Opening the "Black Box" on Tezepelumab's Effect on Chronic Rhinosinusitis With Severe Asthma

The study explores how chronic rhinosinusitis (CRS) and asthma share a common inflammatory process, particularly affecting patients with both conditions. Interaction between immune cells (Interleukins) and Th2 cytokines, such as TSLP, exacerbates asthma control in CRS patients, especially those with nasal polyps (CRSwNP). TSLP plays a pivotal role in initiating and maintaining airway inflammation in both diseases. Tezepelumab, a biologic therapy targeting TSLP, shows promise in reducing inflammation markers in severe asthma but its impact on CRSwNP and quality of life remains unclear. The study proposes investigating Tezepelumab's efficacy in treating CRSwNP and severe asthma to inform future biologic therapies.

Study Overview

• Status: Not yet recruiting
• Conditions: Asthma; Chronic Rhinosinusitis With Nasal Polyps
• Intervention / Treatment: Biological: Tezepelumab

Detailed Description

The investigators hypothesize that TSLP blockade with Tezepelumab will a) reduce upper airway inflammation based on histological, inflammatory, and remodeling biomarkers, that are evident in the airway remodeling process and b) correlate to a positive clinical response. Thus, nasal samples from chronic rhinosinusitis with nasal polyps (CRSwNP) patients with Severe Asthma (SA) pre- and post-treatment will exhibit inflammatory biomarkers and histopathological evidence that could prove responsive to the Tezepelumab.

The overall research objectives are to evaluate the effect of study intervention (Tezepelumab) on CRSwNP-SA outcomes through a) evaluating the sinonasal inflammatory profile, histopathological features, and remodeling biomarkers and b) investigating the impact of Tezepelumab on the CRSwNP-related clinical outcomes in the treated study subjects.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Leonora Beltran; Phone Number: 604-250-4174; Email: lbeltranjimenez@providencehealth.bc.ca
• Study Contact Backup: Name: Andrew Thamboo, MD; Phone Number: 604-250-4174; Email: andrew.thamboo@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Must be ≥19 of age at the time of signing the informed consent form
• Capable of giving signed informed consent.

• Having CRSwNP based on clinical symptoms and/or radiographic or endoscopic evidence of inflammation in their upper airways (Diagnosis consistent with EPOS 2020)(2)and severe asthma:

  • SA based on GINA criteria (37) and confirmed with spirometry and assessmenton the previous history of asthma (a pre-post bronchodilator spirometry ormethacholine challenge to document the positive or negative history of asthmawill be performed if there is no clinical record).
  • Nasal polyp score (NPS) of at least 2 on each side
• Females of childbearing potential must commit using an acceptable method of birthcontrol for the duration of the study and they must have a negative urine pregnancy test ateach study visit
• Not expecting to have surgery within the next 7 months

Exclusion Criteria:

• Have previously undergone sinus surgery or nasal polypectomy
• A history of organ transplantation such as lung transplantation
• Previously or currently using immunomodulator medications or antihistamines
• A history of auto-immune diseases
• Current or past sinonasal or bronchial tumors
• Currently using systemic or oral corticosteroids
• Women who are pregnant, plan to become pregnant, or breastfeed during the trial
• Current participation in any other interventional treatment trials
• Compliance: is unlikely to comply with study visits based on investigator judgment:
• Diagnosed or suspected malignant or premalignant nasal disease (e.g. SchniderianPapilloma, unilateral nasal polyposis)
• Fungal rhinosinusitis (CT/Histology), positive Aspergillus skin prick testing and/orpositive Aspergillus IgE RAST (Radioallergosorbent) testing
• Malignant neoplasm within 5 years (from screening) excluding basal cell or squamouscell carcinoma of the skin treated with local resection only or carcinoma in situ of the uterinecervix treated locally and without metastatic disease for 3 years.
• Active bleeding disorders, and/or inability to support interruption to anticoagulant or anti-platelet therapies for nasal biopsy.
• Severe nasal deformity precluding endoscopic assessment/biopsy of postnasal space

• Have an acute or chronic infection (excluding that related to CRS) requiring managementas follows:

  • Currently on any treatment for a chronic infection such as pneumocystis,cytomegalovirus, herpes simplex virus, herpes zoster, or atypical mycobacteria
  • Hospitalisation solely for the treatment of proven infection requiring parenteral (IV orIM) antibiotics (antibacterial, antiviral, antifungal, or anti-parasitic agents) within 60days of Day 1
  • Proven severe infection requiring outpatient treatment with parenteral (IV or IM)antibiotics (antibacterial, antiviral, antifungal, or anti-parasitic agents) within 60 daysof Day 1. Prophylactic anti-infective treatment is allowed.
• Known positive human immunodeficiency virus (HIV) status
• Known positive Hepatitis B (HB) or Hepatitis C status
• Have clinical evidence of significant unstable or uncontrolled acute or chronic diseaseswhich, in the opinion of the principal investigator, could confound the results of the study orput the participant at undue risk
• Have a planned surgical procedure, laboratory abnormality, or condition that, in theopinion of the principal investigator, makes the participant unsuitable for the study.
• Have received any investigational agent (that is not approved for sale in Canada) within60 days of Day 1
• Smoking history; current or former smokers with a smoke history of packs year >15
• Subjects with parasitic (helminthic) infection
• Subjects with hypersensitivity; with allergy/intolerance to a monoclonal antibody or biologics
• Subjects allergic to Aspirin (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tezepelumab; Tezepelumab 210 mg subcutaneous injection every 4 weeks to all 10 participants	Biological: Tezepelumab; 10 patients will receive teszpire; Other Names: Teszpire

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Eosinophil Count	Measurement of eosinophil count in tissue samples. Cells per high power field (HPF) or cells per millimeter squared (cells/mm²).	From baseline to 24 weeks
Neutrophil count	Measurement of neutrophil count in tissue samples. Cells per high power field (HPF) or cells per millimeter squared (cells/mm²).	From baseline to 24 weeks.
Basement Membrane Thickness	Measurement of the thickness of the basement membrane in tissue samples. Micrometers (µm)	From baseline to 24 weeks
Fibrosis	Assessment of the extent of fibrosis in tissue samples, which may involve scoring systems or quantitative measurements	From baseline to 24 weeks
Squamous Metaplasia	Immunohistochemical staining will be used to identify the presence of squamous metaplasia, with scoring based on percentage of positive cells.	From baseline to 24 weeks
Lymphocytic Proliferation	Lymphocytic proliferation will be assessed using immunohistochemistry (IHC) to measure the Ki-67 proliferation index in tissue samples, specifically identifying the percentage of Ki-67-positive lymphocytes	From baseline to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunoglobulin leves	IgE, IgG, IgA,	24 weeks
Th2 Cytokines	Measurement of Th2 cytokines such as IL-4, IL-5, IL-13	24 weeks
Th1/Th17 Cytokines	Measurement of Th1/Th17 cytokines such as IFN-γ and IL-17.	24 weeks
Myeloperoxidase (MPO)	Measurement of MPO levels in sinonasal samples or serum.	24 weeks
Interferon-γ (IFN-γ)	Measurement of IFN-γ levels in sinonasal samples or serum.	24 weeks
SNOT-22 (Sino-Nasal Outcome Test 22-item)	Assessment of sinonasal symptoms and their impact on quality of life using a 22-item questionnaire.	24 weeks
Health-Related Quality of Life	Measurement of health-related quality of life using the EuroQualityOfLife 5-Dimension 5-Level (EQ-5D-5L) instrument. The EQ-5D-5L includes 5 dimensions of health (Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression) with 5 levels of severity for each dimension (no problems, slight problems, moderate problems, severe problems, and extreme problems). For the overall EQ-5D-5L index score, it typically ranges from: Minimum Value: 0 (representing death) Maximum Value: 1 (representing perfect health) In some versions, a negative score can be obtained, which represents a state "worse than death."	24 weeks
Asthma Control Questionnaire	Asthma control will be assessed using the 5-question Asthma Control Questionnaire (ACQ-5), which includes the following domains: symptoms, reliever medication use, and limitations on daily activities. Each question is rated on a scale from 0 (no symptoms) to 6 (maximum symptoms). The total score is the sum of the individual responses, with possible scores ranging from 0 to 30	24 weeks
Epithelial Changes	Measurement of epithelial changes in sinonasal tissues, including alterations in epithelial thickness, cell type, and structural modifications.	24 weeks
Modified Lund-Kennedy Endoscopy Score	Evaluation of sinonasal pathology using the Modified Lund-Kennedy endoscopy scoring system, which assesses factors like nasal polyp size, discharge, and mucosal appearance. Typically ranges from 0 to 24, where higher scores indicate more severe disease.	24 weeks
Lund-Mackay CT Scan Score	Evaluation of sinus opacifications and other CT scan findings using the Lund-Mackay scoring system, which assesses the extent of sinus disease. Typically ranges from 0 to 24. 0 (no opacification) to 2 (complete opacification)	24 weeks
Changes in smell	Measurement of changes in olfactory function using the University of Pennsylvania Smell Identification Test (UPSIT)	24 weeks

Collaborators and Investigators

• Sponsor: Dr. Andrew Thamboo, MD
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Andrew Thamboo, St Paul's Sonis Centre Director

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2025
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): June 1, 2025

Study Registration Dates

• First Submitted: August 13, 2024
• First Submitted That Met QC Criteria: December 13, 2024
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 13, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathological Conditions, Anatomical; Immune System Diseases; Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Nose Diseases; Otorhinolaryngologic Diseases; Rhinitis; Paranasal Sinus Diseases; Polyps; Rhinosinusitis; Asthma; Nasal Polyps; Sinusitis
• Other Study ID Numbers: H24-02151

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No