Headache, Migraine
Conditions
Keywords
headache, migraine, depression, disability evaluation, weight gain
Brief summary
The purpose of this study is to determine whether ethosuximide works better than placebo in the prevention of episodic migraine among veterans.
Detailed description
Chronic and episodic headaches in veteran populations include migraine, transformed migraine, and post-traumatic headache with migrainous features. More and better prophylactic drugs with fewer side effects (such as weight gain) are needed to treat these disabling, refractory conditions which generally have less than a 50% response rate to preventative treatments. Rare forms of severe familial hemiplegic migraine (FHM) are considered channelopathies and can be caused by mutations in a calcium channel gene. Serotonin is also known to be a critical neurotransmitter in migraine based on the pharmacology of acute and preventative treatments. We previously identified a migraine signaling pathway in an invertebrate C. elegans hemiplegic migraine model of a mutant calcium channel upstream from transforming growth factor-beta (TGF-beta) and showed that low serotonin levels can be rescued by treatment with the childhood antiepileptic drug ethosuximide (ESX). Objective: We propose to test our findings from this invertebrate migraine model to determine its relevance to humans in the prevention of episodic migraine. Primary Aim: Determine whether ethosuximide (ESX) will be significantly more effective than placebo in reducing migraine headache days. We propose a 3 year, double blind, phase 1/2 randomized, 2:1 ESX:placebo controlled parallel trial in episodic migraineurs comparing migraine headache days during the last 4 weeks of treatment to a pre-treatment 4 week baseline.
Interventions
DRUGethosuximide
ethosuximide (ESX)
OTHERplacebo comparator
placebo
Sponsors
Thomas Jefferson University
University of Pittsburgh
US Department of Veterans Affairs
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Must be a veteran. * The number of migraine days per 4-week period is to be 4-14 for a period of 3 months prior to screening for entry into the trial. * Migraine must have been occurring for 6 months preceding entry into the trial and age of onset should be before age 60 years. * Migraine must be at least moderate severity and interrupt daily activities in some respect at least 3 times per month. * As long as the veteran can easily distinguish nonmigraine headaches from migraine, there is no limit on the number of non migraine headache days allowed. Transformed migraine headaches due to medication over usage will be excluded according to
Exclusion criteria
#4. * Migraine diagnosis: Veterans with headache must have migraine categorized using the International Headache Society (I.H.S.) criteria as illustrated below for the two main types with and without aura. Criteria for migraine without aura (I.H.S. 1.1) * \> 5 attacks * headache lasting 4-72 hours when untreated or not successfully treated. * headache with two of the following characteristics * unilateral, * pulsating, * moderate to severe intensity, * aggravation by exertion. * one of the following occurs with headache * nausea and/or vomiting * photophobia and phonophobia Criteria for migraine with aura (I.H.S. 1.2) * at least 2 attacks * at least three of the following characteristics: * One or more fully reversible aura symptoms indicating focal cerebral cortical - and/or brain stem dysfunction. One or more aura symptoms of the following types: * Homonymous visual disturbance * Unilateral parenthesis and/or numbness * Unilateral weakness * Aphasia or unclassifiable speech difficulty * At least one aura symptom develops gradually over more than 4 minutes or, 2 or more symptoms occur in succession. * No aura symptom lasts more than 60 minutes. If more than one aura symptom is present, accepted duration is proportionally increased. * Headache follows aura with a free interval of less than 60 minutes. (It may also begin before or simultaneously with the aura). Headache, nausea and/or photophobia usually follow neurological aura symptoms directly or after a free interval of less than an hour. The headache usually lasts 4-72 hours, but may be completely absent (1.2.5, acephalgic migraine).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Migraine Headache Days Per 4 Week Period Comparing the Last 4 Weeks of Treatment to a 4 Week Pre-treatment Baseline. | 4 weeks, end of treatment and pre-treatment baseline | Compare number of migraine headache days pre and post treatment between the ESX and placebo group. Study terminated early-no outcome data available. The single subject assigned to study drug did not actually take it according to subsequent review of ESX drug levels. |
Countries
United States
Participant flow
Recruitment details
Primary Care and Neurology Clinic prescreening and recruitment from VA Pittsburgh hospitals during the following periods: 1/14/11-4/1/11; 1/14/12-3/19/12; 2/4/13-3/12/14. Average prescreening of datawarehouse records for eligibility = 2954 subjects/month. Average prescreening electronic chart review for eligibility = 265 subjects/month.
Pre-assignment details
5 consented. Initial 4 week baseline period uses headache diary to confirm headache days prior to randomization. 3/5 enrollees did not begin baseline phase; 1 lost to f/u, 1 dis-enrolled due to study interruption, 1 dis-enrolled shortly after consent when another physician began a study excluded drug. 2 enrollees did complete baseline phase.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 migraineurs with 4-14 headache days per month that meet all inclusion/exclusion criteria
ethosuximide: ethosuximide (ESX) 250mg blinded capsules; begin 250mg qd titrating up to 1000mg qd (expected) or 1250mg qd, or 1500mg qd /30mg/kg/d maximum for efficacy goal of \< 50% reduction in headache days versus maximum tolerability | 1 |
| Arm 2 placebo same size blinded capsules as the 250mg ESX; similar titration up to 4 capsules qd (expected) or 5 or 6 capsules for efficacy (not to exceed 30mg/kg/d) vs maximum tolerability
placebo comparator: placebo same size blinded capsules as the 250mg ESX; similar titration up to 4 capsules qd (expected) or 5 or 6 capsules for efficacy (not to exceed 30mg/kg/d) vs maximum tolerability | 1 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | study terminated early | 0 | 1 |
Baseline characteristics
| Characteristic | Arm 1 | Arm 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 |
Outcome results
Primary
Migraine Headache Days Per 4 Week Period Comparing the Last 4 Weeks of Treatment to a 4 Week Pre-treatment Baseline.
Compare number of migraine headache days pre and post treatment between the ESX and placebo group. Study terminated early-no outcome data available. The single subject assigned to study drug did not actually take it according to subsequent review of ESX drug levels.
Time frame: 4 weeks, end of treatment and pre-treatment baseline