Duration of Benefit for OnabotulinumtoxinA in Treatment of Chronic Migraine

Exploratory Study of the Natural History, Clinical Outcomes, and Neuronal Endplate Changes in Subjects Reporting Short Duration vs. Long Duration of Benefit for OnabotulinumtoxinA in Treatment of Chronic Migraine

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

Inclusion Criteria:

• male or female 18 years or older.
• able to read, understand, and sign the informed consent.
• a negative urine pregnancy test at visit 1, if female, and of childbearing potential. Note: If female of childbearing potential, subject must agree to maintain true abstinence or use one of the listed methods of birth control for the duration of the study: hormonal contraceptive, intrauterine device (IUD), condoms, diaphragm, and/or have a male partner who has undergone a successful vasectomy. The use of barrier contraceptive (condom or diaphragm) should always be supplemented with the use of a spermicide.

Note: To be considered not of childbearing potential, subject must be 6 weeks post-surgical bilateral oophorectomy, hysterectomy, bilateral tubal ligation, postmenopausal for at least one year.

• at least a one year history of migraine
• history of chronic migraine (with or without aura) according to the criteria of the International Classification of Headache Disorders (ICHD)-3 for at least 3 months prior to enrollment (Appendix I)
• able to differentiate migraine headache from any other headache they may experience (e.g., cluster headache)
• onset of migraine before age 50
• willing to provide responses to questionnaires and complete the online diary.
• if taking migraine preventive(s), be on a stable dose of the preventive medication for at least 30 days prior to screening
• concomitant medication dosages approved by the investigator
• email and internet access for completion of online diary

Exclusion Criteria:

• previously used onabotulinumtoxinA as a migraine preventative or has used onabotulinumtoxinA for any other reason during the prior year
• female who is pregnant, planning to become pregnant during the study period, breast feeding, or is of childbearing potential and not practicing a reliable form of birth control
• headache disorders outside ICHD-3 defined chronic migraine that cannot be easily distinguished from CM (Appendix I)
• evidence of underlying pathology contributing to their headaches
• any medical condition that may increase their risk with exposure to BTX including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or any other significant disease that might interfere with neuromuscular function
• profound atrophy or weakness of muscles in the target areas of injection
• skin conditions or infections at any of the injection sites
• allergy or sensitivities to any component of the test medication
• in the opinion of the investigator, has an active major psychiatric disorder including substance abuse and/or substance dependence within the last 12 months as determined by the investigator.
• Medication Overuse Headache as defined by ICHD-3 criteria for opioid or butalbital containing products (Appendix II)
• planning or requiring surgery during the study
• a history of poor compliance with medical treatment
• currently participating in an investigational drug study or has participated in an investigational drug study within the previous 30 days of the screening visit