Add-on Dupilumab for AFRS as Postoperative Therapy (ADAPT)

Study Overview
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Brief Summary
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The purpose of this study is to find a more effective treatment for allergic fungal rhinosinusitis (AFRS). Most people suffering from nasal polyps have elevated levels of white blood cells called eosinophils that are involved in inflammation of the air passages. Despite appropriate treatment with oral/topical corticosteroids, saline irrigations, and surgery, nasal polyps return frequently within months of surgery. Certain proteins made by the body called interleukins, appear to play a major role in the survival and activation of eosinophils. Antibodies are proteins naturally produced by your body that find foreign substances such as bacteria, fungi, viruses, and other substances that enter your body and make them inactive. Dupilumab is an antibody made in the laboratory that has been made to block specific interleukins from activating the eosinophils. This research is being done to find out if the medication dupilumab is effective and safe when used to treat patients with AFRS following recommended sinus surgery. Dupilumab is already approved for the treatment of atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis (CRSwNP); however, it is not approved to treat AFRS. Therefore its use in this study is considered experimental.

Detailed Description
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Allergic fungal rhinosinusitis (AFRS) is a severe form of eosinophilic nasal polyposis with critically inadequate treatment options for the 10% of chronic rhinosinusitis subjects affected by the disease. Occlusive eosinophilic mucus and severe nasal polyposis present in early adulthood, with an unrelenting course marked by sinus expansion and pressure-induced dehiscence of the surrounding orbit and skull base. Despite appropriate therapies with oral/topical corticosteroids, saline irrigations, and comprehensive sinus surgery, nasal polyps aggressively recur, frequently within months of surgery. Medical options beyond topical and systemic steroids are limited. Neither antifungal nor allergen immunotherapy is beneficial. Due to persistent sinonasal inflammation, patients with AFRS receive an average of three corticosteroid bursts per year and revision sinus surgery every 42 months. Patients who meet the eligibility criteria will be enrolled in this randomized, double-blind study and will go through four periods. During the Run-in period, the subjects will receive saline irrigations at least daily for 2-6 weeks. Then subjects will undergo surgery per standard of care, and at this time, Sinonasal mucus, peripheral blood, and ethmoid tissue will be collected. After the surgery period, which lasts 4 weeks, subjects will be randomized to either Dupilumab or Placebo. Dupilumab (300 mg) and placebo will be given subcutaneously every other week for 52 weeks. This treatment period will be followed by a post-treatment period of 12 weeks. Dupilumab 300 mg will be administered subcutaneously (S)C every 2 weeks with an end of treatment (EOT) at week 52. A matching placebo will be administered subcutaneously (SC) at the same time points. Patients will receive a total of 26 doses of the investigational medical product (IMP). Patients will receive IMP directly from the central pharmacy, with compliance assessments via reminder text messages on the day of each scheduled home administration, as well as monthly phone calls and injection device collection at recurring 3-month study visits. Self-administration of IMP will be completed at home to maintain a 2-week treatment schedule. All subjects will undergo standardized background therapy with intranasal corticosteroid sprays (INCS) per standard of care (SoC). This will be continued throughout the entire study. Subjects will either receive fluticasone propionate or mometasone furoate.

Official Title
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A Randomized, 52-week Treatment Double-blind, Placebo-controlled Efficacy and Safety Study of Dupilumab 300 mg Every Other Week After Endoscopic Sinus Surgery in Patients With Allergic Fungal Rhinosinusitis (AFRS) on a Background Therapy With Intranasal Corticosteroid Spray

Conditions
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Allergic Fungal Rhinosinusitis

Intervention / Treatment
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* Drug: Dupilumab 300 MG/2 ML Subcutaneous Solution
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving signed informed consent as listed in the informed consent form (ICF) and this protocol. Patients aged >18 years at the time of signing the ICF. Patients with nasal polyps in the setting of suspected AFRS and electing to undergo comprehensive sinus surgery per established criteria. Diagnosis of nasal polyps by consensus criteria. Failure of appropriate medical therapy, including topical intranasal corticosteroid (spray or irrigation) > 8 weeks duration, systemic corticosteroid trial of 1-3 weeks duration, and nasal saline irrigation of > 4 weeks duration A minimum SNOT-22 score of 20 at the time of enrollment. A minimum CT Lund-MacKay score of > 1 at the time of enrollment. Suspected AFRS based on Bent and Kuhn criteria Patients meet 3/5 criteria at the time of enrollment Environmental atopy by skin or serum testing Nasal polyposis Characteristic CT findings Eosinophilic mucous Fungal identification on histopathology Exclusion Criteria: Patients who have undergone nasal or sinus surgery within 3 months prior to enrollment. Patients with conditions or comorbid disease findings that exclude nasal endoscopy for evaluation of primary outcomes, such as current rhinitis medicamentosa, nasal cavity tumors, occlusive septal deviation following surgery Clinically important comorbidities that may confound the interpretation of clinical efficacy, including aspirin-exacerbated respiratory disease, cystic fibrosis, primary ciliary dyskinesia, Hereditary Hemorrhagic Telangiectasia, antro-choanal polyposis, non-asthma eosinophilic disease, such as bronchopulmonary aspergillosis, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome; Granulomatosis with polyangiitis Any corticosteroid-dependent condition A comorbid health disorder that is not medically controlled in the opinion of the Investigator, and has the potential to affect the safety of the subject throughout the study, impede the subject's ability to complete the duration of the study Patient experiencing a symptomatic asthma exacerbation requiring systemic corticosteroids or hospitalization (>24 hours) within 4 weeks of randomization. Infection requiring systemic antibiotics within 4 weeks of randomization (Parenteral and/or oral antibiotics associated with surgery are allowed) Medical contraindication to receiving dupilumab: Known hypersensitivity to dupilumab or any of its excipients, live vaccine administration within 30 days of randomization or during the study period, known helminth infection Unable to tolerate sinonasal irrigations. Pregnancy, current lactation, or lack of effective contraception plan, as determined by the site investigator. Initiation of allergen immunotherapy within 3 months prior to randomization or a plan to begin therapy or change its dose during the study period. Immunosuppressive medication within 3 months prior to randomization and during the study period from randomization through the end of the study (EOS). Receipt of any marketed or investigational biologic products (monoclonal or polyclonal antibody) within 6 months or 5 half-lives, whichever is longer, prior to randomization during the study period. Previous use of dupilumab. Receipt of immunoglobulin or blood products within 30 days prior to randomization. Receipt of any investigational drug within 30 days or 5 half-lives, whichever is longer prior to randomization. Scheduled systemic corticosteroid treatment during the study period (Standardized corticosteroid taper associated with planned surgery is allowed) Receipt of leukotriene antagonists or modifiers for subjects who were not on a stable dose for > 30 days prior to randomization. Concurrent enrollment in another investigational drug trial during the study period. Patient involvement in the planning or conduct of the study. Investigator assessment that the subject is unlikely to comply with study procedures. Prior randomization in the present study. Unable to undergo sinus surgery due to comorbid medical conditions.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dupilumab<br>150 mg/mL in a pre-filled syringe to deliver 300 mg in 2 mL given subcutaneous every 2 weeks during the treatment period | Drug: Dupilumab 300 MG/2 ML Subcutaneous Solution<br>* 150 mg/mL in pre-filled syringe to deliver 300 mg in 2 mL given Subcutaneously every 2 weeks during the treatment period<br>* Other names: Intervention Group;|
| Placebo Comparator: Placebo<br>Pre-filled syringe to deliver 2 mL given subcutaneous every 2 weeks during the treatment period | Drug: Placebo<br>* Pre-filled syringe to deliver 2 mL given Subcutaneously every 2 weeks during the treatment period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of dupilumab in controlling sinonasal inflammation and preventing nasal polyp recurrence after complete sinus surgery for allergic fungal rhinosinusitis (AFRS) by using the modified Lund-Kennedy score | Modified Lund-Kennedy score (mLK) is a validated measure of sinonasal inflammation, as evaluated by means of nasal endoscopy. The composite score ranges from 0 to 12, with an increasing score representing worsening inflammation among three separate findings (Nasal polyps, Discharge, Edema). Each finding is rated from 0 (absent) to 2 (severe). A ≥ 2-point increase from baseline total postoperative score represents a clinically significant worsening of sinonasal inflammation | Baseline and 52 weeks | 
| Incidence of oral/topical corticosteroid utilization per participant | Count of participants who during study treatment and off treatment follow-up, based on clinical evaluation, present worsening signs and/or symptoms and are started on oral corticosteroids rescue treatment. | Baseline and 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of revision sinus surgery for recurrent nasal polyps, and comparison of survival curves | Documentation of the number of revision sinus surgery per participant, that are deemed clinically necessary for the treatment of an acute exacerbation of chronic rhinosinusitis (AECRS) | Baseline and 52 weeks | 
| Change in the endoscopic nasal polyp score (NPS) | NPS is a physician-reported tool to grade the extent/severity of nasal polyps based on evaluation by nasal endoscopy. Each nostril is scored on a scale of 0 to 4, with the total score being the sum of left and right nostril scores (range: 0-8). The total NPS is the sum of scores from the right and left nostrils. | Baseline and 52 weeks | 
| Change in vital capacity (VC) following sinus surgery in the subgroup of participants with asthma ( 25%) | Spirometry (is a common office test used to assess how well the participant's lungs work by measuring how much air the participant inhales, how much the participant exhales, and how quickly the participant exhales). Vital capacity (VC) refers to the maximal volume of air that can be expired following maximum inspiration. It is the total of tidal volume, inspiratory reserve volume, and expiratory reserve volume. | Baseline and 52 weeks | 
| Change in 1 second (FEV1) following sinus surgery in the subgroup of participants with asthma ( 25%) | Forced expiratory volume in one second (FEV1) is measured during a spirometry test, also known as a pulmonary function test, which involves forcefully breathing out into a mouthpiece connected to a spirometer machine. FEV1 is the amount of air forced from the lungs in one second. To describe the severity of pulmonary disease, FEV1 can be expressed as a percentage of the predicted value. Values 80% and greater than the predicted value are considered normal. | Baseline and 52 weeks | 
| Change in forced vital capacity (FVC) following sinus surgery in the subgroup of participants with asthma ( 25%) | Forced vital capacity (FVC) is measured during a spirometry test, also known as a pulmonary function test, which involves forcefully breathing out into a mouthpiece connected to a spirometer machine. FVC is the total amount of air exhaled during the FEV test. FVC can be expressed as a percentage of the predicted value. The normal range for the percent of the predicted value is between 80% and 120%. | Baseline and 52 weeks | 
| Change in the FEV1/FVC ratio following sinus surgery in the subgroup of participants with asthma ( 25%) | The FEV1/FVC ratio is the ratio of the forced expiratory volume in the first one second to the forced vital capacity of the lungs. The normal value for this ratio is above 0.75-85, though this is age-dependent, values less than 0.70 are suggestive of airflow limitation with an obstructive pattern. | Baseline and 52 weeks | 
| Change in the modified Lund-Kennedy (mLK) radiologic score | The mLK Radiologic scoring system assigns a value of 0, 1, or 2 to each of the following sinuses: maxillary, anterior ethmoid, posterior ethmoid, frontal, and sphenoid. Score assignments are 0 if the sinus is totally patent, 1 if the sinus is partially opacified, and 2 if the sinus is completely opacified. The osteomeatal complex is scored either 0 if not occluded or 2 if occluded. The maximum score for each side is thus 12, with a total score determined out of 24. Baseline Lund- MacKay (LM) scores will be counted as zero in accordance with recent sinus surgery. | 52 weeks and 64 weeks | 
| Change in the endoscopic nasal polyp score (NPS) | Endoscopic nasal polyp score is determined by the treating Investigator. Unlike prior study of dupilumab in nasal polyps, we will separately record the Nasal Polyp Score for each side, with a maximum unilateral score of 4. This is appropriate for monitoring efficacy in AFRS, as a subgroup of participants may present with unilateral disease. | 52 weeks and 64 weeks | 
| Change in the 22-item sinonasal outcomes test (SNOT-22) | The SNOT-22 score is a validated disease-specific questionnaire quantifying the quality of life among participants with chronic rhinosinusitis. The individual question scores range from 0 (no problem) to 4 (as bad as can be) among 22 individual questions. The threshold value for minimal clinically significant change is ≥ 8.90 | 52 weeks and 64 weeks | 
| Change in the RhinoSinusitis Disability Index (RSDI) | The Rhinosinusitis Disability Index (RSDI) is a validated measure of the health-related quality of life (HRQL) in rhinitis. A 30-item questionnaire developed for use in persons with nasal or sinus disease. Each item is rated on a 5-point Likert scale ranging from 'never' (scored as 0) to 'always' (scored as 4). The total score possible, calculated by summing the individual items, ranges from 0 to 120, with higher scores reflecting worse HRQL. The RSDI has 3 subscale domains: physical (11 items), functional (9 items), and emotional (10 items). | 52 weeks and 64 weeks | 
| Change in the asthma Control Test (ACT) | The Asthma Control Test (ACT) is a validated, self-administered survey used to assess participants' perception of disease control over the preceding 4-week period using Likert scale responses (range: 0-5). The ACT consists of 5 items surveying the frequency of asthma-related symptoms, the need for rescue medications, and perceived control of disease. Higher total scores (range: 0-25) indicate better levels of asthma control, however, scores less than 20 reflect uncontrolled asthma at the time of completion. A score change of at least 3 points has been previously defined as a minimal clinically important difference (MCID). | 52 weeks and 64 weeks | 
| Prevalence of oral/topical corticosteroid utilization per treatment cohort | Count of participants who during study treatment and off treatment follow-up, based on clinical evaluation, have to continue on oral corticosteroid rescue treatment due to worsening signs and/or symptoms. | 52 weeks and 64 weeks | 
| Incidence of oral/topical antibiotic utilization per participant | Count of participants who during study treatment and off treatment follow-up, based on clinical evaluation, present worsening signs and/or symptoms and are started on oral/topical antibiotic rescue treatment. | 52 weeks and 64 weeks | 
| Prevalence of oral/topical antibiotic utilization per treatment cohort | Count of participants who during study treatment and off treatment follow-up, based on clinical evaluation, have to continue on oral/topical antibiotic rescue treatment due to worsening signs and/or symptoms. | 52 weeks and 64 weeks |