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

• ClinicalTrials.gov Identifier: NCT04684524
• Recruitment Status: Active, not recruiting
• First Posted: December 24, 2020
• Last Update Posted: February 5, 2024
• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: December 21, 2020
• First Posted Date: December 24, 2020
• Last Update Posted Date: February 5, 2024
• Actual Study Start Date: December 1, 2020
• Estimated Primary Completion Date: December 10, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 11, 2023)

Change from baseline in sinus opacifications assessed by computerized tomography (CT) scans using the Lund Mackay (LMK) score at Week 52 [ Time Frame: 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).

Original Primary Outcome Measures (submitted: December 21, 2020)

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

Proportion of patients who receive SCS and/or undergo/plan to undergo surgery of AFRS during the planned study treatment period.

Current Secondary Outcome Measures (submitted: May 11, 2023)

• Change from baseline in sinus opacifications assessed by CT scans using the LMK score at Week 24 [ Time Frame: 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 systemic corticosteroids (SCS) and/or undergo/plan to undergo surgery for AFRS during the planned study treatment period [ Time Frame: Baseline to Week 52 ]
• Change from baseline in monthly average nasal congestion/obstruction score from the Nasal symptom Diary at Week 24 and Week 52 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline to Week 52 ]
• Incidence of treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) [ Time Frame: Baseline to Week 64 ]
• Dupilumab concentration in serum over time [ Time Frame: Baseline to Week 52 ]
• Percent change from baseline in total IgE in serum compared to placebo over the 52 weeks treatment period [ Time Frame: Baseline to Week 52 ]
• Percent change from baseline in fungal-specific IgE in serum compared to placebo over the 52 weeks treatment period [ Time Frame: Baseline to Week 52 ]
• Incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab over time [ Time Frame: Baseline to Week 64 ]
  Enter Endpoint Secondary

Original Secondary Outcome Measures (submitted: December 21, 2020)

• Change from baseline in sinus opacifications assessed by computerized tomography (CT) scans using the Lund Mackay (LMK) score at Week 52 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline to Week 52 ]
• Proportion of patients who undergo or plan to undergo surgery of AFRS during the planned study treatment period [ Time Frame: Baseline to Week 52 ]
• Total SCS dose during the planned study treatment [ Time Frame: Baseline to Week 52 ]
• Total number of SCS courses during the planned study treatment [ Time Frame: Baseline to Week 52 ]
• Days with SCS treatment during the planned study treatment [ Time Frame: Baseline to Week 52 ]
• Change from baseline in monthly average nasal congestion/obstruction score from the Nasal symptom Diary at Week 24 and Week 52 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) at Week 24 and Week 52 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline to Week 52 ]
• Incidence of treatment-emergent adverse events (TEAEs) or serious adverse events (SAEs) through Week 52 [ Time Frame: Baseline to Week 64 ]
• Dupilumab concentration in serum over time [ Time Frame: Baseline to Week 52 ]
• Percent change from baseline in total IgE in serum compared to placebo over the 52 weeks treatment period [ Time Frame: Baseline to Week 52 ]
• Percent change from baseline in fungal-specific IgE in serum compared to placebo over the 52 weeks treatment period [ Time Frame: Baseline to Week 52 ]
• Incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab over time [ Time Frame: Baseline to Week 64 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)

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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Allergic Fungal Rhinosinusitis

Intervention

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

Study Arms

• Experimental: Dupilumab
  Dupilumab administered every 2 or 4 weeks based on weights
  Intervention: Drug: Dupilumab SAR231893
• Placebo Comparator: Matching placebo
  Placebo administered every 2 or 4 weeks based on weights
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: May 11, 2023): 62
• Original Estimated Enrollment (submitted: December 21, 2020): 120
• Estimated Study Completion Date: March 4, 2025
• Estimated Primary Completion Date: December 10, 2024 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Canada, China, India, Israel, Japan, Saudi Arabia, Turkey, United States

Administrative Information

• NCT Number: NCT04684524
• Other Study ID Numbers: EFC16724; U1111-1246-7549 ( Registry Identifier: ICTRP ); 2020-002999-12 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

• Current Responsible Party: Sanofi
• Original Responsible Party: Same as current
• Current Study Sponsor: Sanofi
• Original Study Sponsor: Same as current
• Collaborators: Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: February 2024