REVErsing Airway Remodelling With Tezepelumab

The aim of this protocol is to perform a first randomized controlled trial evaluating how Tezepelumab affects the bronchial morphology (and computed tomographic variables in general) of asthmatic patients. In parallel, the investigators also hope to reproduce clinical benefits and perform a transcriptomic study that will juxtapose changes in genetic expression with changes in bronchial morphology and inflammatory signatures. The general hypothesis is that tezepelumab treatment is capable of at least partially reversing bronchial remodelling as detected on computed-tomographic (CT) scans. The investigators also expect such reversal to occur within a unique physiological repair environment that will be reflected by transcriptomic profiles

Tezepelumab is a human IgG2l monoclonal antibody (mAb) directed against TSLP. Double-blind, randomized controlled trials comparing Tezepelumab treatment against placebo demonstrate net positive benefits in asthma patients. Animal research currently indicates that blocking TSLP can prevent bronchial remodelling in murine models (Chen et al. 2013), but no such observations have been attempted in humans. Within this context, the aim of this protocol is to perform a first randomized controlled trial evaluating how Tezepelumab affects the bronchial morphology (and computed tomographic variables in general) of asthmatic patients. In parallel, the investigators also hope to reproduce clinical benefits and perform a transcriptomic study that will juxtapose changes in genetic expression with changes in bronchial morphology and inflammatory signatures.

The general hypothesis is that tezepelumab treatment is capable of at least partially reversing bronchial remodelling as detected on computed-tomographic (CT) scans. The investigators also expect such reversal to occur within a unique physiological repair environment that will be reflected by transcriptomic profiles.

The primary objective of this protocol is therefore to compare the change-from-baseline in the average percentage bronchial wall area (%WA = (wall area (mm2)/ (wall area (mm2) + lumen area (mm2)))×100) for patients with asthma and undergoing 6 months of tezepelumab treatment with a similar population treated via placebo. Secondarily, continued treatment effects associated with longer treatment (12 months) or remanence after treatment stopping at 6 months will also be quantified. Study arms will additionally be compared in terms of:

* Changes in radiomics (CT-scan data);
* Changes in exacerbation rates and lung function;
* Changes in serum club cell secretory protein (CCSP);
* Changes in nasal single-cell transcriptomic signatures.

This study also has an exploratory component designed to characterize the physiological repair environment. In depth radiomic and transcriptomic (including single-cell analyses) profiling will be performed. Finally, the capacity of baseline data to predict the response to tezepelumab will also be explored.

Eligibility Criteria:
Inclusion Criteria:

Admitted to screening visit:

* Minimum age: 18
* Maximum age: 85
* Able to perform an inspiratory and expiratory thoracic computed tomography (CT) scan, plus a nasal CT
* In stable condition for CT scan
* Physician-diagnosed asthma according to GINA criteria
* Disease with clinical impact: at least 1 severe or 2 moderate exacerbations in the previous 12 months despite treatment according to the best standards of care
* Maximal inhaled therapy comprising high dose ICS and at least a second controller according to GINA

Based on results of screening visit and run-in:

* Post-bronchodilator forced expiratory volume in 1 second (FEV1) predicted values must be at 25-90%
* Asthma Control Questionnaire 6 (ACQ6) \> 1.5
* Oral corticosteroid maintenance therapy (if used) ≤7.5 mg/day
* On CT scan, the average percentage wall area index at the B1 and B8 bronchi (generation 3, 4, 5) is \>65%

Exclusion Criteria:

* CT abnormalities evocative of any respiratory condition other than asthma
* Treatment regimen discordant with best practices
* Pulmonary disease other than asthma requiring treatment during the previous 12 months
* A smoking history of \>20 pack years
* Receipt of any marketed or investigational biologic agent§ within 3 months or 5 halflives (whichever is longer) prior to randomization or receipt of any investigational non biologic agent within 30 days or 5 half-lives (whichever is longest) prior to randomization or receipt of live attenuated vaccines 30 days prior to the date of randomization. Participants enrolled in current or previous tezepelumab studies will not be included. Participants on previous biologics treatment are allowed to enter the study provided the appropriate washout period is fulfilled.
* Absence of signed consent
* Non-beneficiary of the French social security, single-payer health insurance system
* Presence of any condition (physical, psychological or other) that might, in the investigator's opinion, hinder study performance
* The patient is unavailable or unwilling to participate in future visits
* Potential interference from other studies
* Protected populations according to the French public health code
* Male or female patients seeking to conceive a child
* Women of childbearing potential and fertile men not using birth control method
* Pregnant, breastfeeding or lactating women
* History of a clinically significant infection, including upper (URTI) or lower respiratory tract infection (LRTI), requiring treatment with antibiotics or antiviral medications finalised \< 2 weeks before randomization. Patients with preexisting serious infections should be treated before initiating therapy with tezepelumab.
* A helminth parasitic infection diagnosed within 6 months prior to Visit 1 that has not been treated with, or has failed to respond to, standard of care therapy.
* Patients using vaping products, including electronic cigarettes (because may induce abnormality at CT scan).
* Bronchial thermoplasty in the last 12 months prior to Visit 1.
* History of documented immune complex disease (Type III hypersensitivity reactions) following any biologic therapy.
* History of known immunodeficiency disorder including a positive human immunodeficiency virus test or the participant taking antiretroviral medications as determined by medical history and/or participant's verbal report.
* Receipt of the T2 cytokine inhibitor Suplatast tosilate within 15 days prior to randomization.
* Treatment with systemic immunosuppressive/immunomodulating drugs (eg, methotrexate, cyclosporine, etc.), except for OCS used in the treatment of asthma/asthma exacerbations, within the last 12 weeks or 5 half-lives (whichever is longer) prior to randomization.
* Receipt of immunoglobulin or blood products within 30 days prior to randomization.
* Receipt of allergen immunotherapy not stable within 30 days prior to randomization or with anticipated change during the treatment period.