Dupilumab in Allergic Fungal Rhinosinusitis (AFRS) (LIBERTY-AFRS-AI)

Study Overview
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Brief Summary
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Primary Objective: To evaluate the efficacy of treatment with dupilumab to reduce sinus opacification in a population with allergic fungal rhinosinusitis (AFRS) Secondary Objectives: To evaluate the efficacy of treatment with dupilumab to reduce sinus opacification in a population with allergic fungal rhinosinusitis (AFRS) at Week 24 To assess the efficacy of dupilumab to reduce the need for rescue treatments To evaluate the efficacy of treatment with dupilumab in improving symptoms in AFRS To evaluate the efficacy of dupilumab to reduce nasal polyp formation in participants with AFRS To evaluate the efficacy of dupilumab in improving overall symptom severity and quality of life in AFRS To evaluate the efficacy of dupilumab in improving sense of smell in participants with AFRS To explore the effect of dupilumab as assessed by three-Dimensional CT volumetric measurement of the paranasal sinuses To evaluate the safety and tolerability of dupilumab when administered to participants with AFRS To evaluate the pharmacokinetics (PK) of dupilumab in participants with AFRS To characterize the effect of dupilumab on total IgE and specific IgE To assess immunogenicity to dupilumab in participants with AFRS

Detailed Description
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The duration of study for each participant will include 2-4 weeks of screening period (2 additional weeks could be allowed), 52 weeks of 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 Parallel Group Study Assessing the Efficacy and Safety of Dupilumab in Patients With Allergic Fungal Rhinosinusitis (AFRS)

Conditions
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Allergic Fungal Rhinosinusitis

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 6 years of age (or the minimum legal age for adolescents in the country of the investigational site) at the time of signing the informed consent. Participants with the diagnosis of AFRS adapted from criteria by Bent and Kuhn (meeting all): IgE mediated inflammatory response to fungal hyphae (specific IgE serology or skin test) Evidence of sensitization to fungus by skin testing (at screening or documented historical positive skin test in the previous 12 months), or positive fungal-specific IgE in serum at screening. Nasal polyposis confirmed by nasal endoscopy at screening. Characteristic CT signs to be performed during screening period and can include any of the below signs as assessed by central reader: hyperdensities bony demineralization bone erosion of sinus Eosinophilic mucin/mucus identified within 5 years prior to screening or at screening with or without positive fungal stain AFRS patients with the following: An endoscopic NPS of at least 2 out of 4 for unilateral polyps or 3 out of 8 for bilateral polyps at Visit 1 (central reading) and Visit 2 (local reading) and, Sinus opacification in CT scan with an LMK score of 9 for patients with unilateral polyps or 12 for patients with bilateral polyps during screening period and, Body weight ≥15 kg Exclusion Criteria: Patients with nasal conditions/concomitant nasal diseases making them non-evaluable at Visit 1 or for the primary efficacy Nasal cavity malignant tumor and benign tumors. Known of fungal invasion into sinus tissue. Severe concomitant illness(es) that, in the investigator's judgment, would adversely affect the patient's 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 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. Treatment with commercially available dupilumab within 12 months, participation in prior dupilumab clinical trial, or 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. Patients who are on intranasal corticosteroids (INCS) spray unless they have received stable dose for at least 4 weeks prior to Visit 1. 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. - 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: 6 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: Dupilumab<br>Dupilumab administered every 2 or 4 weeks based on weights | Drug: Dupilumab SAR231893<br>* Pharmaceutical form:Injection solution Route of administration: Subcutaneous<br>|
| Placebo Comparator: Matching placebo<br>Placebo administered every 2 or 4 weeks based on weights | 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 in sinus opacifications assessed by computerized tomography (CT) scans using the Lund Mackay (LMK) score at Week 52 | 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 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in sinus opacifications assessed by CT scans using the LMK score at Week 24 | 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 | 
| Proportion of patients who receive systemic corticosteroids (SCS) and/or undergo/plan to undergo surgery for AFRS during the planned study treatment period |  | Baseline to Week 52 | 
| Change from baseline in monthly average nasal congestion/obstruction score from the Nasal symptom Diary at Week 24 and Week 52 | The nasal congestion/obstruction scores are scored from 0 ('No symptoms') to 3 ('Severe symptoms'). | Baseline to Week 24 and Week 52 | 
| Change from Baseline in the monthly average anterior/posterior rhinorrhea score from the Nasal Symptom Diary at Week 24 and Week 52 | The rhinorrhea scores are scored from 0 ('No symptoms') to 3 ('Severe symptoms'). | Baseline to Week 24 and Week 52 | 
| Change from baseline in endoscopic NPS compared to placebo at Week 24 and Week 52 | The total nasal polyps score (NPS) is the sum of the right and left nostrils, ranging from 0 (no polyps) to 8 (large polyps causing complete obstruction). | Baseline to Week 24 and Week 52 | 
| Change from baseline in 22-item sino-nasal outcome test (SNOT-22) total score at Week 24 and Week 52 | SNOT-22 is a patient-reported outcome (PRO) questionnaire. Score ranges from 0 to 110 with higher score indicating greater rhinosinusitis related health burden. | Baseline to Week 24 and Week 52 | 
| Change from baseline in monthly average total symptom score (TSS) derived from the Nasal Symptom Diary at Week 24 and Week 52 | TSS ranges from 0 to 9. Higher scores on the TSS indicate greater symptom severity. | Baseline to Week 24 and Week 52 | 
| Change from baseline in visual analog scale (VAS) rhinosinusitis at Week 24 and Week 52 | VAS score ranges from 0 ('not troublesome') to 10 ('worst thinkable troublesome'). | Baseline to Week 24 and Week 52 | 
| Change from baseline in University of Pennsylvania smell identification test (UPSIT) at Week 24 and Week 52 | The UPSIT score ranges from 0 to 40, with 40 being the best possible score. | Baseline to Week 24 and Week 52 | 
| Change from baseline in the score of decreased/loss of smell using the Nasal Symptom Diary at Week 24 and Week 52 | The decreased/loss of smell scores are scored from 0 ('No symptoms') to 3 ('Severe symptoms'). | Baseline to Week 24 and Week 52 | 
| Change from baseline to Week 52 in three Dimensional CT volumetric measurement of the paranasal sinuses |  | Baseline to Week 52 | 
| Incidence of treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) |  | Baseline to Week 64 | 
| Dupilumab concentration in serum over time |  | Baseline to Week 52 | 
| Percent change from baseline in total IgE in serum compared to placebo over the 52 weeks treatment period |  | Baseline to Week 52 | 
| Percent change from baseline in fungal-specific IgE in serum compared to placebo over the 52 weeks treatment period |  | Baseline to Week 52 | 
| Incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab over time | Enter Endpoint Secondary | Baseline to Week 64 |