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.