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Introduction The dysregulation of both reduced (IL-33 red) and oxidised (IL-33ox) interleukin (IL)-33 has been implicated in chronic obstructive pulmonary disease (COPD) inflammation and remodelling processes. Tozorakimab, an anti-IL-33 monoclonal antibody, inhibits both IL-33red and IL-33ox activity.Methods and analysis The tozorakimab LUNA programme comprises four ongoing, multicentre, randomised, double-blind, parallel-group, placebo-controlled, phase III studies evaluating the efficacy and safety of tozorakimab in participants with symptomatic COPD and a history of exacerbations receiving optimised inhaled therapy. In OBERON ( NCT05166889) and TITANIA (NCT05158387), 1132 and 1172 participants, respectively, were randomised to receive tozorakimab 300 mg every 4 or 8 weeks or placebo for 52 weeks. In MIRANDA (NCT06040086), 1454 participants were randomised 3:2 to tozorakimab 300 mg every 2 weeks or placebo for ≥52 weeks. In PROSPERO (NCT05742802), participants who completed treatment with tozorakimab in OBERON or TITANIA will continue treatment for an additional 28 weeks or 52 weeks; participants recruited from the placebo arm will be re-randomised 1:1 to tozorakimab or placebo. The primary endpoint in OBERON, TITANIA and MIRANDA is the annualised rate of moderate-to-severe COPD exacerbations; the primary endpoint in PROSPERO is the annualised rate of severe COPD exacerbations. For all studies, the primary endpoint will be first assessed in former smokers, then in current and former smokers. Secondary key endpoints include measures of lung function, respiratory symptoms, health status and safety. The tozorakimab LUNA programme is assessing the efficacy and safety of tozorakimab in participants with COPD. It is the largest pivotal programme of any biologic therapy in COPD to date.Ethics and dissemination The protocols were approved by independent ethics committees and institutional review boards. Results of the studies will be submitted to the EU Clinical Trials Information System within a year from the global end of trial data in all participating countries and will be published or presented at scientific meetings.Trial registration number OBERON: NCT05166889; TITANIA: NCT05158387; MIRANDA: NCT06040086; PROSPERO: NCT05742802.