Dupilumab Severe Eosinophilic Chronic Sinusitis Without Nasal Polyposis

Study Overview
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Brief Summary
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The investigators will investigate the efficacy of dupilumab in patients with severe eosinophilic CRSsNP who are resistant to the conventional treatment with intranasal corticosteroids and have significantly extensive disease involving more than 2 sinuses bilaterally in sinus CT scan and Lund-Mackay sinus (LMK) CT score >=10 at baseline.

Detailed Description
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The investigators will use high blood eosinophils (>=200) as a biomarker for eosinophilic CRSsNP and investigate the efficacy of dupilumab in patients with severe eosinophilic CRSsNP who are resistant to the conventional treatment with intranasal corticosteroids and have significantly extensive disease involving more than 2 sinuses bilaterally in sinus CT scan and Lund-Mackay sinus (LMK) CT score >=10 at baseline. In addition, the investigators will have a prespecified enrollment goal of at least 50% of patients with type 2 inflammatory diseases such as asthma, allergic rhinitis, and/or atopic dermatitis on the basis of patient-reported history and will stratify subject numbers between dupilumab treatment and placebo group.

Official Title
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An Evaluation of Dupilumab in Patients With Severe Eosinophilic Chronic Sinusitis Without Nasal Polyposis

Conditions
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Severe Eosinophilic Chronic Sinusitis Without Nasal Polyposis

Intervention / Treatment
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* Drug: Dupilumab 300 MG/2 ML Subcutaneous Solution [DUPIXENT]
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 or older LMK-CT score ≥ 10 (out of maximum of 24) at screening. Bilateral sinusitis with at least more than 2 sinus involvement despite completion of a prior intranasal corticosteroid (INCS) treatment for at least 8 weeks prior to screening Presence of at least two of the following symptoms prior to screening: Nasal blockage/obstruction/congestion Nasal discharge (anterior/posterior nasal drip) Facial pain/pressure Reduction or loss of smell Must have Eosinophilic CRSsNP (blood eos ≥ 200) within 6 months prior to screening Able and willing to undergo regular intervention as well as evaluation per study protocol Must agree not to participate in a clinical study involving another investigational drug or device throughout the duration of this study Must be competent to understand the information given in IRB approved ICF and must sign the form prior to the initiation of any study procedure Exclusion Criteria: Age < 18 With CRS with nasal polyps Treated in any clinical trial of dupilumab Has taken: Biologic therapy/systemic immunosuppressant to treat inflammatory disease or autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc) within 2 months before screening or 5 half-lives, whichever is longer An experimental monoclonal antibody within five half-lives or within 6 months before screening if the half-life is unknown Anti-immunoglobulin E (IgE) therapy (omalizumab) within 130 days prior to screening Leukotriene antagonists/modifiers unless patient is on a continuous treatment for at least 30 days prior to screening Initiation of allergen immunotherapy within 3 months prior to screening or a plan to begin therapy or change its dose during the run-in period or the randomized treatment period Have had a sino-nasal surgery changing the lateral wall structure of the nose making impossible the evaluation of NPS Patients with conditions/concomitant diseases making them non-evaluable at screening or for the primary efficacy endpoint such as: Antrochoanal polyps Nasal septal deviation that would occlude at least one nostril Acute sinusitis, nasal infection or upper respiratory infection at screening Ongoing rhinitis medicamentosa Allergic granulomatous angiitis (Churg-Strauss syndrome), granulomatosis with polyangiitis (Wegener's granulomatosis), Young's syndrome, Kartagener's syndrome or other dyskinetic ciliary syndromes, concomitant cystic fibrosis Radiologic suspicion, or confirmed invasive or expansive fungal rhinosinusitis With co-morbid asthma are excluded if forced expiratory volume (FEV1) is 50% (of predicted normal) or less With known active bacterial, viral, fungal, mycobacterial infection, or other infection or any major episode of infection that required hospitalization or treatment with IV antibiotics within 30 days of screening or during screening or oral antibiotics within 14 days prior to screening. Fungal infection of nail beds is allowed Have human immunodeficiency virus/acquired immune deficiency syndrome Have acute or chronic hepatitis B/hepatitis C infection History of an opportunistic infection (eg, pneumocystis carinii, cryptococcal meningitis, progressive multifocal leukoencephalopathy) or serious bacterial, viral, or fungal infections (eg, disseminated herpes simplex, disseminated herpes zoster) and requiring IV medication(s) ≤ 3 weeks prior to randomization History of or currently active primary or secondary immunodeficiency History of cancer within the last 5 years, including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have been excised and resolved) or colonic mucosal dysplasia History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma History of alcohol or drug abuse within 1 year prior to randomization Receipt of live vaccine within 4 weeks prior to randomization Pregnant or breastfeeding Participation in another clinical study or treatment with an investigational drug or device Serious or active medical or psychiatric condition which, in the opinion of the Investigator, may interfere with treatment, assessment, or compliance with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Active drug vs placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active drug<br>Dupilumab 300 mg every other week for 24 weeks | Drug: Dupilumab 300 MG/2 ML Subcutaneous Solution [DUPIXENT]<br>* 300 mg every other week for 24 weeks<br>|
| Placebo Comparator: Placebo<br>Placebo | Other: Placebo<br>* No active drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Lund-Mackay sinus computed tomography (LMK-CT) score | Change in LMK-CT score in dupilumab group compared to control group. The total score ranges from 0 (normal) - 24 (more opacified): higher score indicates worse status. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in participant-reported symptoms scores of sinusitis | Change in baseline in participant-reported symptoms scores of sinusitis in dupilumab group compared to control group. Morning symptoms of sinusitis will be assessed using a 0 (no symptoms) - 3 (severe symptoms) categorical scale, where a higher score indicates severe symptoms. | 24 weeks | 
| Change in visual analogue scale score for sinusitis | Change in visual analogue scale score for sinusitis in dupilumab group compared to control group. the severity of sinusitis symptoms will be assessed on a 0 cm (not troublesome) - 10 cm (worst thinkable troublesome) where a higher score indicates worst thinkable troublesome. | 24 weeks | 
| Change in nasal peak inspiratory flow | Change in nasal peak inspiratory flow in dupilumab group compared to placebo group. | 24 weeks | 
| Change in University of Pennsylvania smell identification test (UPSIT) scores | Change in UPSIT scores in dupilumab group compared to placebo group. Total score ranges from 0 (anosmia)-40 (normal sense of smell), a lower score indicates severe smell loss. | 24 weeks | 
| Time to first response in LMK-CT score | 50 percent improvement in LMK-CT score in dupilumab group compared to placebo group | 24 weeks | 
| Change in sinonasal outcome test (SNOT-22) score | Change in 22-item SNOT-22 test score in dupilumab group compared to placebo group. The total score may range from 0 (no problem)-110 (worst quality of life), higher scores represent the worst quality of life; minimal clinically important change ≥ 8.90. | 24 weeks | 
| Change in biomarkers concentrations in nasal secretion measured by enzyme-linked immunosorbent assay (ELISA) | Change in biomarkers concentrations in nasal secretion in dupilumab group compared to placebo group. ELISA will be done to measure biomarkers concentrations (pg/mL): ECP, IL-4, IL-5, IL-13, periostin, eotaxin-3, TARC, and IgE | 24 weeks |