135 Rationale and protocol of the WHAT! Trial 6 will be prescribed ethinylestradiol 25 μg once daily for 7 days. Participants should continue other prescribed prophylactic treatments and are allowed to take their acute treatment in case of a migraine attack. Participants will be contacted twice (t=1 and t=2) to evaluate (serious) adverse events ((S)AEs), which will be asked using open-ended questions Follow-up visit 3 (t=3) includes questionnaires (15 minutes) and evaluation of therapy (Figure 1). If necessary, regular clinical follow-up visits will be planned. Data storage All data gathered during this study will be stored in compliance with the European Union General Data Protection Regulation (EU GDPR). Data collection will be conducted by authorized investigators using two-factor authenticated, passwordprotected web-based interfaces, ensuring secure access. To further safeguard participant privacy, all data will be assigned a unique four-digit study code that cannot be linked back to the participant’s identity. Participants can withdraw their consent for the current use of their data, as well as for use in future research, at any time without consequences. Sample size calculation To achieve the primary objective of the study at least 168 participants are estimated to be needed for random allocation into the two treatment arms (84 per group). The study is designed to have 90% power and a type 1 error of 0.05 for the detection of a between-group difference in MMD of 2 days. Based on previous studies on preventive therapy, we expect a standard deviation (SD) of 4.0 days for the MMD. n (number needed per group) = (1.96 + 1.28)2 * ((2*SD2)/(diff2)) n = 10.5 * (32/4) = 84 Considering potential drop-out, we aim to include n=90 participants per treatment group (n=180 in total) (Figure 1). Outcome measurements An intention-to-treat approach (all participants who were randomly assigned and received at least one dose of study drug) will be used for the primary analysis. In addition, an as-treated analysis will be performed with only those participants who used study medication daily during three months (without a stop week and estrogen supplementation). A p-value less than 0.05 will be considered significant. All statistical analysis will be performed using R.
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