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

Primary Purpose

Chronic Rhinosinusitis With Nasal Polyps, Asthma; Eosinophilic, Eosinophilia

Status
Recruiting
Phase
Phase 4
Locations
Denmark
Study Type
Interventional
Intervention
dupilumab
mepolizumab
Sponsored by
Rigshospitalet, Denmark
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Rhinosinusitis With Nasal Polyps

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Aalborg Universitetssygehus Syd
  • Aarhus Universitetshospital Skejby
  • RigshospitaletRecruiting
  • Sydvestjysk Sygehus Esbjerg
  • Regionshospitalet Gødstrup
  • Nordsjællands Hospital
  • Sjællands Universitetshospital KøgeRecruiting
  • Odense UniversitetshospitalRecruiting
  • Sygehus Lillebælt VejleRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

Dupilumab week 0-24 300 mg/2 weeks

Mepolizumab week 0-24 100 mg/4 weeks

Dupilumab week 24-48 300 mg/4 weeks

Dupilumab week 24-48 300 mg/2 weeks

Mepolizumab week 24-48 100 mg/4 weeks

Arm Description

Normal dose and interval of Dupixent i.e. 300 mg s.c. every 2 weeks

Normal dose and interval of Nucala i.e. 100 mg s.c. every 4 weeks

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

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.

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.

Outcomes

Primary Outcome Measures

SNOT-22
Sino-Nasal Outcome Test 22 - change in score since baseline is measured.
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.

Secondary Outcome Measures

SNOT-22
Sino-Nasal Outcome Test 22 - change in score since week 24 and week 0 if applicable
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
Smell score (Sniffin' Sticks Identification Test-16- SSIT-16)
Change since baseline in SSIT-16 (range 0-16, where 0-8 is anosmia)
Asthma control (Asthma Control Questionnaire)
Proportion of patients with ACQ score > 0,5 indicating well-controlled asthma.
Nasal Congestion Score (NCS)
Range 0-3. Change since baseline
Visual Analogue Scale of: smell/asthma/Chronic rhinosinusitis/N-ERD
Change in VAS-score (range 0-10) since baseline
Proportion meeting the evaluation criteria set by the DMC
The DMC criteria is available at medicinraadets website medicinraadet.dk
Fraction of Nitrous Oxide in expired air (FeNO)
A score above 25 indicates eosinophilic inflammation.
Proportion needing rescue treatment
A rescue treatment is defined as systemic oral corticoids or endoscopic sinus surgery.

Full Information

First Posted
May 22, 2023
Last Updated
July 3, 2023
Sponsor
Rigshospitalet, Denmark
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1. Study Identification

Unique Protocol Identification Number
NCT05942222
Brief Title
A Randomized, Real-world Head-to-head Study of Dupilumab Versus Mepolizumab in Danish CRSwNP Patients
Acronym
TORNADO
Official Title
Treatment of Rhinosinusitis With Nasal Polyposis With Dupilumab and Mepolizumab: A Randomized, Multi-centre, Head-to-head Comparison in Real-world Danish Patients
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 27, 2023 (Actual)
Primary Completion Date
October 30, 2025 (Anticipated)
Study Completion Date
January 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Rigshospitalet, Denmark

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Rhinosinusitis With Nasal Polyps, Asthma; Eosinophilic, Eosinophilia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
220 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dupilumab week 0-24 300 mg/2 weeks
Arm Type
Active Comparator
Arm Description
Normal dose and interval of Dupixent i.e. 300 mg s.c. every 2 weeks
Arm Title
Mepolizumab week 0-24 100 mg/4 weeks
Arm Type
Active Comparator
Arm Description
Normal dose and interval of Nucala i.e. 100 mg s.c. every 4 weeks
Arm Title
Dupilumab week 24-48 300 mg/4 weeks
Arm Type
Active Comparator
Arm Description
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
Arm Title
Dupilumab week 24-48 300 mg/2 weeks
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Mepolizumab week 24-48 100 mg/4 weeks
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
dupilumab
Other Intervention Name(s)
Dupixent
Intervention Description
Subcutaneus injections in standard doses, i.e. 300 mg s.c. every 2 weeks.
Intervention Type
Biological
Intervention Name(s)
mepolizumab
Other Intervention Name(s)
Nucala
Intervention Description
Subcutaneus injections in standard doses, i.e. 100 mg s.c. every 4 weeks.
Primary Outcome Measure Information:
Title
SNOT-22
Description
Sino-Nasal Outcome Test 22 - change in score since baseline is measured.
Time Frame
Week 24
Title
NPS
Description
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.
Time Frame
Week 24
Secondary Outcome Measure Information:
Title
SNOT-22
Description
Sino-Nasal Outcome Test 22 - change in score since week 24 and week 0 if applicable
Time Frame
Week 48
Title
NPS
Description
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
Time Frame
Week 48
Title
Smell score (Sniffin' Sticks Identification Test-16- SSIT-16)
Description
Change since baseline in SSIT-16 (range 0-16, where 0-8 is anosmia)
Time Frame
Week 48
Title
Asthma control (Asthma Control Questionnaire)
Description
Proportion of patients with ACQ score > 0,5 indicating well-controlled asthma.
Time Frame
Week 48
Title
Nasal Congestion Score (NCS)
Description
Range 0-3. Change since baseline
Time Frame
Week 48
Title
Visual Analogue Scale of: smell/asthma/Chronic rhinosinusitis/N-ERD
Description
Change in VAS-score (range 0-10) since baseline
Time Frame
Week 48
Title
Proportion meeting the evaluation criteria set by the DMC
Description
The DMC criteria is available at medicinraadets website medicinraadet.dk
Time Frame
Week 48
Title
Fraction of Nitrous Oxide in expired air (FeNO)
Description
A score above 25 indicates eosinophilic inflammation.
Time Frame
Week 48
Title
Proportion needing rescue treatment
Description
A rescue treatment is defined as systemic oral corticoids or endoscopic sinus surgery.
Time Frame
Week 48

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Christian Pedersen, MD
Phone
+4525301186
Email
christian.korsgaard.pedersen.01@regionh.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christian Pedersen, MD
Organizational Affiliation
Department of ORL, Head and Neck Surgery & Audiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Christian von Buchwald
Organizational Affiliation
Department of ORL, Head and Neck Surgery & Audiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
Official's Role
Study Director
Facility Information:
Facility Name
Aalborg Universitetssygehus Syd
City
Aalborg
ZIP/Postal Code
9000
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Søren Pauli, MD
Phone
+4597660000
Email
s.bro@rn.dk
First Name & Middle Initial & Last Name & Degree
Søren Pauli, MD
Facility Name
Aarhus Universitetshospital Skejby
City
Aarhus
ZIP/Postal Code
8200
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristian Bruun Petersen, MD,Ph.d.
Phone
+4578450000
Email
krispete@rm.dk
First Name & Middle Initial & Last Name & Degree
Kristian Bruun Petersen, MD, Ph.d.
Facility Name
Rigshospitalet
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christian K Pedersen, MD
Phone
+4525301186
Email
christian.korsgaard.pedersen.01@regionh.dk
First Name & Middle Initial & Last Name & Degree
Christian von Buchwald, Prof., DMSc
Phone
+4534452370
Email
christian.von.buchwald@regionh.dk
First Name & Middle Initial & Last Name & Degree
Christian K Pedersen, MD
First Name & Middle Initial & Last Name & Degree
Vibeke Backer, Prof., DMSc
First Name & Middle Initial & Last Name & Degree
Kasper Aanaes, MD, Ph.d.
First Name & Middle Initial & Last Name & Degree
Tonny Petersen, MD, Ph.d.
Facility Name
Sydvestjysk Sygehus Esbjerg
City
Esbjerg
ZIP/Postal Code
6700
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Knud Larsen, MD, Ph.d
Phone
+4579182774
Email
knud.larsen@rsyd.dk
First Name & Middle Initial & Last Name & Degree
Knud Larsen
Facility Name
Regionshospitalet Gødstrup
City
Herning
ZIP/Postal Code
7400
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Adnan Madzak, MD, Ph.d
Phone
+4531339445
Email
adnanmadzak@gmail.com
First Name & Middle Initial & Last Name & Degree
Adnan Madzak, MD, Ph.d
Facility Name
Nordsjællands Hospital
City
Hillerød
ZIP/Postal Code
3400
Country
Denmark
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Grethe Samuelsen
Phone
+4548297536
Email
grethe.badsberg.samuelsen@regionh.dk
First Name & Middle Initial & Last Name & Degree
Grethe Samuelsen, MD.,Ph.d.
Facility Name
Sjællands Universitetshospital Køge
City
Køge
ZIP/Postal Code
4600
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bent Ivan Larsen, MD
Phone
+4547329628
Email
bele@regionsjaelland.dk
First Name & Middle Initial & Last Name & Degree
Bent Ivan Larsen
Facility Name
Odense Universitetshospital
City
Odense
ZIP/Postal Code
5000
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anette Kjeldsen
Phone
+4566113333
Email
anette.kjeldsen@rsyd.dk
First Name & Middle Initial & Last Name & Degree
Anette Kjeldsen, Prof., DMSc
Facility Name
Sygehus Lillebælt Vejle
City
Vejle
ZIP/Postal Code
7100
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lars Christian Meyer, MD
Phone
+4579405995
Email
lars.christian.meyer@rsyd.dk
First Name & Middle Initial & Last Name & Degree
Lars Christian Meyer

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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