Aspirin Exacerbated Asthma, Asthma, Aspirin-Induced
Conditions
Keywords
Aspirin, Prasugrel, Asthma, AERD, Aspirin challenge, Aspirin desensitization, Aspirin induced asthma
Brief summary
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.
Interventions
DRUGPlacebo Oral Tablet
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.
DRUGPrasugrel Oral Tablet
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.
Sponsors
Brigham and Women's Hospital
Elliot Israel, MD
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Evaluated at visits 1 and 4 (weeks 4 and 22) | 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. |
| 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 | 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 | 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)) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Nasal Symptom Score(TNSS)From Baseline to Peak During Aspirin Challenge on Placebo Versus Prasugrel. | Data obtained at visits 2 and 3 (weeks 8 and 14) and change calculated at visit 3 | 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). |
| Change in Urinary LTE4 During Aspirin Challenge on Placebo Versus Prasugrel | Change from visits 2 at visit 3 (weeks 8, 14), calculated and reported at visit 3 | 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 Baseline in Asthma Control Questionnaire-7 (ACQ-7) Score After Aspirin Desensitization and High Dose Aspirin Treatment at 8 Weeks | Evaluated at baseline and reported 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 ) |
| Change From Baseline in Prostaglandin Metabolites (PGD-M) Measurement After Aspirin Desensitization and High Dose Aspirin Treatment at 8 Weeks | Evaluated at baseline and reported 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 ) |
| Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) Measurement After Aspirin Desensitization and High Dose Aspirin Treatment at 8 Weeks | Evaluated at baseline and reported 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 ) |
| Difference in Participant's Provocative Dose of Aspirin When Pretreated With Prasugrel Versus Placebo | Evaluated at visits 2 and 3 (weeks 8 and 14) | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Baseline Differences in Platelet Chemistry in Subjects With AERD Compared to Controls | Evaluated at visit 1 (week 4) | To determine if there are baseline differences in the percentages of activated platelets, platelet-leukocyte aggregates, or the plasma levels of soluble platelet products in subjects with AERD, compared to aspirin tolerant asthmatics (ATA) and non-asthmatic controls. |
| Effect of Prasugrel on Platelet Chemistry in Subjects With AERD During Aspirin Challenge. | Evaluated at visit 2 and 3 (week 8 and 14) | To determine if treatment with prasugrel changes the baseline percentages of activated platelets or platelet-leukocyte aggregates or changes the plasma levels of soluble platelet products during clinical reaction to aspirin |
Countries
United States
Participant flow
Recruitment details
A total of 51 potential participants were screened at Brigham and Women's Hospital.
Pre-assignment details
46 of whom underwent randomization per protocol, and 40 of whom completed the trial and were analyzed.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants who were randomized to receive either Prasugrel or Placebo oral tablets and who successfully completed both treatment assignments. | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (4 Weeks) | Lost to Follow-up | 0 | 1 |
| First Intervention (4 Weeks) | Needed surgery | 1 | 0 |
| First Intervention (4 Weeks) | Uncontrolled Asthma | 1 | 0 |
| Second Intervention | Failed to react at both Aspirin | 1 | 1 |
| Washout (2 Weeks) | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants |
| Age, Continuous | 47 years STANDARD_DEVIATION 10 |
| Region of Enrollment United States | 40 Participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 0 / 42 |
| other Total, other adverse events | 13 / 43 | 13 / 42 |
| serious Total, serious adverse events | 0 / 43 | 0 / 42 |
Outcome results
Primary
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.
Time frame: Evaluated at visits 1 and 4 (weeks 4 and 22)
Population: The planned experimental protocol for COX-2 analysis at the lab bench was unsuccessful, therefore no data was collected for this Outcome Measure
Primary
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))
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 | 79 mg | Standard Error 15 |
| Prasugrel | 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 | 139 mg | Standard Error 32 |
Secondary
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 )
Time frame: Evaluated at baseline and reported at 8 weeks
Population: This was assessed across all participants with no planned comparisons between placebo and prasugrel.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Asthma Control Questionnaire-7 (ACQ-7) Score After Aspirin Desensitization and High Dose Aspirin Treatment at 8 Weeks | -0.11 score on a scale | Standard Deviation 0.11 |
Secondary
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 )
Time frame: Evaluated at baseline and reported at 8 weeks
Population: This was assessed across all participants with no planned comparisons between placebo and prasugrel.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) Measurement After Aspirin Desensitization and High Dose Aspirin Treatment at 8 Weeks | 15.8 parts per billion | Standard Deviation 5.8 |
Secondary
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 )
Time frame: Evaluated at baseline and reported at 8 weeks
Population: This was assessed across all participants with no planned comparisons between placebo and prasugrel.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Prostaglandin Metabolites (PGD-M) Measurement After Aspirin Desensitization and High Dose Aspirin Treatment at 8 Weeks | -1.4957 ng/mg creatinine | Standard Deviation 6.9651 |
Secondary
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).
Time frame: Data obtained at visits 2 and 3 (weeks 8 and 14) and change calculated at visit 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Total Nasal Symptom Score(TNSS)From Baseline to Peak During Aspirin Challenge on Placebo Versus Prasugrel. | 7 units on scale | Standard Error 0.8 |
| Prasugrel | Change in Total Nasal Symptom Score(TNSS)From Baseline to Peak During Aspirin Challenge on Placebo Versus Prasugrel. | 6.5 units on scale | Standard Error 0.8 |
Secondary
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.
Time frame: Change from visits 2 at visit 3 (weeks 8, 14), calculated and reported at visit 3
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Urinary LTE4 During Aspirin Challenge on Placebo Versus Prasugrel | 37 percentage change from baseline | Standard Deviation 70 |
| Prasugrel | Change in Urinary LTE4 During Aspirin Challenge on Placebo Versus Prasugrel | 19 percentage change from baseline | Standard Deviation 48 |
Secondary
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.
Time frame: Evaluated at visits 2 and 3 (weeks 8 and 14)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Difference in Participant's Provocative Dose of Aspirin When Pretreated With Prasugrel Versus Placebo | 109 mg | Standard Error 15 |
| Prasugrel | Difference in Participant's Provocative Dose of Aspirin When Pretreated With Prasugrel Versus Placebo | 164 mg | Standard Error 31 |
Other Pre-specified
Baseline Differences in Platelet Chemistry in Subjects With AERD Compared to Controls
To determine if there are baseline differences in the percentages of activated platelets, platelet-leukocyte aggregates, or the plasma levels of soluble platelet products in subjects with AERD, compared to aspirin tolerant asthmatics (ATA) and non-asthmatic controls.
Time frame: Evaluated at visit 1 (week 4)
Other Pre-specified
Effect of Prasugrel on Platelet Chemistry in Subjects With AERD During Aspirin Challenge.
To determine if treatment with prasugrel changes the baseline percentages of activated platelets or platelet-leukocyte aggregates or changes the plasma levels of soluble platelet products during clinical reaction to aspirin
Time frame: Evaluated at visit 2 and 3 (week 8 and 14)