Chronic Rhinosinusitis With Nasal Polyps

Dupilumab for Prevention of Recurrence of CRSwNP After ESS

Sponsored by Centre hospitalier de l'Université de Montréal (CHUM)

About this trial

Last updated a year ago

Study ID

CE20.201

Status

Completed

Type

Interventional

Phase

Phase 4

Placebo

Yes

Accepting

18 to 70 Years

All Sexes

Trial Timing

Ended 2 years ago

What is this trial about?

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.

What are the participation requirements?

Inclusion Criteria

* 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.

Exclusion Criteria

* 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 V1.

* Patients who are receiving leukotriene antagonists/modifiers at V1 unless they are on a continuous treatment for at least 30 days prior to V1.

* 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 V1.

* 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 V1. 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 V1.

* 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/mm3. OR,

* Eosinophils >1500 cells/mm3.

* Conditions/Situations such as: Patients considered by the Investigator or any sub-Investigator as inappropriate for this study for any reason, eg,:

* Those deemed unable to meet specific protocol requirements, such as scheduled visits.

* Those deemed unable to administer or tolerate long-term injections as per the patient or the Investigator

* Presence of any other conditions (eg, geographic, social….) actual or anticipated, that the Investigator feels would restrict or limit the patient's participation for the duration of the study.

* Patient who has withdrawn consent before enrollment/randomization.