Therapeutic Control of Aspirin-Exacerbated Respiratory Disease (Aspirin)

Study Overview
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Brief Summary
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The investigators are doing this research study to find out if giving a drug called prasugrel, which is used to prevent blood clots, can reduce reactions to aspirin in people with aspirin exacerbated respiratory disease (AERD), and to learn why taking aspirin every day can work as a treatment for people with AERD. People with AERD have symptoms of asthma, severe runny nose, polyps in the nose, and develop allergic reactions if they take medications like aspirin. People with AERD can be desensitized to aspirin in order to be able to safely use it daily, but the investigators do not know if prasugrel may prevent reactions to aspirin and provide a safer way for people with AERD to tolerate aspirin. The investigators also want to understand what is different about the cells and urine from subjects who have AERD, in comparison to subjects who have asthma but do not have AERD and subjects who have allergic rhinitis but do not have asthma. Lastly, the investigators want to understand how aspirin acts differently in subjects who have AERD, in comparison to subjects who have asthma but do not have AERD.

Official Title
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Therapeutic Control of Aspirin-Exacerbated Respiratory Disease (Aspirin)

Conditions
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Asthma, Aspirin-Induced, Aspirin Exacerbated Asthma

Intervention / Treatment
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* Drug: Placebo Oral Tablet
* Drug: Prasugrel Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Participants with AERD: History of physician-diagnosed asthma History of nasal polyposis History of at least one clinical reaction to oral aspirin or other nonselective COX inhibitor with features of both lower (cough, chest tightness, wheezing, dyspnea) and upper (rhinorrhea, sneezing, nasal obstruction, conjunctival itching and discharge) airway involvement. Stable asthma (post-bronchodilator FEV1 of 70% or better, no increase in baseline dose of oral glucocorticoids for at least 3 months, and no history of hospitalization or emergency room visits for asthma for at least the prior 6 months). No current smoking, defined as no daily tobacco smoking for at least 6 months and not more than one instance of tobacco smoking in the last 3 months. Non-pregnant Only those individuals who would otherwise meet clinical qualifications for aspirin desensitization and treatment with high-dose aspirin will be considered for enrollment in the study. Inclusion Criteria for Participants who are Aspirin Tolerant Asthmatics: History of physician-diagnosed asthma. No current nasal polyposis confirmed by nasal examination. No history of any adverse reaction to aspirin or a COX inhibitor. Stable asthma (post-bronchodilator FEV1 of 70% or better, no increase in baseline dose of oral glucocorticoids for at least 3 months, and no history of hospitalization or emergency room visits for asthma for at least the prior 6 months). No current smoking Non-pregnant Inclusion Criteria for Non Asthmatics with Allergic Rhinitis: No history of physician-diagnosed asthma. No current nasal polyposis confirmed by nasal examination. No history of any adverse reaction to aspirin or a COX inhibitor. No current smoking Non-pregnant Clinical history of symptoms consistent with allergic rhinitis and previously documented allergy to at least one environmental,immunoglobulin E (IgE) testing). Normal lung function (baseline FEV1 of 80% of predicted or better). A score of 4 or below on the Asthma Screening Questionnaire (33) and negative responses to asthma history questions Exclusion Criteria for participants with AERD: Current breastfeeding History of bleeding diathesis or current use of anticoagulant or antiplatelet drugs Hypersensitivity to montelukast or thienopyridines History of peptic ulcer disease or gastrointestinal bleed Current severe gastro-esophageal reflux disease (GERD), defined as patient currently requiring more than 2 total doses of medication per day to treat persistent symptoms: either more than 2 doses of any single medication type (antacid, proton pump inhibitor, or H2 receptor antagonist), or more than 2 types of medication per day to treat symptoms History of systemic or life-threatening respiratory reaction to aspirin requiring intubation or administration of adrenalin Current use of any oral beta blocker (due to the risk of bronchospasm associated with beta blockers). History of transient ischemic attack or stroke, or diabetes. Current presence of uncontrolled hypertension. History of hepatic impairment or alcoholism, or evidence of abnormal liver function at Screening Visit. Aspartate transaminase (AST) and alanine transaminase (ALT) levels may not exceed 1.5x the upper limit of normal at Screening Visit (AST may not exceed 52 IU/L, ALT may not exceed 78 IU/L). Exclusion Criteria for Participants with Aspirin Tolerant Asthma and Non Asthmatics with Allergic Rhinitis: Current breastfeeding History of bleeding diathesis or current use of anticoagulant or antiplatelet drugs Hypersensitivity to montelukast or thienopyridines History of peptic ulcer disease or gastrointestinal bleed Current severe GERD Current use of any oral beta blocker.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo then Prasugrel<br>Subjects with AERD first received placebo oral tablet for 4 weeks prior to their aspirin challenge/desensitization. After aspirin challenge/desensitization subjects were discharged to home to washout the study drug from the first treatment phase. At the end of the 2-week washout period, subjects crossed over to the alternate treatment for 4 weeks of Prasugrel oral tablets [ (5 mg (for patients <60kg) or 10mg (> 60kg) daily, following a 60mg loading dose)] and returned for the second aspirin challenge. Because no period effect was observed, data obtained from all subjects while on placebo from either visit 2 or 3 were combined. | Drug: Placebo Oral Tablet<br>* Participants will take a 60 mg loading dose. After they will take 10 mg by mouth daily if they weigh >60kg or 5 mg by mouth daily if they weigh <60 kg. They will take the drug for 4 weeks prior to the aspirin challenge/desensitization.<br>* Other names: Placebo;Drug: Prasugrel Oral Tablet<br>* Participants will take a 60 mg loading dose. After they will take 10 mg by mouth daily if they weigh >60kg or 5 mg by mouth daily if they weigh <60 kg. They will take the drug for 4 weeks prior to the aspirin challenge/desensitization.<br>* Other names: Effient;|
| Experimental: Prasugrel then Placebo<br>Subjects with AERD first received prasugrel oral tablets [ (5 mg (for patients <60kg) or 10mg (> 60kg) daily, following a 60mg loading dose)] prior to their aspirin challenge/desensitization. After aspirin challenge/desensitization subjects were discharged to home to washout the study drug from the first treatment phase. At the end of the 2-week washout period, subjects crossed over to the alternate treatment for 4 weeks of Placebo oral tablet. Because no period effect was observed, data obtained from all subjects while on Prasugrel from either visit 2 or 3 were combined. | Drug: Placebo Oral Tablet<br>* Participants will take a 60 mg loading dose. After they will take 10 mg by mouth daily if they weigh >60kg or 5 mg by mouth daily if they weigh <60 kg. They will take the drug for 4 weeks prior to the aspirin challenge/desensitization.<br>* Other names: Placebo;Drug: Prasugrel Oral Tablet<br>* Participants will take a 60 mg loading dose. After they will take 10 mg by mouth daily if they weigh >60kg or 5 mg by mouth daily if they weigh <60 kg. They will take the drug for 4 weeks prior to the aspirin challenge/desensitization.<br>* Other names: Effient;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in PD2 (Provocative Dose of Aspirin That Elicits an Increase in Nasal Symptom Score of 2 During an Aspirin Challenge) on Prasugrel Versus Placebo | The PD2 is the provocative dose of aspirin that elicits an increase in nasal symptom score of 2 during an aspirin challenge. The PD2 is calculated by: inverse〖log〗_10 (((2-(PrevTNSS-BaselineTNSS))×(〖log〗_10 ProvocDose-〖log〗_10 PrevDose))/((MaxTNSS-BaselineTNSS)-(PrevTNSS-BaselineTNSS) )+(〖log〗_10 PrevDose)) | Difference in PD2 (provocative dose of aspirin that elicits an increase in nasal symptom score of 2 during an aspirin challenge) between Visits 2 and 3 (weeks 8 and 14), calculated at visit 3 | 
| Change From Baseline Expression Levels of COX-2 Transcript and Protein in Peripheral Blood Leukocytes of Subjects With AERD After 8 Weeks of Treatment With Aspirin. | This study will compare this outcome within each participant between baseline (established at Visit 1, prior to initiation of prasugrel therapy) and at the completion of 8 weeks of aspirin therapy. | Evaluated at visits 1 and 4 (weeks 4 and 22) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Participant's Provocative Dose of Aspirin When Pretreated With Prasugrel Versus Placebo | We will monitor the dose of aspirin at which the participant shows symptoms (increased discomfort, 15% drop in FEV1) during the aspirin challenge/desensitization. We will compare the provocative aspirin dose obtained from the aspirin challenge occurring after pretreatment with prasugrel to the dose obtained after pretreatment with placebo. | Evaluated at visits 2 and 3 (weeks 8 and 14) | 
| Change in Total Nasal Symptom Score(TNSS)From Baseline to Peak During Aspirin Challenge on Placebo Versus Prasugrel. | The primary outcome in Part 1 will be the maximum Total Nasal Symptom Score (TNSS) attained for subjects with AERD during the clinical reaction to aspirin challenge. The primary analysis will compare this outcome within each participant after treatment with prasugrel versus placebo. Nasal symptoms including congestion, rhinorrhea, runny nose, itchy nose, sneezing, itchy eyes, teary eyes, itchy ears/throat, and eye redness were assessed on a 0- to 5-point scale (0, none-5, very severe) in response to the provocative dose of aspirin during aspirin challenge/desensitization and summed together to generate the TNSS score (range 0-40). | Data obtained at visits 2 and 3 (weeks 8 and 14) and change calculated at visit 3 | 
| Change in Urinary LTE4 During Aspirin Challenge on Placebo Versus Prasugrel | We will compare the participant's Leukotriene E4 (LTE4) obtained from the aspirin challenge done after pretreatment with prasugrel, the aspirin challenge done after pretreatment with placebo. | Change from visits 2 at visit 3 (weeks 8, 14), calculated and reported at visit 3 | 
| Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) Measurement After Aspirin Desensitization and High Dose Aspirin Treatment at 8 Weeks | We will note difference in the fractional exhaled nitric oxide (FeNO) obtained before any treatment ( baseline ) and after one day Aspirin desensitization followed by 8 weeks Aspirin treatment ( 650 mg oral aspirin tablet twice daily ) | Evaluated at baseline and reported at 8 weeks | 
| Change From Baseline in Asthma Control Questionnaire-7 (ACQ-7) Score After Aspirin Desensitization and High Dose Aspirin Treatment at 8 Weeks | We will note difference in the Asthma Control Questionnaire-7 (ACQ-7) score [ The ACQ has 7 questions on a 7-point scale (minimum score of 0=no impairment, maximum score of 6= maximum impairment)] obtained before any treatment ( baseline ) and after one day Aspirin desensitization followed by 8 weeks Aspirin treatment ( 650 mg oral aspirin tablet twice daily ) | Evaluated at baseline and reported at 8 weeks | 
| Change From Baseline in Prostaglandin Metabolites (PGD-M) Measurement After Aspirin Desensitization and High Dose Aspirin Treatment at 8 Weeks | We will note difference in the Prostaglandin metabolites (PGD-M) measurement obtained before any treatment ( baseline ) and after one day Aspirin desensitization followed by 8 weeks Aspirin treatment ( 650 mg oral aspirin tablet twice daily ) | Evaluated at baseline and reported at 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aspirin, Prasugrel, Asthma, AERD, Aspirin challenge, Aspirin desensitization, Aspirin induced asthma