Clinical trial NCT04684524: Dupilumab in Allergic Fungal Rhinosinusitis (AFRS) (LIBERTY-AFRS-AI)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Allergic Fungal Rhinosinusitis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Regeneron Pharmaceuticals
First posted: 2020-12-24
Enrollment: 62
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change from baseline in sinus opacifications assessed by computerized tomography (CT) scans using the Lund Mackay (LMK) score at Week 52
timeFrame: Baseline to Week 52
Secondary outcomes:
measure: Change from baseline in sinus opacifications assessed by CT scans using the LMK score at Week 24
timeFrame: Baseline to Week 24
measure: Proportion of patients who receive systemic corticosteroids (SCS) and/or undergo/plan to undergo surgery for AFRS during the planned study treatment period
timeFrame: Baseline to Week 52
measure: Change from baseline in monthly average nasal congestion/obstruction score from the Nasal symptom Diary at Week 24 and Week 52
timeFrame: Baseline to Week 24 and Week 52
measure: Change from Baseline in the monthly average anterior/posterior rhinorrhea score from the Nasal Symptom Diary at Week 24 and Week 52
timeFrame: Baseline to Week 24 and Week 52
measure: Change from baseline in endoscopic NPS compared to placebo at Week 24 and Week 52
timeFrame: Baseline to Week 24 and Week 52
measure: Change from baseline in 22-item sino-nasal outcome test (SNOT-22) total score at Week 24 and Week 52
timeFrame: Baseline to Week 24 and Week 52
measure: Change from baseline in monthly average total symptom score (TSS) derived from the Nasal Symptom Diary at Week 24 and Week 52
timeFrame: Baseline to Week 24 and Week 52
measure: Change from baseline in visual analog scale (VAS) rhinosinusitis at Week 24 and Week 52
timeFrame: Baseline to Week 24 and Week 52
measure: Change from baseline in University of Pennsylvania smell identification test (UPSIT) at Week 24 and Week 52
timeFrame: Baseline to Week 24 and Week 52
measure: Change from baseline in the score of decreased/loss of smell using the Nasal Symptom Diary at Week 24 and Week 52
timeFrame: Baseline to Week 24 and Week 52
measure: Change from baseline to Week 52 in three Dimensional CT volumetric measurement of the paranasal sinuses
timeFrame: Baseline to Week 52
measure: Incidence of treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs)
timeFrame: Baseline to Week 64
measure: Dupilumab concentration in serum over time
timeFrame: Baseline to Week 52
measure: Percent change from baseline in total IgE in serum compared to placebo over the 52 weeks treatment period
timeFrame: Baseline to Week 52
measure: Percent change from baseline in fungal-specific IgE in serum compared to placebo over the 52 weeks treatment period
timeFrame: Baseline to Week 52
measure: Incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab over time
timeFrame: Baseline to Week 64
Other outcomes:
Locations:
city: Tampa
country: United States
facility: Asthma Allergy & Immunology Clinical Research Unit Site Number : 8400001
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital Midtown Campus Site Number : 8400009
state: Georgia
city: Louisville
country: United States
facility: Advanced ENT and Allergy Site Number : 8400004
state: Kentucky
city: Mandeville
country: United States
facility: South Louisiana Ear, Nose, Throat and Facial Plastic Surgery Site Number : 8400019
state: Louisiana
city: Charleston
country: United States
facility: National Allergy and Asthma Research, LLC Site Number : 8400002
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center Site Number : 8400013
state: Tennessee
city: Beaumont
country: United States
facility: REX Clinical Trials Site Number : 8400017
state: Texas
city: Houston
country: United States
facility: Ut- Houston Medical School Site Number : 8400010
state: Texas
city: San Antonio
country: United States
facility: USA Clinical Trials Site Number : 8400020
state: Texas
city: San Antonio
country: United States
facility: Alamo ENT Associates Site Number : 8400018
state: Texas
city: Norfolk
country: United States
facility: Eastern Virginia Medical School (EVMS) Medical Group - Otola Site Number : 8400008
state: Virginia
city: Caba
country: Argentina
facility: Investigational Site Number : 0320003
state: Buenos Aires
city: Caba
country: Argentina
facility: Investigational Site Number : 0320001
state: Buenos Aires
city: Rosario
country: Argentina
facility: Investigational Site Number : 0320005
state: Santa Fe
city: Buenos Aires
country: Argentina
facility: Investigational Site Number : 0320002
city: Mendoza
country: Argentina
facility: Investigational Site Number : 0320004
city: Vancouver
country: Canada
facility: Investigational Site Number : 1240001
state: British Columbia
city: Beijing
country: China
facility: Investigational Site Number : 1560005
city: Beijing
country: China
facility: Investigational Site Number : 1560001
city: Changsha
country: China
facility: Investigational Site Number : 1560004
city: Chengdu
country: China
facility: Investigational Site Number : 1560003
city: Fuzhou
country: China
facility: Investigational Site Number : 1560013
city: Hangzhou
country: China
facility: Investigational Site Number : 1560006
city: Hefei
country: China
facility: Investigational Site Number : 1560012
city: Nanjing
country: China
facility: Investigational Site Number : 1560002
city: Qingdao
country: China
facility: Investigational Site Number : 1560011
city: Shanghai
country: China
facility: Investigational Site Number : 1560009
city: Taiyuan
country: China
facility: Investigational Site Number : 1560008
city: Coimbatore
country: India
facility: Investigational Site Number : 3560003
city: Jodhpur
country: India
facility: Investigational Site Number : 3560006
city: New Delhi
country: India
facility: Investigational Site Number : 3560008
city: Petah-Tikva
country: Israel
facility: Investigational Site Number : 3760001
city: Rehovot
country: Israel
facility: Investigational Site Number : 3760002
city: Isehara
country: Japan
facility: Investigational Site Number : 3920010
state: Kanagawa
city: Shizuoka-shi
country: Japan
facility: Investigational Site Number : 3920006
state: Shizuoka
city: Bunkyo-ku
country: Japan
facility: Investigational Site Number : 3920008
state: Tokyo
city: Meguro-ku
country: Japan
facility: Investigational Site Number : 3920001
state: Tokyo
city: Shinagawa-ku
country: Japan
facility: Investigational Site Number : 3920003
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Investigational Site Number : 3920009
state: Tokyo
city: Riyadh
country: Saudi Arabia
facility: Investigational Site Number : 6820002
city: Riyadh
country: Saudi Arabia
facility: Investigational Site Number : 6820001
city: Adana
country: Turkey
facility: Investigational Site Number : 7920004
city: Istanbul
country: Turkey
facility: Investigational Site Number : 7920001
city: Istanbul
country: Turkey
facility: Investigational Site Number : 7920007
city: Izmir
country: Turkey
facility: Investigational Site Number : 7920006
city: Izmir
country: Turkey
facility: Investigational Site Number : 7920003
city: Malatya
country: Turkey
facility: Investigational Site Number : 7920005
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: