Anti-IL4/IL13 Therapy With Dupilumab for Prevention of Refractory Chronic Rhinosinusitis After Endoscopic Sinus Surgery for CRSwNP
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Number of participants with non-recurrence of sinus cavity oedema as assessed endoscopically
研究概览
简要总结
The investigators believe that administering Dupilumab during the pre- and peri-operative period of surgery for chronic rhinosinusitis with nasal polyps (CRSwNP) will safely downregulate Type 2 inflammation of the healing sinus environment and will allow for better coordinated and more effective mucosal healing. Specifically, the investigators believe that endoscopic signs and symptoms of recurrence will be reduced in the Dupilumab-treated group, and that this will be reflected in quality of life (QOL). Additionally, by reducing Type 2 inflammation at the time of surgery, Dupilumab may offer an additional benefit by decreasing operative bleeding.
The investigators propose to perform a placebo-controlled, prospective, real-world trial in patients with CRSwNP undergoing revision surgery for CRSwNP to verify whether recurrences after endoscopic sinus surgery (ESS) can be prevented by controlling Type 2 inflammation during the peri-operative period using Dupilumab. A series of seven injections of Dupilumab (or placebo) will be administered to symptomatic patients undergoing ESS for CRSwNP. Beginning 4 weeks prior to surgery and continuing for 8 weeks post-surgery, q2 weekly injections will be administered to reduce Type 2 inflammation at time of ESS and during the post-operative recovery period.
Principal outcome will be absence of recurrence of mucosal oedema of the sinus cavity as assessed by endoscopy. Secondary objectives will assess Polyp size, sinus symptomatology, quality of life, smell and asthma control. Exploratory analyses will assess microbiome and gene expression profiles to better understand molecular mechanisms implicated in CRSwNP pathophysiology, and to identify the pathways implicated by modulation of Type 2 inflammation.
详细描述
Chronic rhinosinusitis (CRS) affects an estimated one in fourteen (7%) Canadians, making it one of the most frequent inflammatory diseases. The human and economic cost of CRS are substantial. Patients affected with chronic sinus disease suffer from headache, facial pain and sinus infections, and experience a reduced quality of life (QOL).The disease has a prolonged course and is frequently resistant to medical therapy.
Current therapeutic strategies involve a combination of nasal irrigations, corticosteroids and antibiotics. Unfortunately, these are rarely curative and raise concerns regarding safety. Oral corticosteroid therapy can lead to severe short and long term adverse effects including diabetes, fractures, psychosis, depression, glaucoma and cataracts. Antibiotic over use is a major driver of development of antibiotic resistance, and antibiotic use in humans in Canada is believed to contribute significantly to this.
In the absence of a response to medical therapy, endoscopic sinus surgery is indicated. Operations for CRS are among the most commonly performed, with over 400 000 surgeries for CRS performed annually in the USA and another 40 000 annually in Canada. However, success is not uniform and a high percentage of patients will continue to manifest signs and symptoms of the disease. Even when managed with a topical intranasal corticosteroid, endoscopic signs of recurrence are observed rapidly after endocopic sinus surgery (ESS) (Stjärne, 2009). In a trial comparing topical mometasone via conventional nasal spray dispenser to placebo, median time to relapse was 173 and 61 days for the mometasone and placebo groups, respectively. This may be improved by use of a more effective form of distribution, such as using budesonide irrigations which improve deposition of steroid in the sinus cavities. In a retrospective analysis of our group limited to a more severely diseased group at higher risk of recurrence, 33% of subjects still showed signs of endoscopic recurrence at 4 month point after surgery (Maniakis, 2014).
Endoscopic sinus surgery may be challenging for patient and surgeon, with risk of complications from trauma to adjacent structures increased by extent of disease and bleeding at time of surgery reducing bleeding. In addition, despite the risks of ESS, recurrence after ESS represents a very important issue as it is rapid and almost ubiquitous.
Patients resistant to surgery generate an individual cost estimated at $10 077/year (Rudmik, 2014). Additional therapeutic options for these patients are currently limited and these patients are currently doomed to continue to suffer despite repeated bouts of antibiotics and surgeries, with patient and society bearing the risks and costs of therapies. Given the frequency, the human and economic burden of refractory CRS, and the deficiencies in effectiveness and adverse effects of current therapies, novel avenues of therapy for CRS are urgently required. Identifying new strategies will require a better understanding of the underlying disease process and identification of new therapeutic targets.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients ≥ 18 years of age.
- •Patients with bilateral sino-nasal polyposis scheduled for a revision surgery for CRSwNP, according to usual clinical criteria of untolerable obstruction, anosmia, recurrent infections or difficulty with control of asthma.
- •Ongoing symptoms (for at least 8 weeks before V1).
- •Signed written informed consent.
排除标准
- •Patient who has previously been treated with Dupilumab studies
- •Patient who has taken:
- •Biologic therapy/systemic immunosuppressant to treat inflammatory disease or autoimmune disease (e.g., rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.) within 2 months before V1 or 5 half-lives, whichever is longer.
- •Any experimental mAB within 5 half-lives or within 6 months before V1 if the half-life is unknown.
- •Anti-immunoglobulin E therapy (omalizumab) within 130 days prior to V
- •Patients who are receiving leukotriene antagonists/modifiers at V1 unless they are on a continuous treatment for at least 30 days prior to V
- •Initiation of allergen immunotherapy within 3 months prior to V1 or a plan to begin therapy or change its dose during the run-in period or the randomized treatment period.
- •Patients who have undergone any and/or sinus intranasal surgery (including polypectomy) within 6 months before V
- •Patients who have had a sino-nasal surgery changing the lateral wall structure of the nose making impossible the evaluation of NPS.
- •Patients with conditions/concomitant diseases making them non evaluable at V1 or for the primary efficacy endpoint such as:
- •Antrochoanal polyps.
- •Nasal septal deviation that would occlude at least one nostril.
- •Acute sinusitis, nasal infection or upper respiratory infection.
- •Ongoing rhinitis medicamentosa.
- •Underlying systemic disorders, including:
- •Cystic fibrosis, allergic granulomatous angiitis (Churg-Strauss syndrome), eosinophilic granulomatosis with polyangiitis (EGPA, Wegener's granulomatosis), Young's syndrome, Kartagener's syndrome or other dyskinetic ciliary syndromes.
- •Local complications
- •Radiologic suspicion, or confirmed invasive or expansive fungal rhinosinusitis
- •Mucoceles
- •Patients with nasal cavity malignant tumor and benign tumors (eg, papilloma, hemangioma, etc).
- •Patients receiving concomitant treatment prohibited in the study.
- •Patient is the Investigator or any Sub-Investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol.
- •Patients meet any contraindications or warning on National Product labeling for MFNS.
- •Pregnant or intent to become pregnant during the study, or breast-feeding women.
- •Women of childbearing potential (WOCBP) (pre-menopausal female biologically capable of becoming pregnant) who do not fulfill:
- •A confirmed negative serum beta-human chorionic gonadotrophin (β-hCG) test at V
- •AND either:
- •An established use of an acceptable contraceptive method: i)Oral, injected, inserted or implanted hormonal contraceptive; ii) Intrauterine device (IUD) with or intrauterine system (IUS) with progestogen; iii) Barrier contraceptive (condom, diaphragm or cervical/vault caps) used with spermicide (foam, gel, film, cream or suppository), if allowed by local regulation. OR,
- •Female sterilization (eg, tubal occlusion, hysterectomy or bilateral salpingectomy).
- •True abstinence in keeping with the preferred and usual lifestyle and if allowed by local regulation; periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) is not an acceptable method of contraception.
- •Postmenopausal women (defined as at least 12 consecutive months with no menses without an alternative medical cause) are not required to use additional contraception.
- •Diagnosed active parasitic infection (helminthes); suspected or high risk of parasitic infection, unless clinical and (if necessary) laboratory assessments have ruled out active infection before randomization.
- •History of human immunodeficiency virus (HIV) infection or positive HIV screen (Anti HIV-1 and HIV-2 antibodies) at V
- •A subject with a history of clinically significant renal, hepatic, cardiovascular, metabolic, neurologic, hematologic, ophthalmologic, respiratory, gastrointestinal, cerebrovascular or other significant medical illness or disorder which, in the judgment of the Investigator, could interfere with the study or require treatment that might interfere with the study. Specific examples include but are not limited to uncontrolled diabetes, uncontrolled hypertension, active hepatitis.
- •Known or suspected history of immunosuppression, including history of invasive opportunistic infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis), despite infection resolution; or unusually frequent, recurrent or prolonged infections, per Investigator's judgment.
- •Active tuberculosis, latent untreated tuberculosis or a history of incompletely treated tuberculosis or non-tuberculous mycobacterial infection will be excluded from the study unless it is well documented by a specialist that the patient has been adequately treated and can now start treatment with a biologic agent, in the medical judgment of the Investigator and/or infectious disease specialist. Tuberculosis testing would be performed on a country by country basis according to local guidelines if required by regulatory authorities or ethic committees.
- •Evidence of acute or chronic infection requiring treatment with systemic antibacterials, antivirals, antifungals, antiparasitics, or antiprotozoals within 4 weeks before V1 or during the run-in period, or significant viral infections within 4 weeks before V1 that may not have received antiviral treatment.
- •Live attenuated vaccinations within 4 weeks prior to Visit 1 or planned live attenuated vaccinations during the study.
- •Patients with active autoimmune disease and/or patients using immunosuppressive therapy for autoimmune disease (eg, Hashimoto's thyroiditis, Graves' disease, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematous, multiple sclerosis, and other neuro-inflammatory disease, psoriasis vulgaris, rheumatoid arthritis), or patients with high titer autoantibodies at V1 who are suspected of having high risk for developing autoimmune disease at the discretion of the Investigator or the Sponsor.
- •History of malignancy within 5 years before V1, except completely treated in situ carcinoma of the cervix, completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin.
- •Known or suspected alcohol and/or drug abuse.
- •Patients with a history of a systemic hypersensitivity reaction, other than localized injection site reaction, to any biologic drug.
- •Active hepatitis
- •Patients with the following liver injury related criteria at V1:
- •Clinically significant/active underlying hepatobiliary disease. OR,
- •Alanine aminotransferase (ALT) >3 upper limit of normal (ULN).
- •Abnormal laboratory values at V1:
- •Creatine phosphokinase (CPK) >10 ULN. OR,
- •Platelets <100 000 cells/mm
- •Eosinophils >1500 cells/mm
- 另有 5 项未显示
研究组 & 干预措施
Dupilumab
Sterile Dupilumab 150 mg/mL will be provided in pre-filled syringes (2.25 total volume) to deliver 300 mg in 2 mL.
干预措施: Dupilumab 300 MG in 2 ML Prefilled Syringe (Drug)
Dupilumab
Sterile Dupilumab 150 mg/mL will be provided in pre-filled syringes (2.25 total volume) to deliver 300 mg in 2 mL.
干预措施: Mometasone Furoate nasal spray (Drug)
Placebo
Sterile placebo for Dupilumab will be provided in identically matching pre-filled syringes to deliver 2 mL.
干预措施: Placebo (Other)
Placebo
Sterile placebo for Dupilumab will be provided in identically matching pre-filled syringes to deliver 2 mL.
干预措施: Mometasone Furoate nasal spray (Drug)
结局指标
主要结局
Number of participants with non-recurrence of sinus cavity oedema as assessed endoscopically
时间窗: Baseline to Week 52
As it is expected that during the trial period recurrences will remain limited to the confines of the ethmoid sinus cavity and will not extend beyond the middle turbinate, a measuring system capable of capturing oedema as a measure of early changes of polyp formation is required. To this end, a modified version of the Lund-Kennedy grading scale (LK) will be used to assess oedema of the post-ESS sinus cavity. Assessment of degree of oedema in patients where nasal polyps do not extend beyond the middle turbinate: 0= No oedema; 1= Mild oedema not obstructing visualisation of surface landmarks or visualisation of the accessory sinus ostia; 2= Oedema obstructing or preventing visualisation of the frontal or sphenoid sinus ostia but not completely filling the sinus cavity; 3= Oedema completely filling the sinus cavity but not extending beyond the middle turbinate.
次要结局
- Percentage of participants with polyp recurrence outside the confines of the sinus cavity(ies)(Baseline to Week 52)
- Percentage of participants requiring a course of oral steroids for recurrence of nasal polyposis.(Baseline to Week 52)
- Percentage of participants requiring re-operation for recurrence of nasal polyposis(Baseline to Week 52)
- Difference in per-operative bleeding(Week 0 (Day of surgery))
- Change in nasal obstruction(Baseline to Week 52)
- Change in facial pain(Baseline to Week 52)
- Change in total nasal symptomatology(Baseline to Week 52)
- Change in nasal secretions(Baseline to Week 52)
- Change in rhinosinusitis severity visual analog scale (VAS)(Baseline to Week 52)
- Change in Computerized tomography (CT) Scan opacification(Week -4 (4 weeks prior to surgery) to Week 16)
- Change in sense of smell(Baseline to Week 52)
- Change in 22-item Sino-nasal Outcome Test (SNOT-22)(Baseline to Week 52)
- Change in asthma control(Baseline to Week 52)