Aspirin-exacerbated Respiratory Disease, Aspirin-Sensitive Asthma With Nasal Polyps, Asthma, Aspirin-Induced, Nasal Polyps
Conditions
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.
Interventions
DRUGIfetroban
4-week, double-blind, placebo-controlled parallel-design trial of oral ifetroban (a TP receptor antagonist) in patients with AERD
DRUGPlacebo
4-week, double-blind, placebo-controlled parallel-design trial of oral ifetroban (a TP receptor antagonist) in patients with AERD
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. History of AERD, defined as meeting the diagnostic triad with: * History of physician-diagnosed asthma and * History of physician-diagnosed nasal polyposis and * History of pathognomonic reactions aspirin or other nonselective cyclooxygenase (COX) inhibitors. 2. Stable asthma (post-bronchodilator forced expiratory volume at one second (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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Provocative Dose 2 (PD2) During Aspirin Challenge | 6 weeks from screening visit ( at visit 2) | 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 TNSS: A higher TNSS score suggests more severe symptoms, on a scale from 0-65 PD2: A higher PD2 suggests that the patient's threshold of reactivity of aspirin was higher |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Aspirin-induced Leukotriene E4 (LTE4) Levels | Visit 2. The change in LTE4 levels from the morning baseline to the aspirin-induced highest value in LTE4 during reaction to aspirin challenge that same day. | Increase of urinary 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. LTE4 levels were calculated in a specialized laboratory. |
| Change in Chronic Disease Control by Measurement of Lung Function Through FEV1 | 1 month (between Visit 1 and Visit 2) | Change from Visit 1 in baseline FEV1,compared between patients on placebo vs ifetroban. |
| Percentage Change From Baseline of FEV1 During Aspirin Challenge (Bronchoconstriction) | At Visit 2. The change in FEV1 from the morning baseline to the aspirin-induced lowest value in FEV1 during reaction to aspirin challenge later that same day. | Severity of bronchoconstriction 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. Measured by an aspirin-induced decrease in FEV1. |
| Clinical Improvement of Chronic Disease - Sino-Nasal Outcome Test (SNOT-22) Score | 1 month (between Visit 1 and Visit 2) | Change from Visit 1 in baseline SNOT-22 score at Visit 2, compared between patients on placebo vs ifetroban. The SNOT-22 is a patient-reported questionnaire with a summed scale that goes from 0-110 and a lower score suggests better sinonasal control. |
| Fractional Exhaled Nitric Oxide (FeNO) | 1 month (between Visit 1 and Visit 2) | Change from Visit 1 in baseline FeNO levels at Visit 2, compared between patients on placebo vs ifetroban. |
| Change in Chronic Disease by Measurement of Asthma Control Through Asthma Control Questionnaire (ACQ) Score | 1 month (between Visit 1 and Visit 2) | Change from Visit 1 in baseline ACQ (Asthma Control Questionnaire) score, compared between patients on placebo vs ifetroban. ACQ is a patient-reported questionnaire measurement of asthma control from 0-6, where lower scores suggest better asthma control. The score is the average result of the answer choices picked by the patient. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Urinary Eicosanoid (TXB2 and LTE4) Levels | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Change in levels of other urinary eicosanoids,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. Measurements include urinary thromboxane B2 (TXB2) and LTE4. |
| Platelet Activation - Percentages of Platelet-leukocyte Aggregates | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Change in percentages of 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. |
| Nasal Eicosanoid Changes | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Change in levels of nasal eicosanoids, 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. |
| Plasma/Serum Tryptase Changes | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Change in levels of plasma/serum 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. |
| Nasal Tryptase Changes | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Change in levels of 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. |
| Platelet Activation - Numbers of Activated Platelets | 1 month (between Visit 1 and Visit 2) and during aspirin challenge visit | Change in numbers of activated platelets 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. |
| Platelet Activation - Percentages of Activated Platelets | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Change in percentages of activated platelets 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. |
| Platelet Activation - Numbers of Platelet-leukocyte Aggregates | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Change in numbers of 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. |
Countries
United States
Participant flow
Recruitment details
A total of 38 potential participants were screened at Brigham and Women's Hospital.
Pre-assignment details
36 of whom underwent randomization per protocol, and 35 of whom completed the trial and were analyzed.
Participants by arm
| Arm | Count |
|---|---|
| Ifetroban Subjects will be randomized to receive ifetroban (200 mg dose per day) for 4 weeks.
Ifetroban: 4-week, double-blind, placebo-controlled parallel-design trial of oral ifetroban (a TP receptor antagonist) in patients with AERD | 18 |
| Placebo Subjects will be randomized to receive placebo for 4 weeks.
Placebo: 4-week, double-blind, placebo-controlled parallel-design trial of oral ifetroban (a TP receptor antagonist) in patients with AERD | 18 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | COVID pandemic: subject recalled to her country | 1 | 0 |
Baseline characteristics
| Characteristic | Ifetroban | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 35 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 32 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Provocative Dose 2 (PD2) During Aspirin Challenge | 121 mg STANDARD_DEVIATION 48 | 132 mg STANDARD_DEVIATION 47 | 142 mg STANDARD_DEVIATION 46 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 32 Participants | 16 Participants |
| Region of Enrollment United States | 18 participants | 36 participants | 18 participants |
| Sex: Female, Male Female | 11 Participants | 18 Participants | 7 Participants |
| Sex: Female, Male Male | 7 Participants | 18 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 18 |
| other Total, other adverse events | 11 / 18 | 12 / 18 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 |
Outcome results
Primary
Provocative Dose 2 (PD2) During Aspirin Challenge
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 TNSS: A higher TNSS score suggests more severe symptoms, on a scale from 0-65 PD2: A higher PD2 suggests that the patient's threshold of reactivity of aspirin was higher
Time frame: 6 weeks from screening visit ( at visit 2)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ifetroban | Provocative Dose 2 (PD2) During Aspirin Challenge | 121 mg | Standard Error 48 |
| Placebo | Provocative Dose 2 (PD2) During Aspirin Challenge | 142 mg | Standard Error 46 |
Secondary
Aspirin-induced Leukotriene E4 (LTE4) Levels
Increase of urinary 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. LTE4 levels were calculated in a specialized laboratory.
Time frame: Visit 2. The change in LTE4 levels from the morning baseline to the aspirin-induced highest value in LTE4 during reaction to aspirin challenge that same day.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ifetroban | Aspirin-induced Leukotriene E4 (LTE4) Levels | 0.72 ng/mg creatinine | Standard Deviation 0.3 |
| Placebo | Aspirin-induced Leukotriene E4 (LTE4) Levels | 0.15 ng/mg creatinine | Standard Deviation 0.1 |
Secondary
Change in Chronic Disease by Measurement of Asthma Control Through Asthma Control Questionnaire (ACQ) Score
Change from Visit 1 in baseline ACQ (Asthma Control Questionnaire) score, compared between patients on placebo vs ifetroban. ACQ is a patient-reported questionnaire measurement of asthma control from 0-6, where lower scores suggest better asthma control. The score is the average result of the answer choices picked by the patient.
Time frame: 1 month (between Visit 1 and Visit 2)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ifetroban | Change in Chronic Disease by Measurement of Asthma Control Through Asthma Control Questionnaire (ACQ) Score | 0.17 scores on a scale | Standard Deviation 0.16 |
| Placebo | Change in Chronic Disease by Measurement of Asthma Control Through Asthma Control Questionnaire (ACQ) Score | -0.03 scores on a scale | Standard Deviation 0.11 |
Secondary
Change in Chronic Disease Control by Measurement of Lung Function Through FEV1
Change from Visit 1 in baseline FEV1,compared between patients on placebo vs ifetroban.
Time frame: 1 month (between Visit 1 and Visit 2)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ifetroban | Change in Chronic Disease Control by Measurement of Lung Function Through FEV1 | -0.2 percent change from baseline | Standard Deviation 1.3 |
| Placebo | Change in Chronic Disease Control by Measurement of Lung Function Through FEV1 | -0.5 percent change from baseline | Standard Deviation 1.2 |
Secondary
Clinical Improvement of Chronic Disease - Sino-Nasal Outcome Test (SNOT-22) Score
Change from Visit 1 in baseline SNOT-22 score at Visit 2, compared between patients on placebo vs ifetroban. The SNOT-22 is a patient-reported questionnaire with a summed scale that goes from 0-110 and a lower score suggests better sinonasal control.
Time frame: 1 month (between Visit 1 and Visit 2)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ifetroban | Clinical Improvement of Chronic Disease - Sino-Nasal Outcome Test (SNOT-22) Score | 1.5 scores on a scale | Standard Deviation 3 |
| Placebo | Clinical Improvement of Chronic Disease - Sino-Nasal Outcome Test (SNOT-22) Score | -2.0 scores on a scale | Standard Deviation 2.3 |
Secondary
Fractional Exhaled Nitric Oxide (FeNO)
Change from Visit 1 in baseline FeNO levels at Visit 2, compared between patients on placebo vs ifetroban.
Time frame: 1 month (between Visit 1 and Visit 2)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ifetroban | Fractional Exhaled Nitric Oxide (FeNO) | 7.9 parts per billion | Standard Deviation 9 |
| Placebo | Fractional Exhaled Nitric Oxide (FeNO) | -3.4 parts per billion | Standard Deviation 3 |
Secondary
Percentage Change From Baseline of FEV1 During Aspirin Challenge (Bronchoconstriction)
Severity of bronchoconstriction 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. Measured by an aspirin-induced decrease in FEV1.
Time frame: At Visit 2. The change in FEV1 from the morning baseline to the aspirin-induced lowest value in FEV1 during reaction to aspirin challenge later that same day.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ifetroban | Percentage Change From Baseline of FEV1 During Aspirin Challenge (Bronchoconstriction) | -18.8 percentage change from baseline | Standard Deviation 3.6 |
| Placebo | Percentage Change From Baseline of FEV1 During Aspirin Challenge (Bronchoconstriction) | -8.4 percentage change from baseline | Standard Deviation 2.1 |
Other Pre-specified
Nasal Eicosanoid Changes
Change in levels of nasal eicosanoids, 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.
Time frame: 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2)
Other Pre-specified
Nasal Tryptase Changes
Change in levels of 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.
Time frame: 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2)
Other Pre-specified
Percent Change in Urinary Eicosanoid (TXB2 and LTE4) Levels
Change in levels of other urinary eicosanoids,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. Measurements include urinary thromboxane B2 (TXB2) and LTE4.
Time frame: 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2)
Other Pre-specified
Plasma/Serum Tryptase Changes
Change in levels of plasma/serum 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.
Time frame: 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2)
Other Pre-specified
Platelet Activation - Numbers of Activated Platelets
Change in numbers of activated platelets 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.
Time frame: 1 month (between Visit 1 and Visit 2) and during aspirin challenge visit
Other Pre-specified
Platelet Activation - Numbers of Platelet-leukocyte Aggregates
Change in numbers of 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.
Time frame: 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2)
Other Pre-specified
Platelet Activation - Percentages of Activated Platelets
Change in percentages of activated platelets 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.
Time frame: 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2)
Other Pre-specified
Platelet Activation - Percentages of Platelet-leukocyte Aggregates
Change in percentages of 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.
Time frame: 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2)