Background <p>Glioblastoma, IDH wildtype is the most common primary malignant brain tumor in adults. Despite best available treatment, prognosis remains poor. Current standard therapy consists of surgical tumor removal followed by radiotherapy and chemotherapy with the alkylating agent temozolomide. Antisecretory factor (AF), an endogenous protein, may potentiate the effect of temozolomide and alleviate cerebral edema. Salovum® is an egg-yolk powder enriched for AF and is classified as a medical food in the European Union. Salovum® has shown preliminary clinical effect on glioblastoma in a recent pilot study. Here, we aim to assess if add-on Salovum® to temozolomide therapy can improve outcomes in patients with newly diagnosed glioblastoma.</p> Methods <p>This is a multi-center, double-blinded, randomized, placebo-controlled phase II-III clinical trial to investigate superiority of Salovum® over placebo as add-on treatment for glioblastoma during concomitant and adjuvant temozolomide therapy. Patients with newly diagnosed glioblastoma that are planned for temozolomide treatment are screened for eligibility and randomized to receive Salovum® (<i>n</i> = 150) or placebo (<i>n</i> = 150). An interim analysis will be performed after 80 included patients to guide whether to continue or terminate. Primary endpoint is 12-month overall survival. Secondary outcome is 24-month overall survival.</p> Discussion <p>This study will likely produce high-grade evidence to support or reject Salovum® as add-on treatment for glioblastoma.</p> Trial registration <p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT05669820">NCT05669820</a>. Registered on January 3, 2023.</p>