Efficacy and exploratory treatment-response modeling of acupuncture for acute migraine based on DIA proteomics: a study protocol for a randomized controlled trial.

Background: According to estimates from the 2019 Global Burden of Disease (GBD) study, approximately 1.1 billion people worldwide suffer from migraine, with a prevalence rate of about 14% to 15%. Despite the development of various medications for different types of migraine, such as acetaminophen and caffeine combination preparations, most patients still experience suboptimal symptom control. Therefore, identifying effective and safer alternative treatments holds significant clinical importance. Acupuncture was formally recommended by the World Health Organization as a migraine therapy as early as 1979. In recent years, substantial domestic and international research evidence has demonstrated the distinct advantages of acupuncture in treating migraine. Proteomics technology can assess the final products of adaptive changes in the body following acupuncture, thereby establishing a close association with disease progression. Objective: This study aims to evaluate the efficacy of a single acupuncture session for acute migraine, identify subgroups with different short-term treatment responses, and explore baseline plasma protein biomarkers potentially associated with acupuncture response. An exploratory proof-of-concept model will be developed to assess whether a small set of prespecified clinical and proteomic features may contain preliminary predictive information regarding short-term treatment response. Methods: This study is divided into three parts. First, this randomized controlled trial will recruit 86 acute migraine patients. All participants will be randomly assigned in a 1:1 ratio to either the real acupuncture (RA) group or the sham acupuncture (SA) group. Each patient will receive one acupuncture treatment session. The primary outcome is the between-group difference in the change in visual analog scale (VAS) scores from baseline to 24 h post-treatment. Secondary outcomes include assessment of VAS scores at 72 h and 1 week post-needling; Hamilton Anxiety Scale/Hamilton Depression Scale (HAMA/HAMD) at 1 week post-needling; clinical response rates at 24 h, 72 h, and 1 week post-needling; and migraine attack count, attack frequency, and attack duration at 24 h, 72 h, and 1 week post-needling. Second, using the prespecified percentage change in VAS as the efficacy metric, 20 participants will be selected from the 43 participants in the RA group, including 10 high-responders and 10 low-responders. Baseline plasma samples collected before acupuncture will be analyzed using DIA-based proteomics to identify differentially expressed proteins and explore biological pathways potentially associated with short-term acupuncture response. Third, an exploratory proof-of-concept treatment-response model will be developed using the clinical and proteomic data from these 20 participants. Because of the limited sample size, no training-test split will be performed and complex machine-learning algorithms will not be compared. A parsimonious penalized logistic regression model will be assessed using nested leave-one-out cross-validation, with all data-dependent preprocessing and feature-selection procedures performed within each resampling iteration. The results will be considered hypothesis-generating and will require independent external validation. Conclusion: This protocol describes a randomized, single-blind trial that will evaluate the efficacy of acupuncture for acute migraine and explore plasma protein biomarkers potentially associated with short-term acupuncture response. The exploratory model is intended to assess methodological feasibility and generate hypotheses rather than provide a validated clinical decision-support tool. Clinical Trial Registration: www.chictr.org.cn, identifier ITMCTR2026000359.