Dupilumab in CRSsNP

Study Overview
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Brief Summary
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Primary Objective: To evaluate the efficacy of dupilumab as assessed by the reduction at Week 24 in sinus opacification on computerized tomography (CT) scan in the dupilumab group only Secondary Objectives: To evaluate the efficacy of dupilumab as assessed by the reduction at Week 24 in sinus opacification on CT scan and sinus total symptom score (sTSS) compared to placebo To evaluate the safety and tolerability of dupilumab in CRSsNP patients compared to placebo To evaluate the pharmacokinetics (PK) of dupilumab in CRSsNP patients compared to placebo Assessment of immunogenicity to dupilumab over time compared to placebo

Detailed Description
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The duration of study for each participant will include 2-4 weeks of screening period, 24-52 weeks randomized investigational medicinal product (IMP) intervention period and 12 weeks of follow-up period.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Dupilumab in Patients With Uncontrolled, Chronic Rhinosinusitis Without Nasal Polyposis (CRSsNP)

Conditions
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Chronic Rhinosinusitis Without Nasal Polyps, Sinusitis, Chronic Sinusitis, Sinus Disorder, Respiratory Disorder

Intervention / Treatment
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* Drug: Dupilumab SAR231893
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be at least 18 years of age at the time of signing the informed consent form (ICF). Participants must have bilateral inflammation of paranasal sinuses in CT scan with LMK ≥8 and bilateral ethmoid opacification before randomization. Participants must have ongoing symptoms of loss of smell and rhinorrhea (anterior/posterior) of any severity, with or without facial pain/pressure for at least 12 consecutive weeks by Visit 1. Participants must have ongoing symptoms of nasal congestion (NC)/obstruction at least 12 consecutive weeks before Visit 1 and a NC score of ≥ 2 at Visit 1 (day score) and Visit 2 (weekly average score). Participants must have sTSS (NC, rhinorrhea, facial pain/pressure) ≥5 at Visit 1 (day score) and Visit 2 (weekly average score). Participants must have one of the 2 following features: Prior sinonasal surgery (see note at end of section 5.2 for definitions of sinonasal surgery) for CRS, Treatment with systemic corticosteroids (SCS) therapy for CRS as defined by any dose and duration within the prior 2 years before screening (Visit 1) or intolerance/contraindication to SCS. Exclusion Criteria: Patients with nasal conditions/concomitant nasal diseases such as nasal polyposis in endoscopy at Visit 1 or with history of nasal polyposis etc., making them non-evaluable at Visit 1 or for the primary efficacy Nasal cavity malignant tumor and benign tumors. Forced expiratory volume (FEV1) ≤50% of predicted normal at Visit 1. Radiologic suspicion or confirmed invasive or expansive fungal rhinosinusitis. Severe concomitant illness(es) that, in the investigator's judgment, would adversely affect participation in the study Active tuberculosis or non-tuberculous mycobacterial infection, or a history of incompletely treated tuberculosis unless documented adequately treated. Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic infection Known or suspected immunodeficiency History of malignancy within 5 years before Visit 1, except completely treated in situ carcinoma of the cervix, and completely treated and resolved nonmetastatic squamous or basal cell carcinoma of the skin. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks before the Screening Visit 1 or during the screening period. History of systemic hypersensitivity or anaphylaxis to dupilumab or any of its excipients. Patients in prior dupilumab clinical trial or have been treated with commercially available dupilumab within 12 months or who discontinued dupilumab use due to adverse event. Patients who are treated with intranasal corticosteroid drops; intranasal steroid emitting devices/stents; nasal spray using exhalation delivery system, such as Xhance™, during screening period. Participants on unstable dose of intranasal corticosteroids (INCS) spray 4 weeks prior to Screening Visit (Visit1) and during screening period. Patients who have undergone sinus intranasal surgery (including polypectomy) within 6 months prior to Visit 1. Patients who have taken: Biologic therapy/systemic immunosuppressant to treat inflammatory disease or autoimmune disease within 5 half-lives prior to Visit 1 Any investigational mAb within 5 half-lives prior to Visit 1 Anti-IgE therapy (omalizumab) within 4 months prior to Visit 1. Treatment with a live (attenuated) vaccine within 4 weeks prior to Visit 1 Leukotriene antagonists/modifiers unless patient is on a continuous treatment for at least 30 days prior to Visit 1. Initiation of allergen immunotherapy within 3 months prior to Visit 1 or a plan to begin therapy or change its dose during the screening or treatment period. Patients received SCS during screening period (between Visit 1 and Visit 2). Either intravenous immunoglobulin therapy and/or plasmapheresis within 30 days prior to Screening Visit (Visit 1). The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A and B: Dupilumab<br>Dupilumab administered every 2 weeks. | Drug: Dupilumab SAR231893<br>* Pharmaceutical form:Injection solution Route of administration: Subcutaneous<br>|
| Placebo Comparator: Part A and B: Matching placebo<br>Placebo administered every 2 weeks | Drug: Placebo<br>* Pharmaceutical form:Injection solution Route of administration: Subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to Week 24 in opacification of sinuses assessed by CT scan using the Lund Mackay (LMK) score in the dupilumab group only | LMK total score is based on assessment of the CT scan findings for each sinus area. The extent of opacification is rated between 0 (normal) to 24 (total opacification). | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to Week 24 in opacification of sinuses assessed by CT scan using the LMK score | LMK total score is based on assessment of the CT scan findings for each sinus area. The extent of opacification is rated between 0 (normal) to 24 (total opacification). | Baseline to Week 24 | 
| Change from baseline to Week 24 in sTSS | The sTSS is a composite score derived from the following individual items: NC, anterior/posterior rhinorrhea, and facial pain/pressure. The total score ranges from 0-9. Higher scores on sTSS indicate greater overall symptom severity. | Baseline to Week 24 | 
| Incidence of treatment-emergent adverse events (TEAEs), of treatment-emergent serious AEs (TESAEs), and TEAEs leading to treatment discontinuation | Incidence of treatment-emergent adverse events (TEAEs), of treatment-emergent serious AEs (TESAEs), and TEAEs leading to treatment discontinuation. | Baseline to Week 64 | 
| Dupilumab concentration in serum | Dupilumab concentration in serum. | Baseline to Week 52 | 
| Incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab over time | Incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab over time. | Baseline to Week 64 |