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)
This study tests whether an asthma medication called dupilumab can help people achieve complete asthma control (called remission) when given earlier in their disease, before asthma becomes severe. Currently, most people with asthma only receive advanced treatments like biologics after their condition has worsened significantly and caused lung damage. This study explores whether treating high-risk patients earlier could prevent asthma attacks and lung function decline, potentially achieving remission before permanent damage occurs. The study is looking for adults aged 18-79 with moderate asthma who have had at least one asthma attack requiring steroid pills in the past 2 years, use medium or high-dose inhaled steroids regularly, have high levels of inflammation markers in their blood and breath tests, but don't yet meet criteria for severe asthma requiring biologic therapy. Participants receive either dupilumab or placebo injections every 2 weeks for one year, alongside their regular asthma medications. They attend clinic visits every 3 months for breathing tests, questionnaires, and safety monitoring. Neither participants nor doctors know who receives the real medication until the study ends. The goal is to learn whether early treatment with dupilumab helps more people achieve complete asthma control compared to standard care alone, potentially changing how asthma is treated from waiting until severe to preventing severe disease. The study runs in Canada, the United Kingdom, and Australia, involving 150 participants
• 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.