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

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.

Study Overview

• Status: Recruiting
• Conditions: Migraine; Migraine;Menstrual
• Intervention / Treatment: Drug: Ethinylestradiol/levonorgestrel; Drug: Vitamin E

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 Type: Interventional
• Enrollment (Estimated): 360
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Britt WH van der Arend, MSc; Phone Number: +31715266065; Email: B.W.H.van_der_Arend@lumc.nl

Study Locations

• Netherlands
  • Zuid Holland
    • Leiden, Zuid Holland, Netherlands, 2333 ZA
      • Recruiting
      • Leiden University Medical Center
      • Contact: Britt WH van der Arend, MD; Phone Number: +31715266065; Email: B.W.H.van_der_Arend@lumc.nl

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of migraine days	Change in monthly migraine days	From baseline to the last 4 weeks of treatment (weeks 9-12)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of headache days	Change in monthly headache days	From baseline to the last 4 weeks of treatment (weeks 9-12)
Number of migraine attacks	Change in monthly migraine attacks	From baseline to the last 4 weeks of treatment (weeks 9-12)
Number of probable migraine attacks	Change in monthly probable migraine attacks	From baseline to the last 4 weeks of treatment (weeks 9-12)
Number of 50% responders	Patients who had ≥50% reduction in the number of migraine days	From baseline to the last 4 weeks of treatment (weeks 9-12)
(Serious) adverse events	Occurrence of adverse events and serious adverse events	Up to 3 months

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Erasmus Medical Center; ZonMw: The Netherlands Organisation for Health Research and Development; Netherlands Brain Foundation
• Investigators: Principal Investigator: Gisela M Terwindt, MD,PhD, LUMC

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2019
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: June 28, 2019
• First Submitted That Met QC Criteria: July 2, 2019
• First Posted (Actual): July 5, 2019

Study Record Updates

• Last Update Posted (Actual): December 8, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Women; Migraine; Vitamin E; Oral contraceptive pill; Hormones
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protective Agents; Estrogens; Micronutrients; Vitamins; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral, Combined; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Antioxidants; Contraceptives, Oral, Hormonal; Levonorgestrel; Ethinyl Estradiol; Vitamin E; Ethinyl estradiol, levonorgestrel drug combination
• Other Study ID Numbers: WHATT; 2018-004096-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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