Trial Outcomes & Findings for Therapeutic Control of Aspirin-Exacerbated Respiratory Disease With Ifetroban (NCT NCT03326063)

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

38 participants

Primary outcome timeframe

6 weeks from screening visit ( at visit 2)

Results posted on

2023-07-14

Participant Flow

A total of 38 potential participants were screened at Brigham and Women's Hospital.

36 of whom underwent randomization per protocol, and 35 of whom completed the trial and were analyzed.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	18	18
Overall Study COMPLETED	17	18
Overall Study NOT COMPLETED	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study COVID pandemic: subject recalled to her country	1	0

Baseline Characteristics

36 subjects were randomized, but 1 subject in ifetroban arm was lost to follow-up and did not complete primary outcome for analysis.

Baseline characteristics by cohort

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Ifetroban n=17 Participants 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	Placebo n=18 Participants 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
Provocative Dose 2 (PD2) During Aspirin Challenge	121 mg Standard Error 48	142 mg Standard Error 46

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ifetroban n=17 Participants 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	Placebo n=18 Participants 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
Percentage Change From Baseline of FEV1 During Aspirin Challenge (Bronchoconstriction)	-18.8 percentage change from baseline Standard Deviation 3.6	-8.4 percentage change from baseline Standard Deviation 2.1

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ifetroban n=17 Participants 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	Placebo n=18 Participants 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
Aspirin-induced Leukotriene E4 (LTE4) Levels	0.72 ng/mg creatinine Standard Deviation 0.30	0.15 ng/mg creatinine Standard Deviation 0.10

SECONDARY outcome

Timeframe: 1 month (between Visit 1 and Visit 2)

Change from Visit 1 in baseline FEV1,compared between patients on placebo vs ifetroban.

Outcome measures

Outcome measures
Measure	Ifetroban n=17 Participants 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	Placebo n=18 Participants 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
Change in Chronic Disease Control by Measurement of Lung Function Through FEV1	-0.2 percent change from baseline Standard Deviation 1.3	-0.5 percent change from baseline Standard Deviation 1.2

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ifetroban n=17 Participants 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	Placebo n=18 Participants 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
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	-0.03 scores on a scale Standard Deviation 0.11

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ifetroban n=17 Participants 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	Placebo n=18 Participants 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
Clinical Improvement of Chronic Disease - Sino-Nasal Outcome Test (SNOT-22) Score	1.5 scores on a scale Standard Deviation 3.0	-2.0 scores on a scale Standard Deviation 2.3

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Ifetroban n=17 Participants 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	Placebo n=18 Participants 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
Fractional Exhaled Nitric Oxide (FeNO)	7.9 parts per billion Standard Deviation 9.0	-3.4 parts per billion Standard Deviation 3.0

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Ifetroban

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Tanya Laidlaw, MD

Brigham and Women's Hospital

Phone: 617-525-1034

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Ifetroban n=18 Participants 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	Placebo n=18 Participants 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	Total n=36 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=18 Participants	0 Participants n=18 Participants	0 Participants n=36 Participants
Age, Categorical Between 18 and 65 years	18 Participants n=18 Participants	17 Participants n=18 Participants	35 Participants n=36 Participants
Age, Categorical >=65 years	0 Participants n=18 Participants	1 Participants n=18 Participants	1 Participants n=36 Participants
Sex: Female, Male Female	11 Participants n=18 Participants	7 Participants n=18 Participants	18 Participants n=36 Participants
Sex: Female, Male Male	7 Participants n=18 Participants	11 Participants n=18 Participants	18 Participants n=36 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=18 Participants	2 Participants n=18 Participants	4 Participants n=36 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	16 Participants n=18 Participants	16 Participants n=18 Participants	32 Participants n=36 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=18 Participants	0 Participants n=18 Participants	0 Participants n=36 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=18 Participants	0 Participants n=18 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Asian	0 Participants n=18 Participants	1 Participants n=18 Participants	1 Participants n=36 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=18 Participants	0 Participants n=18 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Black or African American	1 Participants n=18 Participants	1 Participants n=18 Participants	2 Participants n=36 Participants
Race (NIH/OMB) White	16 Participants n=18 Participants	16 Participants n=18 Participants	32 Participants n=36 Participants
Race (NIH/OMB) More than one race	1 Participants n=18 Participants	0 Participants n=18 Participants	1 Participants n=36 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=18 Participants	0 Participants n=18 Participants	0 Participants n=36 Participants
Region of Enrollment United States	18 participants n=18 Participants	18 participants n=18 Participants	36 participants n=36 Participants
Provocative Dose 2 (PD2) During Aspirin Challenge	121 mg STANDARD_DEVIATION 48 • n=17 Participants • 36 subjects were randomized, but 1 subject in ifetroban arm was lost to follow-up and did not complete primary outcome for analysis.	142 mg STANDARD_DEVIATION 46 • n=18 Participants • 36 subjects were randomized, but 1 subject in ifetroban arm was lost to follow-up and did not complete primary outcome for analysis.	132 mg STANDARD_DEVIATION 47 • n=35 Participants • 36 subjects were randomized, but 1 subject in ifetroban arm was lost to follow-up and did not complete primary outcome for analysis.

Measure	Placebo n=18 participants at risk Subjects with AERD who received Placebo	Ifetroban n=18 participants at risk Subjects with AERD who received Ifetroban
Respiratory, thoracic and mediastinal disorders Upper Respiratory Tract Infection/Sinusitis, Grade 2	11.1% 2/18 • Number of events 2 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Pregnancy, puerperium and perinatal conditions Pregnant partner	5.6% 1/18 • Number of events 1 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Skin and subcutaneous tissue disorders Rash, maculo-papular, Grade 1	11.1% 2/18 • Number of events 2 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Ear and labyrinth disorders Ear Pain, Grade 1	5.6% 1/18 • Number of events 1 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Gastrointestinal disorders Stomach Pain, Grade 1	5.6% 1/18 • Number of events 1 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Eye disorders Eye disorder- Stye, Grade 1	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	5.6% 1/18 • Number of events 1 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Injury, poisoning and procedural complications Systemic reaction to aspirin challenge with extrapulmonary symptoms	11.1% 2/18 • Number of events 2 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	16.7% 3/18 • Number of events 3 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Infections and infestations Lung Infection (influenza B-related pneumonia), Grade 2	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	5.6% 1/18 • Number of events 1 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Respiratory, thoracic and mediastinal disorders Wheezing, Grade 1	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	11.1% 2/18 • Number of events 2 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Blood and lymphatic system disorders Sinus disorder (bloody nose), Grade 1	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	5.6% 1/18 • Number of events 1 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Blood and lymphatic system disorders Bruising, Grade 1	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	5.6% 1/18 • Number of events 1 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Infections and infestations Otitis Media, Grade 2	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	5.6% 1/18 • Number of events 1 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Gastrointestinal disorders Constipation, Grade 1	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	5.6% 1/18 • Number of events 1 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Respiratory, thoracic and mediastinal disorders Nasal Congestion, Grade 1	5.6% 1/18 • Number of events 1 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Gastrointestinal disorders Lower gastrointestinal hemorrhage, Grade 1	5.6% 1/18 • Number of events 1 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.
Gastrointestinal disorders Vomiting, Grade 1	0.00% 0/18 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.	5.6% 1/18 • Number of events 1 • Adverse events were reported from the time of randomized subject enrollment through study completion, about 8 weeks.