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

Asthma is a prevalent chronic respiratory disease for which 44% of people require oral corticosteroids (OCS) every year 1 . Whilst asthma is still managed on a damage-based schema allowing for unacceptable toxicities and irreversible airway remodelling, dupilumab and other type-2 targeting biologics have taught us that people with the highest type-2 inflammatory burden can achieve life-changing responses 2-6 . The term 'remission' has been used to describe the best possible outcome with biologics 5 . Across studies and molecules, remission was more likely to be achieved in people with shorter disease duration, lower morbidity, and higher type-2 inflammatory biomarkers 5,7-9 . These observations have increased interest in the earlier use of biologics in a Predict and Prevent framework 5,10-12 .

The HOTHOT study is a double-blind, placebo-controlled study assessing the effect of dupilumab on induction of clinical remission outcomes in type-2 high patients recruited before they develop severe uncontrolled asthma meeting current biological treatment recommendations. Dupilumab will be compared with placebo in 150 patients undergoing traditional symptom-based inhaled corticosteroid (ICS) up- and down-titration (as per current asthma guidelines). The target population is at-risk type-2 high asthma, defined as at-least medium-dose ICS, with a previous history of a systemic corticosteroid (SCS)-treated asthma attack in the last 24 months and blood eosinophils ≥ 0.3×109/L plus exhaled nitric oxide ≥35 ppb. These inclusion criteria are unique because they will target people with asthma who are at risk of severe asthma attacks and lung function decline, also not meeting current biological prescription/reimbursement criteria. The one-year active treatment adjustment period of the study will test the hypothesis that remission outcomes are more likely to be achieved with early targeted intervention with dupilumab compared to traditional symptom-guided management, where ICS up- and down-titration occurs independently of the presence of type-2 inflammation. The primary outcome, the win ratio based on remission criteria, assesses the likelihood of achieving remission 'wins' based on a hierarchy of criteria, while the secondary remission multi-component (yes/no) outcome, a binary (yes/no) multi-component endpoint for remission, offers a straightforward and comprehensive measure. The primary and secondary remission outcome measurements are both powered to be statistically and clinically impactful to move the need forward in the field of asthma. If correct, the hypothesis that earlier intervention with dupilumab significantly induces remission will shift the treatment paradigm from the usual 'wait and react' approach to a proactive risk-based 'predict and prevent' intervention using earlier targeted therapy in at-risk type-2 inflammatory disease.

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.

OR 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.

4.2 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).
• 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