WHATT: Oral Contraceptive Pill Compared With Vitamin E in Women With Migraine

Sponsor

Leiden University Medical Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04007874

Collaborator

Erasmus Medical Center (Other), Netherlands Brain Foundation (Other), ZonMw: The Netherlands Organisation for Health Research and Development (Other)

360

Enrollment

Location

Arms

42.7

Anticipated Duration (Months)

8.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Open-label randomized controlled trial to study the efficacy of continuous daily use of ethinylestradiol/levonorgestrel (30/150 µg/day) compared with vitamin E (400 IU/day) in the treatment of women with menstrually-related and perimenopausal migraine.

Condition or Disease	Intervention/Treatment	Phase
Migraine Migraine;Menstrual	Drug: Ethinylestradiol/levonorgestrel Drug: Vitamin E	Phase 3

Detailed Description

Rationale: The prevalence of migraine is three times higher in women than in men. Clinical and epidemiological studies suggest a prominent role for sex hormones in female migraine patients. Menstruation is an important factor increasing the susceptibility for an upcoming attack. Perimenstrual migraine attacks are also more disabling, longer lasting, and more difficult to treat than other attacks. Hormonal fluctuations during menopausal transition are associated with increased susceptibility for migraine as well, whereas hormonal changes in migraine during pregnancy seem to be associated with decreased attack frequency. Thus, sex hormonal conditions seem to affect the susceptibility for migraine attacks in women, but there is a lack of understanding the underlying pathophysiological mechanism. Currently, there is no clear evidence-based hormonal intervention for the treatment of migraine in women. The investigators hypothesize that continuous daily use of an oral contraceptive pill will be an effective, well-tolerated preventive treatment for 1) menstrually-related migraine and 2) perimenopausal migraine.

Objective: To study the efficacy of continuous daily use of ethinylestradiol/levonorgestrel (30/150 µg/day) compared with vitamin E (400 IU/day) in the treatment of menstrually-related and perimenopausal migraine.

Study design: Open-label randomized controlled trial. Study population: Women with menstrually-related or pure menstrual migraine and women with perimenopausal migraine.

Intervention: Continuous daily use of ethinylestradiol/levonorgestrel (30/150 µg/day) compared with vitamin E (400 IU/day).

Primary endpoint: Change in monthly migraine days from baseline to the last 4 weeks of treatment (weeks 9-12).

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The study will encompass a period of 4 months (1 baseline month and 3 treatment months). Patients have to fill out daily headache diaries throughout the study using a web-based app (≈ 5 min). Patients visit the headache clinic thrice, once for inclusion, once during the baseline period and once after 3 months of therapy (duration ≈ 1 hour). During the first and last visit blood samples will be taken. Patients will be contacted twice during follow-up to evaluate (S)AE's. Treatment with the oral contraceptive pill is accompanied by a very low risk of developing thromboembolisms. Participation might benefit participants by reducing their migraine attack frequency or intensity.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

360 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Open-label randomized controlled trialOpen-label randomized controlled trial

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official 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 and Migraine During Perimenopause

Actual Study Start Date :

Sep 10, 2019

Anticipated Primary Completion Date :

Apr 1, 2023

Anticipated Study Completion Date :

Apr 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ethinylestradiol/levonorgestrel Ethinylestradiol/levonorgestrel 30/150 µg oral tablets once daily without a stopweek for 3 months	Drug: Ethinylestradiol/levonorgestrel Ethinylestradiol/levonorgestrel 30/150 µg oral tablets once daily without a stopweek for 3 months Other Names: Microgynon 30 RVG 08204
Active Comparator: Vitamin E Vitamin E 400 IU oral capsules once daily for 3 months	Drug: Vitamin E Vitamin E 400 IU oral capsules once daily for 3 months

Arm

Intervention/Treatment

Experimental: Ethinylestradiol/levonorgestrel

Ethinylestradiol/levonorgestrel 30/150 µg oral tablets once daily without a stopweek for 3 months

Drug: Ethinylestradiol/levonorgestrel

Ethinylestradiol/levonorgestrel 30/150 µg oral tablets once daily without a stopweek for 3 months

Other Names:

Microgynon 30

RVG 08204

Active Comparator: Vitamin E

Vitamin E 400 IU oral capsules once daily for 3 months

Drug: Vitamin E

Vitamin E 400 IU oral capsules once daily for 3 months

Outcome Measures

Primary Outcome Measures

Number of migraine days [From baseline to the last 4 weeks of treatment (weeks 9-12)]
Change in monthly migraine days

Secondary Outcome Measures

Number of headache days [From baseline to the last 4 weeks of treatment (weeks 9-12)]
Change in monthly headache days
Number of migraine attacks [From baseline to the last 4 weeks of treatment (weeks 9-12)]
Change in monthly migraine attacks
Number of probable migraine attacks [From baseline to the last 4 weeks of treatment (weeks 9-12)]
Change in monthly probable migraine attacks
Number of 50% responders [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 [Up to 3 months]
Occurrence of adverse events and serious adverse events

Other Outcome Measures

Number of 75% responders [From baseline to the last 4 weeks of treatment (weeks 9-12)]
Patients who had ≥75% reduction in the number of migraine days
Number of complete responders [From baseline to the last 4 weeks of treatment (weeks 9-12)]
Patients who had 100% reduction in the number of migraine days
Number of acute treatment days [From baseline to the last 4 weeks of treatment (weeks 9-12)]
Change in monthly acute treatment days
Mean migraine severity score/day [From baseline to the last 4 weeks of treatment (weeks 9-12)]
Change in migraine severity (four-point anchored scales (0=none, 1=mild, 2=moderate, and 3=severe))
Mean migraine-related symptom severity score/day [From baseline to the last 4 weeks of treatment (weeks 9-12)]
Change in migraine-related symptom severity (four-point anchored scales (0=none, 1=mild, 2=moderate, and 3=severe))
Migraine-Specific Quality of life questionnaire (MSQ) [From baseline to the last 4 weeks of treatment (weeks 9-12)]
Change in Migraine-Specific Quality of life questionnaire (MSQ) total score (range from 14 (mild impact) to 84 (severe impact))
Headache Impact Test (HIT-6) [From baseline to the last 4 weeks of treatment (weeks 9-12)]
Change in Headache Impact Test (HIT-6) total score (range between 36 (mild impact) - 78 (severe impact))
Perceived Stress Scale (PSS) [From baseline to the last 4 weeks of treatment (weeks 9-12)]
Change in Perceived Stress Scale (PSS) total score (range between 0 (mildly stressed) - 40 (severely stressed))

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Female
Premenopausal with menstrual migraine OR migraine during the early menopausal transition phase (a difference of 7 days or more in length of consecutive cycles, which should occur at least twice in a period of 12 menstrual cycles)
Demonstrated at least 80% compliance with eDiary 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 immobilisation
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, haemolytic 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