Effect of Dupilumab on Aspirin Intolerance

Sponsor

Medical University of Vienna (Other)

Overall Status

Recruiting

CT.gov ID

NCT04442256

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To test the efficacy of dupilumab in patients with AERD regarding the intolerance to salicylic acid after 6 months. This will be evaluated by oral drug provocation testing with low dose salicylic acid after 6 months of dupilumab treatment.

Hypothesis:

After 6 months of therapy, patients will tolerate aspirin dose levels as tested with different dosages (125mg, 250mg and 500 mg).

Condition or Disease	Intervention/Treatment	Phase
AERD - Aspirin Exacerbated Respiratory Disease	Drug: Dupilumab	Phase 4

Detailed Description

30 patients suffering from AERD will be included in this single-center, prospective, explorative study for treatment with dupilumab. Before study initiation, informed consent will be obtained from all subjects. All patients with AERD can be included according to inclusion- and exclusion criteria.

AERD patients who had already obtained a monoclonal antibody for the treatment of asthma or polyps will also be included if at least a wash out period of 5 half -lives or 3 months has passed. The first visit will be performed at screening (day 0, V1/before dupilumab therapy). Clinically significant abnormal laboratory values will be ruled out prior to the first dose.

All patients will be administered subcutaneous doses of dupilumab in a biweekly fashion.

For several reasons comparison with placebo will not be performed:

All patients included are in urgent need for an effective treatment.
The only currently available alternative treatment option is a functional endoscopic sinus surgery (FESS). Usually there is a high recurrence rate after surgery.
All included patients have a long medical history concerning AERD. The rate of a spontaneous improvement or resolution in this patient population is negligible.

Spirometry (peak-flow and FEV1) and an asthma control test will be performed prior to dupilumab therapy, after 1, 3 and 6 months. In addition, the sinonasal outcome test-22 and the total nasal endoscopic polyps score as well as nasal congestion score, disease severity (by visual analogue scale=VAS), total symptom score (TSS) will be performed at baseline, after 1,3 and 6 months. To further evaluate the polyp size, a nasal CT will be performed at screening visit. To evaluate the sense of smell we will perform UPSIT testing before and after 6 months dupilumab.

All patients will have routine laboratory testing (blood chemistry, hematology) before and after 6 months of therapy. Adverse events will be recorded at each visit. Biological activity will be evaluated based on peripheral blood eosinophil counts, serum total Immunoglobulin E (IgE) levels and measurement of eosinophilic cationic protein in patients' sera at baseline and after 6 months.

To assess local changes in the nose caused by dupilumab treatment, nasal secretions, nasal mucosa samples (nasal curette), nasal microbiome as well as nasal biopsies will be collected.

After the end of study, treatment will be continued in all patients with significant improvement in asthmatic symptoms, nasal symptoms as well as a reduction of polyps.

For patients who did not experience clinical improvement, dupilumab treatment will be discontinued after 6 months.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Only one groupOnly one group

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Effect of Dupilumab on ASS Intolerance and Its Mechanisms in Patients With Aspirin-exacerbated Respiratory Disease (AERD)

Actual Study Start Date :

Jun 1, 2020

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Other: Dupilumab All patients will be administered subcutaneous doses of dupilumab in a monthly fashion. Observation period will be 30 minutes after injection	Drug: Dupilumab All patients will be administered subcutaneous doses of dupilumab in a biweekly fashion.

Arm

Intervention/Treatment

Other: Dupilumab

All patients will be administered subcutaneous doses of dupilumab in a monthly fashion. Observation period will be 30 minutes after injection

Drug: Dupilumab

All patients will be administered subcutaneous doses of dupilumab in a biweekly fashion.

Outcome Measures

Primary Outcome Measures

Maximally tolerated aspirin dose level (stages 125mg, 250mg and 500mg) [6 months]
Changes in the maximal ASS dose level tolerations (no toleration, 125mg, 250mg and 500mg) at baseline and after 6 months.

Secondary Outcome Measures

Change of nasal polyps (TPS) [6 months]
A secondary endpoint is the change of polyps after 6 months of treatment with dupilumab, which will be evaluated by an ENT specialist. The polyps will be evaluated on each side by means of nasal endoscopy and graded based on polyp size, resulting in scores of 0 to 4 (TPSs).
Change of allergic asthma (Spirometry) [6 months]
Changes in spirometry (FEV1%)
Percentage of T and B cell subsets in nasal polyp tissues of patients treated with dupilumab as assessed with confocal microscopy [6 months]
Biopisies of nasal polyps will be taken at baseline and after 6 months of treatment with Dupilumab. RNA will be isolated from part of the biopsy and subjected to bulk RNA sequencing. Genes up or downregulated upon treatment will be calculated by bioinformaticians. Biopsies will also be assessed by confocal microscopy upon staining for surface specific markers identifiying various T (T mem, reg T cells) and B (Plasma cell, memory cells) as well as other immune cell subpopulations.
Change of allergic asthma (Asthma control test) [6 months]
Change from baseline in allergic asthma on the asthma control test at 6 months.
Change of nasal polyps (SNOT-22) [6 months]
Changes in sinus nasal outcome test-22 (SNOT 22) between baseline and 6 months.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Dupilumab treatment group:

Signed and dated informed consent has been obtained
Age 18 - 70 years
Male or female
Diagnosed with AERD (nasal polyps, allergic asthma, aspirin intolerance)
Chronic rhinosinusitis with nasal polyps (CRSwNP) (according to the European Position Paper on Rhinosinusitis and Nasal Polyps Guidelines)8
Documented aspirin intolerance
Asthma bronchial diagnosed by a respiratory physician (based on Global -Initiative for Asthma guidelines)9

Exclusion Criteria:

Pregnancy
Clinically significant abnormal laboratory values and active infection (Tbc, HIV, hepatitis A/B/C)
History of malignancy or immunodeficiency
Chronic obstructive lung disorders (COPD), other obstructive lung disorders (bronchiolitis)
Need for systemic corticosteroid therapy 1 month prior to screening visit Eosinophilic pneumonia and Churg-Strauss Syndrome