Clinical trial NCT06740045: Opening the "Black Box" on Tezepelumab's Effect on Chronic Rhinosinusitis With Severe Asthma
Official title: Opening the "Black Box" on Tezepelumab's Effect on Chronic Rhinosinusitis With Severe Asthma
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Asthma
Chronic Rhinosinusitis With Nasal Polyps
Lead sponsor: St. Paul's Sinus Centre
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2024-12-18
Enrollment: 10
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The proposed design is a 24-week pilot study to investigate the histo-inflammatory and remodeling profiles and clinical outcomes of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) patients with Severe Asthma (SA) treated with Tezepelumab. The investigators plan to recruit approximately 10 subjects with (CRSwNP) and severe asthma as a "proof of concept" study. Eligible subjects will be requested to participate in the study for a maximum of 24 weeks, during which subjects will remain on their existing standard of care therapy. At Visit 2 (week 0), subjects will receive either add-on Tezepelumab (210 mg) during the 24-week treatment period. Study medication will be administered subcutaneously (SC) every 4 weeks for a total of 6 doses.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Eosinophil Count
timeFrame: From baseline to 24 weeks
measure: Neutrophil count
timeFrame: From baseline to 24 weeks.
measure: Basement Membrane Thickness
timeFrame: From baseline to 24 weeks
measure: Fibrosis
timeFrame: From baseline to 24 weeks
measure: Squamous Metaplasia
timeFrame: From baseline to 24 weeks
measure: Lymphocytic Proliferation
timeFrame: From baseline to 24 weeks
Secondary outcomes:
measure: Immunoglobulin leves
timeFrame: 24 weeks
measure: Th2 Cytokines
timeFrame: 24 weeks
measure: Th1/Th17 Cytokines
timeFrame: 24 weeks
measure: Myeloperoxidase (MPO)
timeFrame: 24 weeks
measure: Interferon-γ (IFN-γ)
timeFrame: 24 weeks
measure: SNOT-22 (Sino-Nasal Outcome Test 22-item)
timeFrame: 24 weeks
measure: Health-Related Quality of Life
timeFrame: 24 weeks
measure: Asthma Control Questionnaire
timeFrame: 24 weeks
measure: Epithelial Changes
timeFrame: 24 weeks
measure: Modified Lund-Kennedy Endoscopy Score
timeFrame: 24 weeks
measure: Lund-Mackay CT Scan Score
timeFrame: 24 weeks
measure: Changes in smell
timeFrame: 24 weeks
Other outcomes:
Locations:
Study officials:
affiliation: St Paul's Sonis Centre Director
name: Andrew Thamboo
role: PRINCIPAL_INVESTIGATOR
References: