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MigrainePhase 3WHATTNCT04007874

Oral Contraceptive Pill Compared With Vitamin E in Women With Migraine

A Phase 3 study testing Ethinylestradiol/levonorgestrel and Vitamin E in people with Migraine and Migraine;Menstrual, run by Leiden University Medical Center at 1 site in Netherlands.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Migraine, Migraine;Menstrual
What is being tested?
Ethinylestradiol/levonorgestrel and Vitamin E
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
360 participants
Where
1 siteNetherlands
Study dates
10 Sep 2019to Dec 2024
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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)
Show all 17Show fewer
  • 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

Trial locations and contacts

1 site in 1 country.

Britt WH van der Arend, MSc contact

+31715266065

B.W.H.van_der_Arend@lumc.nl

Netherlands1 site, 1 recruiting

  • Leiden University Medical Center

    Leiden, South Holland, 2333 ZA

    Britt WH van der Arend, MD, +31715266065, B.W.H.van_der_Arend@lumc.nl

    Recruiting

Other trials in Netherlands

About this study

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

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.

Read the 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.

Being tested
Ethinylestradiol/levonorgestrel, Vitamin E
Keywords
Migraine, Women, Hormones, Oral contraceptive pill, Vitamin E
Medical subject headings
Migraine Disorders

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ethinylestradiol/levonorgestrelDrug

    Also called Microgynon 30, RVG 08204

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

  • Vitamin EDrug

    Vitamin E 400 IU oral capsules once daily for 3 months

Study groups in NCT04007874
Study groupRoleWhat they receive
Ethinylestradiol/levonorgestrelExperimentalEthinylestradiol/levonorgestrel 30/150 µg oral tablets once daily without a stopweek for 3 months
Receives: Drug: Ethinylestradiol/levonorgestrel
Vitamin EActive comparatorVitamin E 400 IU oral capsules once daily for 3 months
Receives: Drug: Vitamin E

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of migraine days

    Change in monthly migraine days

    Measured: From baseline to the last 4 weeks of treatment (weeks 9-12)

Secondary outcomes (5)

  1. Number of headache days

    Change in monthly headache days

    Measured: From baseline to the last 4 weeks of treatment (weeks 9-12)

  2. Number of migraine attacks

    Change in monthly migraine attacks

    Measured: From baseline to the last 4 weeks of treatment (weeks 9-12)

  3. Number of probable migraine attacks

    Change in monthly probable migraine attacks

    Measured: From baseline to the last 4 weeks of treatment (weeks 9-12)

  4. Number of 50% responders

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

    Measured: From baseline to the last 4 weeks of treatment (weeks 9-12)

  5. (Serious) adverse events

    Occurrence of adverse events and serious adverse events

    Measured: Up to 3 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Jul 2019
  2. Study start10 Sep 2019
  3. Primary completionDec 2024 (estimated)
  4. Study completionDec 2024 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Model description
Open-label randomized controlled trial
Masking
None (open label)
Enrolment
360 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04007874
Sponsor's protocol ID
WHATT
Other IDs
2018-004096-12, 2018
Acronym
WHATT
Status last verified
Dec 2023
First submitted
28 Jun 2019
Last updated
8 Dec 2023
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • van der Arend BWH, van Casteren DS, Verhagen IE, MaassenVanDenBrink A, Terwindt GM. Continuous combined oral contraceptive use versus vitamin E in the treatment of menstrual migraine: rationale and protocol of a randomized controlled trial (WHAT!). Trials. 2024 Feb 15;25(1):123. doi: 10.1186/s13063-024-07955-8.

    PubMed 38360739

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Ethinylestradiol/levonorgestrel and Vitamin E in people with Migraine and Migraine;Menstrual, run by Leiden University Medical Center at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 8 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Britt WH van der Arend, MSc (+31715266065, B.W.H.van_der_Arend@lumc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of migraine days (time frame: From baseline to the last 4 weeks of treatment (weeks 9-12)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04007874, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Dec 2023.

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