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

Sponsor

Sanofi (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04684524

Collaborator

Regeneron Pharmaceuticals (Industry)

120

Enrollment

Locations

Arms

45.6

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Primary Objective:

To evaluate the ability of dupilumab to reduce the need for rescue therapy with systemic corticosteroids (SCS) or surgery of AFRS in patients with AFRS who previously have had sino-nasal surgery

Secondary Objectives:

To evaluate the efficacy of treatment with dupilumab to reduce sinus opacification in a population with allergic fungal rhinosinusitis (AFRS)
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 patients 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 patients 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 patients with AFRS
To evaluate the pharmacokinetics (PK) of dupilumab in patients with AFRS
To characterize the effect of dupilumab on total IgE and specific IgE
To assess immunogenicity to dupilumab in patients with AFRS

Condition or Disease	Intervention/Treatment	Phase
Allergic Fungal Rhinosinusitis	Drug: Dupilumab SAR231893 Drug: Placebo	Phase 3

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 IMP intervention period and 12 weeks of follow-up period.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Dec 1, 2020

Anticipated Primary Completion Date :

Jun 28, 2024

Anticipated Study Completion Date :

Sep 20, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dupilumab Dupilumab administered every 2 or 4 weeks based on weights	Drug: Dupilumab SAR231893 Pharmaceutical form:Injection solution Route of administration: Subcutaneous
Placebo Comparator: Matching placebo Placebo administered every 2 or 4 weeks based on weights	Drug: Placebo Pharmaceutical form:Injection solution Route of administration: Subcutaneous

Arm

Intervention/Treatment

Experimental: Dupilumab

Dupilumab administered every 2 or 4 weeks based on weights

Drug: Dupilumab SAR231893

Pharmaceutical form:Injection solution Route of administration: Subcutaneous

Placebo Comparator: Matching placebo

Placebo administered every 2 or 4 weeks based on weights

Drug: Placebo

Pharmaceutical form:Injection solution Route of administration: Subcutaneous

Outcome Measures

Primary Outcome Measures

Proportion of patients who receive SCS and/or undergo/plan to undergo surgery for AFRS during the planned study treatment period [Baseline to Week 52]
Proportion of patients who receive SCS and/or undergo/plan to undergo surgery for AFRS during the planned study treatment period.

Secondary Outcome Measures

Change from baseline in sinus opacifications assessed by computerized tomography (CT) scans using the Lund Mackay (LMK) score at Week 52 [Baseline to 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).
Change from baseline in sinus opacifications assessed by CT scans using the LMK score at Week 24 [Baseline to 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).
Proportion of patients who receive SCS during the planned study treatment period [Baseline to Week 52]
Proportion of patients who undergo or plan to undergo surgery for AFRS during the planned study treatment period [Baseline to Week 52]
Proportion of patients who receive SCS and/or undergo/plan to undergo surgery for AFRS during the planned study treatment period.
Total SCS dose during the planned study treatment [Baseline to Week 52]
Enter Endpoint Secondary
Total number of SCS courses during the planned study treatment [Baseline to Week 52]
Enter Endpoint Secondary
Days with SCS treatment during the planned study treatment [Baseline to Week 52]
Enter Endpoint Secondary
Change from baseline in monthly average nasal congestion/obstruction score from the Nasal symptom Diary at Week 24 and Week 52 [Baseline to Week 24 and Week 52]
The nasal congestion/obstruction scores are scored from 0 ('No symptoms') to 3 ('Severe symptoms').
Change from Baseline in the monthly average anterior/posterior rhinorrhea score from the Nasal Symptom Diary at Week 24 and Week 52 [Baseline to Week 24 and Week 52]
The rhinorrhea scores are scored from 0 ('No symptoms') to 3 ('Severe symptoms').
Change from baseline in endoscopic NPS compared to placebo at Week 24 and Week 52 [Baseline to 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).
Change from baseline in 22-item sino-nasal outcome test (SNOT-22) total score at Week 24 and Week 52 [Baseline to 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.
Change from baseline in monthly average total symptom score (TSS) derived from the Nasal Symptom Diary at Week 24 and Week 52 [Baseline to Week 24 and Week 52]
TSS ranges from 0 to 9. Higher scores on the TSS indicate greater symptom severity.
Change from baseline in visual analog scale (VAS) rhinosinusitis at Week 24 and Week 52 [Baseline to Week 24 and Week 52]
VAS score ranges from 0 ('not troublesome') to 10 ('worst thinkable troublesome').
Change from baseline in University of Pennsylvania smell identification test (UPSIT) at Week 24 and Week 52 [Baseline to Week 24 and Week 52]
The UPSIT score ranges from 0 to 40, with 40 being the best possible score.
Change from baseline in the score of decreased/loss of smell using the Nasal Symptom Diary at Week 24 and Week 52 [Baseline to Week 24 and Week 52]
The decreased/loss of smell scores are scored from 0 ('No symptoms') to 3 ('Severe symptoms').
Change from baseline to Week 52 in three Dimensional CT volumetric measurement of the paranasal sinuses [Baseline to Week 52]
Incidence of treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) through Week 52 [Baseline to Week 64]
Dupilumab concentration in serum over time [Baseline to Week 52]
Percent change from baseline in total IgE in serum compared to placebo over the 52 weeks treatment period [Baseline to Week 52]
Percent change from baseline in fungal-specific IgE in serum compared to placebo over the 52 weeks treatment period [Baseline to Week 52]
Incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab over time [Baseline to Week 64]
Enter Endpoint Secondary

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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,

History of sino-nasal surgery(ies).

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.
Participation in prior dupilumab clinical study or have been treated with commercially available dupilumab. - 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 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number :8400005	Roseville	California	United States	95661
2	Investigational Site Number :8400001	Tampa	Florida	United States	33613
3	Investigational Site Number :8400009	Atlanta	Georgia	United States	30308
4	Investigational Site Number :8400004	Louisville	Kentucky	United States	40220
5	Investigational Site Number :8400002	Charleston	South Carolina	United States	29407
6	Investigational Site Number :8400013	Nashville	Tennessee	United States	37232
7	Investigational Site Number :8400010	Houston	Texas	United States	77030
8	Investigational Site Number :8400008	Norfolk	Virginia	United States	23507
9	Investigational Site Number :0320003	Caba	Buenos Aires	Argentina	C1414AIF
10	Investigational Site Number :0320001	Caba	Buenos Aires	Argentina	C1425BEN
11	Investigational Site Number :0320005	Rosario	Santa Fe	Argentina	2000
12	Investigational Site Number :0320002	Buenos Aires		Argentina	C1121ABE
13	Investigational Site Number :0320004	Mendoza		Argentina	5500
14	Investigational Site Number :1560005	Beijing		China	100050
15	Investigational Site Number :1560001	Beijing		China	100730
16	Investigational Site Number :1560004	Changsha		China	410013
17	Investigational Site Number :1560003	Chengdu		China	610041
18	Investigational Site Number :1560013	Fuzhou		China	350005
19	Investigational Site Number :1560010	Haikou		China	570311
20	Investigational Site Number :1560006	Hangzhou		China	310003
21	Investigational Site Number :1560012	Hefei		China
22	Investigational Site Number :1560002	Nanjing		China	210029
23	Investigational Site Number :1560011	Qingdao		China	266555
24	Investigational Site Number :1560009	Shanghai		China	200030
25	Investigational Site Number :1560008	Taiyuan		China	030001
26	Investigational Site Number :3760001	Petah-Tikva		Israel	49100
27	Investigational Site Number :3760002	Rehovot		Israel	76100
28	Investigational Site Number :3920005	Narita-shi	Chiba	Japan	286-8520
29	Investigational Site Number :3920006	Shizuoka-shi	Shizuoka	Japan	420-0853
30	Investigational Site Number :3920008	Bunkyo-ku	Tokyo	Japan	113-8431
31	Investigational Site Number :3920007	Bunkyo-ku	Tokyo	Japan	113-8603
32	Investigational Site Number :3920001	Meguro-ku	Tokyo	Japan	153-8515
33	Investigational Site Number :3920004	Ota-ku	Tokyo	Japan	143-8541
34	Investigational Site Number :3920003	Shinagawa-ku	Tokyo	Japan	141-0001
35	Investigational Site Number :7920004	Adana		Turkey	01380
36	Investigational Site Number :7920001	Istanbul		Turkey	34093
37	Investigational Site Number :7920002	Istanbul		Turkey	34764
38	Investigational Site Number :7920006	Izmir		Turkey	35100
39	Investigational Site Number :7920003	Izmir		Turkey	35340
40	Investigational Site Number :7920005	Malatya		Turkey	44280

Sponsors and Collaborators

Sanofi
Regeneron Pharmaceuticals

Investigators

Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

EFC16724 Allergic Fungal Rhinosinusitis website

Publications

None provided.

Responsible Party:

Sanofi

ClinicalTrials.gov Identifier:

NCT04684524

Other Study ID Numbers:

EFC16724
2020-002999-12
U1111-1246-7549

First Posted:

Dec 24, 2020

Last Update Posted:

Jul 13, 2022

Last Verified:

Jul 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Yes

Additional relevant MeSH terms:

Sinusitis

Study Results

No Results Posted as of Jul 13, 2022