Table 2 Trial registration data

1. Primary registry and trial identifying number

ClinicalTrials.gov

NCT04007874

2. Date of registration in primary registry

28 June, 2019

3. Secondary identifying numbers

2018–004096-12 (EudraCT)

4, Source(s) of monetary or material support

Netherlands Organization for Health Research (849200007) and the Dutch Brain Foundation (HA2017.01.05)

5. Primary sponsor

Leiden University Medical Center, Leiden, The Netherlands

6. Secondary sponsor(s)

Erasmus Medical Center, Rotterdam, The Netherlands

7. Contact for public queries

B.W.H.van_der_Arend@lumc.nl

8. Contact for scientific queries

B.W.H.van_der_Arend@lumc.nl

9. Public title

Oral Contraceptive Pill Compared With Vitamin E in Women With Migraine (WHATT)

10. Scientific title

Open-label Randomized Controlled Trial for the Effects of Continuous Ethinylestradiol/Levonorgestrel (30/150 μg/Day) Compared With Vitamin E (400 IU/Day) in the Treatment of Menstrually-related Migraine

11. Countries of recruitment

Netherlands

12. Health condition(s) or problem(s) studied

• Migraine

• Migraine; menstrual

13. Intervention(s)

Active comparator: ethinylestradiol/levonorgestrel

• Ethinylestradiol/levonorgestrel 30/150 μg oral tablets once daily without a stop week for 3 months

• Other names:

◦ Microgynon 30

◦ RVG 08204

Placebo comparator: vitamin E

• Vitamin E 400 IU oral capsules once daily for 3 months

14. Key inclusion and exclusion criteria

Inclusion criteria:

• Female

• Menstrual migraine

• Demonstrated at least 80% compliance with E-diary during baseline period

• No or stable for at least two months on prophylactic medication

Exclusion criteria:

• Smoking

• Migraine with aura

• Chronic migraine with 15 or more headache days per month/with 8 or more migraine days per month

• Medication-overuse headache (ICHD-3 criteria)

• Women who are breastfeeding, pregnant, or planning to become pregnant

• Oral contraceptive use and not willing to undergo washout period (stop for two consecutive months)

• Vitamin E use at start of the study

• Use of other sex hormone containing treatments

• Increased risk of VTE: history of VTE or thrombophlebitis, hereditary predisposition for VTE (APC resistance, protein C or S deficiency, antithrombin deficiency), VTE in first-degree family member at young age, long-term immobilization

• Increased risk of ATE: history of ATE, hereditary predisposition for ATE (hyperhomocysteinemia, antiphospholipid antibodies), ATE in first-degree family member at young age, diabetes mellitus, total cholesterol ≥ 6.5

• Other contraindication for oral contraceptives: liver malignancy, schistosomiasis, HIV/aids, use of immunosuppressives, tuberculosis, sex-hormone-dependent malignancies (breast, endometrial or ovary carcinomas), pancreatitis, vaginal bleeding with unknown cause, other diseases that can influence vessels (malignancies, heart valve disorders, atrial fibrillation, SLE, hemolytic uremic syndrome, chronic inflammatory bowel disease, sickle cell disease)

• Contraindication for vitamin E: vitamin K deficiency

• Hypersensitivity for any of the compounds in oral contraceptive or vitamin E

• Spontaneous postmenopausal status (menstrual bleedings have ceased for 12 consecutive months)

• Iatrogenic postmenopausal status

• Inability to complete the electronic diary in an accurate manner

• Any serious illness that can compromise study participation

15. Study type

Interventional

Allocation: randomized intervention model. Parallel assignment masking: none (open-label)

Primary purpose: prevention

Phase III

16. Date of first enrolment

June 2019

17. Target sample size

180

18. Recruitment status

Recruiting

19. Primary outcome(s)

• Number of migraine days [time frame: from baseline to the last 4 weeks of treatment (weeks 9–12)]

◦ Change in monthly migraine days

20. Key secondary outcomes

• Number of headache days [time frame: from baseline to the last 4 weeks of treatment (weeks 9–12)]

◦ Change in monthly headache days

• Number of migraine attacks [time frame: from baseline to the last 4 weeks of treatment (weeks 9–12)]

◦ Change in monthly migraine attacks

• Number of probable migraine attacks [time frame: from baseline to the last 4 weeks of treatment (weeks 9–12)]

◦ Change in monthly probable migraine attacks

• Number of 50% responders [time frame: from baseline to the last 4 weeks of treatment (weeks 9–12)]

◦ Patients who had ≥ 50% reduction in the number of migraine days

• (Serious) adverse events [time frame: up to 3 months]

◦ Occurrence of adverse events and serious adverse events

21. Ethics review

Ethical approval was assigned by the CCMO of the Netherlands (NL67994.058.19). All participating patients will provide written informed consent

22. Completion date

2024–12 (Final data collection date for primary outcome measure)

23. Summary results

Not completed yet

24. IPD sharing statement

Plan to Share IPD: no