Protocol for a multinational, investigator-initiated, parallel group, randomised, double-blind, placebo-controlled phase 3b superiority trial assessing the effect of dupilumab on inducing clinical remission outcomes in at-risk type-2 inflammatory asthma (HOTHOT)

INTRODUCTION: Asthma is a prevalent chronic respiratory disease in which up to 44% of patients require systemic corticosteroids (SCS) annually. Many have active type-2 inflammation, characterized by elevated blood eosinophils and/or exhaled nitric oxide (FeNO), type-2 biomarkers that predict asthma attacks and lung-function decline. Biologics such as the interleukin-4/13 targeting dupilumab have shown efficacy in patients with moderate-to-severe asthma and raised type-2 biomarkers, yet their role in inducing clinical remission earlier in the disease course remains untested. We speculate that dupilumab intervention can induce clinical remission in adults with at-risk type-2 inflammatory asthma.

METHODS AND ANALYSIS: We report the protocol for a multinational, investigator-initiated, parallel-group, randomized, double-blind, placebo-controlled, phase 3b superiority trial (HOTHOT). Adults with established asthma, blood eosinophils ≥0.3 × 109/L, FeNO ≥35 ppb, ≥1 severe asthma attack in the past 24 months and maintained on at-least medium-dose inhaled corticosteroids (ICS) will be eligible. One hundred fifty participants will be randomized 1:1 to fortnightly dupilumab or volume-matched placebo over 56 weeks. Background ICS therapy will be adjusted every three months based on symptoms and spirometry, blinded to biomarker data. The primary endpoint is the win ratio based on remission criteria at Week 56, hierarchically comparing absence and number of severe attacks, preserved forced expiratory volume in 1 second (FEV1), maintenance on medium-dose ICS or less, and 5-item Asthma Control Questionnaire score <1.5. Secondary outcomes include the annualized severe-attack rate, remission win ratio in the medium-dose ICS subgroup, FEV1 change, and a binary remission endpoint.

ETHICS AND DISSEMINATION: Approved by the Research Ethics Committee of CIUSSS de l'Estrie-CHUS (MP-31-2026-6116). The protocol follows SPIRIT 2025 guidelines. Results will be disseminated at international meetings and in peer-reviewed journals in accordance with CONSORT.