Metformin for the Prevention of Episodic Migraine (MPEM)
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Migraine Headaches |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 2/8/2019 |
| Start Date: | February 2016 |
| End Date: | June 2019 |
Metformin for the Prevention of Episodic Migraine: a Randomized, Double-blind, Placebo-controlled, Crossover Study
Migraine is the third most prevalent disease in the world. Preventive treatment is indicated
in about 40% of individuals with episodic migraine. Although 4 treatments are approved by the
US Food and Drug Administration for prevention of episodic migraine, none were designed to
prevent migraine, efficacy is modest, and all have significant adverse-event profiles. As a
result, less than 1/3 of migraine sufferers with who are candidates for prevention receive
drug treatment and of those who are treated, more than 85% have discontinued the preventive
drug within one year. Migraine pain is associated with the activation and sensitization of
specific receptors involved in pain-promoting pathways. Metformin, which is a widely
available, well-tolerated anti-diabetic medication, can downregulate pain-promoting pathways.
Metformin has demonstrated positive results in animal models of migraine in the laboratory.
Given the longstanding use and established safety record of metformin, the investigators will
evaluate the safety and efficacy of metformin for preventive treatment of migraine in a
randomized, double-blind, placebo-controlled, crossover trial.
in about 40% of individuals with episodic migraine. Although 4 treatments are approved by the
US Food and Drug Administration for prevention of episodic migraine, none were designed to
prevent migraine, efficacy is modest, and all have significant adverse-event profiles. As a
result, less than 1/3 of migraine sufferers with who are candidates for prevention receive
drug treatment and of those who are treated, more than 85% have discontinued the preventive
drug within one year. Migraine pain is associated with the activation and sensitization of
specific receptors involved in pain-promoting pathways. Metformin, which is a widely
available, well-tolerated anti-diabetic medication, can downregulate pain-promoting pathways.
Metformin has demonstrated positive results in animal models of migraine in the laboratory.
Given the longstanding use and established safety record of metformin, the investigators will
evaluate the safety and efficacy of metformin for preventive treatment of migraine in a
randomized, double-blind, placebo-controlled, crossover trial.
The investigators will obtain approval from the Mayo Clinic Institutional Review Board, and
all patients will provide written, informed consent before study enrollment.
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.
Inclusion criteria are as follows: 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 (2013), and 3) 5-25 migraine days per month on average during the preceding 3
months. Women of reproductive ability must use a reliable form of contraception beginning 3
months before study enrollment, throughout the study, and for at least 1 month after study
completion.
Exclusion criteria are as follows: 1) a diagnosis of diabetes mellitus or polycystic ovarian
syndrome, 2) overuse of acute migraine treatments, 3) failure to respond to 3 or more
previous 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, and 7) pregnant or breastfeeding.
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.
A statistician will create a randomized treatment allocation schedule by using a computerized
random number generator. The randomized treatment allocation schedule will be stored using
the REDCap randomization module. The Mayo Clinic Pharmacy will allocate patients to the
metformin-placebo sequence or the placebo-metformin sequence in a 1:1 ratio.
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.
The primary end point is the number of migraine days per month during treatment with
metformin vs placebo. The secondary end point is the percentage of patients with >50%
reduction in migraine days per month (response rate). Adverse events will be recorded. Mean
4-week migraine frequency for patients receiving metformin vs placebo treatment will be
assessed by using the Hills-Armitage method. Response rate will be assessed by using the
McNemar test. The statistician will create Web-based case report forms using REDCap. Study
coordinators will record data using REDCap forms.
If this crossover study demonstrates that metformin is an effective and well-tolerated
medication for patients with migraine, it will serve as pilot data for a large double-blind,
randomized, controlled study.
These studies will not only present a new, safe, well-tolerated therapeutic option for
patients with migraine, but also further elucidate the neurobiology of migraine. If AMPK is
confirmed as a novel target for migraine treatment, drug discovery could identify
more-powerful and safe activators of AMPK with improved efficacy and tolerability.
all patients will provide written, informed consent before study enrollment.
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.
Inclusion criteria are as follows: 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 (2013), and 3) 5-25 migraine days per month on average during the preceding 3
months. Women of reproductive ability must use a reliable form of contraception beginning 3
months before study enrollment, throughout the study, and for at least 1 month after study
completion.
Exclusion criteria are as follows: 1) a diagnosis of diabetes mellitus or polycystic ovarian
syndrome, 2) overuse of acute migraine treatments, 3) failure to respond to 3 or more
previous 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, and 7) pregnant or breastfeeding.
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.
A statistician will create a randomized treatment allocation schedule by using a computerized
random number generator. The randomized treatment allocation schedule will be stored using
the REDCap randomization module. The Mayo Clinic Pharmacy will allocate patients to the
metformin-placebo sequence or the placebo-metformin sequence in a 1:1 ratio.
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.
The primary end point is the number of migraine days per month during treatment with
metformin vs placebo. The secondary end point is the percentage of patients with >50%
reduction in migraine days per month (response rate). Adverse events will be recorded. Mean
4-week migraine frequency for patients receiving metformin vs placebo treatment will be
assessed by using the Hills-Armitage method. Response rate will be assessed by using the
McNemar test. The statistician will create Web-based case report forms using REDCap. Study
coordinators will record data using REDCap forms.
If this crossover study demonstrates that metformin is an effective and well-tolerated
medication for patients with migraine, it will serve as pilot data for a large double-blind,
randomized, controlled study.
These studies will not only present a new, safe, well-tolerated therapeutic option for
patients with migraine, but also further elucidate the neurobiology of migraine. If AMPK is
confirmed as a novel target for migraine treatment, drug discovery could identify
more-powerful and safe activators of AMPK with improved efficacy and tolerability.
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.
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