Duration of Benefit for OnabotulinumtoxinA in Treatment of Chronic Migraine

July 11, 2016 updated by: Cady, Roger, M.D.

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
44

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • Springfield, Missouri, United States, 65807
        • Clinvest/A Division of Banyan Group, Inc.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Other: onabotulinumtoxinA
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).
Drug: onabotulinumtoxinA
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).
Other Names:
  • Botox

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Subject Global Impression of Change
Time Frame: Weeks 12, 24, and 36 Post Randomization
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.
Weeks 12, 24, and 36 Post Randomization
Duration of onabotulinumtoxinA Over 3 Injection Cycles in Groups A, B, and C
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
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.
From day 29 (first day of injection cycle 1) to day 281 (84th day of injection cycle 3) plus or minus 12 days

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Headache Days
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
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.
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)
Time Frame: Baseline, Week 12, Week 24, and Week 36 Post Randomization

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.
Baseline, Week 12, Week 24, and Week 36 Post Randomization
Social Readjustment Rating Scale (SRRS)
Time Frame: Baseline, Week 12, Week 24, and Week 36 Post Randomization
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.
Baseline, Week 12, Week 24, and Week 36 Post Randomization
Physician Global Impression of Change (PGIC)
Time Frame: Week 12, Week 24, and Week 36 Post Randomization
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.
Week 12, Week 24, and Week 36 Post Randomization
Beck Depression Inventory II (BDI-II)
Time Frame: Baseline, Week 12, Week 24, and Week 36 Post Randomization
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
Baseline, Week 12, Week 24, and Week 36 Post Randomization
State-Trait Anxiety Inventory (STAI)
Time Frame: Baseline, Week 12, Week 24, and Week 36 Post Randomization
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.
Baseline, Week 12, Week 24, and Week 36 Post Randomization
Sleep Quality Question
Time Frame: Baseline, Week 12, Week 24, and Week 36 Post Randomization
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.
Baseline, Week 12, Week 24, and Week 36 Post Randomization
Acute Medication Usage
Time Frame: From day 1 (first day of baseline) to day 281 (84th day of injection cycle 3) plus or minus 12 days
Comparison of acute medication usage between Groups A, B, and C during baseline, Treatment Period 1, 2, and 3.
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
Time Frame: Weeks 12, 24, and 36 Post Randomization
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.
Weeks 12, 24, and 36 Post Randomization
Duration of onabotulinumtoxinA Over 3 Injection Cycles
Time Frame: Weeks 9, 10, 11, 12, 21, 22, 23, 24, 33, 34, 35, 36 Post Randomization
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.
Weeks 9, 10, 11, 12, 21, 22, 23, 24, 33, 34, 35, 36 Post Randomization

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Neuronal Regrowth
Time Frame: Baseline & Week 12 Post Randomization
Compare neuronal regrowth in the skin biopsies with duration of benefit of onabotulinumtoxinA in Groups A, B, C from baseline to 12 weeks post randomization. Neuronal regrowth change was scored on a 0-3 point scale with 0 being no change from baseline in regrowth and 3 being significant change from baseline.
Baseline & Week 12 Post Randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Cady, Roger, M.D.

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Allergan

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Roger K Cady, M.D., Clinvest

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 1, 2014

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 1, 2015

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 1, 2015

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 14, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 14, 2014

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 16, 2014

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 11, 2016

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 11, 2016

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 13-002AL

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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