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

This study is currently recruiting participants.
Verified February 2013 by Department of Veterans Affairs
Sponsor:
Collaborators:
Thomas Jefferson University
University of Pittsburgh
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT01122381
First received: May 10, 2010
Last updated: February 15, 2013
Last verified: February 2013
History of Changes
  Purpose

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


Condition Intervention Phase
Headache, Migraine
 Drug: ethosuximide
Other: placebo comparator
 Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Pharmacologic and Genetic Evaluation of a C. Elegans Model for Migraine

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • Migraine headache days per 4 week period comparing the last 4 weeks of treatment to a 4 week pre-treatment baseline. [ Time Frame: 4 weeks, end of treatment and pre-treatment baseline ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Determine the percentage with a > 50% reduction and >75% reduction in migraine days last 4 weeks of treatment compared with 4 week baseline [ Time Frame: last 4 weeks of treatment period ] [ Designated as safety issue: No ]
  • Determine changes in frequency /quantity of acute medication use for migraines during last 4 weeks of treatment compared with 4 week baseline [ Time Frame: last 4 weeks of treatment period ] [ Designated as safety issue: No ]
  • Determine changes in duration of migraine during last 4 weeks of treatment compared with 4 week baseline [ Time Frame: last 4 weeks of treatment period ] [ Designated as safety issue: No ]
  • Identify and characterize side effects, especially weight gain compared with baseline 4 week period and placebo response group [ Time Frame: duration of treatment period for side effects, end of treatment period compared with start of baseline for weight ] [ Designated as safety issue: Yes ]
  • Provide CBC, LFT, AED (antiepileptic level) monitoring for possible though unlikely bone marrow or liver toxicity and to ensure drug compliance to be drawn at start, end of study, and with monthly visits [ Time Frame: start of study, every 4 weeks, and end of study ] [ Designated as safety issue: Yes ]
  • Compare scoring on the MIDAS migraine disability scale at the end of pretreatment baseline and end of treatment [ Time Frame: end of baseline pre-treatment period to end of treatment period ] [ Designated as safety issue: Yes ]
  • Compare scoring on the Beck Depression Inventory II at end of treatment with end of pretreatment baseline and to the placebo response group [ Time Frame: end of pre-treatment baseline to end of treatment ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 128
Study Start Date: December 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1
migraineurs with 4-14 headache days per month that meet all inclusion/exclusion criteria
 Drug: 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
Other Name: zarontin
Placebo Comparator: 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
 Other: 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

Detailed Description:

Chronic and episodic headaches in veteran populations include migraine, transformed migraine, and post-traumatic headache with migraineous 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 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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Must be a veteran.
  2. 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.
  3. Migraine must have been occurring for 6 months preceding entry into the trial and age of onset should be before age 60 years.
  4. Migraine must be at least moderate severity and interrupt daily activities in some respect at least 3 times per month.
  5. 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.
  6. 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)

  1. > 5 attacks
  2. headache lasting 4-72 hours when untreated or not successfully treated.

  3. headache with two of the following characteristics

    1. unilateral,
    2. pulsating,
    3. moderate to severe intensity,
    4. aggravation by exertion.

  4. one of the following occurs with headache

    1. nausea and/or vomiting
    2. photophobia and phonophobia

Criteria for migraine with aura (I.H.S. 1.2)

  1. at least 2 attacks

  2. at least three of the following characteristics:

    1. 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:

      1. Homonymous visual disturbance
      2. Unilateral parenthesis and/or numbness
      3. Unilateral weakness
      4. Aphasia or unclassifiable speech difficulty
    2. At least one aura symptom develops gradually over more than 4 minutes or, 2 or more symptoms occur in succession.
    3. No aura symptom lasts more than 60 minutes. If more than one aura symptom is present, accepted duration is proportionally increased.

    4. 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:

      1. Veterans with migraine plus other systemic disorder will be excluded if migraine onset was temporally related to onset of the systemic disorder.
      2. 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.
      3. Use of other prophylactic migraine drugs (requires a washout phase) and cannot have failed more than two other prophylactic drugs for migraine.
      4. Excessive use of acute pain medicines, including narcotics (>10 days month). Those using non-narcotics could be tapered off over 4-8 weeks.
      5. Receiving disability or seeking disability for headache or chronic pain. 6.Significant neck pain or cervicogenic contributors to chronic headache.

      7.Significant depression, anxiety, post-traumatic stress disorder, or other disabling psychiatric condition.

      8.Known allergies or serious side effects with ESX or succinimides in the past. 9.Known liver or significant renal disease. 10.Women veterans of child-bearing age who do not have adequate birth control. 11.Chronic bone marrow suppression. 12.Using psychogenic or other sedating maintenance drugs. 13.History of porphyria. 14.History of cluster headache. 15.History of other CNS disease. 16.Age younger than 18 years and greater than 65. 17.Women veterans who are breastfeeding. 18. Veterans with familial hemiplegic migraine (FHM).

      Ongoing exclusions during the study:

      1. The addition of other migraine prophylactic headache med

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01122381

Contacts
Contact: Kathy L Gardner, MD (412) 360-6185 kathy.gardner@va.gov
Contact: Greg A Owens, BA (412) 360-1792 gregory.owens@va.gov

Locations
United States, Pennsylvania
VA Pittsburgh Health Care System Recruiting
Pittsburgh, Pennsylvania, United States, 15240
Contact: Nicholas L Squeglia     412-954-5387     nicholas.squeglia@va.gov    
Contact: Steven H Graham, MD PhD     (412) 954-5386     steven.graham@va.gov    
Principal Investigator: Kathy L Gardner, MD            
Sponsors and Collaborators
Department of Veterans Affairs
Thomas Jefferson University
University of Pittsburgh
Investigators
Principal Investigator: Kathy L Gardner, MD VA Pittsburgh Health Care System
  More Information

No publications provided

Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT01122381     History of Changes
Other Study ID Numbers: B5043-R
Study First Received: May 10, 2010
Last Updated: February 15, 2013
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by Department of Veterans Affairs:
headache, migraine
depression
disability evaluation
weight gain

Additional relevant MeSH terms:
Headache
Migraine Disorders
Pain
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Headache Disorders, Primary
Headache Disorders
 Brain Diseases
Central Nervous System Diseases
Ethosuximide
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 16, 2013