Treatment of Rhinosinusitis With Nasal Polyposis With Dupilumab and Mepolizumab: A Randomized, Multi-centre, Head-to-head Comparison in Real-world Danish Patients
Phase: PHASE4
Conditions: Chronic Rhinosinusitis With Nasal Polyps, Asthma; Eosinophilic, Eosinophilia
Sponsor: Rigshospitalet, Denmark

 
TORNADO 
 
 
 
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EU CT no.: 2022-502250-14-00 
Ver. 1.7 – 23.06.23 
Rigshospitalet Page 1 of 44 
PROTOCOL 
 
Treatment of rhinosinusitis with nasal polyposis with dupilumab 
and mepolizumab: A randomized, multi-centre, head-to-head 
comparison in real-world Danish patients 
 
Trial ID: TORNADO 
EU CT no.: 2022-502250-14-00 
 
TITLE PAGE ................................................................................................................................................................. 1 
ABBREVIATIONS ......................................................................................................................................................... 4 
1.        PROTOCOL SYNOPSIS/SUMMARY ..................................................................................................................... 5 
2.        TRIAL SCHEDULE ............................................................................................................................................... 9 
3.        BACKGROUND/RATIONALE ............................................................................................................................. 10 
3.1        DISEASE BACKGROUND ............................................................................................................................................ 10 
3.2        TREATMENT OF CRSWNP........................................................................................................................................ 10 
3.3        TRIAL RATIONALE ................................................................................................................................................... 10 
3.4        BENEFIT-RISK ASSESSMENT AND ETHICAL CONSIDERATIONS ............................................................................................. 12 
4.        HYPOTHESIS .................................................................................................................................................... 12 
5.        OBJECTIVES ..................................................................................................................................................... 12 
5.1        PRIMARY OBJECTIVE ................................................................................................................................................ 12 
5.2        SECONDARY OBJECTIVE ............................................................................................................................................ 12 
5.3        PRIMARY ENDPOINTS .............................................................................................................................................. 13 
5.4        SECONDARY ENDPOINTS .......................................................................................................................................... 13 
6.        TRIAL DESIGN .................................................................................................................................................. 13 
6.1        SUMMARY OF TRIAL DESIGN ..................................................................................................................................... 13 
6.2        DISCUSSION OF TRIAL DESIGN ................................................................................................................................... 15 
6.3        TRIAL SCHEDULE ..................................................................................................................................................... 16 
7.        TRIAL POPULATION ......................................................................................................................................... 16 
7.1        INCLUSION CRITERIA ................................................................................................................................................ 16 
7.2        EXCLUSION CRITERIA ............................................................................................................................................... 17 
7.3        RECRUITING .......................................................................................................................................................... 17 
7.4        DISCONTINUATION ................................................................................................................................................. 17 
7.5        PREGNANCY AND ANTICONCEPTION ........................................................................................................................... 17 
7.6        RESCUE TREATMENT ............................................................................................................................................... 18 

 
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8.        RANDOMIZATION, BLINDING AND SAMPLE SIZE ............................................................................................. 18 
8.1        RANDOMIZATION ................................................................................................................................................... 18 
8.2        BLINDING ............................................................................................................................................................. 18 
8.3        SAMPLE SIZE .......................................................................................................................................................... 18 
9.        TRIAL PRODUCTS ............................................................................................................................................ 19 
9.1        ADMINISTRATION OF TRIAL PRODUCTS ........................................................................................................................ 19 
9.1.1    COMPLIANCE/ADHERENCE WITH THE TRIAL MEDICINE .................................................................................................... 19 
9.2        DUPILUMAB: IMP1 ................................................................................................................................................ 19 
9.2.1   Undesired effects: ......................................................................................................................................... 20 
9.3        MEPOLIZUMAB: IMP2 ............................................................................................................................................ 23 
9.4        RESCUE TREATMENT: SYSTEMIC CORTICOSTEROID OR FESS ............................................................................................ 26 
9.4.1     Systemic corticosteroid (prednisolone) ....................................................................................................... 26 
9.4.2    Endoscopic Sinus Surgery ............................................................................................................................. 26 
9.5        IMP ACCOUNTABILITY ............................................................................................................................................. 27 
10.       METHODS/PROCEDURES ............................................................................................................................... 27 
10.1       VISIT SCHEDULE .................................................................................................................................................... 27 
10.2       TRIAL PROCEDURES ............................................................................................................................................... 29 
10.3      INFORMED CONSENT .............................................................................................................................................. 29 
10.4       FUTURE CONTACT ................................................................................................................................................. 30 
10.5       CONSENT FOR LONG-TERM STORAGE OF BLOOD SAMPLES AND TISSUE IN A BIOBANK ........................................................... 30 
10.6       SUBJECT ID AND E-CRF INCLUSION .......................................................................................................................... 30 
10.7       DEMOGRAPHY ...................................................................................................................................................... 30 
10.8       MEDICAL HISTORY AND CONCOMITANT DISEASE .......................................................................................................... 30 
10.9       CONCOMITANT AND PREVIOUS MEDICATION .............................................................................................................. 31 
10.10     VITAL SIGNS AND WEIGHT ...................................................................................................................................... 31 
10.11     PHYSICAL EXAMINATION ........................................................................................................................................ 31 
10.12     QUESTIONNAIRES ................................................................................................................................................. 33 
10.13     TREATMENT FAILURE ............................................................................................................................................. 34 
10.14     ELECTRONIC MEDICAL RECORD (SUNDHEDSPLATFORMEN, EPJ SYD, MIDTEPJ, NORDEPJ, FMK-ONLINE) ............................ 34 
11.       ASSESSMENT OF SAFETY ................................................................................................................................ 34 
11.1       DEFINITIONS – ADVERSE EVENT (AE) ....................................................................................................................... 35 
11.2       DEFINITIONS – SERIOUS ADVERSE EVENT (SAE) / SERIOUS ADVERSE REACTION (SAR) / SUSPECTED   UNEXPECTED SERIOUS 
ADVERSE REACTION (SUSAR) ............................................................................................................................................. 35 
11.3       ASSESSMENTS OF AES AND SAES/SUSARS ............................................................................................................... 35 
11.4       REPORTING .......................................................................................................................................................... 36 
11.5       ANNUAL REPORTING .............................................................................................................................................. 37 
12.       DATA HANDLING / DATA MANAGEMENT ...................................................................................................... 37 
12.1       CASE REPORT FORM (CRF)..................................................................................................................................... 37 
12.2       LABORATORY DATA ............................................................................................................................................... 37 
13.       STATISTICAL EVALUATION ............................................................................................................................. 38 
13.1       ANALYSIS POPULATIONS ......................................................................................................................................... 38 
14.       END OF TRIAL ................................................................................................................................................. 38 
14.1       EARLY TERMINATION OF THE TRIAL ........................................................................................................................... 38 
14.2       SUBJECT DISCONTINUATION .................................................................................................................................... 39 
15.       ADMINISTRATIVE PROCEDURES ..................................................................................................................... 39 
15.1       SOURCE DATA AND SUBJECT DATA PROTECTION ........................................................................................................... 39 
15.2       QUALITY CONTROL AND ASSURANCE ......................................................................................................................... 40 

 
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15.3       MONITORING (GOOD CLINICAL PRACTICE, GCP) ......................................................................................................... 40 
15.4       RESEARCH BIOBANK .............................................................................................................................................. 40 
15.5       FINANCING .......................................................................................................................................................... 40 
15.6       FINANCIAL COMPENSATION TO SUBJECTS ................................................................................................................... 41 
15.7       INSURANCE .......................................................................................................................................................... 41 
15.8       ETHICAL CONSIDERATIONS ...................................................................................................................................... 41 
15.9       PUBLICATION ....................................................................................................................................................... 41 
16.       REFERENCE LIST ............................................................................................................................................. 41 
 
 
 

 
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Abbreviations 
ACQ: Asthma control questionnaire  
CRS: Chronic Rhinosinusitis 
CRSwNP: Chronic Rhinosinusitis with polyposis 
CRSsNP: Chronic Rhinosinusitis without (sine) polyposis 
CTIS: Clinical Trials Information System 
DMC: Danish Medicines Council  
EMA: European medicines agency 
EOS: Eosinophils – white blood cells with high activity in type 2 inflammation  
EPOS2020: European Position Paper on Rhinosinusitis and Nasal Polyps 2020 
ESS and FESS: (functional) Endoscopic sinus surgery  
FeNO: Fractional exhaled nitrous oxide 
Hpf: High power field – the field of view under a microscope with x400 magnification  
HRQoL: Health-related quality of life 
ICS: inhaled corticosteroid – used for asthma treatment   
Ig: Immunoglobulin 
INCS: Intranasal corticosteroids – topical corticosteroids used in the nose for CRS  
LoS: Loss of smell 
LPLV: last patient, last visit 
MCID: Minimal clinically important difference  
NCS: Nasal congestion score – Subjective measure of nasal congestion (0-3).  
N-ERD: NSAIDs Exacerbated Respiratory Disease – intolerance to NSAIDs  
NPS: Nasal polyp score – objective measure of nasal polyp size (0–4 on either side, total 0–8)  
NSAID: non-steroidal anti-inflammatory drugs 
OCS: Oral corticosteroids  
PROM: Patient reported outcome measure 
QoL: Quality of life 
SNOT-22: Sino-nasal outcome test – 22 (HRQoL) 
SSIT-16: Sniff’n Sticks Identification Test 16 – Test of ability to identify house-hold smells (0–16) 
STARR-15: Standard Tests of Asthma, Allergic rhinitis and Rhinosinusitis – 15 items (HRQoL) 
VAS: visual analogue scale 
 
 

 
TORNADO 
 
 
 
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1.        Protocol synopsis/summary 
Title of trial:  
Treatment of rhinosinusitis with nasal polyposis with Dupilumab and Mepolizumab 
(TORNADO): A randomised, multi-center, head-to-head comparison in real-world Danish 
patients  
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: 
We aim to include 220 patients with severe, uncontrolled CRSwNP (110 patients in each treatment 
group). 
Main inclusion criteria:  
Age ≥18 and able to speak and read Danish language. 
Furthermore, in accordance with the criteria set by the Danish Medicines Council (DMC): 
 
Patients must have: 
• 
Bilateral polyps in nose and sinuses 
• 
ESS within the last three years (unless unfit for surgery - 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 (as per EPOS2020 – see table 3) 
 
Furthermore, patients must fulfil three out of 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) 

 
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• 
NPS ≥5 (with a score of at least 2 on either side) 
• 
Asthma diagnosis (requiring inhaled corticosteroid (ICS)) 
 
 
 
Patients who intend to achieve pregnancy within the one year follow up period are not eligible.  
Main 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—in another investigational drug trial with monoclonal 
antibodies for asthma, CRSwNP, atopic dermatitis or allergic rhinitis. 
• 
Pronounced fear of needles 
• 
Pregnant or breastfeeding patients. 
Methods: 
Subjects fulfilling the 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) we 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 endpoints: 
The coprimary endpoints are:  
• 
Change in NPS-score from baseline to week 24  
• 
Change in SNOT-22 score from baseline to week 24 
 
Secondary endpoints 
• 
Change in NPS-score from baseline to week 48  
• 
Change in SNOT-22 score from baseline to week 48 
• 
Proportion of subjects meeting the Danish Medicines Council response criteria (table 2) at 24 
and 48 weeks 
• 
Change in loss of smell (LoS) measured by Sniffin’ Sticks Identification Test 16 (SSIT-16) at 
weeks 24 and 48 
• 
Change in Asthma Control Questionnaire (ACQ) score at weeks 24 and 48 
• 
Change in CRS visual analogue scale (VAS) score at weeks 24 and 48 
• 
Change in perceived sense of smell - VAS score at weeks 24 and 48 
• 
Change in lung fractional exhaled nitrous oxide at weeks 24 and 48  
• 
Change in Tympanometry at weeks 24 and 48  
• 
Change in allergy/N-ERD symptoms – VAS score at weeks 24 and 48 
• 
Change in FEV1 at weeks 24 and 48 

 
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• 
Nasal Congestion Score at weeks 24 and 48 
• 
The Lund-Mackay score at weeks 24 and 48  
• 
Proportion of subjects requiring rescue treatment 

 
TORNADO 
 
 
 
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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 
(1,2). Mepolizumab is administered subcutaneously as 100 mg sc. every four weeks. Patients will 
continue their 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.  
The treatment response will be evaluated after 24 weeks, and in case the criteria are not met, subjects 
will cross-over to the opposite treatment arm.  
 
Trial schedule: 
 
Planned first subject first visit 
March 2023 
 
 
Planned last subject randomized 
March 2024 
 
 
Planned last subject last visit: 
June 2025 
 
 
End of trial 
October 2025 
 
 
 

 
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2.        Trial schedule 
 
Figure 1 – Trial Schedule (see details in section 10) 
 
 
 
TORNADO trial
visit 
1$
visit 
2$
visit 
3£
visit 
4£
visit 
5$ 
visit 
6£
visit 
7$
visit 
7b$
visit 
8£
visit 
9£
visit 
10£
visit 
11£
visit 
11##
visit 
12£
visit 
13$
visit 
14##
Week no. (+/- 7 days)
(-4)–0
4
8
12
16
20
24
26
28
32
36
40
42
44
48
50
Informed consent
x
Randomisation
x
CRS and asthma history
x
Asthma test*
x
Clinical examination
x
x
x
x##
Medicine adherence check
x
x
x
x#
x##
x
x##
Smell test (SSIT-16)
x
x
x
x##
Nasal polyp score
x
x
x
x##
SNOT22
x
x
x
x#
x##
x
x##
ACQ
x
x
x
x#
x##
x
x##
VAS-scores ****
x
x
x
x#
x##
x
x##
Nasal congestion score
x
x
x
x#
x##
x
x##
STARR15
x
FEV1
x
x
x
x##
FeNO
x
x
x
x##
Tympanometry
x
x
x
x##
Blood test (blood EOS)
x
x
x
x
x##
x#
x#
x##
x
x##
Allergy testing
x
Polyp biopsy
x**
Lund-Mackey Score
x
x#
x
x##
Evaluation of AE/SAE/SUSAR 
x
x
x
x# 
x##
x
x#/x##
Response evaluation/possible cross-over
x
x
x##
Injection w. biologic***
x
x
x
x
x
x
x¤
x¤##
x
x
x
x
x
x
End of Study
X
X##
# = Only necessary if participant crosses-over from mepolizumab to dupilumab
## =  Only necessary if participant crosses-over from dupilumab to mepolizumab
¤ = First injection with new drug if participant crosses-over.
Bold writing = evaluation criteria, underlining = primary endpoint, parentheses () = last injection with trial medication   
$ = mandatory visit
£ = Visit not mandatory. Can be omitted if patient can self-administer injections 
* = Carried out if not previously done. Diagnosis is to be made by a medical specialist. 
** = unless one was already taken within <12 months 
*** = Dupilumab will be administered every 2 weeks for the first 24 weeks of treatment 
**** = VAS scores: Asthma, CRS, allergic rhinitis, smell 

 
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3.        Background/Rationale 
 
3.1        Disease background  
Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disease of the nasal and 
paranasal mucosa leading to mucosa thickening and polyp formation from the ethmoid sinuses. The 
estimated prevalence of CRSwNP is 2-4% in European adults (3). Common symptoms include nasal 
obstruction, reduced sense of smell, nasal discharge, and sleep disturbances—resulting in a 
significantly decreased quality of life (4,5). In many cases, CRSwNP patients have co-existing asthma, 
allergic rhinitis and/or aspirin sensitivity (N-ERD) (6,7). This correlation is due to the fact that these 
diseases share a common inflammatory pathway—so-called type 2 inflammation—characterized by 
the presence of interleukins (IL) -4, -5 and -13 in combination with eosinophilic cells and 
immunoglobulin E (IgE) (8) 
Danish studies have shown that 40% of patients with CRSwNP in primary ENT clinics and 65% of 
patients referred to a tertiary hospital for ESS surgery had co-existing asthma – a large proportion of 
them previously undiagnosed (9,10). This association between upper and lower airway disease has 
coined the term Global Airways and has led to the growing awareness that disease in both upper and 
lower airways should be treated simultaneously, preferably in a multidisciplinary effort (1–3) (11).  
The current cornerstone of treatment for patients with CRSwNP is daily saline irrigation and topical 
steroids, sometimes supplemented by courses of antibiotic treatment. In cases where this treatment is 
insufficient, courses of systemic oral corticosteroid (OCS) and/or endoscopic sinus surgery (ESS) is 
added (8). The surgical treatment reduces the inflammatory load by removal of inflamed mucus 
membrane, as well as widening the natural drainage openings in the sinus system, thereby facilitating 
access for topical steroids. Furthermore, it reduces symptoms such as nasal congestion, reduced smell 
and facial pressure. By this combined treatment approach most patients can achieve a satisfactory 
result. However, for about 10% of patients with the most severe disease, repeated courses of OCS or 
surgery are needed, resulting in a severely reduced health-related quality of life (HRQoL) with many 
sick-days from work (absenteeism) as well as feelings of fatigue, depression and poor concentration 
(presenteeism) (5, 6). 
 
3.2        Treatment of CRSwNP 
Daily treatment with intranasal steroids is recommended in the European Position Paper on 
Rhinosinusitis and Nasal Polyps 2020 (8). They are generally well tolerated and have minor to no 
systemic effects. Systemic oral corticosteroids are effective but are associated with many unwanted 
systemic side effects (7). Endoscopic sinus surgery is generally a safe procedure and serious adverse 
effects are rare, however they lead to several sick days, and 40% of patients in an American study had 
polyp recurrence at 18 months follow-up (12,13).  
Monoclonal antibodies (MABs)—also referred to as biologics—target various key drivers in the 
pathophysiological immunological response and have proven effective and safe for the treatment of 
CRSwNP caused by type 2 inflammation, with or without concurrent asthma (2,14).  
 
3.3        Trial rationale 
Biologics have been used to treat asthma for more than 15 years, but were recently approved for the 
treatment of CRSwNP, and only very recently were two different MABs approved in Denmark; 
mepolizumab (Nucala) and dupilumab (Dupixent). Both drugs have shown excellent efficacy and 
safety, with comparable improvements in both objective and subjective measures and low risk of 

 
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adverse effects (AEs) (2,14). However, the phase-III trials varied slightly, for example in the handling 
of missing data, and patients in the SYNAPSE study generally had a higher disease burden, thus making 
direct comparison of the two drugs difficult (15). To date, a few meta-analyses exist that seek to 
indirectly compare the different available biologics for CRSwNP (16–18). The conclusion in these 
studies is similar; dupilumab is superior to the rest (including mepolizumab) on most subjective and 
objective parameters, including improvements of olfaction. However, due to the before-mentioned 
uncertainties and differences, the Danish Medicines Council (DMC) concluded that the differences 
between mepolizumab and dupilumab were insignificant, and hence a recommendation to the five 
health regions of Denmark to primarily prescribe the cheapest (mepolizumab) was made (15). It was 
noted that in some cases clinicians may wish to prescribe dupilumab—for example in cases where 
olfactory improvements are of special significance—and hence it was recommended to use 
mepolizumab over dupilumab in an 80/20-fashion (15). In the report, the DMC also encourages that 
an RCT is performed to enable direct comparison between the two, and it also states that it will re-
assess the recommendations in two-three years based on the observational data.  
 
The positive effects of mepolizumab and dupilumab on both upper and lower airway disease are well 
documented, and the introduction of biologics are commonly regarded as game-changers for patients 
with uncontrolled CRSwNP and healthcare providers. Their high price, however, warrants cost-
effective use of them. There is international controversy whether their use is cost-effective compared 
to basic supportive care (BSC) in combination with ESS. One US study found that dupilumab was ten 
times costlier and slightly less effective than ESS (8.95 quality-adjusted life years (QALY) vs. 9.80 
QALYs with ESS)—regardless of revision surgery rates (19). However, this study only considered 
direct costs of treatment in relation to health benefit and did not bring into the equation the indirect 
costs associated with decreased productivity due to absenteeism, presenteeism and later in life; costs 
of treating long-term adverse effects of repeated courses of systemic corticosteroids (osteoporosis, 
diabetes, cataracts, obesity, hypertension, and glaucoma). In contrast, a recent Italian study concluded 
that dupilumab as an add-on to conventional BSC was cost-effective in gained quality-adjusted life-
years compared to BSC alone (20). The true costs of uncontrolled disease are difficult to estimate, as 
several factors such as absenteeism, presenteeism and indirect costs of long-term adverse effects of 
OCS tend to be underestimated. A recent European study, however, estimated that total direct costs pr. 
Patient year for CRSwNP patients were €1501 whereas indirect costs were almost four times as high 
(€5659). Direct costs were mainly attributable to hospitalization and outpatient visits, whereas 
indirect costs were due to absenteeism and presenteeism (21). The study shows that indirect costs far 
exceed direct costs, even without including the costs of treating the long-term complications of 
repeated courses of systemic steroid. 
 
We aim to perform a randomized, prospective, multi-centre, head-to-head study in real-world Danish 
patients. To our knowledge, this will be the first of its kind in the world, and it will provide much-
needed knowledge to healthcare workers and policy makers all around the world, and aid them in 
making rational, cost-effective decisions on how to use these new promising—but very costly—
biologic drugs. The knowledge gained will be of benefit not only to healthcare providers and 
taxpayers, but particularly to CRSwNP patients. A major strength of our study is that it is investigator-
initiated and 100% uninfluenced by financial interests of the pharmaceutical industry. The trial is 
exclusively funded by the public health system and a non-profit organization. Furthermore, the 

 
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healthcare system in all regions of Denmark is completely reimbursed by the state, so inclusion of 
participants in our study will be free from economic bias.  
 
3.4        Benefit-risk assessment and ethical considerations 
This will be an RCT where all study participants will be randomized to one of two effective drugs (i.e. 
no placebo group), and therefore all participants stand to gain from participating in the study. When 
the DMC allowed the prescription of biologics for CRSwNP in Denmark, it was strongly encouraged 
that an observational study be undertaken to measure effects and adverse effect to enable an analysis 
after two-three years. This quality assessment study was already planned before the second biologic 
(mepolizumab) was approved in Denmark thereby laying the ground for this RCT, meaning that there 
was already a strategy for the number and types of diagnostic tests before treatment and at follow-up 
visits. The number and types of tests and follow-up visits in our study are identical, so participants will 
not be exposed to extra testing or discomfort by joining our trial.  
The adverse effects of both drugs are generally very mild, and in phase III studies data actually showed 
that adverse events were slightly more common in the placebo group than in the treatment group 
(2,14). The most common adverse events in both studies were nasopharyngitis, headache, nose 
bleeding, and irritation or tenderness at the site of injection. In the LIBERTY NP SINUS 52-study seven 
cases of non-severe conjunctivitis was reported in the treatment group, and one in the placebo group. 
Four patients experienced eosinophilia along with clinical symptoms that were reported as treatment-
emergent adverse events: one patient experienced eosinophilic granulomatosis with polyangiitis 
(EGPA) while receiving dupilumab; one patient experienced eosinophilia along with arthralgia, asthma 
exacerbation, and insomnia while receiving dupilumab; one patient experienced EGPA more than 300 
days after receiving. In the SYNAPSE study, there was no difference in adverse events between the 
treatment group and placebo group.  
 
4.        Hypothesis 
 
This is a non-inferiority study where we expect to find no clinically relevant difference in treatment 
outcome between dupilumab and mepolizumab for the treatment of severe, uncontrolled CRSwNP.  
 
5.        Objectives  
 
5.1        Primary objective 
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. 
 
5.2        Secondary objective 
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.  
 

 
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5.3        Primary endpoints 
The coprimary endpoints are:  
• 
Change in NPS-score from baseline to week 24  
• 
Change in SNOT-22 score from baseline to week 24 
 
Baseline values will be recorded at randomization. 
The null hypothesis will be proven if we find a difference of ≥1 on NPS-score and ≥12 points on SNOT-
22.   
 
The Nasal polyp score is a grading system for polyp size ranging from 0 to 4 in each nostril, thus giving 
a total score ranging from 0 to 8. The polyp size is assessed by the examiner and graded as follows; 0 = 
no polyps, 1 = polyps confined to the middle meatus, 2 = multiple polyps occupying the middle meatus, 
3 = polyps extending beyond middle meatus, 4 = polyps completely obstructing the nasal cavity.  
 
SNOT-22 is a patient-reported measure of outcome (PROM) consisting of 22 individual questions for 
use in CRS with or without nasal polyposis. The SNOT-22 covers a broad range of disease-specific 
HRQOL topics including physical complaints, functional limitations, and emotional consequences. The 
SNOT-22 has shown to be reliable and valid in clinical practice to assess the impact of CRSwNP on 
disease-specific HRQOL and to measure treatment-related change. The minimal clinically relevant 
difference is 8.9 points (22) 
 
5.4        Secondary endpoints 
• 
Change in NPS-score from baseline to week 48  
• 
Change in SNOT-22 score from baseline to week 48 
• 
Proportion of subjects meeting the Danish Medicines Council response criteria (table 2) at 24 
and 48 weeks 
• 
Change in loss of smell (LoS) measured by Sniffin’ Sticks Identification Test 16 (SSIT-16) at 
weeks 24 and 48 
• 
Change in Asthma Control Questionnaire (ACQ) score at weeks 24 and 48 
• 
Change in CRS visual analogue scale (VAS) score at weeks 24 and 48 
• 
Change in perceived sense of smell - VAS score at weeks 24 and 48 
• 
Change in lung fractional exhaled nitrous oxide at weeks 24 and 48  
• 
Change in Tympanometry at weeks 24 and 48  
• 
Change in allergy/N-ERD symptoms – VAS score at weeks 24 and 48 
• 
Change in FEV1 at weeks 24 and 48 
• 
Nasal Congestion Score at weeks 24 and 48 
• 
The Lund-Mackay score at weeks 24 and 48  
• 
Proportion of subjects requiring rescue treatment 
 
6.        Trial design 
 
6.1        Summary of trial design 
A randomized, multi-centre non-inferiority trial (phase IV RCT). The trial is unblinded since patients, 
caregivers and local investigators can guess which group the patient is in due to differences in 
treatment interval. We decided to not inject placebo every other time in the mepolizumab due to 
ethical and practical reasons.  

 
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We will seek to get the trial approved as a low intervention clinical trial (LICT) with the European 
Clinical Trials Information System (CTIS) under European Medicines Agency (EMA). We believe the trial 
qualifies as a LICT since the included pharmaceuticals are being used for their approved indications in 
either standard dosages and intervals, or dosage intervals that are well founded in the scientific 
literature, and since participants will undergo no additional discomfort compared to standard clinical 
practice for biologics in Denmark1. 
 
We expect to include 220 subjects with a drop-out rate of 20%, leaving 176 patients for statistical 
analysis.  
Patients with severe, uncontrolled CRSwNP with/without concomitant asthma referred for evaluation 
and possible treatment with a biologic—and who fulfil the inclusion criteria (see section 7.1)—will be 
invited to participate in the study. At the first visit they will be screened for disease severity and 
possible comorbidity with several diagnostic tests and standardized questionnaires (see section 10).  
Following inclusion in the study, participants will be stratified by smell loss (SSIT-16 0-8 and 9-16), 
gender and geographic location and then randomized 1:1 to receive treatment with either  
• 
dupilumab (Dupixent) 300 mg injection every two weeks, or 
• 
mepolizumab (Nucala) 100 mg injection every four weeks 
 
The trial subjects will receive treatment for 24 weeks by which time treatment response will be 
evaluated based on the response criteria (table 2). Depending on the results, patients will either 
change dosage intervals, switch-over to the other drug or stay on the drug there are on. This will take 
place in the following way (see also figure 2): 
• 
dupilumab-group:  
• 
If the response criteria are fulfilled (table 2): participants will change to a prolonged 
dosage interval, i.e. every 4 weeks2 from week 24. 
• 
If the response criteria are not met: participants will switch to mepolizumab 100 mg 
every four weeks.   
• 
mepolizumab-group:  
• 
If the response criteria are fulfilled: participants will continue same treatment regimen 
until week 48 
• 
If the response criteria are not met: participants will switch to dupilumab 300 mg 
every two weeks 
In addition to the trial medicine, patients will continue basic treatment of INCS and saline irrigation, 
unless contraindicated. 
In cases where participants cross-over to the opposite treatment arm, a CT scan of the sinuses will be 
repeated. 
 
 
 
 
 
 
1 Since biologics are being introduced on a trial period of 2-3 years, their use and effect is strictly monitored by 
the Danish Medicines Council.  
2 This dosage interval was proven in the LIBERTY NP SINUS-52 study to be effective for patients who had 
responded in the first 24 weeks(2), and was recently supported in a real-world study from the Netherlands (42). 
It was recommended by the DMC to switch to this interval after 24 weeks in dupilumab-responders(15). 

 
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Figure 2 – trial design 
 
 
Table 2 – Minimal response criteria (as stated by the Danish Medicines Council) 
 
6.2        Discussion of trial design 
This is a head-to-head, real-world study directly comparing two relatively new drugs for the indication 
CRSwNP. We therefore decided on a design with two active arms and no placebo arm, as the intention 
is to test the hypothesis by the DMC that the two drugs are non-inferior to each other. Participants will 
start treatment in the standard dosage and -interval, but the cross-over design enables switching to 
the other drug in the case of absence of treatment response. This gives us the opportunity to 
investigate if some patients might benefit from one drug, and not the other. By comparing non-
responders to their endotype (tissue biomarkers obtained from tissue biopsies) we are hoping to learn 
how to better predict who will gain most from one drug, and not the other—and thereby move one 
step closer to personalized medicine.  
   Furthermore, we decided to increase injection intervals for participants in the dupilumab-arm, to see 
if the previously found sustained benefit in the LIBERTY NP SINUS-52 will hold true in these real-
24 weeks 
52 weeks* 
NPS 
≥ 1 point 
≥ 2 points 
SNOT-22  
≥ 12 points 
≥ 12 points 
Evaluation of sense of smell 
Depends on the value at the start of treatment. Either 
-  normal sense of smell (i.e. SSIT-16 >8) 
Or 
-  If the sense of smell was good before biological treatment, it 
must not deteriorate. 
Improvement of comorbidity 
The desired minimum improvement is 0.5 points on the 
Asthma Control Questionnaire (ACQ) . 
• 
If patients do not achieve an improvement of 2 out of 4 items the treatment is discontinued 
• 
If there is effect of treatment, reduction in treatment (e.g., 1 injection per month) should be 
contemplated 
*For the sake of equally long observation periods in cases of cross-over, the final evaluation takes 
place after 48 weeks of follow-up, and not 52 weeks in this study.  

 
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world Danish patients. If symptoms return/worsen, the dosage interval will be returned to every two 
weeks. 
   Lastly, we will stratify patients into two groups based on their LoS; patients who are anosmic (score 
0-8 in SSIT-16) and patients with normal or only mild loss of smell (SSIT-16 score 9-16). We decided 
this approach since LoS is one of the most significant effectors of HRQoL for CRSwNP-patients, and 
because we wish to include change in LoS as one of the most important secondary endpoints (7). 
There are suspicions that dupilumab is mepolizumab superior in terms of improvement on smell, and 
with this direct comparison we expect to be able to add knowledge to this suspicion.   
 
6.3        Trial schedule 
 
Planned first subject first visit 
March 2023 
 
 
Planned last subject randomized 
March 2024 
 
 
Planned last subject last visit: 
March 2025 
 
 
End of trial 
November 2025 
 
7.        Trial population 
 
7.1        Inclusion criteria 
Subjects must be 18 or over and be able to speak and read Danish language. Furthermore, the 
inclusion criteria follow the criteria determined for treatment with biologics by the DMC, i.e.: 
 
Patients must have: 
• 
Bilateral polyps in nose and sinuses 
• 
ESS within the last three years (unless unfit for surgery - 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 (as per EPOS2020 – see table 3) 
 
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)) 
 
 
 
 

 
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Table 3 – Criteria for evidence of type 2 inflammation (as stated by EPOS2020) (8) 
Type 2 inflammation (at least one of the following) 
– Current blood eosinophilia (≥250 106 cells/L / ≥0,25 109cells/L) 
– Previous blood eosinophilia (>0,30 x 109 cells/L during last 12 months) 
– Polyp eosinophilia (cell count in at least 2 out of 3 hotspots with x40 magnification) 
                  ≥10 cells/high power field             
– Total serum IgE ≥100 IU/mL  
– Late onset eosinophilic asthma 
– FeNO ≥ 25 ppb 
 
7.2        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 (see further explanation in section 9). 
 
7.3        Recruiting 
Eligible subjects, either from the out-patient clinic or hospitalized, will be identified by medical 
professionals (MD or nurse) involved in their treatment. The subjects will be asked if they are 
interested in information about the trial. If they accept, they will be informed about the trial by either 
that same medical professional or specific trial personnel. Written consent from an eligible subject 
must be obtained before any transfer of information on the subject from a medical professional 
involved in the treatment to trial personnel. Written consent must be obtained by a medical doctor.  
Furthermore, the author group will send out a letter to all private ENT practices in Denmark informing 
them about the study and the new possibility of referring patients with severe, uncontrolled CRSwNP 
to treatment with biologics and possible enrolment in this trial, or one of the other trials investigating 
the effects of biologics in Denmark. 
 
7.4        Discontinuation 
Subjects will be informed about the possibility of discontinuing the trial at any time and without giving 
a reason. We will encourage subjects to inform the investigator as soon as they have decided to 
discontinue the trial whereby the last administration of trial medication will be registered. In case of 
discontinuation, we will ask the subject to indicate a reason for the discontinuation which will be 
registered 
Subjects will be discontinued from the trial in case of failure to adhere to the trial. If subjects fail to 
meet for treatment i.e., not receiving two or more injections, they are discontinued.  
In cases of discontinuation, subjects will be booked for a final check for AEs/SAEs four weeks after the 
last treatment injection.  
 
7.5        Pregnancy and anticonception  
No teratogenic/foetal adverse effects have been reported in the literature and no formal 
contraindication due to pregnancy has been made for neither mepolizumab nor dupilumab (23–25). 
However, since scarce data exists, especially in the case of dupilumab, pregnant or breastfeeding 
subjects will be excluded if pregnancy is present or occurs during the run-in period before the CT scan 

 
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and first injection. Women in the fertile age will take a pregnancy test before entering the study. 
Fertile women included in the study shall use safe contraception (intrauterine contraception or 
hormonal contraception). This treatment shall be continued for minimum six weeks after terminating 
the treatment (see section 9.2).  
If pregnancy occurs after treatment has started, subjects will be discontinued in the study, and their 
data will be included in the intention to treat analysis in a manner of last observation carried forward 
(see also section 7.4). Finally, patients who wish to become pregnant during the study period will not 
be eligible. 
 
7.6        Rescue treatment 
If participants need to receive rescue treatment (for example due to intolerable symptoms/intolerable 
adverse events) they will be offered rescue-treatment in the form of tablet Prednisolone 37.5 mg once 
daily for 7–10 days (injections are contraindicated in this trial due to their longer-lasting effect).  
Surgery will be reserved for acute and threatening disease complications such as intra-orbital or intra-
cranial infections, in accordance with normal clinical practice. 
Results from the subject will be excluded in the “protocol analysis” but will be included in the 
“intended to treat (ITT)” analysis. Data will be analysed in a “last observation carried forward” (LOCF) 
fashion. Patients needing rescue treatment will be encouraged to stay on the prescribed drug until 
week 24, where they will be offered to cross-over to the other treatment arm.  
If the reason for discontinuation is treatment failure and the subject is determined to discontinue in 
the study, time of treatment failure will be registered, and the participant will be offered rescue 
treatment (in the form of OCS or ESS in case of severe, acute complications such as intra-orbital or 
intra-cranial infections) following normal treatment guidelines (see also section 7.4).  
 
Asthma exacerbations:  
Subjects experiencing asthma exacerbations during the trial period will be guided to increase the ICS 
treatment, in accordance with normal clinical practice as per the Global Initiative for Asthma (GINA)-
guidelines (26).  
 
8.        Randomization, blinding and sample size  
 
8.1        Randomization 
Subjects will be randomized in a 1:1 ratio and stratified by sense of smell (SSIT-16 0-8 and >8),  
geography (national multi-centre study) as well as gender. 
Randomization will be performed with the built-in randomization module in REDCap. The method will 
be variable block randomization in blocks of 4-8 subjects. This design is to reduce bias of being able to 
guess/predict randomization patterns.  
 
8.2        Blinding  
The IMPs are off-the-shelf, and not specially labelled. Participants and caregivers will therefore be 
unblinded. The final data analysis will, however be performed with the investigator/statistician 
blinded to the treatment given.  
 
8.3        Sample size 
Based on the estimate by the DMC, we expect to be able to include 220 patients within 18 months (27) 

 
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By including 220 participants (effectively 176 participants after dropouts) we 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 the previously found standard deviation (SD) values 1.9 for NPS and 22 for SNOT-22 
(14,28),  
– an expected superior effect of 0.7 for NPS 7 on SNOT-22 (17) and  
– a minimal clinically relevant difference (MCID) of 1 for NPS and 12 for SNOT-22, and  
– assuming no negative correlation between the two co-primary endpoints, respectively (29). 
We do not expect the study to have power to show superiority or equality between mepolizumab and 
dupilumab, but superiority analyses will be performed if the null hypothesis for non-superiority is 
rejected for both co-primary outcomes.  
 
 
9.        Trial products 
 
9.1        Administration of trial products  
Each subject will be randomly assigned to receive either dupilumab (investigational medicinal product 
(IMP) 1) or mepolizumab (IMP2). Please refer to figure 1 for a visual on the trial design. Trial 
medication will be provided by local hospital pharmacies in accordance with Good Manufacturing 
Practice (GMP). Trial medicine will not be specially labelled. 
At visit 3 on day “0” each subject will be injected with one of the two; IMP1 or IMP2. 
The first time the participant is injected, he/she will remain in the department for at least 30 minutes 
for observation of acute adverse events. Here the participant will be under constant supervision by a 
nurse or doctor.  This also applies to subjects who have crossed-over and is injected with the new IMF 
for the first time.  
In case of serious/life-threatening adverse events such as anaphylaxis, the patient will be already 
located at a tertiary hospital with quick access to advanced resuscitation, including anti-anaphylactic 
drugs, and in severe cases intubation or emergency crico-thyroidectomy.   
 
The first three to five injection will take place at the hospital department, but after this there will be 
the possibility of the patient injection them self at home 
 
9.1.1    Compliance/adherence with the trial medicine 
Participants will be asked at each appointment if they are adhering to the treatment plan. An “injection 
diary” (see appendix 1) will be provided once participants switch to home-injections. Furthermore, 
FMK-online.dk will be checked in some cases, to check whether the patient has collected their 
medicine from the pharmacy (in cases where this is applicable).  
 
 
9.2        Dupilumab: IMP1 (25) 
Dupilumab (Dupixent, Sanofi) is a recombinant, monoclonal antibody that inhibits signalling by IL-4 
and IL-13, cytokines that are key drivers of type 2 inflammation. Dupilumab is approved in several 
countries for the treatment of type 2 inflammation-derived diseases such as severe asthma, ectopic 
dermatitis and CRSwNP.  
 

 
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The EMA approved dosage is 300 mg s.c. every two weeks, but in the phase-III trial an increased 
dosage interval of every 4 weeks proved efficient to sustain clinical response after the initial 24 weeks 
of treatment (2). Based on these finding it was recommended by the DMC, that patients meeting 
response criteria (see table 2) after week 24 can try the prolonged dosage interval (30). 
 
Dupilumab is administered subcutaneously. Median times to maximum serum concentration is 3-7 
days. The absolute bioavailability ranges from 61-64%. Steady concentration is reached by week 16 
(standard dose interval) and ranges across different clinical trials from 69.2±36.9 mcg/mL to 
80.2±35.3 mcg/mL for 300 mg dose.  
Elimination happens by parallel linear and non-linear pathways. Time to non-detectable 
concentrations for 300 mg s.c./2 weeks were 6-7 weeks  (25). 
 
Pregnancy: There is little data available for safety in pregnancy. Animal studies have shown no direct 
or indirect harmful effects. The EMA recommends use of dupilumab in pregnancy only if the benefits 
outweigh the risks.  
Breastfeeding: It is unknown if dupilumab is excreted in breast milk. As for pregnancy, it must be 
assessed if the potential benefits justify the potential risks to the child.  
 
In this trial it was decided to not include pregnant or breastfeeding women, as well as women 
planning to get pregnant within the study period. See section 7.5 for more details.  
 
9.2.1   Undesired effects: 
The following is an exert from (25). The section about paediatric populations have been removed since 
this study only includes adults. For full text and reference list, please refer to (25). 
 
Summary of the safety profile  
The most common adverse reactions are injection site reactions (includes erythema, oedema, pruritus, 
pain, and swelling), conjunctivitis, conjunctivitis allergic, arthralgia, oral herpes, and eosinophilia. Rare 
cases of serum sickness, serum sickness-like reaction, anaphylactic reaction, and ulcerative keratitis 
have been reported (see section 4.4).  
 
Tabulated list of adverse reactions  
The dupilumab safety data presented in Table 4 were predominantly derived from 12 randomised, 
placebo-controlled trials, including atopic dermatitis, asthma, and CRSwNP patients. These studies 
involved 4,206 patients receiving dupilumab and 2,326 patients receiving placebo during the 
controlled period are representative of the overall safety profile for dupilumab.  
 
Listed in Table 4 are adverse reactions observed in clinical trials and/or postmarketing setting 
presented by system organ class and frequency, using the following categories: very common (≥ 
1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 
1/1,000); very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in 
order of decreasing seriousness.  
 
 
 

 
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Table 4: List of adverse reactions  
MedDRA System Organ Class 
Frequency 
Adverse Reaction 
Infections and infestations 
Common 
Conjunctivitis*  
Oral herpes* 
Blood and lymphatic system 
disorders 
Common 
Eosinophilia 
 
 
Immune system disorders 
Uncommon 
Rare 
Angioedema#  
Anaphylactic reaction Serum sickness 
reaction Serum sickness-like reaction 
Eye disorders 
Common 
Uncommon 
 
 
 
Rare 
Conjunctivitis allergic*  
Keratitis*#  
Blepharitis*†  
Eye pruritus*†  
Dry eye*†  
Ulcerative keratitis*†# 
Skin and subcutaneous tissue 
disorders 
Uncommon 
Facial rash# 
Musculoskeletal and connective 
tissue disorders 
Common 
Arthralgia# 
General disorders and 
administration site conditions 
Common 
Injection site reactions (includes erythema, 
oedema, pruritus, pain, and swelling) 
*eye disorders and oral herpes occurred predominately in atopic dermatitis studies. † the frequencies 
for eye pruritus, blepharitis, and dry eye were common and ulcerative keratitis was uncommon in 
atopic dermatitis studies. # from postmarketing reporting.  
 
Description of selected adverse reactions  
 
Hypersensitivity  
Cases of anaphylactic reaction, angioedema, and serum sickness/serum sickness-like reaction have 
been reported following administration of dupilumab (see section 4.4).  
 
Conjunctivitis and keratitis related events  
Conjunctivitis and keratitis occurred more frequently in atopic dermatitis patients who received 
dupilumab compared to placebo in atopic dermatitis studies. Most patients with conjunctivitis or 
keratitis recovered or were recovering during the treatment period. In the long-term OLE atopic 
dermatitis study (AD-1225) at 3 years, the respective rates of conjunctivitis and keratitis remained 
similar to those in the dupilumab arm in the placebo controlled atopic dermatitis studies. Among 
asthma patients frequency of conjunctivitis and keratitis was low and similar between dupilumab and 
placebo. Among CRSwNP patients the frequency of conjunctivitis was higher in dupilumab than 
placebo, though lower than that observed in atopic dermatitis patients. There were no cases of 
keratitis reported in the CRSwNP development program (see section 4.4).  
 
Eczema herpeticum  
Eczema herpeticum was reported in < 1% of the dupilumab groups and in < 1 % of the placebo group 
in the 16-week atopic dermatitis monotherapy adult studies. In the 52-week atopic dermatitis 

 
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dupilumab + TCS adult study, eczema herpeticum was reported in 0.2 % of the dupilumab + TCS group 
and 1.9 % of the placebo + TCS group. These rates remained stable at 3 years in the long-term OLE 
study (AD-1225).  
 
Eosinophilia  
Dupilumab-treated patients had a greater mean initial increase from baseline in eosinophil count 
compared to patients treated with placebo. Eosinophil counts declined to near baseline levels during 
study treatment and returned to baseline during the asthma open-label extension safety study 
(TRAVERSE). The mean blood eosinophil levels decreased to below baseline by week 20 and was 
maintained up to 3 years in the long-term OLE study (AD-1225). Treatment-emergent eosinophilia (≥ 
5,000 cells/mcL) was reported in < 2 % of dupilumab-treated patients and < 0.5 % in placebo-treated 
patients (SOLO1, SOLO2, AD-1021, DRI12544, QUEST, SINUS-24 and SINUS-52 studies) (see section 
4.4).  
 
Infections  
In the 16-week atopic dermatitis monotherapy clinical adult studies, serious infections were reported 
in 1.0 % of patients treated with placebo and 0.5 % of patients treated with dupilumab. In the 52-week 
atopic dermatitis CHRONOS adult study, serious infections were reported in 0.6 % of patients treated 
with placebo and 0.2 % of patients treated with dupilumab. The rates of serious infections remained 
stable at 3 years in the long-term OLE study (AD-1225).  
 
No increase was observed in the overall incidence of infections with dupilumab compared to placebo 
in the safety pool for asthma clinical studies. In the 24-week safety pool, serious infections were 
reported in 1.0% of patients treated with dupilumab and 1.1% of patients treated with placebo. In the 
52-week QUEST study, serious infections were reported in 1.3% of patients treated with dupilumab 
and 1.4% of patients treated with placebo.  
 
No increase was observed in the overall incidence of infections with dupilumab compared to placebo 
in the safety pool for CRSwNP clinical studies. In the 52-week SINUS-52 study, serious infections were 
reported in 1.3 % of patients treated with dupilumab and 1.3 % of patients treated with placebo.  
 
Immunogenicity  
As with all therapeutic proteins, there is a potential for immunogenicity with dupilumab.  
 
Anti-Drug-Antibodies (ADA) responses were not generally associated with impact on dupilumab 
exposure, safety, or efficacy.  
 
Approximately 5 % of patients with atopic dermatitis, asthma, or CRSwNP who received dupilumab 
300 mg Q2W for 52 weeks developed ADA to dupilumab; approximately 2 % exhibited persistent ADA 
responses and approximately 2 % had neutralizing antibodies. Similar results were observed in 
paediatric patients (6 to 11 years of age) with atopic dermatitis who received dupilumab 200 mg Q2W 
or 300 mg Q4W for 16 weeks and patients (6 to 11 years of age) with asthma who received dupilumab 
100 mg Q2W or 200 mg Q2W for 52 weeks. Similar ADA responses were observed in adult patients 
with atopic dermatitis treated with dupilumab for up to 3 years in the long-term OLE study (AD1225).  
 

 
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Approximately 16 % of adolescent patients with atopic dermatitis who received dupilumab 300 mg or 
200 mg Q2W for 16 weeks developed antibodies to dupilumab; approximately 3 % exhibited 
persistent ADA responses, and approximately 5 % had neutralizing antibodies. Approximately 9 % of 
patients with asthma who received dupilumab 200 mg Q2W for 52 weeks developed antibodies to 
dupilumab; approximately 4 % exhibited persistent ADA responses and approximately 4 % had 
neutralizing antibodies.  
Regardless of age or population, approximately 2 to 4 % of patients in the placebo groups were 
positive for antibodies to dupilumab; approximately 2 % exhibited persistent ADA response and 
approximately 1 % had neutralizing antibodies.  
 
Less than 1 % of patients who received dupilumab at approved dosing regimens exhibited high titer 
ADA responses associated with reduced exposure and efficacy. In addition, there was one patient with 
11 serum sickness and one with serum sickness-like reaction (< 0.1 %) associated with high ADA 
titers. 
 
 
9.3        Mepolizumab: IMP2 (24) 
Mepolizumab (Nucala) is a recombinant, human, monoclonal antibody that selectively bind to IL-5 
thereby inactivating it. In Europe it is approved for the treatment of severe eosinophilic asthma, 
CRSwNP, eosinophilic granulomatosis with polyangiitis (EGPA) and hyper eosinophilic syndrome.  
 
The EMA recommended dose for CRSwNP is 100 mg s.c. every four weeks. In this trial we intend to 
keep participants at this dose and dosage interval, unless cross-over to dupilumab is warranted.  
 
Mepolizumab is administered subcutaneously. Median time to maximum serum concentration is 4-8 
days. The absolute bioavailability ranges from 74-80% if injected in the arm, and slightly lower if 
administered in the thigh or abdomen.  
Elimination happens at a mean terminal half-life of 16-22 days (24) 
 
Pregnancy: mepolizumab was shown to cross the placental barrier in monkeys, but studies do not 
indicate reproductive toxicity. The potential for harm to a human foetus is unknown. The EMA 
discourages the use of mepolizumab unless the benefits are considered to outweigh the risks.  
Breastfeeding: It is unknown if mepolizumab is excreted in human breast milk. However, it was found 
in breast milk of monkeys. As for pregnancy, it must be assessed if the potential benefits justify the 
potential risks to the child.  
 
In this trial it was decided to not include pregnant or breastfeeding women, as well as women 
planning to get pregnant within the study period.  
 
9.3.1   Undesired effects: 
The following is an exert from (24). The section about paediatric populations have been removed since 
this study only includes adults. For full text and reference list, please refer to (24). 
 
Summary of the safety profile  
 

 
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Severe eosinophilic asthma  
In placebo-controlled studies in adult and adolescent patients with severe refractory eosinophilic 
asthma, the most commonly reported adverse reactions during treatment were headache (20%), 
injection site reactions (8%) and back pain (6%).  
CRSwNP  
In a placebo-controlled study in patients with CRSwNP, the most commonly reported adverse 
reactions during treatment were headache (18%) and back pain (7%).  
 
EGPA   
In a placebo-controlled study in patients with EGPA, the most commonly reported adverse reactions 
during treatment were headache (32%), injection site reactions (15%) and back pain (13%). Systemic 
allergic/hypersensitivity reactions were reported by 4% of EGPA patients.  
 
HES 
In a placebo-controlled study in patients with HES, the most commonly reported adverse reactions 
during treatment were headache (13%), urinary tract infection (9%), injection site reactions and 
pyrexia (7% each).  
 
Tabulated list of adverse reactions  
The table below presents the adverse reactions from placebo-controlled severe eosinophilic asthma 
studies from patients receiving mepolizumab 100 mg subcutaneously (SC) (n=263), from a 
randomised, double-blind placebo-controlled 52-week study in patients with CRSwNP receiving 
mepolizumab 100 mg SC (n=206), in patients with EGPA receiving mepolizumab 300 mg SC (n=68), in 
a double-blind placebo-controlled 32-week study in patients with HES receiving mepolizumab 300 mg 
SC (n= 54), and from spontaneous post-marketing reports. Safety data is also available from open-
label extension studies in severe refractory eosinophilic asthma patients (n=998) treated for a median 
of 2.8 years (range 4 weeks to 4.5 years). The safety profile of mepolizumab in HES patients (n=102) 
enrolled in a 20-week open label extension study was similar to the safety profile of patients in the 
pivotal placebo-controlled study.  
 
The frequency of adverse reactions is defined using the following convention: very common (≥1/10); 
common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100); rare e (≥1/10 000 to <1/1000); very 
rare (<1/10.000) and not known (cannot be estimated from available data). Within each frequency 
grouping, adverse reactions are presented in order of decreasing seriousness. 
 
System Organ Class  
Adverse reactions 
Frequency 
Infections and infestations 
Lower respiratory tract infection  
Urinary tract infection  
Pharyngitis 
Common 
Immune system disorders 
Hypersensitivity reactions (systemic allergic)* 
Anaphylaxis** 
Common 
Rare 
Nervous system disorders 
Headache 
Very common 
Respiratory, thoracic and 
mediastinal disorders 
Nasal congestion 
Common 
Gastrointestinal disorders 
Abdominal pain upper 
Common 

 
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Skin and subcutaneous 
tissue disorders 
Back pain 
Common 
General disorders and 
administration site 
conditions 
Administration-related reactions (systemic non 
allergic)***  
Local injection site reactions  
Pyrexia 
Common 
* Systemic reactions including hypersensitivity have been reported at an overall incidence comparable 
to that of placebo in the severe eosinophilic asthma studies. For examples of the associated 
manifestations reported and a description of the time to onset, see section 4.4. **From spontaneous 
post marketing reporting. *** The most common manifestations associated with reports of systemic 
non-allergic administrationrelated reactions from patients in the severe eosinophilic asthma studies 
were rash, flushing and myalgia; these manifestations were reported infrequently and in <1% of 
patients receiving mepolizumab 100 mg subcutaneously. 
 
Description of selected adverse reactions  
 
Systemic reactions, including hypersensitivity reactions, in CRSwNP  
 
In the 52-week placebo-controlled study, systemic allergic (type I hypersensitivity) reactions were 
reported in 2 patients (<1%) in the group receiving mepolizumab 100 mg and in no patients in the 
placebo group. Other systemic reactions were reported by no patients in the group receiving 
mepolizumab 100 mg and in 1 patient (<1%) in the placebo group.  
 
Systemic reactions, including hypersensitivity reactions, in EGPA  
 
In the 52-week placebo-controlled study the percentage of patients who experienced systemic 
(allergic and non-allergic) reactions was 6% in the group receiving 300 mg of mepolizumab and 1% in 
the placebo group. Systemic allergic/hypersensitivity reactions were reported by 4% of patients in the 
group receiving 300 mg of mepolizumab and 1% of patients in the placebo group. Systemic non-
allergic reactions (angioedema) were reported by 1 (1%) patient in the group receiving 300 mg of 
mepolizumab and no patients in the placebo group.  
 
Systemic reactions, including hypersensitivity reactions, in HES  
 
In the 32-week placebo-controlled study, 1 patient (2%) reported a systemic (other) reaction in the 
group receiving 300 mg of mepolizumab (multifocal skin reaction) and no patients in the placebo 
group.  
 
Local injection site reactions  
 
Severe eosinophilic asthma  
In placebo-controlled studies the incidence of local injection site reactions with mepolizumab 100 mg 
subcutaneous and placebo was 8% and 3%, respectively. These events were all non-serious, mild to 
moderate in intensity and the majority resolved within a few days. Local injection site reactions 
occurred mainly at the start of treatment and within the first 3 injections with fewer reports on 

 
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subsequent injections. The most common manifestations reported with these events included pain, 
erythema, swelling, itching, and burning sensation.  
CRSwNP  
In the placebo-controlled study, local injection site reactions (e.g., erythema, pruritus) occurred in 2% 
of patients receiving mepolizumab 100 mg compared with <1% in patients receiving placebo.  
 
EGPA  
In the placebo-controlled study, local injection site reactions (e.g., pain, erythema, swelling) occurred 
at a rate of 15% in patients receiving mepolizumab 300 mg compared with 13% in patients receiving 
placebo.  
 
HES  
In the placebo-controlled study, local injection site reactions (e.g., burning, itching) occurred at a rate 
of 7% in patients receiving mepolizumab 300 mg compared with 4% in patients receiving placebo. 
 
9.4        Rescue treatment: Systemic corticosteroid or FESS 
 
9.4.1     Systemic corticosteroid (prednisolone) 
Short courses of moderate to high dose OCS are standard treatment for severe, uncontrolled CRSwNP, 
and recommended in EPOS2020 with grade 1a evidence (8).  
Standard dosage in Denmark is 37.5 mg Prednisolone orally for 7–10 days.  
Prednisolone has been added as an auxiliary product in the CTIS file.  
 
Adverse effects: 
The list of adverse effects for corticosteroids is long, and the risks well-known. The risk of adverse 
effects generally increases with repeated use, i.e. there is a dose-response relation for the frequency of 
events. Below is a list based on frequency of their appearance and in order of seriousness (33) 
 
>10%: 
leucopoenia, lymphopenia, growth retardation (in children), increased intraocular 
pressure, cataracts, dampening infections, infections, adrenal insufficiency, decreased 
glucose tolerance, myopathy, osteoporosis, lung abscess. 
1-10%: 
Thrombocytosis, heart-failure (worsening), hypogonadism, decreased wound healing, 
 candidiasis, hypercholesterolemia, hypercortisolism, hypertriglyceridemia, 
hypokalaemia, natrium-retention, depression, euphoria, psychosis, dermatitis, erythema, 
purpura, hypertension, oedema, leucocytosis, weight increase, increased appetite, 
nycturia, hirsutism, skin atrophy, rashes, striation, telangiectasia, increased sweating,  
0.1-1%: 
Peptic ulcers, allergic reactions, worsening of diabetes, porphyria, myopathy, 
osteonecrosis, hallucinations, mood-swings, mania, personality changes, urolithiasis, 
sleep disturbances. 
0.01-0.1%: 
Thyroid imbalance, glaucoma, tendon rupture, epidural lipomatosis, cognitive 
dysfunction, thrombosis, falsely negative skin-prick test, affected thyroid hormone-test. 
<0.01%: 
Serious cardiac events (bradycardia, cardiomyopathy, infarction), central serous 
chorioretinopathy, exophthalmos, blurry vision, pancreatitis, Steven-Johnson syndrome, 
hyperosmolar coma, hyperparathyroidism, ketoacidosis, sclerodermic renal crisis, 
tumor lysis syndrome, benign intracranial hypertension, loss of consciousness, epilepsy, 
toxic epidermal necrolysis, circulation collapse, dyspepsia, tendinopathy. 
 
9.4.2    Endoscopic Sinus Surgery 
Endoscopic sinus surgery (ESS) is a safe and effective procedure with good short-term effects on  

 
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symptoms and quality of life. However, recurrence rates are high and are  
generally reported to range between 20–60% (7,34) 
 
Adverse events: 
Serious adverse events are generally uncommon for benign ESS. There is a 5% risk of minor  
complications, and a 0.5–1% risk of major/serious complications (13,35) 
Peri-/post-operative complications will be treated following normal clinical practice.  
The list of complications includes the following:  
 
>5%: 
Post-operative pain, bleeding, nasal blockage, fatigue, nausea, reduced sleep quality 
1-5%: 
Post-operative infection, orbital emphysema, ecchymosis of the eyelid, minor peri-
operative bleeding, hyposmia, synechia, hypoesthesia of the infraorbital nerve, slight 
exacerbation of asthma symptoms.   
0.1-1%: 
CSF-leak, orbital injury, peri-operative haemorrhage requiring transfusion,  
<0.1%: 
Death 
 
9.5        IMP accountability 
 
There will be an accountability log on subject level in the electric patient journal 
(SP/EPJ/MidtEPJ/NordEPJ) to aid in traceability and compliance. This log will contain 
• 
Drug name 
• 
Dispensed by: date and initials 
• 
Batch number 
 
10.       Methods/Procedures 
 
10.1       Visit schedule  
Below is a list of procedures to be performed at various times during the trial. To account for possible 
problems with meeting exact dates due to weekends, public holidays etc., dates may be exceeded or 
preceded with +/- 7 days. However, baseline screening data can be collected up to 4 weeks before first 
injection. The different clinical tests are discussed in detail later in this section. See also Figure 1 for 
trial schedule. 
 
Visit ID 
Procedures to be performed at the visit 
Screening Visit(s)  
Week (-4)–0  
 
Obtain written informed consent for the trial before any other trial procedures are 
performed 
Assess inclusion and exclusion criteria 
Obtain demographic data 
Record medical history  
Record use of relevant previous medications and concomitant medications 
Obtain STARR-15, ACQ, SNOT-22, VAS-nose score 
Perform clinical examination including basic ENT examination + nasal endoscopy 
(rhinoscopy) + tympanometry  
Perform asthma tests: FEV1, FeNO, provocation test (if not previously done) 
Perform allergy test (skin prick/blood test) if not previously done 
Perform smell test (SSIT-16) 
Collect blood samples (EOS and differential count) 
Collect polyp biopsy (if not previously done within 12 months) 
CT scan of the paranasal sinuses is performed, unless a scan maximum 12 months 
old exist.  The Lund-Mackey score is assessed. 

 
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Visit ID 
Procedures to be performed at the visit 
Possibly re-test of asthma provocation. 
Endotype determined (pathology department) 
 Randomization 
And first injection 
Week 0 (+/- 7 days) 
Randomization 
First injection of treatment (both groups) 
Check for acute hypersensitivity reaction for 30 mins at department. 
Week 2 (+/- 7 days) 
Treatment injection (dupilumab group) 
Week 4 (+/- 7 days) 
Blood sample (EOS) – check for hypereosinophilia. 
Treatment injection (both groups) 
Week 6(+/- 7 days) 
Treatment injection (dupilumab group) 
Week 8(+/- 7 days) 
Treatment injection (both groups) 
Week 10(+/- 7 days) 
Treatment injection (dupilumab group) 
Week 12(+/- 7 days) 
Treatment injection (dupilumab group) 
Week 12–24* 
(+/- 7 days) 
Treatment injection (both groups) 
Treatment injections are self-administered or study nurse-administered every two- 
or four weeks depending on treatment group 
Week 16 
(+/- 7 days) 
Obtain ACQ, SNOT-22 score, VAS scores, NCS 
Check for compliance and possible side effects. 
Blood sample (EOS) 
- Halfway evaluation - 
Week 24 
(+/- 7 days) 
 
 
Possible cross-over 
 
Obtain ACQ, SNOT-22, VAS-nose score 
Check for AEs/SAEs 
Perform clinical examination including basic ENT examination + nasal endoscopy 
(rhinoscopy) + tympanometry + smell test (SSIT-16) 
Perform asthma tests: FEV1, FeNO 
Perform allergy test (skin prick/blood test) 
Perform smell test (SSIT-16) 
Collect blood samples (EOS)  
Check for response criteria 
Possible cross-over or increased dose interval. 
• 
Dupilumab group: +Effect: increased dose interval to every four weeks 
-effect: switch over to mepolizumab in standard dosing (treatment starts 
after a four-week treatment pause, and following a check for side effects, 
see below). 
• 
Mepolizumab group: +Effect: continue standard dosing and dose interval.  
-effect: switch over to dupilumab in standard dose  
   First injection with new IMF if cross-over is from mepolizumab to dupilumab** 
   CT scan paranasal sinuses in subjects who are crossing-over** (to allow for 
evaluation of 24w effect of the first drug) 
Week 26*** 
First injection with new IMF (if crossed-over from dupilumab to mepolizumab) 
Week 24–48*  
(+/- 7 days) 
Treatment injections are self-administered or study nurse-administered every two- 
or four weeks depending on treatment group 
   Blood sample (EOS) after 8 days (+/- 3 days) for patients who have crossed over. 
Week 40 (+/- 7 days)** 
(Week 42 +/- 7 days)*** 
 
Obtain ACQ, SNOT-22 score, VAS scores, NCS 
Check for compliance and possible side effects. 
- Endpoint evaluation- 
 
Week 48 (+/-7 days) 
(Week 50 +/- 7 
days)**/*** 
 
 
Obtain ACQ, SNOT-22, VAS-nose score 
Perform clinical examination including: basic ENT examination + nasal endoscopy 
(rhinoscopy) + tympanometry + smell test (SSIT-16) 
Perform asthma tests: FEV1, FeNO 
Perform allergy test (skin prick/blood test) 
Perform smell test (SSIT-16) 
Collect blood samples (EOS) 

 
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Visit ID 
Procedures to be performed at the visit 
CT scan paranasal sinuses (all subjects) 
Check for response criteria 
Final check for adverse effects 
End of trial 
* From week 12 most participants are expected to be able to auto-inject the medication. Those who are not 
able will continue injections at the study site by a study nurse. 
** This applies only to subjects who have crossed-over from mepolizumab to dupilumab 
*** This applies only to subjects who have crossed-over from dupilumab to mepolizumab. 
 
 
 
10.2       Trial procedures 
This section outlines the procedures that will be performed during the trial. For further details on the 
specific timing of the procedures please refer to the visit schedule above. 
The tasks listed below must be performed by a physician: 
• 
Obtainment of informed consent 
• 
Evaluation of in- and exclusion criteria 
• 
Assessment of AEs/SAEs 
• 
Assessment of CT scans and other laboratory results (including EOS counts). 
• 
Physical examination 
The remaining below may be performed by a physician or an appropriately trained nurse to whom the 
local investigator has delegated the tasks: 
• 
Tests of lung function, smell and allergy tests and smell tests 
• 
Observation for acute anaphylactic adverse events after the first injections.  
 
10.3      Informed Consent  
Before any trial activities are performed the written informed consent-form must be obtained (i.e. 
signed and dated by the subject). The written consent form will be uploaded to the e-CRF (REDCap). 
Each participant will be informed that participation in the trial is voluntary and that he/she may 
withdraw from the trial at any time and that withdrawal of consent will not affect his/her subsequent 
medical treatment or relationship with the treating physician. 
Subjects will be made aware that they can bring with them a relative to any appointment in relation to 
the trial. 
Subjects meeting the inclusion criteria for the trial will be given thorough verbal and written 
information about the trial (see “Patientinformation”). This information will be given by a trial 
authorized physician or nurse directly affiliated with the trial. Information must take place in an 
undisturbed room. The subject will be given time to ask questions and allowed sufficient time 
(minimum 24 hours) to consider the trial before deciding whether to participate.  
If subjects so desire, they may make a later appointment with the site investigator after having 
reviewed the written information about the trial, at which they can meet and discuss participation in 
the trial. Such a meeting must take place in an undisturbed room and the subject may bring a family 
member or friend to aid the decision-making. After this meeting, the subject may deliberate on trial 
participation for up to seven days. 
The subjects will be informed of any potential risks associated with the trial. 

 
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It is the responsibility of the principal investigator or a sub-investigator to obtain the written informed 
consent from the subject. 
After completion of the trial, all participating subjects will be informed of the overall results. 
Information of individual data and the interpretation hereof will be provided by the investigator. The 
individual subject’s right not to know of own data will be respected.  
 
10.4       Future contact 
When subjects are asked to consent to participation in the trial, they will be asked specifically if they 
will accept possible future contact for the purpose of further research regarding biologics for CRSwNP. 
The answer to this question will be recorded on the informed consent form as well as on the e-CRF. 
Subjects will be able to participate in the trial without giving consent to future contact and they can 
withdraw their consent at any time. 
 
10.5       Consent for long-term storage of blood samples and tissue in a biobank  
Subjects will also be asked specifically if they can accept the storage of their biologic samples in a 
biobank. The answer to this question will be recorded on the informed consent form as well as on the 
e-CRF. Subjects will be able to participate in the trial without giving consent to long-term storage of 
biologic samples. Subjects may withdraw this consent at any time, and any samples stored in the 
biobank will then be destroyed. 
 
10.6       Subject ID and e-CRF inclusion 
The subject’s social security number (CPR number) will be entered in the e-CRF (REDCap) at the first 
visit. A subject ID will be created, by which the subject will be pseudo-anonymized. An identification 
log containing the name and CPR-number linked to the subject ID will be created in an encrypted file 
in the Trial Master File (TMF). The TMF will be inaccessible to the sponsor or third parties. The 
anonymization can be lifted in case of AEs/SAEs/SUSARs. 
 
10.7       Demography 
The following data will be recorded directly in REDCap: 
• 
Age 
• 
Sex 
• 
Educational background (no. of years) 
 
10.8       Medical history and concomitant disease 
Medical history is a medical event that the subject has experienced in the past. Only medical history 
considered relevant by the Investigator should be reported. 
Concomitant disease is any illness that is present at the start of the trial (i.e at the screening visit or 
found as a result of the screening procedure). 
Smoking status, i.e. current smoking or previous smoking, type of tobacco and number of “pack years” 
(i.e. years of smoking 20 cigarettes daily).  
This will be recorded directly in the e-CRF. 
 

 
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10.9       Concomitant and previous medication 
All medication related to asthma or CRS will be recorded, including medicine the subject is taking 
currently, as well as medication (related to CRS or asthma) including OCS courses within the last year.  
Subjects will be interviewed about their adherence to medication, whereby the e-CFR (REDCap) will 
automatically calculate a Foster-score (Score ranging from 0-7 based on the question: “how many days 
out of a week do you take your medication as it is prescribed?” – the score should be minimum 80%) 
At each visit the Investigator or delegate should ask the subject about use of concomitant medication 
including rescue medication. All concomitant medication and changes hereto must be documented in 
the subject’s medical records and directly in the e-CRF.  
 
10.10     Vital signs and weight 
Blood pressure (BP) and pulse will be measured. 
Weight and height will be measured according to local procedures, and BMI automatically calculated. 
This will be recorded directly in the e-CRF. 
 
10.11     Physical Examination 
A physical examination will be performed by a local investigator. 
 
Significant findings that are present at screening must be recorded as medical history in the e-CRF. 
Significant findings found at the following visits, which meet the definition of an AE, must be recorded 
on an AE page in the e-CRF. 
The physical examination includes: 
Examination of the nose and paranasal sinuses including polyp biopsy: 
- 
Basic ENT-examination with inspection of the ears, nasal- and oral cavity, and 
palpation if mandated.  
- 
Test of middle ear pressure (tympanometry). 
- 
Nasal endoscopy with a rigid or flexible endoscope of the nasal cavity 
(preceded by local anaesthesia with lidocaine-adrenaline 2%, if the patient 
wishes it). The examination takes about two minutes, and is slightly 
uncomfortable, but not painful. An assessment of the “nasal polyp score” (NPS) 
will be made: 
• 
The NPS is a score ranging from 0–4 on either side (total score range: 
0–8) with 0 representing no polyps, 1=polyps confined to the middle 
meatus, 2=polyps extending below the inferior border of the middle 
turbinate, 3=polyps extending beyond the middle meatus, i.e. either 
inferiorly below the lower border  of the middle turbinate to the lower 
border of the inferior turbinate, or in the anterior/posterior direction 
beyond the (normal) placement of the middle turbinate and/or medial 
to the middle turbinate, and 4=complete obstruction of the nasal cavity.  
- 
Polyp biopsy (approximate size 0.5x0.5x0.5 cm) with small forceps under 
direct vision from the endoscope. This too can be somewhat uncomfortable to 
some subjects, however not painful. There can be a small bleeding, which 
usually subsides spontaneously. If not, they are easily controlled by 
compression for a few minutes with a cotton swap. Polyp tissue will be 

 
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microscopically analysed for eosinophilic cell count in accordance with 
EPOS2020 guidelines (8).  
*Polyp tissue might be further analysed for specific biomarkers via flow-
cytometry or another assay testing (TBD).   
- 
Sniff’n Sticks-evaluation Identification test 16 (SSIT-16): The sense of smell 
will be evaluated using identification test 16 (Sniffin’ Sticks® Burghartt, 
Germany) (36). The test consists of 16 odour pens with household odours 
(orange, cinnamon, garlic, etc.). The patient must identify the odour by a forced 
multiple-choice of four written descriptors. The maximum score of the test is 
16 points. A score 0-8 indicates anosmia, a score between 9 and 11 indicates 
hyposmia, and a score >11 indicates normosmia.  
 
Lung examination and asthma provocation tests: 
- 
Lung auscultation with a stethoscope 
- 
Pulmonary function test: Lung function will be measured with the usual 
spirometer. The expected values (% pred) will be calculated from reference 
values for healthy Caucasian adults. In the case of airway obstruction, with a 
FEV1/FVC ratio less than 70%, a reversibility test will be performed after 
inhalation of four puffs of salbutamol. An increase of 200 mL and 12% is 
diagnostic for asthma.  
- 
Asthma-provocation test (Methacholine or mannitol challenge): Patients 
with an FEV1% pred < 60% will be excluded from the airway 
hyperresponsiveness (AHR) test (at baseline). Inhalation of methacholine will 
be done from 0 to 8.0 microg. The test is positive if there is a 20% or more 
decrease in lung function (PD20) from baseline. The inhalation of mannitol 
capsules from 0 to 635 mg will be performed in a standardised stepwise 
method. The test is positive if lung function drops 15% or more from baseline 
(PD15, mannitol) and 20% from baseline (PD20, methacholine), depending on 
the bronchial challenge agent. The two tests will be done on two different days 
or, if possible, on the same day with mannitol first followed by methacholine 
(37). The dose-response ratio will be calculated for all patients (38). 
Withholding of medication prior to provocation will be carried out (ICS/LABA 
24 hours, UltraLABA 48 hours, ICS 12 hours, SABA and SAMA 6 hours and 
LAMA 48 hours). 
- 
FeNO (fractional expired nitrous oxide). The FeNO level will be measured 
before spirometry (NIOX VERO or MINOR; Circassia UK). The patient will be 
instructed to inhale NO-free air to total lung capacity and immediately exhale 
fully into the device, keeping a steady flow rate of 50 ml/s. It usually takes 1–2 
minutes and is not uncomfortable.  
 
Additional tests: 
CT scan of the paranasal sinuses: Will be carried out with enrolment in the 
study, unless one was already performed within the previous three months. 
Furthermore, the CT scan will be repeated at 24 weeks if a patient crosses over 
to the other treatment arm. A CT scan involves a low dose of radiation. The risk 
of radiation-induced damages are low due to modern technology. The first CT 
scan of the sinuses will be part of the routine assessment of these patients. 
Females will undergo a pregnancy test prior to the CT scan. All patients will 

 
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give informed consent, here with an emphasis on the additional yet small dose 
of radiation from the CT scans (<2 mSv).  
CT scans will be scored in accordance with the Lund-Mackey score, see below.  
• 
The Lund-Mackey score is a widely used radiologic reference for 
staging CRS (39). By assigning a score ranging from 0=no opacification 
to 2=complete opacification, to each of the six segments; frontal sinus, 
anterior ethmoid cells, posterior ethmoid cells, maxillary sinus, 
sphenoid cells, ostio-meatal complex on either side, a total sum-score of 
0–24 is calculated.  
- 
Allergy test (blood or skin prick): The standard panel of birch (Betula), grass 
(phl. praetense), mugwort, dog, cat (fel d), house dust mites (Der p1. og Der f2) 
and mould (Alternaria, Cladosporium and aspergillus fumigatus) will be used in 
testing atopy. A positive response can be viewed as a blood IgE measurement > 
0.35 or positive skin prick test. 
- 
Blood samples: Blood will be continuously sampled (4 weeks after starting a 
new treatment, and hereafter at 16 weeks and 24 weeks) as a measure of safety, 
as there is a risk of hypo- or hyper-eosinophilia. On-treatment eosinophil counts 
>3000 cells/μL (3.0 G/L) are to be reported as AEs. Eosinophilia ≥1500 will 
warrant closer observation of eosinophilic blood count, and more frequent blood 
testing (for example every 14 days) will be considered by local investigators 
(doctors).  
 
10.12     Questionnaires 
Questionnaires will be answered digitally, directly in the e-CRF via subjects’ mobile phones. If this is 
not possible the questionnaire will be answered either via a tablet provided by the department, or 
alternatively on a piece of paper, which is subsequently entered in the e-CRF.   
 
Sino-nasal Outcome Test 22 (SNOT-22) (22): The SNOT-22 is a 22-item questionnaire covering aspects 
related to sino-nasal disease and HRQoL. Each item is scored on Likert-scale ranging from 0 (“No 
problem”) to 5 (“Problem as bad as it can be”), thus producing a score ranging from 0 to 110. The 
recall period is two weeks.  A score of up to 8 is normal, 8-20 is mild disease, 21-50 moderate, and >50 
is severe disease. Completion time is about 5–10 minutes.  
 
Visual analogue scales (VAS) asthma/ASA-intolerance/CRS/sense of smell: subjects are asked to place 
a marker on a visual analogue scale, indicating how much they are bothered by their asthma/ASA-
intolerance/chronic rhinosinusitis. The range is from “very much” to “not at all”.  
 
Standard Test for Asthma, Allergic Rhinitis and chronic Rhinosinusitis (STARR-15)(40): The STARR-15 
is newly developed global airways PROM, designed as a screening tool to raise clinicians’ awareness of 
coexisting double (or triple) disease in patients suspected of type 2 inflammation disease. There are 
three disease sub-domains; allergic rhinitis, CRS and asthma. Each of the 15 items are scored on a 3-
point Likert scale ranging from 0=no problem to 2=severe problem. No sum-score is obtained. 
Completion time is about 2 minutes. 
 
Asthma Control Questionnaire (ACQ) (41): The original ACQ evaluation tool contains five patient-
reported items scored on a seven-point Likert scale, with levels of control ranging from 0 (no 
impairment) to 6 (extreme impairment), using the past seven days as a recall period, and with all 
items equally weighted. The remaining two items is one concerning medical use and one is reserved 

 
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for an objective measure of FEV1. A score of ≤1.5 points means well-controlled asthma. Completion 
time is 2–4 minutes.  
 
10.13     Treatment failure 
Treatment failure will be registered if a subject decides to discontinue the trial because of insufficient 
symptom relief. Time of treatment failure will be registered directly in the e-CRF by the investigator or 
a delegate. 
Failure to meet treatment response will not be considered a failure. The subject will be encouraged to 
stay on the treatment until 24 weeks, where they can cross-over. 
As mentioned in section 7.4 subjects will be evaluated for AEs/SAEs four weeks following their last 
treatment injection. 
 
10.14     Electronic medical record (Sundhedsplatformen, EPJ SYD, MidtEPJ, NordEPJ, FMK-
online) 
The electronic medical records will be viewed in the process of recruiting subjects and assessing 
compliance with in- and exclusion criteria. The subjects will have to confirm compliance with these 
criteria prior to starting the trial.  
The subjects are all patients at the departments, so regardless if they participate in the study or not, 
investigators will assess their electronic medical information. 
 
The following data will be obtained from the subject’s electronic medical record and entered in the e-
CRF (REDCap) (if available): 
Prior to enrolment: 
• 
Number of ESS’es and date of latest ESS 
• 
Number of courses with systemic corticosteroids and date of latest course 
• 
Type of INCS and ICS as well as other medication related to treatment of asthma, CRS, atopy, 
allergic rhinitis, and medicine related to eosinophilic, rheumatoid or autoimmune disease. 
• 
Result (Lund-MACKEY score) of CT-scan performed prior to enrolment.  
• 
Pathology report from any pre-existing polyp biopsies. 
• 
Pre-existing diagnosis of relevant chronic disease 
• 
Surgery/out-patient reports from any previous ESS/out-patient visits in the ENT or 
pulmonology department.  
11.       Assessment of Safety 
 
Information about Adverse Events (AEs), whether reported by the subject, discovered by the 
investigator, detected through physical examination, laboratory test or other means, must be collected 
and recorded on the AE form and followed up as appropriate.  
Evaluation of AEs including severity, causality, outcome and seriousness assessments must be 
performed by a physician. 
Any AE occurring from the time of the first IMP injection and until the day of the last control visit 
(week 48or week 50 if the subject has crossed-over) must be recorded and reported on an AE page in 
the e-CRF.  
If the subject discontinues, registration of AEs will continue until 30 days after the last injection.  
Standardized report forms for AEs and SAEs will be provided as part of the e-CRF. 
 

 
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11.1       Definitions – Adverse Event (AE) 
An AE is any unexpected medical occurrence in a subject treated with a medicinal product/device 
even if it does not necessarily have a causal relationship with this treatment. It can be a symptom, 
diagnosis, or a change in a laboratory value or any other measure of health status.  
The following events should not be recorded as AEs: 
• A pre-planned procedure, e.g. a surgical intervention, unless the condition for which the 
procedure was planned has worsened since the informed consent form was signed.   
• Pre-existing conditions documented as medical history. Any worsening in severity or frequency 
of a pre-existing condition during the clinical trial period must be regarded as an AE. 
 
11.2       Definitions – Serious Adverse Event (SAE) / Serious Adverse Reaction (SAR) / Suspected   
Unexpected Serious Adverse Reaction (SUSAR) 
A serious adverse event (SAE)/reaction (SAR) is an AE that at any dose results in any of the following: 
 
• 
Results in death 
• 
Is life-threatening  
• 
Requires hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Leads to a congenital anomaly or birth defect 
• 
Is otherwise medically significant (this refers to an event that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed above). 
 
A suspected unexpected serious adverse reaction (SUSAR) is defined as: 
A SAR that was unexpected based on previous knowledge/experience.  
 
11.3       Assessments of AEs and SAEs/SUSARs 
When assessing AEs and SAEs/SUSARs the investigator will refer to the product resumés (24,25) 
 
Severity: 
The severity of an AE/SAE is a clinical observation assessed by the investigator using the following 
definitions: 
• 
Mild: Transient symptoms, not interfering with the subject’s daily activities 
• 
Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
• 
Severe: Considerable interference with the subject’s daily activities, unacceptable 
Potential AEs/SAEs will be treated according to standard practice and if relevant follow-ups will be 
scheduled with relevant specialists. 
 
Causality / Causal Relationship to IMP: 
The following terms and definitions are used when assessing the relationship between an AE/SAE and 
the relevant trial product (IMP): 
 
• 
Probable: good reason for sufficient documentation to assume a causal relationship 
• 
Possible: a causal relationship is conceivable and cannot be dismissed 

 
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• 
Unlikely: the event is most likely related to an etiology other than the trial product 
 
Final outcome: 
The outcome of an AE/SAE is assessed by the investigator using the following definitions: 
 
• 
Recovered/resolved: Fully recovered or has returned to baseline 
• 
Recovered with sequelae: As a result of the AE the subject suffered persistent and significant 
disability/incapacity 
• 
Not recovered: The condition has not returned to baseline, however symptoms may have 
improved 
• 
Fatal: Event that results in death – An AE with fatal outcome must be reported as an SAE 
• 
Unknown: The outcome is unknown. This term should only be used when no other definition is 
possible e.g. the subject is lost to follow-up 
 
11.4       Reporting 
SAEs/SARs/SUSARs will be reported the e-CRF and reviewed by the sponsor. In case of IT 
breakdown/power shortages/other emergencies, printed versions of the SAE form will be available at 
all study sites. 
Both the sponsor and the primary investigator must be notified of SAE/SAR/SUSARs via e-mail or 
phone within 24 hours: 
 
Sponsor: 
Email address: 
Primary investigator: 
Christian von Buchwald 
Christian.von.buchwald@regionh.dk 
Christian K. Pedersen 
Email address: 
Christian.korsgaard.pedersen.01@regionh.dk 
Emergency phone: 
(+45) 25 30 11 86 
 
Serious Adverse Events:  
SAEs must be reported to the above-mentioned persons immediately (within 24 hours of awareness). 
Any follow-up data must be detailed in a subsequent SAE form in due time. 
The initial SAE report must contain as much information as possible including relevant information 
from the e-CRF (e.g., medical history, concomitant medication) and must be provided via the e-CRF 
system. If the reporter does not have access to the e-CRF, e-mail may be used.  
The SAE report will remain open as long as the trial is active. Should new relevant data on the event 
emerge, a follow-up report will be sent. 
 
Suspected unexpected serious adverse reaction (SUSAR): 
Definition: An unexpected serious adverse reaction where source or severity is not consistent with 
information in the current Summary of Product Characteristics (SmPC). 
 
It is the responsibility of the Sponsor to determine whether a reported SAE is a SAR and whether a 
SAR is a SUSAR. A SUSAR resulting in death or life threatening must be reported within 7 days after the 
Sponsor becomes aware of the reaction. Within 8 days after reporting, the sponsor must enter the 

 
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information in the EudraVigilance-database. Any other SUSAR must be reported to the above-
mentioned agencies within 15 days after the Sponsor becomes aware the reaction. SUSARs must also 
be reported to all local investigators on all study sites. 
 
Pregnancy  
• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor and/or primary investigator within 24 hours of 
learning about the pregnancy. Although pregnancy itself is not considered an AE/SAE/SUSAR, 
any pregnancy complication or elective termination of a pregnancy for medical reasons will be 
reported as an SAE/SUSAR 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such.  
• 
The participants will be followed up to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and neonate, and the 
information will be forwarded to the sponsor. 
 
11.5       Annual reporting 
The Sponsor is responsible for creating an annual subject safety report and list of SARs and submit it 
in the EUclinicaltrials database (CTIS) as well as to all local investigators on the involved study sites. 
The sponsor is responsible for notifying the EMA, the Danish Health authorities as well as all local 
investigators in case the safety profile of one of the IMP changes.  
 
12.       Data handling / Data Management 
 
Data will be handled according to the General Data Protection Regulation (EU) 2016/679 (GDPR, or 
“persondataforordningen”).  
The trial e-CFR has been reported to ‘Datatilsynet’ via the Danish central region’s (Region 
Hovedstaden) data centre (Pactius). Approval is pending. 
 
The trial will be reported to all involved regions ahead of initiating the trial in each region.  
Data will be stored for 25 years, after which they will be transferred to “Dansk Data Arkiv” or deleted 
or anonymized. 
 
12.1       Case Report Form (CRF) 
All data related to the trial will be recorded in an electronic CRF (REDCap) which will thus provide the 
basis for a central database. 
Source data will be recorded and kept for minimum 25 years, as per requirement in Denmark. 
The e-CRF is to be completed by the investigator or a delegate at the time of the subject’s visit to the 
clinic so that it always reflects the latest observations on the subject. 
At the subject’s final visit, the e-CRF should be verified and signed off by the responsible investigator 
or delegate at the site. 
 
12.2       Laboratory Data 
Values from previous blood samples, tissue biopsies, and CT scans will be obtained from the medical 
journal and be entered manually into the e-CRF.  

 
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13.       Statistical evaluation 
 
The primary analysis will consist of a linear mixed effects model taking the full longitudinal design into 
account. The model will be adjusted for olfactory function and site (categorical variable) due to the 
stratified design. Subjects will be included in the intention to treat analysis irrespectively of their 
adherence to the protocol. The treatment effect for the co-primary outcomes will be presented as the 
average difference between the dupilumab and mepolizumab groups in changes in SNOT-22 score and 
NCS from baseline to week 24. These comparisons will be based on the standard errors from the linear 
mixed model. Sensitivity analyses will be performed using multiple imputation where the imputation 
model will include all available baseline variables. 
 
Note: Since this trial investigates two IMPs that have already been proven comparable in effectivity, no 
real control group exists. In the two phase 3 studies (SINUS 24/52 and SYNAPSE) the drop-out rates 
were similar (<10%), and hence, we estimate that the risk of bias due to differences in discontinuation 
rates is low.  
 
Before the randomization code will be added to the cleaned dataset, a prespecified statistical analysis 
plan (SAP) will be elaborated and accepted by the statistician and investigators. 
 
All data will be described including data-incompleteness as well as reasons for data-incompleteness. 
Data will be analyzed blinded by the statistician. Any changes to the statistical analysis plan will be 
described in any future publications. 
 
13.1       Analysis populations 
The primary analyses will be performed on all subjects randomized in the trial (intention to treat). 
Sensitivity analyses will be performed on the per protocol population.  
 
 
14.       End of trial 
Within 15 days after the trial completion (I.e. the last patient’s last visit (LPLV)) the sponsor must 
report the completion of the trial in CTIS. Trial results will be submitted to CTIS within 12 months 
from LPLV (see also section 15.9). 
 
14.1       Early termination of the trial 
The sponsor reserves the right to terminate the trial under the following conditions: 
- 
Safety concerns  
If the trial is prematurely terminated or suspended, the investigator should promptly inform the 
subjects and ensure appropriate therapy and follow-up. Furthermore, the investigator and/or Sponsor 
should promptly inform the pertinent ethics committee and regulatory authorities.  

 
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14.2       Subject Discontinuation 
The subject will be advised in the informed consent form that he/she has the right to withdraw from 
the trial at any time without prejudice. Where discontinuation from the trial is initiated by the subject, 
the investigator is to ascertain the primary reason for discontinuation from the list below: 
 
• 
An AE for which the investigator did not consider discontinuation from the trial necessary 
• 
Co-existing disease 
• 
Withdrawal of consent 
• 
Other reasons including treatment failure 
 
The subject may at any time be discontinued from the trial at the discretion of the investigator. 
 
Subjects must be discontinued from the trial under the following circumstances: 
 
• 
If a criterion equivalent to an exclusion criterion occurs 
• 
If, in the investigator’s opinion, continuation in the trial would be detrimental to the subject’s 
well-being 
• 
Occurrence of intolerable AE(s) as determined by the investigator and/or subject 
• 
Subject lost to follow-up 
• 
If informed consent is withdrawn 
 
In all cases, the primary reason for discontinuation must be recorded in the e-CRF and in the subject’s 
medical records. Follow-up on the subject is necessary to establish whether the reason was an AE. If 
so, this must be reported in accordance with the appropriate procedures. 
As far as possible, all examinations scheduled for the final visit must be performed on subjects who 
receive the IMP but do not complete the trial according to the protocol.  
Data obtained until discontinuation will be entered in the clinical database and used for statistical 
analyses. 
 
15.       Administrative procedures 
 
15.1       Source data and subject data protection 
Source data will be registered in patient records or on source data sheets or directly in the e-CRF. 
 
Prior to start of data recording from subjects, the investigator will prepare a Source Data Location 
Agreement to document where the first recording of data is done.  
As a minimum requirement, the following data must be source data-verifiable in source 
documentation other than the e-CRF: 
▪ Subjects informed consent 
▪ Date of informed consent 
▪ List of randomised subjects 
 

 
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A common e-CRF will be constructed and provide the basis for a central database. Data will in the 
central database will be stored in coded form according to the rules of the Danish Data Protection 
Agency (Datatilsynet) with whom the trial is registered.  
 
In accordance with the Danish Data Protection Agency data processing will be completed within 25 
years of this submission. 
Afterwards, data in paper form will be destroyed and electronic data will be transferred and stored at 
the Danish Data Archives (Statens Arkiver). 
Christian K Pedersen will be responsible for data collection and processing. 
In addition, Christian von Buchwald, Vibeke Backer, Kasper Aanæs, and Tonny Studsgaard Petersen 
will be involved in data processing. 
 
The investigator will have direct access to source data and documents in case of monitoring, auditing 
or inspection from health authorities (Lægemiddelstyrelsen, Videnskabsetisk komité, GCP-enhederne). 
 
15.2       Quality control and assurance 
The trial will be carried out according to the EU Clinical trials regulation (regulation (EU) no. 
536/2014), the protocol, ICH-GCP principles (https://www.ema.europa.eu/en/documents/scientific-
guideline/ich-e-6-r2-guideline-good-clinical-practice-step-5_en.pdf) and current national and 
international law.  Furthermore, it will follow the Declaration of Helsinki.  
Quality control and assurance will be carried out in accordance with ICH-GCP and standard 
procedures will be followed including monitoring, auditing or inspection from health authorities 
(Lægemiddelstyrelsen, Videnskabsetisk Komité, GCP-enhederne). 
 
15.3       Monitoring (Good clinical practice, GCP) 
Regular monitoring visits will be performed according to ICH-GCP. Data will be evaluated for 
compliance with the protocol and accuracy in relation to source documents. The GCP monitor will 
verify that the clinical trial is conducted, and data are generated, documented and reported in 
compliance with the protocol, GCP and the applicable regulatory requirements. 
The local-regional GCP units will conduct the monitoring, regulatory compliance, and review of e-CRFs 
to source documents. The monitoring will be coordinated from the GCP-unit at Bispebjerg-
Frederiksberg University Hospital, Copenhagen, Denmark. It is the responsibility of the Sponsor that 
the trial is monitored. 
 
15.4       Research Biobank 
 
Although permission for a biobank was initially applied for and permission was granted by The Danish 
National Centre for Ethics, the plans to collect samples for a biobank was abandoned. Hence, no 
biobank exists for this trial 
 
15.5       Financing 
The initiative for this trial was taken by the sponsor, investigator and advisors, none of whom have 
any financial interest in the trial. 
Financial support in the form of a salary grant for the principal investigator CKP for the conduct of this 
study has been made to sponsor’s research account at Rigshospitalet (PSP-account F-22214-35) from 
a private non-profit organization (Mauritzen La Fontaine Family Fond). The foundation has donated 
723.000 DKK. This will cover salary expenses for the principal investigator during the first 11 months 

 
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of the trial period. Further applications will be made to cover the full salary expenses during the trial 
period just as an additional application will be made to cover running expenses for the primary 
investigator such as travel expenses, a laptop, admission fee to scientific congresses etc.  
The remaining trial expenses such as salaries of involved physicians and nurses, test and equipment 
costs, laboratory costs, radiology costs, medicine expenses, costs of treatment of possible SAEs etc. are 
all part of standard running costs and will be covered by the relevant involved region belonging to the 
hospital. 
 
15.6       Financial compensation to subjects 
The trials subjects will not be financially compensated for participating in the trial. 
 
15.7       Insurance 
Patients will be covered according to current regulations. Trials in the Danish regions are covered by 
the patient-insurance (Patienterstatningen). 
 
15.8       Ethical Considerations 
Irrespective of the outcome of the trial it will provide useful information on biologic treatment of 
CRSwNP. The result of the trial will thereby provide physicians and patients with new relevant 
information guiding their choice of treatment. To date, no direct comparison between mepolizumab 
and dupilumab exists, and since the treatments are both very costly, however with one being less 
expensive than the other, there is a huge global interest in learning more of cost-effectiveness of these 
new drugs.  
Based on already solid clinical experience with both agents, we consider both treatments safe to use, 
especially in comparison with the best available alternatives (OCS or ESS).  
Both groups will be allowed to ask for corticosteroids as rescue medication so no subjects are 
completely excluded from effective treatment. Furthermore, both treatment arms contain drugs that 
have already proven effective and safe, and they are given in scientifically proven doses and intervals.  
 
15.9       Publication 
The trial is investigator-initiated, and data are owned by Region Hovedstaden. As soon as possible and 
no later than one year after the trial has ended, the trial results will be submitted to the CTIS portal. 
Subsequently, data will be published on clinicaltrialsregister.eu. Furthermore, results will be 
published in an international peer-reviewed scientific journal.  Christian K. Pedersen will draft the first 
manuscript. Christian von Buchwald will be last author. Local investigators who aids in including 
subjects and also contributed in the planning of the trial, or in data analysis or other academic work 
will be offered a co-authorship.   
16.       Reference list 
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dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP 
SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, 
placebo-controlled, parallel-group phase 3 trials. The Lancet. 2019 Nov 2;394(10209):1638–50.  
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%20CRSwNP/DUPILUMAB/medicinra%CC%8Adets-anbefaling-vedr-mepolizumab-til-
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Danish Medicines Council. Medicinrådets opstarts-, monitorerings- og stopkriterier for 
biologiske lægemidler til svær kronisk rhinosinuitis med næsepolypper [Internet]. 2022 Jun. 
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Dansk laegemiddelinformation A/S. Dupilumab (Dupixent) Adverse effects [Internet]. 2022 
[cited 2022 Nov 10]. Available from: https://pro.medicin.dk/Medicin/Praeparater/8524#a060 
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