Therapeutic Control of Aspirin-Exacerbated Respiratory Disease With Ifetroban

Therapeutic Control of Aspirin-Exacerbated Respiratory Disease

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).

Study Overview

• Status: Completed
• Conditions: Nasal Polyps; Aspirin-exacerbated Respiratory Disease; Aspirin-Sensitive Asthma With Nasal Polyps; Asthma, Aspirin-Induced
• Intervention / Treatment: Drug: Ifetroban; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Asthma Research Center, Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ifetroban; Subjects will be randomized to receive ifetroban (200 mg dose per day) for 4 weeks.	Drug: Ifetroban; 4-week, double-blind, placebo-controlled parallel-design trial of oral ifetroban (a TP receptor antagonist) in patients with AERD; Other Names: ifetroban sodium
Placebo Comparator: Placebo; Subjects will be randomized to receive placebo for 4 weeks.	Drug: Placebo; 4-week, double-blind, placebo-controlled parallel-design trial of oral ifetroban (a TP receptor antagonist) in patients with AERD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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)

Secondary Outcome Measures

Outcome Measure	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.
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)

Other Outcome Measures

Outcome Measure	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.	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)

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Elliot Israel, MD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2018
• Primary Completion (Actual): March 30, 2022
• Study Completion (Actual): April 15, 2023

Study Registration Dates

• First Submitted: August 16, 2017
• First Submitted That Met QC Criteria: October 25, 2017
• First Posted (Actual): October 30, 2017

Study Record Updates

• Last Update Posted (Actual): July 14, 2023
• Last Update Submitted That Met QC Criteria: June 21, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Otorhinolaryngologic Diseases; Pathological Conditions, Anatomical; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Nose Diseases; Drug-Related Side Effects and Adverse Reactions; Drug Hypersensitivity; Asthma; Nasal Polyps; Polyps; Respiration Disorders; Respiratory Tract Diseases; Asthma, Aspirin-Induced; Platelet Aggregation Inhibitors; Ifetroban
• Other Study ID Numbers: 2017P001523

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No