Background Severe eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) remains the most relapsed subtype of uncontrolled CRSwNP. CM310, a humanised anti-interleukin (IL)-4 receptor alpha monoclonal antibody, inhibits IL-4 and IL-13 signaling which underlying eosinophilic inflammation. This study aims to evaluate the efficacy and safety of CM310 in patients with severe ECRSwNP. Methods A multicentre, randomised, double-blind, and placebo-controlled phase 2 clinical trial was conducted. 56 eligible adult patients with severe ECRSwNP were randomised 1:1 to receive subcutaneously either CM310 (300 mg) or placebo every 2 weeks under the background therapy of mometasone furoate nasal spray (MFNS) for 16 weeks, with 8 weeks of follow-up. Coprimary endpoints included the changes from baseline in nasal polyp score (NPS) and nasal congestion score (NCS) at week 16. Key secondary endpoints included sinus Lund-Mackay CT score, change in sinus volume occupied by disease, University of Pennsylvania Smell Identification Test score, 22-item Sino-nasal Outcome Test score, and total symptom score. Safety, pharmacodynamics, and changes in type 2 inflammation biomarkers were assessed. This study is registered with ClinicalTrials.gov, NCT04805398. symbolscript Between April 6, 2021, and March 18, 2022, 27 patients respectively in both the CM310 and placebo groups completed the study.Findings suggested that CM310 improved the coprimary efficacy endpoints of decreasing nasal polyp size and alleviating nasal congestion compared with the placebo. Least squares (LS) mean differences (CM310 vs placebo) of change from baseline in NPS and NCS at week 16 were -2.1 (95% CI -2.9, -1.4; p < 0.0001) and -0.9 (95% CI -1.4, -0.5; p < 0.0001), respectively. Sinus CT scan revealed that Lund-Mackay CT score (LS mean difference [95% CI] -7.6, [-9.4, -5.8]; p < 0.0001) and sinus volume occupied by disease (LS mean difference [95% CI] -37%, [-47%, -28%]; p < 0.0001) were significantly improved with CM310 compared with placebo. In addition, CM310 significantly relieved the daily symptoms of patients with CRSwNP and improved their quality of life reflected by the improvements in the TSS (-2.6 [95% CI -3.5,-1.6]), UPSIT (10.4 [95% CI 6.8, 14.0]) and SNOT-22 score (-19.1 [95% CI -29.8,-8.5]). Compared with placebo, CM310 administration significantly reduced type 2-related biomarkers including the serum TARC and total IgE, and tissue eosinophils. The most common adverse events were upper respiratory tract infection, blood cholesterol increased, and tinnitus, but none were considered drug-related.Interpretation These findings support CM310 as an effective additional treatment option to the standard of care in patients with severe ECRSwNP.