To obtain a patient specific understanding of response to treatment with onabotulinumtoxinA by collecting and correlating pre and post treatment subject specific history, clinical outcomes, and histological changes.
Recognizing a commitment to evidence-based science as the pathway to optimize clinical outcomes for patients with chronic migraine (CM) we believe this investigator initiated study (IIS) will: 1. Help clinicians recognize the importance of scheduling patients with CM at intervals not exceeding 12 weeks. 2. Provide biopsy evidence supporting sensory mechanisms involved in the mechanism of action (MOA) of onabotulinumtoxinA (BTX). This does not exclude potential valuable contributions of denervation of motor neurons, but may support a more balanced and understandable mechanism for BTX in treating CM. 3. Provide clinicians important educational information for patients to better manage expectations of using BTX in managing CM and answering critical questions such as: 1. How long does it take for BTX to begin providing a clinical benefit? 2. What is the expected duration of this benefit? * Failure to understand unmet expectations either real or otherwise results in defining BTX treatment as a failure by patients and/or clinicians. 4. Provide validation for patients' reports of shorter duration of action of BTX so patients will not be misinterpreted as non-responders to BTX prematurely. 5. Ascertain if subjects initially reporting short duration of BTX response continue to experience this similar pattern of effect with repeated injection cycles. 6. Provide the first detailed longitudinal assessment of BTX response. 7. Correlate the onset and duration of benefit for subjects receiving BTX. 8. Observe factors predictive of duration of BTX response. This study proposes to accomplish these goals through an exploratory comparison of the clinical efficacy and natural history of BTX measured at weekly time intervals. Subjects reporting short (\<10 weeks) duration of benefit and subjects reporting long (\>10 weeks) duration of clinical benefit will provide the primary comparison. Histological examinations (in a subset of subjects) of neuronal changes associated with regeneration of terminal neuronal endplates will be used to support these clinical observations. This study will follow subjects through 3 injection cycles or 36 weeks. Biopsies will be performed on consenting subjects prior to their first and second injection cycles. Group Assignment At Visit 3, subjects will be assigned to one of three groups (Groups A, B, C) based on their answers to the following questions: 1. Since your last BTX treatment, do you think there has been improvement in your chronic migraine? If the answer to Q1 is yes, subject will answer Q2 and Q3. If the answer is no, subject is assigned to Group C and no further answers are required: 2. How many days did it take for you to first notice benefit from BTX injections? 3. How long did you feel you received benefit from BTX (number of weeks)? Subjects will be assigned into 3 groups: 1. Group A are subjects reporting 10 or less weeks of benefit from BTX; 2. Group B are subjects reporting \>10 weeks of benefit from BTX; 3. Group C are subjects reporting no or minimal (\< 30%) benefit from BTX. Consistency of subjects' perception of BTX benefit at 12 weeks will be compared to responses at 24 and 36 weeks, though Group assignment will remain as defined at 12 weeks. This exploratory study will be conducted at the Headache Care Center in Springfield, MO. Thirty-six subjects, 18 years and older with a history of chronic migraine will be enrolled. The study will consist of 5 visits for all subjects. At Visit 1 (day 1 of baseline) the following study procedures will be performed: * Informed Consent obtained * Migraine, medical and medication history obtained * Physical and neurological exam performed * Urine pregnancy test performed if applicable * Vital signs collected At Visit 2 (day 29 +/- 3 days) the following study procedures will be performed: * Update medical and medication history * Urine pregnancy test performed if applicable * Vital signs collected * Review baseline diary * Complete Migraine Disability Assessment Scale (MIDAS) * Complete Social Readjustment Rating Scale (SRRS) * Complete Beck Depression Inventory II (BDI-II) * Complete State-Trait Anxiety Inventory (STAI) * Complete Sleep Quality Questionnaire * Punch biopsy for neuronal regrowth (subset of subjects) * onabotulinumtoxinA injections At Visit 3 (day 113 +/- 3 days) the following study procedures will be performed: * Update medical and medication history * Urine pregnancy test performed if applicable * Vital signs collected * Complete Subject Global Impression of Change (SGIC) * Complete Physician Global Impression of Change (PGIC) * Complete Migraine Disability Assessment Scale (MIDAS) * Complete Social Readjustment Rating Scale (SRRS) * Complete Beck Depression Inventory II (BDI-II) * Complete State-Trait Anxiety Inventory (STAI) * Complete Sleep Quality Questionnaire * Complete duration of response to onabotulinumtoxinA questions * Punch biopsy for neuronal regrowth (subset of subjects) * onabotulinumtoxinA injections At Visit 4 (day 197 +/- 3 days) the following study procedures will be performed: * Update medical and medication history * Urine pregnancy test performed if applicable * Vital signs collected * Complete Subject Global Impression of Change (SGIC) * Complete Physician Global Impression of Change (PGIC) * Complete Migraine Disability Assessment Scale (MIDAS) * Complete Social Readjustment Rating Scale (SRRS) * Complete Beck Depression Inventory II (BDI-II) * Complete State-Trait Anxiety Inventory (STAI) * Complete Sleep Quality Questionnaire * Complete duration of response to onabotulinumtoxinA questions * onabotulinumtoxinA injections At Visit 5 (day 281 +/- 3 days) the following study procedures will be performed: * Update medical and medication history * Urine pregnancy test performed if applicable * Vital signs collected * Complete Subject Global Impression of Change (SGIC) * Complete Physician Global Impression of Change (PGIC) * Complete Migraine Disability Assessment Scale (MIDAS) * Complete Social Readjustment Rating Scale (SRRS) * Complete Beck Depression Inventory II (BDI-II) * Complete State-Trait Anxiety Inventory (STAI) * Complete Sleep Quality Questionnaire * Complete duration of response to onabotulinumtoxinA questions
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
44
BOTOX® (Formulation Number 9060X) contains 200 International Units (IU) of Clostridium botulinum Toxin Type A, reconstituted with 4 cc of normal saline providing 5 units per 0.1 cc. At visit 2, subjects will receive their first treatment at Day 29 (+/-3 days). All subjects will receive 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. Injections will be repeated at day 113 (+/- 3 days) and at day 197 (+/- 3 days).
Clinvest/A Division of Banyan Group, Inc.
Springfield, Missouri, United States
Subject Global Impression of Change
Changes in the Subject's Global Impression of Change (SGIC) measured at weeks 12, 24, and 36 for Groups A, B, and C. Subject global impression of change was measured on a 7 point scale with 0 being Very Much Worse and 7 Very Much Improved.
Time frame: Weeks 12, 24, and 36 Post Randomization
Duration of onabotulinumtoxinA Over 3 Injection Cycles in Groups A, B, and C
Compare the duration of onabotulinumtoxinA response through the 3 injection cycles of the study for Groups A, B, and C as measured by headache days during each period (Baseline (28 days), Treatment Period 1(84 days), Treatment Period 2(84 days), and Treatment Period 3(84 days). Duration of response is defined as a 30% reduction in the number of headache days compared to baseline.
Time frame: From day 29 (first day of injection cycle 1) to day 281 (84th day of injection cycle 3) plus or minus 12 days
Headache Days
Comparison of headache days per month over each injection cycle between Groups A, B, and C (Baseline (28 days), Treatment Period 1(84 days), Treatment Period 2(84 days), and Treatment Period 3(84 days). Subjects will remain in their assigned groups based on assessment at 12 weeks.
Time frame: From day 29 (first day of injection cycle 1) to day 281 (84th day of injection cycle 3) plus or minus 12 days
Migraine Disability Assessment Scale (MIDAS)
Comparison between Group A, B, and C for MIDAS total scores (effect migraine headaches have on subjects daily function) measured at baseline and weeks 12, 24, and 36. Total score of disability ranges: * 0 to 5, MIDAS Grade I, Little or no disability * 6 to 10, MIDAS Grade II, Mild disability * 11 to 20, MIDAS Grade III, Moderate disability * 21+, MIDAS Grade IV, Severe disability Score ranges from 0-450. No subscales are present.
Time frame: Baseline, Week 12, Week 24, and Week 36 Post Randomization
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Social Readjustment Rating Scale (SRRS)
Comparison between Group A, B, and C for SRRS scores (impact of common stressors) measured at baseline and weeks 12, 24, and 36. Scores can range from 0 to an undetermined amount, as subjects are allowed to rate unlisted events according to their own sense of stress. A total lower than 150 suggests a low level of stress and a low probability of developing a stress-related disorder. Scores greater than 150 suggest higher levels of stress and higher probabilities of developing stress-related disorders.
Time frame: Baseline, Week 12, Week 24, and Week 36 Post Randomization
Physician Global Impression of Change (PGIC)
Comparison between Group A, B, and C for PGIC scores measured at weeks 12, 24, and 36. the PGIC scale scores range from 0-7 with 0 being Very Much Worse and 7 being Very Much Improved. A higher score indicates a greater impression of change.
Time frame: Week 12, Week 24, and Week 36 Post Randomization
Beck Depression Inventory II (BDI-II)
Comparison between Group A, B, and C for BDI-II scores measured at baseline and weeks 12, 24, and 36. A total score of 0-10 = these ups and downs are considered normal, 11-16 = mild mood disturbance,17-20 = borderline clinical depression, 21-30 = moderate depression, 31-40 = severe depression, over 40 = extreme depression
Time frame: Baseline, Week 12, Week 24, and Week 36 Post Randomization
State-Trait Anxiety Inventory (STAI)
Comparison between Group A, B, and C for STAI scores measured at baseline and weeks 12, 24, and 36. Scores range from 20-80, with 20 indicating lower levels of anxiety most generally, and 80 indicating higher levels of anxiety most generally.
Time frame: Baseline, Week 12, Week 24, and Week 36 Post Randomization
Sleep Quality Question
Comparison between Group A, B, and C for sleep quality scores measured at baseline and weeks 12, 24, and 36 post-randomization. A single sleep quality question was asked indicating quality of sleep over the past four weeks. The scale ranged from 1-5, with 1 being very poor quality and 5 being very good quality of sleep.
Time frame: Baseline, Week 12, Week 24, and Week 36 Post Randomization
Acute Medication Usage
Comparison of acute medication usage between Groups A, B, and C during baseline, Treatment Period 1, 2, and 3.
Time frame: From day 1 (first day of baseline) to day 281 (84th day of injection cycle 3) plus or minus 12 days
Consistency of Response to onbotulinumtoxinA Over Three Injection Cycles
Compare the consistency of duration of onabotulinumtoxinA response by the group assignment at 12 weeks to assessments at 24, and 36 weeks evaluations as measured by the number of responders. A responder is defined as a 30% reduction from baseline in the number of headache days.
Time frame: Weeks 12, 24, and 36 Post Randomization
Duration of onabotulinumtoxinA Over 3 Injection Cycles
Compare duration of benefit of onabotulinumtoxinA response through 3 injection cycles as measured by headache days per week (including the last 4 weeks of every injection cycle). A percent of responders was calculated using a 30% reduction of the number of headache days compared to average number of headache per week during baseline.
Time frame: Weeks 9, 10, 11, 12, 21, 22, 23, 24, 33, 34, 35, 36 Post Randomization