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

This study has been terminated.
(poor recruitment)
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: May 1, 2014
Last verified: April 2014

May 10, 2010
May 1, 2014
December 2011
April 2014   (final data collection date for primary outcome measure)
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 ]
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 baselin ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01122381 on ClinicalTrials.gov Archive Site
  • 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 ]
  • 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 ]
  • 5)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 ]
Not Provided
Not Provided
 
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.

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.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Headache, Migraine
  • 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
  • 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
  • Experimental: Arm 1
    migraineurs with 4-14 headache days per month that meet all inclusion/exclusion criteria
    Intervention: Drug: ethosuximide
  • 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
    Intervention: Other: placebo comparator
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
128
April 2014
April 2014   (final data collection date for primary outcome measure)

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
Both
18 Years to 65 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01122381
B5043-R
Yes
Department of Veterans Affairs
Department of Veterans Affairs
  • Thomas Jefferson University
  • University of Pittsburgh
Principal Investigator: Kathy L Gardner, MD VA Pittsburgh Health Care System
Department of Veterans Affairs
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP