Dupilumab in Allergic Fungal Rhinosinusitis (AFRS) (LIBERTY-AFRS-AI)

Allergic Fungal Rhinosinusitis Clinical Trial

Official title:

A Randomized Double-blind Placebo-controlled Parallel Group Study Assessing the Efficacy and Safety of Dupilumab in Patients With Allergic Fungal Rhinosinusitis (AFRS)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04684524
• Other study ID #: EFC16724
• Secondary ID: U1111-1246-75492
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: December 1, 2020
• Est. completion date: March 4, 2025

Study information

• Verified date: February 2024
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Primary Objective:

• To evaluate the efficacy of treatment with dupilumab to reduce sinus opacification in a population with allergic fungal rhinosinusitis (AFRS)

Secondary Objectives:

• To evaluate the efficacy of treatment with dupilumab to reduce sinus opacification in a population with allergic fungal rhinosinusitis (AFRS) at Week 24

• To assess the efficacy of dupilumab to reduce the need for rescue treatments

• To evaluate the efficacy of treatment with dupilumab in improving symptoms in AFRS

• To evaluate the efficacy of dupilumab to reduce nasal polyp formation in participants with AFRS

• To evaluate the efficacy of dupilumab in improving overall symptom severity and quality of life in AFRS

• To evaluate the efficacy of dupilumab in improving sense of smell in participants with AFRS

• To explore the effect of dupilumab as assessed by three-Dimensional CT volumetric measurement of the paranasal sinuses

• To evaluate the safety and tolerability of dupilumab when administered to participants with AFRS

• To evaluate the pharmacokinetics (PK) of dupilumab in participants with AFRS

• To characterize the effect of dupilumab on total IgE and specific IgE

• To assess immunogenicity to dupilumab in participants with AFRS

Description:

The duration of study for each participant will include 2-4 weeks of screening period (2 additional weeks could be allowed), 52 weeks of randomized investigational medicinal product (IMP) intervention period and 12 weeks of follow-up period.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 62
• Est. completion date: March 4, 2025
• Est. primary completion date: December 10, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 6 Years and older

Eligibility

Inclusion Criteria:

Participant must be at least 6 years of age (or the minimum legal age for adolescents in the country of the investigational site) at the time of signing the informed consent.

Participants with the diagnosis of AFRS adapted from criteria by Bent and Kuhn (meeting all):

• IgE mediated inflammatory response to fungal hyphae (specific IgE serology or skin test) Evidence of sensitization to fungus by skin testing (at screening or documented historical positive skin test in the previous 12 months), or positive fungal-specific IgE in serum at screening.

• Nasal polyposis confirmed by nasal endoscopy at screening.

• Characteristic CT signs to be performed during screening period and can include any of the below signs as assessed by central reader:

• hyperdensities

• bony demineralization

• bone erosion of sinus

• Eosinophilic mucin/mucus identified within 5 years prior to screening or at screening with or without positive fungal stain

AFRS patients with the following:

• An endoscopic NPS of at least 2 out of 4 for unilateral polyps or 3 out of 8 for bilateral polyps at Visit 1 (central reading) and Visit 2 (local reading) and,

• Sinus opacification in CT scan with an LMK score of 9 for patients with unilateral polyps or 12 for patients with bilateral polyps during screening period and,

Body weight =15 kg

Exclusion Criteria:

• Patients with nasal conditions/concomitant nasal diseases making them non-evaluable at Visit 1 or for the primary efficacy

• Nasal cavity malignant tumor and benign tumors.

• Known of fungal invasion into sinus tissue.

• Severe concomitant illness(es) that, in the investigator's judgment, would adversely affect the patient's participation in the study

• Active tuberculosis or non-tuberculous mycobacterial infection, or a history of incompletely treated tuberculosis unless documented adequately treated.

• Diagnosed active endoparasitic infections; suspected or high risk of endoparasitic infection

• Known or suspected immunodeficiency

• Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or antifungals within 2 weeks before the Screening Visit 1 or during the screening period.

• History of systemic hypersensitivity or anaphylaxis to dupilumab or any of its excipients.

• Treatment with commercially available dupilumab within 12 months, participation in prior dupilumab clinical trial, or discontinued dupilumab use due to adverse event.

• Patients who are treated with intranasal corticosteroid drops; intranasal steroid emitting devices/stents; nasal spray using exhalation delivery system, such as Xhance™, during screening period.

• Patients who are on intranasal corticosteroids (INCS) spray unless they have received stable dose for at least 4 weeks prior to Visit 1.

• Patients who have undergone sinus intranasal surgery (including polypectomy) within 6 months prior to Visit 1.

• Patients who have taken:

• Biologic therapy/systemic immunosuppressant to treat inflammatory disease or autoimmune disease within 5 half-lives prior to Visit 1

• Any investigational mAb within 5 half-lives prior to Visit 1

• Anti-IgE therapy (omalizumab) within 4 months prior to Visit 1. - Treatment with a live (attenuated) vaccine within 4 weeks prior to Visit 1

• Leukotriene antagonists/modifiers unless patient is on a continuous treatment for at least 30 days prior to Visit 1.

• Initiation of allergen immunotherapy within 3 months prior to Visit 1 or a plan to begin therapy or change its dose during the screening or treatment period. - Patients received SCS during screening period. - Either intravenous immunoglobulin therapy and/or plasmapheresis within 30 days prior to Screening Visit (Visit 1).

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Related Conditions & MeSH terms

• Allergic Fungal Rhinosinusitis
• Allergic Fungal Sinusitis
• Sinusitis

Intervention

Drug:
• Dupilumab SAR231893
Pharmaceutical form:Injection solution Route of administration: Subcutaneous
• Placebo
Pharmaceutical form:Injection solution Route of administration: Subcutaneous

Locations

Country	Name	City	State
Argentina	Investigational Site Number : 0320002	Buenos Aires
Argentina	Investigational Site Number : 0320001	Caba	Buenos Aires
Argentina	Investigational Site Number : 0320003	Caba	Buenos Aires
Argentina	Investigational Site Number : 0320004	Mendoza
Argentina	Investigational Site Number : 0320005	Rosario	Santa Fe
Canada	Investigational Site Number : 1240001	Vancouver	British Columbia
China	Investigational Site Number : 1560001	Beijing
China	Investigational Site Number : 1560005	Beijing
China	Investigational Site Number : 1560004	Changsha
China	Investigational Site Number : 1560003	Chengdu
China	Investigational Site Number : 1560013	Fuzhou
China	Investigational Site Number : 1560006	Hangzhou
China	Investigational Site Number : 1560012	Hefei
China	Investigational Site Number : 1560002	Nanjing
China	Investigational Site Number : 1560011	Qingdao
China	Investigational Site Number : 1560009	Shanghai
China	Investigational Site Number : 1560008	Taiyuan
India	Investigational Site Number : 3560003	Coimbatore
India	Investigational Site Number : 3560006	Jodhpur
India	Investigational Site Number : 3560008	New Delhi
Israel	Investigational Site Number : 3760001	Petah-Tikva
Israel	Investigational Site Number : 3760002	Rehovot
Japan	Investigational Site Number : 3920008	Bunkyo-ku	Tokyo
Japan	Investigational Site Number : 3920010	Isehara	Kanagawa
Japan	Investigational Site Number : 3920001	Meguro-ku	Tokyo
Japan	Investigational Site Number : 3920003	Shinagawa-ku	Tokyo
Japan	Investigational Site Number : 3920009	Shinjuku-ku	Tokyo
Japan	Investigational Site Number : 3920006	Shizuoka-shi	Shizuoka
Saudi Arabia	Investigational Site Number : 6820001	Riyadh
Saudi Arabia	Investigational Site Number : 6820002	Riyadh
Turkey	Investigational Site Number : 7920004	Adana
Turkey	Investigational Site Number : 7920001	Istanbul
Turkey	Investigational Site Number : 7920007	Istanbul
Turkey	Investigational Site Number : 7920003	Izmir
Turkey	Investigational Site Number : 7920006	Izmir
Turkey	Investigational Site Number : 7920005	Malatya
United States	Emory University Hospital Midtown Campus Site Number : 8400009	Atlanta	Georgia
United States	REX Clinical Trials Site Number : 8400017	Beaumont	Texas
United States	National Allergy and Asthma Research, LLC Site Number : 8400002	Charleston	South Carolina
United States	Ut- Houston Medical School Site Number : 8400010	Houston	Texas
United States	Advanced ENT and Allergy Site Number : 8400004	Louisville	Kentucky
United States	South Louisiana Ear, Nose, Throat and Facial Plastic Surgery Site Number : 8400019	Mandeville	Louisiana
United States	Vanderbilt University Medical Center Site Number : 8400013	Nashville	Tennessee
United States	Eastern Virginia Medical School (EVMS) Medical Group - Otola Site Number : 8400008	Norfolk	Virginia
United States	Alamo ENT Associates Site Number : 8400018	San Antonio	Texas
United States	USA Clinical Trials Site Number : 8400020	San Antonio	Texas
United States	Asthma Allergy & Immunology Clinical Research Unit Site Number : 8400001	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	Regeneron Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Canada,  China,  India,  Israel,  Japan,  Saudi Arabia,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in sinus opacifications assessed by computerized tomography (CT) scans using the Lund Mackay (LMK) score at Week 52	LMK total score is based on assessment of the CT scan findings for each sinus area. The extent of opacification is rated between 0 (normal) to 24 (total opacification).	Baseline to Week 52
Secondary	Change from baseline in sinus opacifications assessed by CT scans using the LMK score at Week 24	LMK total score is based on assessment of the CT scan findings for each sinus area. The extent of opacification is rated between 0 (normal) to 24 (total opacification).	Baseline to Week 24
Secondary	Proportion of patients who receive systemic corticosteroids (SCS) and/or undergo/plan to undergo surgery for AFRS during the planned study treatment period		Baseline to Week 52
Secondary	Change from baseline in monthly average nasal congestion/obstruction score from the Nasal symptom Diary at Week 24 and Week 52	The nasal congestion/obstruction scores are scored from 0 ('No symptoms') to 3 ('Severe symptoms').	Baseline to Week 24 and Week 52
Secondary	Change from Baseline in the monthly average anterior/posterior rhinorrhea score from the Nasal Symptom Diary at Week 24 and Week 52	The rhinorrhea scores are scored from 0 ('No symptoms') to 3 ('Severe symptoms').	Baseline to Week 24 and Week 52
Secondary	Change from baseline in endoscopic NPS compared to placebo at Week 24 and Week 52	The total nasal polyps score (NPS) is the sum of the right and left nostrils, ranging from 0 (no polyps) to 8 (large polyps causing complete obstruction).	Baseline to Week 24 and Week 52
Secondary	Change from baseline in 22-item sino-nasal outcome test (SNOT-22) total score at Week 24 and Week 52	SNOT-22 is a patient-reported outcome (PRO) questionnaire. Score ranges from 0 to 110 with higher score indicating greater rhinosinusitis related health burden.	Baseline to Week 24 and Week 52
Secondary	Change from baseline in monthly average total symptom score (TSS) derived from the Nasal Symptom Diary at Week 24 and Week 52	TSS ranges from 0 to 9. Higher scores on the TSS indicate greater symptom severity.	Baseline to Week 24 and Week 52
Secondary	Change from baseline in visual analog scale (VAS) rhinosinusitis at Week 24 and Week 52	VAS score ranges from 0 ('not troublesome') to 10 ('worst thinkable troublesome').	Baseline to Week 24 and Week 52
Secondary	Change from baseline in University of Pennsylvania smell identification test (UPSIT) at Week 24 and Week 52	The UPSIT score ranges from 0 to 40, with 40 being the best possible score.	Baseline to Week 24 and Week 52
Secondary	Change from baseline in the score of decreased/loss of smell using the Nasal Symptom Diary at Week 24 and Week 52	The decreased/loss of smell scores are scored from 0 ('No symptoms') to 3 ('Severe symptoms').	Baseline to Week 24 and Week 52
Secondary	Change from baseline to Week 52 in three Dimensional CT volumetric measurement of the paranasal sinuses		Baseline to Week 52
Secondary	Incidence of treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs)		Baseline to Week 64
Secondary	Dupilumab concentration in serum over time		Baseline to Week 52
Secondary	Percent change from baseline in total IgE in serum compared to placebo over the 52 weeks treatment period		Baseline to Week 52
Secondary	Percent change from baseline in fungal-specific IgE in serum compared to placebo over the 52 weeks treatment period		Baseline to Week 52
Secondary	Incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab over time	Enter Endpoint Secondary	Baseline to Week 64