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

• ClinicalTrials.gov Identifier: NCT04007874
• Recruitment Status: Recruiting
• First Posted: July 5, 2019
• Last Update Posted: April 7, 2022
• Sponsor: Leiden University Medical Center
• Collaborators: Erasmus Medical Center; Netherlands Brain Foundation; ZonMw: The Netherlands Organisation for Health Research and Development
• Information provided by (Responsible Party): G.M. Terwindt, MD, Leiden University Medical Center

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 (Clinical Trial)
• Estimated Enrollment: 360 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Open-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: September 10, 2019
• Estimated Primary Completion Date: April 2023
• Estimated Study Completion Date: April 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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Number of headache days [ Time Frame: From baseline to the last 4 weeks of treatment (weeks 9-12) ]
   Change in monthly headache days
2. Number of migraine attacks [ Time Frame: From baseline to the last 4 weeks of treatment (weeks 9-12) ]
   Change in monthly migraine attacks
3. 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
4. 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
5. (Serious) adverse events [ Time Frame: Up to 3 months ]
   Occurrence of adverse events and serious adverse events

Other Outcome Measures:

1. Number of 75% responders [ Time Frame: From baseline to the last 4 weeks of treatment (weeks 9-12) ]
   Patients who had ≥75% reduction in the number of migraine days
2. Number of complete responders [ Time Frame: From baseline to the last 4 weeks of treatment (weeks 9-12) ]
   Patients who had 100% reduction in the number of migraine days
3. Number of acute treatment days [ Time Frame: From baseline to the last 4 weeks of treatment (weeks 9-12) ]
   Change in monthly acute treatment days
4. Mean migraine severity score/day [ Time Frame: 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))
5. Mean migraine-related symptom severity score/day [ Time Frame: 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))
6. Migraine-Specific Quality of life questionnaire (MSQ) [ Time Frame: 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))
7. Headache Impact Test (HIT-6) [ Time Frame: 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))
8. Perceived Stress Scale (PSS) [ Time Frame: 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

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Iris E Verhagen, MSc; +31715261730; I.E.Verhagen@lumc.nl

Locations

Netherlands

Leiden University Medical Center; Recruiting

Leiden, Zuid Holland, Netherlands, 2333 ZA

Contact: Coordinating investigator +31715261730 I.E.Verhagen@lumc.nl

Sponsors and Collaborators

Leiden University Medical Center

Erasmus Medical Center

Netherlands Brain Foundation

ZonMw: The Netherlands Organisation for Health Research and Development

Investigators

• Principal Investigator: Gisela M Terwindt, MD,PhD; LUMC

More Information

• Responsible Party: G.M. Terwindt, MD, Head of headache clinic, Principal Investigator, Leiden University Medical Center
• ClinicalTrials.gov Identifier: NCT04007874
• Other Study ID Numbers: WHATT; 2018-004096-12 ( EudraCT Number )
• First Posted: July 5, 2019
• Last Update Posted: April 7, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by G.M. Terwindt, MD, Leiden University Medical Center:

Migraine; Women; Hormones; Oral contraceptive pill; Vitamin E

Additional relevant MeSH terms:

Migraine Disorders; Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vitamin E; Levonorgestrel; Ethinyl Estradiol; Ethinyl estradiol, levonorgestrel drug combination; Vitamins; Micronutrients; Physiological Effects of Drugs; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Contraceptives, Oral; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Contraceptives, Oral, Hormonal; Estrogens; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Contraceptives, Oral, Combined