Clinical trial NCT04007874: Oral Contraceptive Pill Compared With Vitamin E in Women With Migraine
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Migraine
Migraine;Menstrual
Keywords: Migraine
Women
Hormones
Oral contraceptive pill
Vitamin E
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
name: Netherlands Brain Foundation
name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2019-07-05
Enrollment: 360
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-label randomized controlled trial
Primary purpose: PREVENTION

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of migraine days
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
Secondary outcomes:
measure: Number of headache days
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
measure: Number of migraine attacks
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
measure: Number of probable migraine attacks
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
measure: Number of 50% responders
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
measure: (Serious) adverse events
timeFrame: Up to 3 months
Other outcomes:
measure: Number of 75% responders
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
measure: Number of complete responders
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
measure: Number of acute treatment days
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
measure: Mean migraine severity score/day
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
measure: Mean migraine-related symptom severity score/day
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
measure: Migraine-Specific Quality of life questionnaire (MSQ)
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
measure: Headache Impact Test (HIT-6)
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
measure: Perceived Stress Scale (PSS)
timeFrame: From baseline to the last 4 weeks of treatment (weeks 9-12)
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
state: Zuid Holland
Study officials:
affiliation: LUMC
name: Gisela M Terwindt, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References: