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 rem

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This is a protocol for the HOTHOT trial, a multinational, investigator-initiated, phase 3b superiority study.
It aims to assess if dupilumab can induce clinical remission in adults with at-risk type-2 inflammatory asthma, characterized by elevated blood eosinophils and FeNO.
The trial design is parallel-group, randomized, double-blind, and placebo-controlled, with 150 participants randomized 1:1 to dupilumab or placebo over 56 weeks.
Eligibility criteria include established asthma, blood eosinophils ≥0.3 × 10^9/L, FeNO ≥35 ppb, at least one severe attack in the past 24 months, and maintenance on medium-dose or higher ICS.
The primary endpoint is a win ratio based on remission criteria at Week 56, hierarchically comparing absence/number of severe attacks, preserved FEV1, ICS dose, and asthma control questionnaire score.
Secondary outcomes include annualized severe-attack rate, remission win ratio in a specific subgroup, FEV1 change, and a binary remission endpoint.
Background ICS therapy will be adjusted every three months based on symptoms and spirometry, with blinding to biomarker data.
Ethical approval has been obtained, and the protocol follows SPIRIT 2025 guidelines, with results to be disseminated via international meetings and peer-reviewed journals per CONSORT.

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