Comparison of a Drug and Placebo in the Prevention of Migraine Headaches

Phase 1

Terminated

Conditions: Headache, Migraine

Interventions: Other: placebo comparator
Drug: ethosuximide

Registration Number: NCT01122381

Lead Sponsor: US Department of Veterans Affairs

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 5

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).

Exclusion Criteria

Veterans with migraine plus other systemic disorder will be excluded if migraine onset was temporally related to onset of the systemic disorder.
Blood pressure elevations (must be < borderline values 135/85 for 4 weeks before enrollment into the study). Current treatment for hypertension with beta-blockers, calcium channel blockers, or ace inhibitors not allowed.
Use of other prophylactic migraine drugs (requires a washout phase) and cannot have failed more than two other prophylactic drugs for migraine.
Excessive use of acute pain medicines, including narcotics (>10 days month). Those using non-narcotics could be tapered off over 4-8 weeks.
Receiving disability or seeking disability for headache or chronic pain.
Significant neck pain or cervicogenic contributors to chronic headache.
Significant depression, anxiety, post-traumatic stress disorder, or other disabling psychiatric condition.
Known allergies or serious side effects with ESX or succinimides in the past.
Known liver or significant renal disease.
Women veterans of child-bearing age who do not have adequate birth control.
Chronic bone marrow suppression.
Using psychogenic or other sedating maintenance drugs.
History of porphyria.
History of cluster headache. 15.History of other CNS disease.
Age younger than 18 years and greater than 65.
Women veterans who are breastfeeding.
Veterans with familial hemiplegic migraine (FHM).

Ongoing exclusions during the study:

The addition of other migraine prophylactic headache medicines is not allowed. 2. New drugs cannot be added that aggravate headache (nitrates, dipyridamole, niacin).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 2-placebo comparator	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
Arm 1-ethosuximide	ethosuximide	ethosuximide blinded capsules of 250mg ESX; titration up to 4 capsules qd (expected) or 5 or 6 capsules for efficacy (not to exceed "30mg"/kg/d) vs maximum tolerability

Primary Outcome Measures

Name	Time	Method
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.

Secondary Outcome Measures