Migraine
Conditions
Brief summary
The investigators will evaluate the safety and efficacy of metformin for preventive treatment of migraine in a randomized, double-blind, placebo-controlled, crossover trial.
Detailed description
This will be a single-center, double-blind, randomized, placebo-controlled, crossover study. The investigators will enroll 40 subjects. Subjects will be recruited from the outpatient Mayo Headache Clinic, Mayo Women's Health Clinic, Mayo Community Internal Medicine, and the Mayo Clinic- Arizona State University Neurology Clinic. The Headache Clinic employs 6 headache specialists and 1 fellow which is sufficient staffing to support this study and recruitment of patients with migraine. Before study enrollment, patients will undergo a 2-hour oral glucose tolerance test to confirm the absence of diabetes mellitus. Subjects will then keep a headache diary for 4 weeks to establish baseline characteristics, including number of migraine days per month, number of moderate to severe headache days per month, and number of days per month of acute medication use. The 4-week baseline period will be followed by 2 treatment periods of 12 weeks each, separated by a washout period of 4 weeks (total study duration, 32 weeks). For the 12-week treatment periods, subjects will receive either metformin 500mg twice daily or matching placebo twice daily. Subjects will have 7 study visits. Routine laboratory studies and a pregnancy test will be performed at enrollment and week 20. Abnormal kidney or liver function will exclude subjects. Pregnancy will exclude subjects. General and neurologic examinations will be performed during 3 of the 7 visits. At each visit, subjects will receive medication for the period until the next visit. A headache diary will be used for the trial. For every day that the subject has a headache of any type, she or he will record headache characteristics, associated features, and medications used.
Interventions
DRUGMetformin
Metformin 500mg twice daily
DRUGMatching Placebo
Matching Placebo twice daily
Sponsors
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. age 18-65 years 2. a diagnosis of migraine with or without aura for \>1 year according to the International Classification of Headache Disorders-IIIb
Exclusion criteria
1. a diagnosis of diabetes mellitus or polycystic ovarian syndrome 2. overuse of acute migraine treatments 3. failure to respond to 3 or more classes of preventive drug treatments 4. change in dose of migraine-preventive medication within 2 months of beginning the baseline diary phase 5. significant somatic or psychiatric disease 6. known alcohol or other substance abuse 7. pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Headache Days | Baseline through end of study for a total of approximately 32 weeks | Total number of moderate and severe headache days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Greater Than >50% Reduction in Migraine Days on Metformin | 12 weeks | Percentage of patients whose migraines reduced by at least 50% on Metformin. |
| Adverse Events | Baseline through end of study for a total of approximately 32 weeks | Total number of subjects with treatment-related adverse events |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin First, Then Matching Placebo Subjects who received Metformin in either the first or last 12 weeks of the study
Subjects will be randomized into the Metformin group, treated for 12 weeks with a 4 week washout period in between treatments, then treated with matching placebo for 12 weeks.
Metformin: Metformin 500mg twice daily
Matching Placebo: Matching Placebo twice daily | 14 |
| Matching Placebo First, Then Metformin Subjects who received matching placebo either the first or last 12 weeks of the study
Subjects will be randomized into the matching placebo group, treated for 12 weeks with a 4 week washout period in between treatments, then treated with Metformin for 12 weeks.
Metformin: Metformin 500mg twice daily
Matching Placebo: Matching Placebo twice daily | 20 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (12 Weeks) | Lost to Follow-up | 1 | 2 |
| First Intervention (12 Weeks) | Withdrawal by Subject | 1 | 2 |
| Second Intervention (12 Weeks) | Lack of Efficacy | 1 | 0 |
| Second Intervention (12 Weeks) | Lost to Follow-up | 1 | 1 |
| Second Intervention (12 Weeks) | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Matching Placebo First, Then Metformin | Total | Metformin First, Then Matching Placebo |
|---|---|---|---|
| Age, Continuous | 46.83 years STANDARD_DEVIATION 10.94 | 45.34 years STANDARD_DEVIATION 8.92 | 43.85 years STANDARD_DEVIATION 6.91 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 20 participants | 34 participants | 14 participants |
| Sex: Female, Male Female | 17 Participants | 28 Participants | 11 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 32 |
| other Total, other adverse events | 12 / 30 | 4 / 32 |
| serious Total, serious adverse events | 0 / 30 | 0 / 32 |
Outcome results
Primary
Headache Days
Total number of moderate and severe headache days
Time frame: Baseline through end of study for a total of approximately 32 weeks
Population: Data was only analyzed for the subjects that completed both interventions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metformin | Headache Days | 23.64 Days | Standard Deviation 2.15 |
| Matching Placebo | Headache Days | 24.33 Days | Standard Deviation 2.19 |
p-value: 0.83Hills-Armitage
Secondary
Adverse Events
Total number of subjects with treatment-related adverse events
Time frame: Baseline through end of study for a total of approximately 32 weeks
Population: Data was only analyzed for the subjects that completed both interventions.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Metformin | Adverse Events | 3 Participants |
| Matching Placebo | Adverse Events | 1 Participants |
Secondary
Greater Than >50% Reduction in Migraine Days on Metformin
Percentage of patients whose migraines reduced by at least 50% on Metformin.
Time frame: 12 weeks
Population: Data was not collected for the matching placebo arm. This outcome measure was specific for metformin, no analysis was done for the placebo.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Greater Than >50% Reduction in Migraine Days on Metformin | 10.1 percentage of subjects |
p-value: 0.16McNemar