A phase IV, randomized double blinded placebo-controlled study on the barrier restoring capacity of Dupilumab in type 2 airway disease: CRSwNP

Overview

Sponsor-declared trial summary

Key facts

Sponsor

UZ Leuven

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Otorhinolaryngologic Diseases [C09]

Trial duration

14 Nov 2023 → 16 Sep 2025

Decision date (initial)

2023-06-23

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

SANOFI Belgium

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy

To study the effect of 24 weeks of add on therapy with Dupilumab or
placebo to the standard CRS and/or asthma care on tight junction
expression in nasal polyp (NP) tissue and nasal biopsies of patients with
CRSwNP

Secondary objectives 3

1. Investigate the effect of 24 weeks of add on treatment with Dupilumab on type 2 inflammatory markers and markers of remodelling in nasal secretions and in blood
2. Investigate the effect of 24 weeks of add on treatment with Dupilumab on lower airway disease control, FeNO levels and markers of small airways dysfunction (IOS: mainly R5) and non-specific airway hyperresponsiveness.
3. To further explore any correlations between markers of inflammation, remodelling, and pathophysiology.

Conditions and MedDRA coding

chronic rhinosinusitis with nasal polyps

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Voluntary written informed consent of the participant or their legally authorized representative has been obtained prior to any screening procedures.
2. Woman of child bearing potential (WOCBP) (i.e. fertile women, following menarche and until becoming post-menopausal unless permanently sterile) and fertile man (man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy) should use highly effective methods of birth control; defined as those that, alone or in combination, result in low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some IUDs, true sexual abstinence (i.e. refraining from heterosexual intercourse during the entire period of risk associated with the Trial treatment(s)) or commitment to a vasectomised partner. WOCBP and fertile men should practice adequate contraception during the study until 3 months post-study. Postmenopausal women (defined as at least 12 consecutive months with no menses without an alternative medical cause) are not required to use additional contraception.
3. Males and females; age >or =18 years
4. Ability to give reliable information and availability to participate in the study in line with the study protocol (i.e., understanding the language, being available and able to comply with the study related procedures)
5. CRSwNP with a combined NP score of >/=5 out of a maximum score of 8 (with a minimal score of 2 in each nasal cavity) and a SNOT22 score >/=30 out of a maximum of 110 at V1 and V2.
6. Patients need to be on a stable dose of intranasal corticosteroids (INCS) for 4 weeks prescreening (V1).
7. With or without concomitant asthma as defined by the Global Initiative for Asthma (GINA).
8. May not receive any live attenuated vaccines mentioned in appendix 3 within 4 weeks before V1 until V6
9. In case of concomitant asthma participant: a.should be on a stable or as needed doses of inhaled corticosteroids (ICS) for a least 12 weeks prescreening and have a good adherence. b.will be allowed long-acting beta agonist (LABA) as add on or as combination therapy. In case any additional maintenance therapy for asthma is required they can be kept in the study at the discretion of the investigator (while medication (type/dose and dosing) will be documented. c.Need to be willing and be able to comply with the required washout periods before every visit see appendix 5. d.If they take Leukotriene antagonists/modifiers they will only be allowed to join the study if they were on continuous treatment for ≥30 days prior to V1.

Exclusion criteria 23

1. Participant has a history of anaphylaxis to components of the study medication
2. Patients with conditions/concomitant diseases making them non evaluable for the primary endpoint such as: a. Antrochoanal polyps b. Nasal septal deviation that would occlude at least one nostril c. Acute sinusitis, nasal infection, or upper respiratory infection at V1 or in the 2 weeks before V1 d. Ongoing rhinitis medicamentosa e. Churg-Strauss syndrome, Young’s syndrome, Kartagener’s syndrome or dyskinetic ciliary syndromes, Cystic fibrosis f.Signs or a CT scan suggestive of Allergic fungal rhinosinusitis
3. Patients with a change in vision or with a history of increased ocular pressure, glaucoma and/or cataracts.
4. Patients with tuberculosis, any type of untreated infection, or recent surgical operation or injury to the nose or mouth (i.e. within 6 months of screening).
5. Patients using cytochrome P450 3A4 inhibitors (e.g. ritonavir).
6. Patients with a psychiatric, addictive, or any disorder of which the investigators feel that this may compromise the ability to give truly informed consent for participation in this study or provide reliable information on the questionnaire or adherence to study related procedures
7. Known or suspected chronic drug or alcohol abuse. In case of infrequent drug abuse exclusion will be decided at the discretion of the investigators.
8. Patients being enrolled in other clinical trials within the last 3 months or received any existing or experimental biologics that was not discontinued 5 half-lives or 6 months before V1 if the half-life is unknown.
9. Patients that underwent allergen immunotherapy less than 3 months prior to V1.
10. Malignancies (except from insitu basalioma or in situ cervix carcinoma) or any severe comorbidity
11. Smoking (ex-smokers can participate if quit smoking at least 6 months prior to screening and less than 10 packyears)
12. Any disorder, which in the Investigator’s opinion might jeopardise the participant’s safety or compliance with the protocol
13. Usage of medication which according to the investigators is deemed to interfere with the study safety/procedures/medication as listed in section 5.3.2.1 “prohibited concomitant medication”
14. Patient is the Investigator or any Sub-Investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol
15. Any prior or concomitant treatment(s) that might jeopardise the participant’s safety or that would compromise the integrity of the Trial
16. Any technical/administrative reason that makes it impossible to randomize the patient in the study
17. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate, highly effective contraceptive
18. Participation in another interventional Trial with an investigational medicinal product (IMP) or device
19. Recent sinus surgery for CRSwNP, within < 4 months before V1
20. Among patients with co-morbid asthma are excluded if one of the following is met: a.Patients with FEV1 < 60% (of predicted normal) b.Patients with an asthma exacerbation requiring systemic (oral and/or parenteral) steroid treatment or hospitalization for >24h for treatment of asthma, within 3 month prior to screening.
21. Patients with a viral upper or lower airway disease (common cold/flu) may be included at least 3 weeks after the symptoms have subsided.
22. Patients with diagnosed active parasitic infection (helminthes); suspected or high risk of parasitic infection, unless clinical and (if necessary) laboratory assessments have ruled out active infection before randomization.
23. Major deficiencies in live and/or live attenuated immunisation according to local guidelines. It is recommended that patients should be brought up to date with live and live attenuated immunisations before treatment with dupilumab in agreement with current immunisation guidelines. Patients may be rescreened 4 weeks after getting appropriate vaccinations according to local guidelines.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Change in tight junction expression (Occludin, ZO -1, -2, -3 claudin-1, -4, -7) between baseline, 12 weeks and 24 weeks of add-on treatment evaluated with RTq-PCR and with immunohistochemistry (IHC)
2. Look at the change in mucosal explant integrity between baseline, 12 weeks, and 24 weeks of add on treatment with Dupilumab by means of Ussing Chambers.
3. Change in gene expression profiling between baseline, 12 weeks and 24 weeks of add on treatment with Dupilumab by bulk RNA sequencing.

Secondary endpoints 7

1. Change in inflammatory markers in blood: IgE, blood eosinophils, ECP, IL-4, IL-5, IL-13 between baseline 12 weeks and 24 weeks of add on treatment with Dupilumab
2. Change in markers of remodelling in serum: MMP-9, MMP-12, CC-16 between baseline, 12 weeks, and 24 weeks of add on treatment with Dupilumab.
3. Evolution of the following patient reported outcomes (PROs) between baseline and 24 weeks of add on treatment with Dupilumab and the follow up visit. o Visual analogue scale (VAS) o Sino-nasal outcome test-22 (SNOT-22) o University of Pennsylvania smell identification test (UPSIT) o Asthma quality of life questionnaire (AQLQ) o Asthma control questionnaires 6-item version (ACQ-6) o Patients’ global impression of change (PGI-Change)
4. Change in FeNo levels between baseline, 12 weeks, and 24 weeks of add on treatment with Dupilumab.
5. Change in IOS measurements between baseline, 12 weeks, and 24 weeks of add on treatment with Dupilumab
6. Change in histamine challenge test between baseline, 12 weeks, and 24 weeks of add on treatment with Dupilumab.
7. Change in NP score between baseline, 12 weeks and 24 weeks of add on treatment with Dupilumab.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

UZ Leuven

Sponsor organisation

UZ Leuven

Address

Herestraat 49

City

Leuven

Postcode

3000

Country

Belgium

Scientific contact point

Organisation

UZ Leuven

Contact name

An-Sofie Viskens

Public contact point

Organisation

UZ Leuven

Contact name

Elien Borgers

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

2 submissions — initial application plus substantial / non-substantial modifications