7 
Sample Size Considerations 
Assuming that there will be a dropout rate of 10-20%, we will seek to recruit 50 individuals with suspected AERD 
from our new referrals to meet a target sample size of 40 to complete the study, with 20 in each treatment arm. 
We will enroll additional subjects if we have an unusually high dropout rate. As detailed in section 13.4.2, with 
this sample size of 20 patients per treatment arm, we will have 83% power to detect a 3-fold shift in PD2 (or an 
average an increase in PD2 to 180 for patients on ifetroban, with a standard deviation of 170), at a 0.05 level of 
significance. 
13. Identification and Access to Source Data 
13.1. 
Source Data 
The Principal Investigator will keep accurate records to ensure that the conduct of the study is fully documented.  Data 
derived from source documents will be transferred to protocol-specific CRFs.  Hard copy results of the following clinical 
evaluations and clinical laboratory evaluations will be maintained in the participant’s protocol-specific binder, housed at 
the Asthma Research Center: 
• 
Patient medical histories, concomitant medications, adverse event forms (results written onto CRF) 
• 
CBC/differential (printed copy) 
• 
PFTs (printed copy) 
• 
FeNO (results written onto CRF by coordinator/investigator) 
• 
Pregnancy test (results written onto CRF by coordinator/investigator) 
• 
Physical exam (results written onto CRF by coordinator/investigator) 
• 
Patient questionnaires (results written onto CRF by patient) 
• 
Details of which biologic specimens collected at each visit (written onto CRF by coordinator/investigator) 
The applicable clinical study data will be transferred to a password-secured REDCap database on a dedicated server.  
Data derived from research laboratory evaluations (flow cytometry, eicosanoid and cytokine levels, cellular assays) will 
be stored as a hard copy (as applicable) within laboratory notebooks, or within the appropriate assay-specific software 
program as required for each type of analysis. 
13.2. 
Access to Source Data 
The site investigators and site staff will make all source data available to the DAIT/NIAID, as well as to relevant health 
authorities at Cumberland Pharmaceuticals.   


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14. Protocol Deviations  
14.1. 
Protocol Deviation Definitions 
Protocol Deviation – The investigators and site staff will conduct the study in accordance to the protocol; no deviations 
from the protocol are permitted.  Any change, divergence, or departure from the study design or procedures constitutes 
a protocol deviation.  As a result of any deviation, corrective actions will be developed by the site and implemented 
promptly. 
 
Major Protocol Deviation (Protocol Violation) - A Protocol Violation is a deviation from the IRB approved protocol that 
may affect the subject's rights, safety, or well-being and/or the completeness, accuracy and reliability of the study data.  
In addition, protocol violations include willful or knowing breaches of human subject protection regulations, or policies, 
any action that is inconsistent with the NIH Human Research Protection Program’s research, medical, and ethical 
principles, and a serious or continuing noncompliance with federal, state, local or institutional human subject protection 
regulations, policies, or procedures.  
 
Non-Major Protocol Deviation - A non-major protocol deviation is any change, divergence, or departure from the study 
design or procedures of a research protocol that does not have a major impact on the subject's rights, safety or well-
being, or the completeness, accuracy and reliability of the study data. 
14.2. 
Reporting and Managing Protocol Deviations 
The study site principal investigator has the responsibility to identify, document and report protocol deviations as 
directed by the study Sponsor.  However, protocol deviations may also be identified during site monitoring visits or 
during other forms of study conduct review.  
Upon determination that a protocol deviation has occurred, the study staff will a) notify the site Principal Investigator, b) 
notify the NIAID Project Manager, and c) will complete a Protocol Deviation form (See Appendix). NIAID may request 
discussion with the Principal Investigator and the Independent Safety Monitor to determine the effect of the protocol 
deviation on the study participant and his/her further study participation, the effect of the protocol deviation on the 
overall study and corrective actions. The Principal Investigator will complete and sign the Protocol Deviation form (See 
Appendix) and submit it to the NIAID Medical Officer and Project Manager, to the Independent Safety Monitor and to 
the site IRB, per IRB regulations. Major protocol deviations will be reported to the SMC by the NIAID Medical Officer. 
It is the responsibility of the PI and study physician Co-Investigators to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 5 working days of the scheduled 
protocol-required activity. All deviations will be promptly reported as above and will be addressed in study subject 
source documents. Deviations from the approved protocol are not allowed.   
15. Ethical Considerations and Compliance with Good Clinical Practice 
15.1. 
Statement of Compliance 
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance for Industry: E6 Good 
Clinical Practice Consolidated Guidance, and according to the criteria specified in this study protocol.  Before study 
initiation, the protocol and the informed consent documents will be reviewed and approved by the IRB.  Any 
amendments to the protocol or to the consent materials will also be approved by the IRB before they are implemented. 
15.2. 
Informed Consent Process 


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The consent process will provide information about the study to a prospective participant and will allow adequate time 
for review and discussion prior to his/her decision.  The principal investigator or designee listed on the FDA 1572 will 
review the consent and answer questions.  The prospective participant will be told that being in the trial is voluntary and 
that he or she may withdraw from the study at any time, for any reason.  All participants (or their legally acceptable 
representative) will read, sign, and date a consent form before undergoing any study procedures.  Consent materials will 
be presented in participants’ primary language. A copy of the signed consent form will be given to the participant. 
The consent process will be ongoing.  The consent form will be revised when important new safety information is 
available, the protocol is amended, and/or new information becomes available that may affect participation in the 
study.  
15.3. 
Privacy and Confidentiality 
A participant’s privacy and confidentiality will be respected throughout the study.  Each participant will be assigned a 
unique identification number and these numbers rather than names will be used to collect, store, and report participant 
information.  Site personnel will not transmit documents containing personal health identifiers (PHI) to the study 
sponsor or their representatives. 
16. Publication Policy 
The ICJME (International Committee of Medical Journal Editors) policy on the publication of study results will apply to 
this trial. 
17. Appendix 1. Schedule of Events 
 
 


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Appendix 2. Protocol Deviation Form 
Subject ID:  ___ ___ ___ ___ ___ ___  
Date of Report:  __ __    / __ __ /   __   __  __   __     Subject Initials:  ___ ___ ___ 
  
 
PROTOCOL DEVIATION REPORTING FORM 
 
(one form per deviation) 
 
1. Date Deviation occurred: __ __/__ __/ __ __ __ __ 
 
2. Date site Staff became aware of Deviation:   __ __/__ __/ __ __ __ __ 
 
3. Description of Deviation: 
__________________________________________________________________________________________________
__________________________________________________________________________________________________
_________(attach continuation form, if needed) 
 
4. Circumstances explaining /contributing to the deviation: 
 
__________________________________________________________________________________________________
__________________________________________________________________________________________________
_________(attach continuation form, if needed) 
 
 
5.   Effect of Deviation on subject’s safety or risk from study participation: 
 
No effect 
Safety concern or increased risk          (A. AE or SAE form required B. Qualifies as “major deviation”) 


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Explain why the deviation has (or has not) an effect on subject’s safety or risk from study participation. In case that 
deviation has an effect please provide extent of potential safety impact: 
__________________________________________________________________________________________________
__________________________________________________________________________________________________
_______  (attach continuation form, if needed) 
 
 
 
 
6. Effect of Deviation on the quality of study data:   
 
No effect 
Potential effect on data quality                (Qualifies as “major deviation”) 
 
Explain why deviation has (or has not) an effect on the quality of study data. In case that deviation has an effect please 
provide extent of potential effect on data quality: 
__________________________________________________________________________________________________
__________________________________________________________________________________________________
______________________________________________________________________________________(attach 
continuation form, if needed) 
7. Major Deviation (as determined by the NIAID Project Manager)      YES 
 
NO 
Subject ID:  ___ ___ ___ ___ ___ ___  
Date of Report:  __ __    / __ __ /   __   __  __   __     Subject Initials:  ___ ___ ___ 
 
 
  
 
8. Corrective action(s) to resolve this Deviation: 
__________________________________________________________________________________________________
____________________________(attach continuation form, if needed) 


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9. Corrective action(s) to prevent similar occurrences in the future: 
__________________________________________________________________________________________________
__________________________________________________________________________________________________
________ (attach continuation form, if needed) 
10. Participant will continue as a study subject:    
YES 
 
 
NO 
Justification: 
__________________________________________________________________________________________________
___________________________(attach continuation form, if needed) 
11. Notifications 
 
Date Notified 
NIAID Project Manager 
 
Independent Safety Monitor 
 
IRB 
 
 
 
 
 
 
 
 
________________________________________________________________________ 
Name and Signature of Independent Safety Monitor (if required) 
___________________________ 
Date Completed 
 
________________________________________________________________________ 
Name and Signature of Principal Investigator 
___________________________ 
Date Completed 


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Participant ID:  ___ ___ ___ ___ ___ ___ 
 
  Date of Report:  __ __    / __ __ /   __  __  __   __  
Participant’s Initials:  ___ ___ ___                                                   
 
 
PROTOCOL DEVIATION REPORTING FORM CONTINUATION PAGE 
 
__________________________________________________________________________________________________
__________________________________________________________________________________________________
__________________________________________________________________________________________________
__________________________________________________________________________________________________
__________________________________________________________________________________________________
__________________________________________________________________________________________________
__________________________________________________________________________________________________
__________________________________________________________________________________________________
__________________________________________________________________________________________________
__________________________________________________________________________________________________
__________________________________________________________________________________________________
__________________________________________________________________________________________________
__________________________________________________________________________________________________
______________________ 
 
 


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