A Study Assessing the Effect of Dupilumab on Inducing Clinical Remission in Asthma

Inclusion criteria

• Study participants are eligible to be included in the study only if all of the following criteria apply:
• Age
• Participant must be 18-\<80 years of age at the time of signing the informed consent.
• Type of participant and disease characteristics
• Physician diagnosis of asthma (according to GINA 2025) for ≥6 months, with documented historical airflow variability by one of the following:
• Positive reversibility test: ≥12% and 200 ml in FEV1 after SABA administration at any point prior to randomisation
• Airflow variability in clinic FEV1 \>12% and 200 mL between historical clinical visits
• Positive bronchial challenge test: fall in FEV1 of ≥20% with standard doses of methacholine (\<16 mg/mL or \<400mcg); or ≥10% with standardised hyperventilation, or exercise challenge test; or ≥15% with hypertonic saline or mannitol challenge
• Peak flow variability of \>20% between two assessments
• Evidence of elevated type-2 biomarkers defined as both of:
• peripheral BEC ≥ 0.3×109/L at screening visit
• FeNO ≥ 35 ppb at screening visit
• At least 1 asthma attack in the last 2 years, defined as acute asthma requiring SCS for ≥ 3 days or an emergency/hospital visit requiring SCS.
• Treatment and evident adherence to a stable at-least medium-dose ICS (fluticasone propionate equivalent \>250 mcg/day) for at least 3 months (including run-in period) \[additional controllers e.g. LABA, LAMA or LTA are allowed\]. The ICS dosage will be defined as the dosage received on a regularly basis, excluding extra reliever doses taken in the context of anti-inflammatory reliever (AIR) therapy from the calculation. AIR is allowed in the context of the study. Thus, the high-dose ICS trial population (fluticasone propionate equivalent \>500 mcg/day)\* will represent patients who are not meeting the exacerbation criteria for biological reimbursement.
• \*As per section 6.2, we will cap recruitment to 60% of target population on medium-dose ICS, 40% on high-dose ICS, with randomisation also stratified by these categories.
• Presence of one (or more) of the following additional risk factors for asthma attacks32 at screening or baseline: (i) uncontrolled asthma symptoms indicated by ACQ5 score of ≥ 1.5; (ii) impaired lung function indicated by post-bronchodilator FEV1 of ≤ 80% predicted; (iii) high-dose maintenance ICS therapy (iv) severe asthma attack in past 1-\<12 months.
• Sex, contraceptive/barrier method and pregnancy testing requirements
• Female participants
• a. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• i. Is a woman of nonchildbearing potential (WONCBP) as defined in the Study Manual.
• R ii. Is a WOCBP and agrees to use a contraceptive method that is highly effective, with a failure rate of \<1%, during the intervention period (to be effective before starting the intervention) and for at least 12 weeks after the last dose of study intervention.
• b. A WOCBP must have a negative highly sensitive serum pregnancy test at V1 (screening visit) and urine or serum pregnancy test (as required by local regulations) on Day 1 before the first dose of study intervention, c. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
• d. Additional requirements for pregnancy testing during and after study intervention are imposed.
• e. The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female participant with an early undetected pregnancy.
• Informed consent
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion criteria

• Participants are excluded from the study if any of the following criteria apply:
• Medical conditions
• Use of SCS \< 1 months prior to screening or on maintenance SCS.
• Current tobacco smoker or recently stopped smoker (\<6 months)
• Ex-smoker with greater than 10 pack-years AND post bronchodilator FEV1/FVC ratio below the lower limit of normal according to GLI race-neutral standards. 69
• Documented nonadherence to ICS, defined as dispensing of less than 75% of the prescribed ICS dose over the past 12 months (or annualised if less than 12 months), based on pharmacy refill records checked at screening.
• Presence of significant and uncorrectable inhaler technique deficiencies, as assessed by the research team during inhaler technique evaluation at screening.
• Contra-indication to study drug
• Immunological disease, condition or medication that may affect the inflammatory response according to Investigator.
• History of other significant lung disease e.g. lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, clinically significant bronchiectasis, chronic obstructive lung disease, or Churg-Strauss.
• Severe concomitant illness (including known or suspected immunodeficiency) that, in the Investigator's judgement will adversely affect the participant's participation in the study.
• Active malignancy or history of malignancy within 5 years (except for basal cell carcinoma of the skin or fully resected Cervical Intraepithelial Neoplasia/dysplasia).
• Exposure to monoclonal antibody therapy for asthma or another investigational medicinal product within 5 half-lives of the drug.
• Eligibility to Dupilumab based on licensed and reimbursed indications in the participant's jurisdiction (e.g. nasal polyposis, atopic dermatitis, eosinophilic esophagitis, prurigo nodularis, etc.)
• Treatment with live (attenuated) vaccine in the past 4 weeks.
• Prohibited medication 15 Current helminth infection