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

Pharmacologic and Genetic Evaluation of a C. Elegans Model for Migraine

The purpose of this study is to determine whether ethosuximide works better than placebo in the prevention of episodic migraine among veterans.

Study Overview

• Status: Terminated
• Conditions: Headache, Migraine
• Intervention / Treatment: Drug: ethosuximide; Other: placebo comparator

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15240
      • VA Pittsburgh Health Care System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1-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	Drug: ethosuximide; ethosuximide (ESX); Other Names: zarontin
Placebo Comparator: Arm 2-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	Other: placebo comparator; placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	4 weeks, end of treatment and pre-treatment baseline

Collaborators and Investigators

• Sponsor: US Department of Veterans Affairs
• Collaborators: University of Pittsburgh; Thomas Jefferson University
• Investigators: Principal Investigator: Kathy L Gardner, MD, VA Pittsburgh Health Care System

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: May 10, 2010
• First Submitted That Met QC Criteria: May 10, 2010
• First Posted (Estimate): May 13, 2010

Study Record Updates

• Last Update Posted (Estimate): August 19, 2015
• Last Update Submitted That Met QC Criteria: August 11, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: depression; weight gain; headache, migraine; disability evaluation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; Headache; Anticonvulsants; Ethosuximide
• Other Study ID Numbers: B5043-R