A Randomized, Real-world Head-to-head Study of Dupilumab Versus Mepolizumab in Danish CRSwNP Patients

Study Overview
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Brief Summary
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The goal of this randomized clinical trial is to compare the effects of two newly available biological drugs for the treatment of severe chronic rhinosinusitis with nasal polyps in Danish patients. The main questions it aims to answer are whether the two drugs are comparable in effect after 24 weeks in terms of: A subjective score (the SNOT-22) An objective score, i.e.the physician-assessed score of nasal polyp size (the Nasal Polyp Score (0-8)) Methods: Participants will be randomized into two groups and receive either drug in the standard dose. After 24 weeks the effect is assessed. If the clinical effect is sufficient in terms of the criteria set by the Danish Medicinal Council (see elsewhere), treatment continues with the same drug for an additional 24 weeks. If the effect criteria are not met, the subject crosses-over to the opposite drug for an additional 24 weeks. After 48 weeks the effect is assessed once more.

Detailed Description
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Objectives: The primary objective is to compare the efficacy of mepolizumab versus dupilumab on objective and subjective symptoms of CRSwNP and related comorbidities in an attempt to determine non-inferiority between the two, or possibly; superiority of dupilumab over mepolizumab. The secondary objective is to explore any other relevant differences between mepolizumab and dupilumab in terms of frequency of AEs, need for rescue treatments, diversity in outcome based on endotype or comorbidity or other factors, that can lead to a patient-centred approach, when choosing treatment for CRSwNP. Trial design: A randomized, multi-center non-inferiority trial (phase IV RCT). The trial is unblinded. Investigational medicinal products (IMPs) will be off-the-shelf and administered in standard dosages and -intervals. Trial population: The trial aims to include 220 patients with severe, uncontrolled CRSwNP (110 patients in each treatment group). The patients will be recruited from 9 different sites all across Denmark. Treatment in Denmark is 100% subsidized by the state. Methods: Subjects fulfilling inclusion criteria will be randomized 1:1 to either dupilumab or mepolizumab. After 24 weeks a halfway evaluation will decide if subjects are to stay in their current treatment arm, or cross-over to the opposite arm. By including 220 participants (effectively 176 participants after 20% drop-outs) the study will achieve a power of >95% to show non-inferiority of dupilumab to mepolizumab for both co-primary endpoints with the following criteria: Level of significance for both endpoints of a one-sided test, p<0.025 and including previously found standard deviation (SD) values 1.9 for NPS and 22 for SNOT-22, an expected superior effect of 0.7 for NPS and 7 on SNOT-22, a minimal clinically relevant difference (MCID) of 1 for NPS and 12 for SNOT-22, respectively. Trial medication: All trial medication will be off the shelf i.e. no special labelling. It will be provided by hospital pharmacies in accordance with GMP. The investigational medicinal products (IMPs) are dupilumab (Dupixent, Sanofi) and mepolizumab (Nucala, GSK). Dupilumab are given as subcutaneous injections of 300 mg every two weeks in the first 24 weeks. If the DMC response criteria (table 2) are met after 24 weeks, the dosing interval will be increased to every four weeks, in accordance with previous research. Mepolizumab is administered subcutaneously as 100 mg sc. every four weeks. Patients will continue basic treatment of INCS and saline irrigation, unless contraindicated. If rescue treatment is needed, a course of oral corticosteroids (Prednisolone) 37.5 mg once daily for 7 days will be given. Trial schedule: Planned first subject first visit May 2023 Planned last subject randomized May 2024 Planned last subject last visit: June 2025 End of trial October 2025

Official Title
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Treatment of Rhinosinusitis With Nasal Polyposis With Dupilumab and Mepolizumab: A Randomized, Multi-centre, Head-to-head Comparison in Real-world Danish Patients

Conditions
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Chronic Rhinosinusitis With Nasal Polyps, Asthma; Eosinophilic, Eosinophilia

Intervention / Treatment
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* Biological: dupilumab
* Biological: mepolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Bilateral polyps in nose and sinuses ESS within the last three years (unless unfit for surgery y- in this study defined as either a severe somatic disease, for which other specialist advise against surgery, e.g., cardiac disease, pulmonary disease, or coagulation disorder OR/AND severe anxiety which can either be due to previous traumatic experiences with surgery or the postoperative period, post-traumatic stress disorder or severe anxiety disorder. In cases of doubt, investigators can ask for a written statement from the general practitioner or a psychiatrists/psychologist)) Optimal local treatment with saline irrigation and topical nasal steroids for at least three months (unless contraindicated) Evidence of type 2 inflammation Furthermore, patients must fulfil three out the following five criteria: Need for systemic corticosteroids (at least two courses/year OR long-term treatment >3 months) or contraindication to systemic steroids Significantly impaired QoL (SNOT-22 score≥50) Significant LoS (SSIT-16 score 0-8) NPS ≥5 (with at least 2 on either side) Asthma diagnosis (requiring inhaled corticosteroid (ICS)) Also: Age of 18 years or more and able to read and/or speak Danish Exclusion criteria Systemic corticosteroid treatment within the last three months Endoscopic sinus surgery (ESS) within the last six months Non-adherent to medicine regimens Hypersensitivity to the active substance or any of the excipients in the two IMPs Not able to understand spoken and/or written Danish Participation-current or previous (within the last year)-in another investigational drug trial with monoclonal antibodies for asthma, CRSwNP, atopic dermatitis or allergic rhinitis. Pronounced fear of needles Pregnant or breastfeeding patients

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dupilumab week 0-24 300 mg/2 weeks<br>Normal dose and interval of Dupixent i.e. 300 mg s.c. every 2 weeks | Biological: dupilumab<br>* Subcutaneus injections in standard doses, i.e. 300 mg s.c. every 2 weeks.<br>* Other names: Dupixent;|
| Active Comparator: Mepolizumab week 0-24 100 mg/4 weeks<br>Normal dose and interval of Nucala i.e. 100 mg s.c. every 4 weeks | Biological: mepolizumab<br>* Subcutaneus injections in standard doses, i.e. 100 mg s.c. every 4 weeks.<br>* Other names: Nucala;|
| Active Comparator: Dupilumab week 24-48 300 mg/4 weeks<br>Increased dosage interval of Dupixent i.e. 300 mg s.c. every 4 weeks - for subjects on Dupixent who met the 24 weeks effect criteria | Biological: dupilumab<br>* Subcutaneus injections in standard doses, i.e. 300 mg s.c. every 2 weeks.<br>* Other names: Dupixent;|
| Active Comparator: Dupilumab week 24-48 300 mg/2 weeks<br>Normal dose and interval of Dupixent i.e. 300 mg s.c. every 2 weeks but for subjects who have crossed over after 24 weeks due to unmet effect criteria. | Biological: dupilumab<br>* Subcutaneus injections in standard doses, i.e. 300 mg s.c. every 2 weeks.<br>* Other names: Dupixent;|
| Active Comparator: Mepolizumab week 24-48 100 mg/4 weeks<br>Normal dose and interval of Nucala i.e. 100 mg s.c. every 4 weeks but for subjects who have crossed-over after 24 weeks due to unmet effect criteria. | Biological: mepolizumab<br>* Subcutaneus injections in standard doses, i.e. 100 mg s.c. every 4 weeks.<br>* Other names: Nucala;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SNOT-22 | Sino-Nasal Outcome Test 22 - change in score since baseline is measured. | Week 24 | 
| NPS | Nasal Polyp Score (0-8): 0 is no polyps, 4 is polyps extending below inferior turbinate's lower border. Each side is scored. The change in score at week 24 since baseline is measured. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SNOT-22 | Sino-Nasal Outcome Test 22 - change in score since week 24 and week 0 if applicable | Week 48 | 
| NPS | Nasal Polyp Score (0-8): 0 is no polyps, 4 is polyps extending below inferior turbinate - lower border. Each side is scored. Change in score since week 24 and week 0 if applicable | Week 48 | 
| Smell score (Sniffin' Sticks Identification Test-16- SSIT-16) | Change since baseline in SSIT-16 (range 0-16, where 0-8 is anosmia) | Week 48 | 
| Asthma control (Asthma Control Questionnaire) | Proportion of patients with ACQ score > 0,5 indicating well-controlled asthma. | Week 48 | 
| Nasal Congestion Score (NCS) | Range 0-3. Change since baseline | Week 48 | 
| Visual Analogue Scale of: smell/asthma/Chronic rhinosinusitis/N-ERD | Change in VAS-score (range 0-10) since baseline | Week 48 | 
| Proportion meeting the evaluation criteria set by the DMC | The DMC criteria is available at medicinraadets website medicinraadet.dk | Week 48 | 
| Fraction of Nitrous Oxide in expired air (FeNO) | A score above 25 indicates eosinophilic inflammation. | Week 48 | 
| Proportion needing rescue treatment | A rescue treatment is defined as systemic oral corticoids or endoscopic sinus surgery. | Week 48 |