126 Chapter 6 of symptoms was also observed in some cases. Extended regimens (without HFI) were found to be more effective than the traditional 21/7 regimen in terms of reducing daily headache days and medication days.19, 20 In a small study a beneficial effect of vitamin E was found with respect to pain severity and functional disability.21 Its effect was suggested to be mediated by a reduction of prostaglandin production in the endometrium. The study, notwithstanding, had methodological shortcomings, such as a short duration of treatment solely during the perimenstrual period and a lack of clearly defined outcome definitions. In clinical practice, combined oral contraceptive pills are frequently prescribed for migraine in women. However, proof of efficacy is lacking and usage may be accompanied by side effects, with an increased relative risk for stroke in young women with migraine.22, 23 Hence, there is a strong need for clarity on this topic. We hypothesize that continuous daily use of a combined oral contraceptive pill will be an effective and well-tolerated preventive treatment for menstrual migraine. METHODS The primary objective of this randomized controlled trial is to investigate the efficacy of continuous daily use of ethinylestradiol/levonorgestrel (30/150 µg/day) compared to vitamin E (400 IU/day) in treating menstrual migraine. This study follows the latest protocol, dated August 1, 2022, version 5.0. This trial employs an open-label randomized controlled design due to ethical and practical considerations regarding the use of a placebo-controlled study with a combined oral contraceptive pill. However, a control group with an alternative treatment, vitamin E (400 IU/day, soft gel capsules), was included to account for potential confounding biases such as treatment expectations, placebo and nocebo effects. Our patient focus group panel was highly in favour of using vitamin E as a comparator treatment for hormonal intervention. Given the nature of the interventions, participants, investigators, and study personnel are aware of the treatment assignments. Blinding is not feasible in this trial due to the distinct characteristics of the interventions and the practical challenges associated with a placebo-controlled study involving a combined oral contraceptive pill. The study design is visualized in Figure 1. All endpoints are defined as the mean change from baseline (week -4 to 0) in a 28-day period as assessed at the 12-week timepoint (week 9 to 12). The primary efficacy endpoint for the trial is the mean change in mean monthly migraine days (MMD) from baseline to the 12-week timepoint. An automated algorithm based on ICHD-3 criteria
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