A Study to Evaluate the Tolerability of Botox and Topiramate or Botox and Placebo and Effect on Cognitive Efficiency
Condition: Chronic Migraine
MeSH terms: Migraine Disorders
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to evaluate sustained tolerability, quality of life, and change
      in cognitive efficiency following treatment with OnabotulinumtoxinA and daily topiramate vs.
      OnabotulinumtoxinA and daily placebo (Group A vs. Group B).
    

Detailed description: 
      Numerous migraine preventive medications are well known to be associated with cognitive
      impairment and disruption of mood.

      Clinvest would propose a pilot study of chronic migraine patients randomized 1:1 to
      onabotulinumtoxinA and daily topiramate or onabotulinumtoxinA and placebo. This pilot study
      will examine the degree to which subjects are able to tolerate and are satisfied with a
      migraine preventive medication in addition to onabotulinumtoxinA over an extended period of
      time and the effect of the subjects' quality of life compared with onabotulinumtoxinA as a
      single therapy. It will also assess short and long term effects of these two treatments on
      cognition. Cognitive performance will be measured by the Mental Efficiency Workload Test
      (MEWT), a repeated measures handheld neuropsychological test battery that measures mental
      efficiency via 4 sub-tests (Simple Reaction Time, Running Memory, Continuous Performance
      Task, Matching to Sample, and Mathematical Processing) to demonstrate short and long term
      changes in mental status compared to their baseline. The Controlled Oral Word Association
      Test (COWAT) will be used to test verbal fluency and screen for anomic aphasia, a known side
      effect of several migraine prophylactic medications including topiramate.

      Visit 1 - Screening / Baseline Following Informed Consent a medical, headache, and medication
      history will be collected and a physical and neurological exam performed on all subjects. A
      urine pregnancy test will be collected from any subject of child-bearing potential. Vital
      signs and ECG (at the discretion of the investigator) will be completed. The Mental
      Efficiency Workload Test (MEWT) will be administered 3 times to establish a cognitive
      efficiency baseline. The COWAT will be completed. Subjects will be instructed regarding
      completion of the online 1-month Baseline Period Migraine Diary and be instructed to treat
      headaches during the 1-month Baseline Period with their usual acute migraine medication in
      their usual manner.

      Visit 2 - Randomization / Injection Following the 1-month Baseline Period, any change in
      medical or medication history since the previous visit will be collected and a pregnancy test
      collected if appropriate. Vital signs will be recorded. Subjects continuing to meet
      eligibility criteria will be instructed to complete the online Treatment Period Migraine
      Diary daily. The MEWT, HIT-6, Migraine Specific Questionnaire (MSQ) and COWAT will be
      completed. The coordinator will assess compliance with online headache diary and any
      deviation outside of 100% compliance should be documented at the site. If in the
      investigator's opinion, the subject maintained a high level of compliance with the online
      headache diary, subjects will then be randomized into the study.

      Eligible subjects will be randomized 1:1 in a blinded fashion to receive onabotulinumtoxinA
      at 31 fixed-site, fixed-dose injections across seven (7) specific head/neck muscle areas and
      daily topiramate (Group A) or onabotulinumtoxinA at 31 fixed-site, fixed-dose injections
      across seven (7) specific head/neck muscle areas and placebo to match topiramate (Group B).

      Daily study medication (topiramate or placebo) will be dispensed for the following 3 months.

      The Group A topiramate titration schedule will be as follows:

      Week 1: topiramate 25 mg qhs (every night at bedtime) Week 2: topiramate 25 mg bid (twice a
      day) Week 3: topiramate 25 mg q am (everyday before noon) + topiramate 50 mg qhs Week 4:
      topiramate 50mg bid

      Only one dosage adjustment (increase or decrease), based on efficacy or tolerability, may be
      made at the investigator's discretion. Subjects must maintain a dose of at least 50 mg/day to
      remain in the Treatment Period.

      The Group B placebo schedule will be as following:

      Week 1: 1 tab qhs Week 2: 1 tab bid Week 3: 1 tab q am + 2 tabs qhs Week 4: 2 tabs bid

      Subjects will be instructed to complete the online daily Treatment Period Migraine Diary
      during the next 3-month period.

      Following Visit 2, subjects will be phoned monthly and any adverse events collected. Subjects
      will also be sent weekly reminders for 8 weeks following Visit 2 via email to take study
      medication, complete online diary and contact their coordinator for any questions or concerns
      they may have. During the titration period, any subject in Group A experiencing an adverse
      event thought to be related to study medication dosage will return to the clinic at an
      Unscheduled Visit for dosage adjustment.

      Visit 3

      Three months following Visit 2, subjects will return and complete the MEWT, HIT-6, MSQ,
      COWAT, and Subject's Global Impression of Change (SGIC). The Investigator will complete a
      Physician's Global Impression of Change (PGIC). Any change in medical or medication history
      since the previous visit will be collected and a pregnancy test collected if appropriate.
      Vital signs will be recorded. The coordinator will assess compliance with online headache
      diary and any deviation outside of 100% compliance should be documented at the site. If in
      the investigator's opinion, the subject maintained a high level of compliance with the online
      headache diary, subjects will be allowed to continue in the study.

      All subjects will be administered a dose of 155 U onabotulinumtoxinA at 31 fixed-site,
      fixed-dose injections across seven (7) specific head/neck muscle areas.

      Any unused study medication and used packaging will be collected, drug accountability will be
      performed, and daily study medication (topiramate or placebo) will be dispensed for the
      following 3 months.

      Subjects will be instructed to complete the online daily Treatment Period Migraine Diary
      during the next 3-month period.

      Following Visit 3, subjects will be phoned monthly and any adverse events collected.

      Visit 4

      Three months following Visit 3, subjects will return and complete the MEWT, HIT-6, MSQ,
      COWAT, and Subject's Global Impression of Change (SGIC). The Investigator will complete a
      Physician's Global Impression of Change (PGIC). Any change in medical or medication history
      since the previous visit will be collected and a pregnancy test collected if appropriate.
      Vital signs will be recorded. The coordinator will assess compliance with online headache
      diary and any deviation outside of 100% compliance should be documented at the site.

      All subjects will be administered a dose of 155 U onabotulinumtoxinA at 31 fixed-site,
      fixed-dose injections across seven (7) specific head/neck muscle areas.

      Any unused study medication and used packaging will be collected, drug accountability will be
      performed, and daily study medication (topiramate or placebo) will be dispensed for the
      following 3 months.

      Subjects will be instructed to complete the online daily Treatment Period Migraine Diary
      during the next 3-month period.

      Following Visit 4, subjects will be phoned monthly and any adverse events collected.

      Visit 5

      Three months following Visit 4, subjects will return and complete the MEWT, HIT-6, MSQ,
      COWAT, and Subject's Global Impression of Change (SGIC). The Investigator will complete a
      Physician's Global Impression of Change (PGIC). Any change in medical or medication history
      since the previous visit will be collected and a pregnancy test collected if appropriate.
      Vital signs will be recorded. The coordinator will assess compliance with online headache
      diary and any deviation outside of 100% compliance should be documented at the site.

      All subjects will be administered a dose of 155 U onabotulinumtoxinA at 31 fixed-site,
      fixed-dose injections across seven (7) specific head/neck muscle areas.

      Any unused study medication and used packaging will be collected, drug accountability will be
      performed, and daily study medication (topiramate or placebo) will be dispensed for the
      following 3 months.

      Subjects will be instructed to complete the online daily Treatment Period Migraine Diary
      during the next 3-month period.

      Following Visit 5, subjects will be phoned monthly and any adverse events collected.

      Visit 6

      Three months following Visit 5, subjects will return and complete the MEWT, HIT-6, MSQ,
      COWAT, and Subject's Global Impression of Change. The Investigator will complete a
      Physician's Global Impression of Change. Any change in medical or medication history since
      the previous visit will be collected and a pregnancy test collected if appropriate. Vital
      signs will be recorded. The coordinator will assess compliance with online headache diary and
      any deviation outside of 100% compliance should be documented at the site.

      Any unused study medication and used packaging will be collected and drug accountability will
      be performed.

      Subjects will exit the study at Visit 6.
    

Intervention name(s): onabotulinumtoxinA; Topiramate; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): All subjects will receive a minimum dose of 155 U Botulinum Toxin Type A Purified Neurotoxin Complex administered at 31 fixed-site, fixed-dose injections across seven (7) specific head/neck muscle areas at Visits 2-5.; Subjects randomized to the onabotulinumtoxinA + topiramate group will receive:
Week 1: topiramate 25 mg qhs Week 2: topiramate 25 mg bid Week 3: topiramate 25 mg q am + topiramate 50 mg qhs Week 4: topiramate 50 mg bid Only one dosage adjustment (increase or decrease), based on efficacy or tolerability, may be made at the investigator's discretion. Subjects must maintain a dose of at least 50 mg/day to remain in the Treatment Period.; Subjects randomized to the onabotulinumtoxinA + placebo group will receive:
Week 1: placebo 25 mg qhs Week 2: placebo 25 mg bid Week 3: placebo 25 mg q am + placebo 50 mg qhs Week 4: placebo 50 mg bid Only one dosage adjustment (increase or decrease), based on efficacy or tolerability, may be made at the investigator's discretion. Subjects must maintain a dose of at least 50 mg/day to remain in the Treatment Period.
Other intervention name(s): Botox, Botulinum Toxin Type A Purified Neurotoxin Complex; Topamax
Intervention MeSH terms: Topiramate; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Migraine; Chronic Migraine; Cognitive Efficiency; Pilot Study; Long Term Effect