REVErsing Airway Remodelling With Tezepelumab

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 theprevious 12 months despite treatment according to the best standards of care

• Maximal inhaled therapy comprising high dose ICS and at least a second controlleraccording to GINA

Based on results of screening visit and run-in:

• Post-bronchodilator forced expiratory volume in 1 second (FEV1) predicted valuesmust 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 12months

• A smoking history of >20 pack years

• Receipt of any marketed or investigational biologic agent§ within 3 months or 5halflives (whichever is longer) prior to randomization or receipt of anyinvestigational non biologic agent within 30 days or 5 half-lives (whichever islongest) prior to randomization or receipt of live attenuated vaccines 30 days priorto the date of randomization. Participants enrolled in current or previoustezepelumab studies will not be included. Participants on previous biologicstreatment are allowed to enter the study provided the appropriate washout period isfulfilled.

• 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 theinvestigator'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 lowerrespiratory tract infection (LRTI), requiring treatment with antibiotics orantiviral medications finalised < 2 weeks before randomization. Patients withpreexisting serious infections should be treated before initiating therapy withtezepelumab.

• A helminth parasitic infection diagnosed within 6 months prior to Visit 1 that hasnot been treated with, or has failed to respond to, standard of care therapy.

• Patients using vaping products, including electronic cigarettes (because may induceabnormality 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 humanimmunodeficiency virus test or the participant taking antiretroviral medications asdetermined by medical history and/or participant's verbal report.

• Receipt of the T2 cytokine inhibitor Suplatast tosilate within 15 days prior torandomization.

• Treatment with systemic immunosuppressive/immunomodulating drugs (eg, methotrexate,cyclosporine, etc.), except for OCS used in the treatment of asthma/asthmaexacerbations, within the last 12 weeks or 5 half-lives (whichever is longer) priorto randomization.

• Receipt of immunoglobulin or blood products within 30 days prior to randomization.

• Receipt of allergen immunotherapy not stable within 30 days prior to randomizationor with anticipated change during the treatment period.