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
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 3
- 主要终点
- Modified Lund-Kennedy (mLK) Score
研究概览
简要总结
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. Participants will be administered a placebo or dupilumab every two weeks for 52 weeks.
详细描述
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.
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.
Patients who meet the eligibility criteria will be enrolled in this randomized, double-blind study and will go through four periods: a run-in period, surgery period, randomized treatment period, and post-treatment period. During the run-in period, patients will perform twice daily saline irrigations followed by intranasal corticosteroid spray (INCS) for 2 to 6 weeks before planned sinus surgery. Saline irrigations/INCS and sinus surgery will be completed by the standard of care (SoC). Patients who continue to meet eligibility criteria following surgery will be randomized to receive a placebo or dupilumab subcutaneously every 2 weeks. Participants will receive 26 doses of the investigational medical product (IMP), via either study personnel or home administration, to maintain a 2-week treatment schedule. Participants 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. Participants will then be monitored on daily saline irrigation and INCS spray for 12 weeks to evaluate potential disease recurrence after discontinuation of IMP. An end-of-study visit will be conducted 12 weeks after the treatment period at Week 64.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
Double-blinded, placebo-controlled, parallel-group
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Capable of giving signed informed consent
- •Patients aged >18 years at the time of signing the informed consent form (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 and 5/5 criteria at time of randomization: environmental atopy by skin or serum testing, nasal polyposis, characteristic CT findings, eosinophilic mucous, fungal identification on histopathology
排除标准
- •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, antrochoanal 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, influence the primary or secondary outcomes 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
- •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
研究组 & 干预措施
Dupilumab
Participants receiving dupilumab for 52 weeks following surgery for allergic fungal rhinosinusitis (AFRS).
干预措施: Dupilumab (Drug)
Dupilumab
Participants receiving dupilumab for 52 weeks following surgery for allergic fungal rhinosinusitis (AFRS).
干预措施: Intranasal Corticosteroid Sprays (INCS) (Drug)
Placebo
Participants receiving a placebo to match dupilumab for 52 weeks following surgery for allergic fungal rhinosinusitis (AFRS).
干预措施: Placebo (Drug)
Placebo
Participants receiving a placebo to match dupilumab for 52 weeks following surgery for allergic fungal rhinosinusitis (AFRS).
干预措施: Intranasal Corticosteroid Sprays (INCS) (Drug)
结局指标
主要结局
Modified Lund-Kennedy (mLK) Score
时间窗: Baseline and End of Treatment at Week 52
The efficacy of dupilumab in controlling sinonasal inflammation and preventing nasal polyp recurrence after complete sinus surgery for allergic fungal rhinosinusitis (AFRS) is assessed by using the modified Lund-Kennedy score. The 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.
Incidence of Oral/Topical Corticosteroid Utilization Per Participant
时间窗: Baseline and End of Treatment at Week 52
The number 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.
次要结局
- Prevalence of Revision Sinus Surgery for Recurrent Nasal Polyps, and Comparison of Survival Curves(Up to End of Treatment at Week 52)
- Endoscopic Nasal Polyp Score (NPS)(52 weeks and 64 weeks)
- Percent Predicted Forced Vital Capacity (%FVC) Following Sinus Surgery in the Subgroup of Participants With Asthma (~25%)(Baseline and End of Treatment at Week 52)
- FEV1/FVC Ratio Following Sinus Surgery in the Subgroup of Participants With Asthma (~25%)(Baseline and End of Treatment at Week 52)
- Forced Expiratory Volume in 1 Second (FEV1) Following Sinus Surgery in the Subgroup of Participants With Asthma (~25%)(Baseline and End of Treatment at Week 52)
- Forced Vital Capacity (FVC) Following Sinus Surgery in the Subgroup of Participants With Asthma (~25%)(Baseline and End of Treatment at Week 52)
- Change in the Modified Lund-Kennedy (mLK) Radiologic Score(52 weeks and 64 weeks)
- The 22-item Sinonasal Outcomes Test (SNOT-22) Score(52 weeks and 64 weeks)
- Change in Asthma Control Questionnaire (ACQ) Score Among Participants With Asthma(52 weeks and 64 weeks)
- Prevalence of Oral/Topical Corticosteroid Utilization Per Treatment Cohort(52 weeks and 64 weeks)
- Prevalence of Oral/Topical Antibiotic Utilization Per Treatment Cohort(52 weeks and 64 weeks)
- Incidence of Oral/Topical Antibiotic Utilization Per Participant(52 weeks and 64 weeks)
研究者
Joshua M. Levy
Adjunct Professor
Emory University