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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ifetroban | Active Comparator | Subjects will be randomized to receive ifetroban (200 mg dose per day) for 4 weeks. |
|
| Placebo | Placebo Comparator | Subjects will be randomized to receive placebo for 4 weeks. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ifetroban | Drug | 4-week, double-blind, placebo-controlled parallel-design trial of oral ifetroban (a TP receptor antagonist) in patients with AERD |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 6 weeks from screening visit ( at visit 2) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Inclusion Criteria:
History of AERD, defined as meeting the diagnostic triad with:
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)
Age between 18 and 70 years
No current smoking (not more than one instance of smoking in the last 3 months)
Non-pregnant
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Elliot Israel, MD | Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Asthma Research Center, Brigham and Women's Hospital | Boston | Massachusetts | 02115 | United States |
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36 of whom underwent randomization per protocol, and 35 of whom completed the trial and were analyzed.
A total of 38 potential participants were screened at Brigham and Women's Hospital.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 thromboxane-prostanoid (TP) receptor antagonist) in patients with aspirin-exacerbated respiratory disease (AERD) Patients were then challenged to aspirin at ascending doses, starting at 40.5mg, 81mg, 162mg, and 325mg, given every 90 minutes until a reaction was provoked. |
| FG001 | 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 thromboxane-prostanoid (TP) receptor antagonist) in patients with aspirin-exacerbated respiratory disease (AERD) Patients were then challenged to aspirin at ascending doses, starting at 40.5mg, 81mg, 162mg, and 325mg, given every 90 minutes until a reaction was provoked. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | Posted | Mean | Standard Error | mg | 6 weeks from screening visit ( at visit 2) |
|
Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | Subjects with AERD who received Placebo | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upper Respiratory Tract Infection/Sinusitis, Grade 2 | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Tanya Laidlaw, MD | Brigham and Women's Hospital | 617-525-1034 | tlaidlaw@bwh.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 24, 2020 | May 22, 2023 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D009298 | Nasal Polyps |
| D055963 | Asthma, Aspirin-Induced |
| ID | Term |
|---|---|
| D009668 | Nose Diseases |
| D012140 | Respiratory Tract Diseases |
| D010038 | Otorhinolaryngologic Diseases |
| D011127 | Polyps |
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| ID | Term |
|---|---|
| C078904 | ifetroban |
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| Placebo | Drug | 4-week, double-blind, placebo-controlled parallel-design trial of oral ifetroban (a TP receptor antagonist) in patients with AERD |
|
| 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. | 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. |
| 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. | 1 month (between Visit 1 and Visit 2) |
| 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. | 1 month (between Visit 1 and Visit 2) |
| 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. | 1 month (between Visit 1 and Visit 2) |
| Fractional Exhaled Nitric Oxide (FeNO) | Change from Visit 1 in baseline FeNO levels at Visit 2, compared between patients on placebo vs ifetroban. | 1 month (between Visit 1 and Visit 2) |
| 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) |
| 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. | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) |
| 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. | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) |
| 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. | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) |
| 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. | 1 month (between Visit 1 and Visit 2) and during aspirin challenge visit |
| 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. | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) |
| 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. | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) |
| 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. | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) |
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 |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
|
| Provocative Dose 2 (PD2) During Aspirin Challenge | 36 subjects were randomized, but 1 subject in ifetroban arm was lost to follow-up and did not complete primary outcome for analysis. | Mean | Standard Deviation | mg |
|
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
|
|
| 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. | Posted | Mean | Standard Deviation | percentage change from baseline | 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. |
|
|
|
| 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. | Posted | Mean | Standard Deviation | ng/mg creatinine | 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. |
|
|
|
| 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. | Posted | Mean | Standard Deviation | percent change from baseline | 1 month (between Visit 1 and Visit 2) |
|
|
|
| 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. | Posted | Mean | Standard Deviation | scores on a scale | 1 month (between Visit 1 and Visit 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. | Posted | Mean | Standard Deviation | scores on a scale | 1 month (between Visit 1 and Visit 2) |
|
|
|
| Secondary | Fractional Exhaled Nitric Oxide (FeNO) | Change from Visit 1 in baseline FeNO levels at Visit 2, compared between patients on placebo vs ifetroban. | Posted | Mean | Standard Deviation | parts per billion | 1 month (between Visit 1 and 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. | Not Posted | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Participants |
| 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. | Not Posted | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Participants |
| 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. | Not Posted | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Participants |
| 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. | Not Posted | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Participants |
| 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. | Not Posted | 1 month (between Visit 1 and Visit 2) and during aspirin challenge visit | Participants |
| 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. | Not Posted | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Participants |
| 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. | Not Posted | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Participants |
| 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. | Not Posted | 1 month (between Visit 1 and Visit 2) and 6 weeks from screening visit ( at visit 2) | Participants |
| 18 |
| 0 |
| 18 |
| 11 |
| 18 |
| EG001 | Ifetroban | Subjects with AERD who received Ifetroban | 0 | 18 | 0 | 18 | 12 | 18 |
| Pregnant partner | Pregnancy, puerperium and perinatal conditions | Systematic Assessment |
|
| Rash, maculo-papular, Grade 1 | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Ear Pain, Grade 1 | Ear and labyrinth disorders | Systematic Assessment |
|
| Stomach Pain, Grade 1 | Gastrointestinal disorders | Systematic Assessment | Includes vomiting, diarrhea, and/or constipation |
|
| Eye disorder- Stye, Grade 1 | Eye disorders | Systematic Assessment |
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| Systemic reaction to aspirin challenge with extrapulmonary symptoms | Injury, poisoning and procedural complications | Systematic Assessment |
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| Lung Infection (influenza B-related pneumonia), Grade 2 | Infections and infestations | Systematic Assessment |
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| Wheezing, Grade 1 | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Sinus disorder (bloody nose), Grade 1 | Blood and lymphatic system disorders | Systematic Assessment |
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| Bruising, Grade 1 | Blood and lymphatic system disorders | Systematic Assessment |
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| Otitis Media, Grade 2 | Infections and infestations | Systematic Assessment |
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| Constipation, Grade 1 | Gastrointestinal disorders | Systematic Assessment |
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| Nasal Congestion, Grade 1 | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Lower gastrointestinal hemorrhage, Grade 1 | Gastrointestinal disorders | Systematic Assessment |
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| Vomiting, Grade 1 | Gastrointestinal disorders | Systematic Assessment |
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| D020763 |
| Pathological Conditions, Anatomical |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D001249 | Asthma |
| D001982 | Bronchial Diseases |
| D012130 | Respiratory Hypersensitivity |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D004342 | Drug Hypersensitivity |
| D064420 | Drug-Related Side Effects and Adverse Reactions |
| D064419 | Chemically-Induced Disorders |
| Unknown or Not Reported |
|
| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|