Allergic Fungal Rhinosinusitis (AFRS), Asthma, Chronic Rhinosinusitis (CRS), Nasal Polyps
Conditions
Keywords
Ethmoid tissue, Intranasal corticosteroids, Nasal polyps, Sinonasal inflammation, Lung Function, Quality of Life
Brief summary
Background: Allergic fungal rhinosinusitis (AFRS) is a severe type of sinus infection. People with AFRS develop heavy mucus and growths called polyps that apply pressure to the sinuses and block their breathing. Surgery can remove the polyps, but they often grow back. Researchers want to test an approved drug they believe may help people with AFRS. Objective: To test a drug (Dupilumab) in people with AFRS. Eligibility: People aged 18 years or older with suspected AFRS who are scheduled to undergo surgery for nasal polyps. Design: Participants will have several tests before their surgery. They will have imaging scans of their sinuses. They will have an endoscopic exam: A tube with a camera and a light will be inserted into their sinuses. They may give blood and mucus samples. They will have standard treatment with nasal sprays for 2 to 6 weeks before their surgery. Excess nasal tissue removed during the surgery will be collected for research. Then they will begin treatment with the study drug. Dupilumab is injected under the skin. Some participants will receive the study drug. Some will receive a placebo injections. The placebo injections are just like the study drug but contain no medicine. Participants will not know which injections they are getting. All participants will administer the injections to themselves at home. They will do this every 2 weeks for 1 year after the surgery. They will have a clinic visit 16 weeks after surgery. Participants will have follow-up for 12 weeks after treatment ends.
Detailed description
Study Description: Multicenter, randomized, double-blind, placebo-controlled study comparing the efficacy of dupilumab to placebo in allergic fungal rhinosinusitis (AFRS) subjects after sinus surgery on a background treatment with intranasal corticosteroid spray. Study periods: The clinical trial consists of 4 periods: -Run-in period (2 weeks + 4 weeks): All participants will enter a run-in period of 2-6 weeks receiving saline irrigations and Intranasal Corticosteroids per the treating physician. All oral steroids and antibiotics will be stopped. -Ethmoid Tissue Collection period (7 days + 4 weeks): Participants will undergo surgery as scheduled per standard of care. Ethmoid tissue will be collected from all subjects at the time of surgery. -Randomized treatment (52 weeks +/- 7 days): Participants will be randomized to one of the following treatments: * Arm A: dupilumab 300 mg subcutaneous (SC) every two weeks for 52 weeks * Arm B: placebo given SC every two weeks for 52 weeks * Posttreatment period (12 weeks +/- 7 days): After completing 52 weeks of treatment with IMP (or following early discontinuation of IMP), subjects will be instructed to: * Return to the study site for the last scheduled visits for physical examination, nasal endoscopy, Nasal Polyps Score (NPS), Patient-Reported Outcomes (PROs)(Sinonasal Outcomes Test-SNOT-22-, and Asthma Control Questionnaire -ACQ-), FEV1 measurement in those with asthma, and safety. * Continue on stable dose of INCS spray during the posttreatment period. * Report any adverse event (AE). Co-Primary Objectives: * Determine the efficacy of dupilumab in controlling sinonasal inflammation and preventing nasal polyp recurrence after complete sinus surgery for AFRS as measured by change in the mLK score. * Evaluate the effect of dupilumab on oral corticosteroid utilization following complete sinus surgery for AFRS. Secondary Objectives: To evaluate the effect of dupilumab on: * Prevention of revision surgery for AFRS * Secondary objective measures of sinonasal inflammation following sinus surgery using NPS and LMS. * Lower airway dysfunction following sinus surgery in the subgroup of participants with asthma (approximately 25%) * Upper and lower airway, disease-specific, health-related quality of life, as measured by ACQ and SNOT-22 * Reducing utilization of rescue medications for acute exacerbations of CRS following sinus surgery Primary Endpoints: Change from baseline at 52 weeks both within and between treatment and placebo arms: * Endoscopic modified Lund-Kennedy (mLK) score * Incidence of oral corticosteroid utilization per participant Secondary Endpoints: Change from baseline at 52 weeks both within and between treatment and placebo arms: * Prevalence of revision sinus surgery for recurrent nasal polyps, and comparison of survival curves * Endoscopic nasal polyp score (NPS) * CT generated Lund-McKay score * Spirometry (for participants with comorbid asthma) * 22-item sinonasal outcomes test (SNOT-22) * Asthma Control Questionnaire (ACQ) * Prevalence of oral / topical corticosteroid utilization per treatment cohort * Incidence of oral / topical antibiotic utilization per subject * Prevalence of oral / topical antibiotic utilization per treatment cohort
Interventions
DRUGDupilumab
Dupilumab (Dupixent) is a human monoclonal antibody administered via subcutaneous injection to treat various conditions such as Chronic Rhinosinusitis with Nasal Polyps, Asthma and Eosinophilic Esophagitis.
Sponsors
National Institute on Deafness and Other Communication Disorders (NIDCD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: Participants are eligible for study participation if all inclusion and no
Exclusion criteria
are met. Non- English-speaking people will be included if they fulfill the criteria. In order to be eligible to participate in this study, an individual must meet all of the following criteria: Informed consent * Participants must be capable of giving signed informed consent as listed in the informed consent form (ICF) and this protocol. * ICF must be signed and dated prior to study specific procedures. Informed consent process is described further below. Age -Participants aged \>=18 years at the time of signing the ICF. Types of subject and disease characteristics * Participants 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 time of enrollment. * A minimum CT Lund-MacKay score of \> 1 at time of enrollment. * Suspected AFRS based on Bent and Kuhn criteria * Participants must meet 3/5 criteria at time of enrollment * Environmental atopy by skin or serum testing * Nasal polyposis * Characteristic CT findings * Eosinophilic mucous * Fungal identification on histopathology * Participants must meet 5/5 criteria at time of randomization. Enrolled subjects are expected to undergo SoC allergy testing and sinus surgery prior to randomization. This will complete evaluation for suspected AFRS, thus enabling further study participation. Allergy testing & sinus surgery, in addition to other SoC items, will be done per clinical guidelines at the treating institution and will not be covered in this protocol. Sinus Surgery -All study participants will have met criteria for sinus surgery and undergo a comprehensive procedure prior to randomization. The procedure will not be assigned and will be completed per SoC at the treating institution for the management of nasal polyps in suspected AFRS. Reproduction * Negative urine pregnancy test will be required at enrollment and study visits 3, 4, 5 and 6, throughout the treatment period for participants of childbearing potential (i.e., post-pubescent, premenopausal females). * Persons of childbearing potential must use an effective form of birth control (confirmed by the Investigator) e.g., total sexual abstinence, vasectomized sexual partner, tubal occlusion, intrauterine device or levonorgestrel Intrauterine system, Depo-Provera injections, oral contraceptive, Evra Patch, or Nuvaring. Women of childbearing potential must agree to use a highly effective method of birth control, as defined above, from enrollment, throughout the study duration and for 12 weeks after the last dose of IMP. * To protect against possible side effects, men should not get a sexual partner pregnant while taking the study drug and for 12 weeks after the last dose. Men should agree on a method of birth control to use throughout the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Dupilumab | Change from baseline at 52 weeks | -Control of sinonasal inflammation.-Prevention of nasal polyp recurrence after complete sinus surgery for AFRS.-Measured by change in the modified Lund-Kennedy (mLK) score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Prevention of Revision Surgery for AFRS | Change from baseline at 52 weeks | Assessment of the need for additional surgery due to recurrent nasal polyps. |
| Secondary Objective Measures of Sinonasal Inflammation | Change from baseline at 52 weeks | Changes in nasal polyp score (NPS) and CT-generated Lund-McKay score (LMS). |
| Effect of Dupilumab on Oral Corticosteroid Utilization | Change from baseline at 52 weeks | Reduction in the use of oral corticosteroids following complete sinus surgery for AFRS. |
| Health-Related Quality of Life | Change from baseline at 52 weeks | Upper and lower airway disease-specific quality of life measured by the Asthma Control Questionnaire (ACQ) and the Sinonasal Outcomes Test (SNOT-22). |
| Utilization of Rescue Medications | Change from baseline at 52 weeks | Reduction in the use of rescue medications for acute exacerbations of chronic rhinosinusitis (CRS) following sinus surgery. |
| Lower Airway Dysfunction in Participants with Asthma | Change from baseline at 52 weeks | Spirometry measurements and other assessments in approximately 25% of participants with asthma |
Outcome results
None listed