Background <p>Migraine is a neurological disorder affecting approximately 12% of the population, more frequent in women, causing disability. Preventive treatment is recommended to prevent chronification and analgesics’ abuse and to improve quality of life, but not all candidates receive it. Common preventive drugs include amitriptyline, flunarizine, propranolol, and topiramate. Their effectiveness and safety have not yet been assessed in our setting. The objective of this study is to evaluate the effectiveness of these drugs in reducing the monthly migraine days (MMD) and to evaluate their safety.</p> Methods <p>Phase IV, pragmatic randomized clinical trial of four parallel groups, open and multicentric, in Primary Care in Catalonia, Spain.</p> <p>We will include adults with migraine eligible for preventive treatment. They will be randomized to the following: (1) propranolol, (2) amitriptyline, (3) flunarizine, or (4) topiramate.</p> <p>The main efficacy measure will be the change in the mean MMD at week 12 in comparison to the mean MMD at baseline. Other secondary efficacy and safety measures will be assessed.</p> <p>The main non-inferiority analysis will be conducted in the per protocol population at week 12, comparing topiramate versus propranolol as the main analysis, and amitriptyline and flunarizine versus propranolol as exploratory analyses.</p> Discussion <p>There are epidemiological, clinical and pharmacological sex-differences in migraine which may result in differences in the use of migraine preventive drugs. However, the effectiveness of the most frequent preventive treatment and the differences in effectiveness and safety between women and men have not yet been studied. Moreover, as new expensive drugs have been authorized for preventive treatment, indicated when the usual drugs have failed, assessing the effectiveness and safety of the usual oral preventive drugs through a clinical trial is especially important. We also plan to evaluate their cost-effectiveness, and the clinical trial will count on an active contribution from patients through an app designed for this purpose, which may help in the management of the disease in the future.</p> Trial registration <p>ClinicalTrials.gov ID: NCT06499116 (<a href="https://clinicaltrials.gov/study/NCT06499116">https://clinicaltrials.gov/study/NCT06499116</a>).</p> <p>Trial registration date: July 12, 2024.</p> <p>EU CT Number: 2024–513597-22.</p> <p>Protocol ID: IJG-PREMI-2024.</p> <p>Sponsor: Fundació d’Investigació en Atenció Primària Jordi Gol i Gurina.</p> <p>Gran Via de les Corts Catalanes 587, àtic. 08007, Barcelona, Spain.</p>