Headache, Migraine, Migraine Disorders, Pediatrics
Conditions
Brief summary
The purpose of the research is to examine the outcomes of pediatric patients receiving Botulinum toxin type A (Botox ®) for the treatment of migraine. There is limited literature on the effectiveness of Botox ® in the treatment of chronic neurological pain in pediatric patients, specifically in the treatment of migraines.
Detailed description
Medical Literature approximates one in three children will experience chronic headaches in their lifetime, which increases as children reach adolescence. Migraines make up nearly 60% of all visits to a pediatric headache specialist. Studies have demonstrated the negative impact of having childhood migraine on overall quality of life is similar to pediatric cancer, heart disease and rheumatic disease. As the frequency of migraine attacks increase, so does proportionally the child's disability in lost school time and family and social interactions, all of which may lead in turn to economic disability. Studies estimate the health care costs are 70% higher for a family with a migraine than a non-migraine affected family, and direct medical costs for children with migraine are reported to be similar to those for adults. A study published in JAMA 2003 found that health care costs, work-related disability for parents and lost educational opportunity for the child leads to an annual economic impact in the US of approximately $36 billion due to both direct medical costs and lost productivity into adulthood. Onaboutlinum (BOTOX) is currently FDA approved as a very successful treatment to prevent migraines in adults, however not yet children. Current treatments for migraine in children appear to be insufficient. No trials currently exist in literature prospectively studying onabotulinumtoxinA for efficacy and/or safety for indication of pediatric migraine, although significant contributions have been made by retrospective case series over the last 10 years. This research will be the first investigator-initiated study to study BOTOX (R) in children prospectively in a randomized controlled placebo, cross-over study. The overriding rationale is to demonstrate efficacy, tolerability and safety of onabotulinumtoxinA for pediatric migraine and thereby potentially hasten the lengthy process to evaluate BOTOX® for approval in the pediatric population.
Interventions
DRUGOnabotulinumtoxinA
The AB subject group will receive OnabotulinumtoxinA in the first treatment and saline placebo in the second.Both groups will then receive OnabotulinumtoxinA in the last two treatments. There will be one treatment at the beginning of each 12 week block, meaning 4 treatments over the 48 week study period total. Progress check-ups will occur every 6 weeks during the study. Randomization will be via selection of sealed envelope.
OTHERPlacebo (Saline)
The BA subject group will receive saline and then Onabotulinumtoxin. A.Both groups will then receive OnabotulinumtoxinA in the last two treatments. There will be one treatment at the beginning of each 12 week block, meaning 4 treatments over the 48 week study period total. Progress check-ups will occur every 6 weeks during the study. Randomization will be via selection of sealed envelope.
Sponsors
American Society of Regional Anesthesia
University of California, Irvine
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
8 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Children aged 8 - 17 years of age with a history of migraine meeting the criteria established in ICHD-II (2004), Section 1. Patients will provide at least 28-day baseline data in the form in the daily diary and must have at least 15 days of reported headache during this period, with at least 4 distinct episodes lasting at least 4 hours each.
Exclusion criteria
* Previous use of botulinum toxin of any serotype for any reason * Pregnancy. * Diagnosis of Myasthenia gravis, Eaton Lambert Syndrome, Amyotrophic Lateral Sclerosis * Treatment of headache using acupuncture, transcutaneous electrical stimulation (TENS), cranial traction, dental splints, or injection of anesthetics/steroids within 4 weeks prior to the week of screening visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Migraines | Baseline (4 weeks) and 12 weeks post each, respective intervention | The frequency of migraines in days. |
| Migraine Duration, in Hours | Baseline (4 weeks) and 12 weeks post each, respective intervention | Duration of migraines in hours. |
| Intensity of Migraines | Baseline (4 weeks) and 12 weeks post each, respective intervention | Median intensity of migraines based on 0-10 Pain Numeric Rating Score (NRS). The higher the score, the more intense the pain. |
| Pediatric Migraine Disability Score (PedMIDAS) | Baseline (4 weeks) and 12 weeks post each, respective intervention | Pediatric Migraine Disability Score consists of 6 questions: 3 addressing school attendance and functioning, and 3 evaluating participation in events outside of school. The questionnaire is based on the patient's recall of the previous 3 months. The questionnaire produces a raw score (0-10, 11-30, 31-50, \>50) corresponding to a disability grade with increasing severity (little to non, mild, moderate, and severe) which was coded (1, 2, 3, and 4). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Emergency Department (ED) Visits | Baseline (4 weeks) and 12 weeks post each, respective intervention | Subject visited an Emergency Department |
| School Plan Enrollment | Baseline (4 weeks) and 12 weeks post each, respective intervention | Subject is enrolled in a school plan such as IEP, 504 plan, or similar modified school schedule. |
| Duration of Benefit | Baseline (4 weeks) and 12 weeks post each, respective intervention | The duration of benefit in weeks |
| Concomitant Headache Medications | Baseline (4 weeks) and 12 weeks post each, respective intervention | Number of concomitant headache medications taken |
| Home School | Baseline (4 weeks) and 12 weeks post, respective intervention | Subject is home schooled full-time. |
| Functionality Improvement | Baseline (4 weeks) and 12 weeks post each, respective intervention | Improvement of functionality as determined by their Pediatric Migraine Disability Score (PedMIDAS). The PedMIDAS consists of 6 questions: 3 addressing school attendance and functioning, and 3 evaluating participation in events outside of school. The questionnaire is based on the patient's recall of the previous 3 months. The questionnaire produces a raw score (0-10, 11-30, 31-50, \>50) corresponding to a disability grade with increasing severity (little to non, mild, moderate, and severe) which was coded (1, 2, 3, and 4). |
| Difficulty Sleeping | Baseline (4 weeks) and 12 weeks post each, respective intervention | Subject reported having difficulty sleeping |
| Hospital Admissions | Baseline (4 weeks) and 12 weeks post each, respective intervention | Admission to hospital |
Other
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Migraines | Open-label Period | 24-48 weeks post-baseline period | The frequency of migraines during the open-label period (2 additional rounds of onabotulinumtoxinA) as compared to the cross-over period. |
| Duration of Migraine | Open-Label Period | 24-48 weeks post-baseline period | Duration of migraine in hours during the open-label period (2 additional rounds of onabotulinumtoxinA) as compared to the cross-over period. |
| Pediatric Migraine Disability Score (PedMIDAS) | Open-Label Period | 24-48 weeks post-baseline period | The PedMIDAS the open-label period (2 additional rounds of onabotulinumtoxinA) as compared to the cross-over period. The PedMIDAS consists of 6 questions: 3 addressing school attendance and functioning, and 3 evaluating participation in events outside of school. The questionnaire is based on the patient's recall of the previous 3 months. The questionnaire produces a raw score (0-10, 11-30, 31-50, \>50) corresponding to a disability grade with increasing severity (little to non, mild, moderate, and severe) which was coded (1, 2, 3, and 4). |
| Intensity of Migraines | Open-Label Period | 24-48 weeks post-baseline period | Intensity of migraines during the the open-label period (2 additional rounds of onabotulinumtoxinA) as compared to the cross-over period. Intensity based on 0-10 Pain Numeric Rating Score (NRS). The higher the score, the more intense the pain. |
Countries
United States
Participant flow
Recruitment details
Pediatric subjects aged 8 to 17 were recruited during an enrollment window from March 1st, 2017 to November 30th, 2018 at the UCI Health Center for Pain and Wellness located at UCI Health's Gottschalk Medical Plaza.
Participants by arm
| Arm | Count |
|---|---|
| Cross-Over: OnabotulinumtoxinA, Then Saline Placebo The AB subject group will receive OnabotulinumtoxinA in the first treatment and saline placebo in the second.Both groups will then receive OnabotulinumtoxinA in the last two treatments. There will be one treatment at the beginning of each 12 week block, meaning 4 treatments over the 48 week study period total. Progress check-ups will occur every 6 weeks during the study. Randomization will be via selection of sealed envelope.
OnabotulinumtoxinA: The AB subject group will receive OnabotulinumtoxinA in the first treatment and saline placebo in the second.Both groups will then receive OnabotulinumtoxinA in the last two treatments. There will be one treatment at the beginning of each 12 week block, meaning 4 treatments over the 48 week study period total. Progress check-ups will occur every 6 weeks during the study. Randomization will be via selection of sealed envelope.
Placebo (Saline): The BA subject group will receive saline and then Onabotulinumtoxin. A.Both groups will then receive OnabotulinumtoxinA in the last two treatments. There will be one treatment at the beginning of each 12 week block, meaning 4 treatments over the 48 week study period total. Progress check-ups will occur every 6 weeks during the study. Randomization will be via selection of sealed envelope. | 9 |
| Cross-Over: Saline Placebo, Then OnabotulinumtoxinA The BA subject group will receive saline and then Onabotulinumtoxin. A.Both groups will then receive OnabotulinumtoxinA in the last two treatments. There will be one treatment at the beginning of each 12 week block, meaning 4 treatments over the 48 week study period total. Progress check-ups will occur every 6 weeks during the study. Randomization will be via selection of sealed envelope.
OnabotulinumtoxinA: The AB subject group will receive OnabotulinumtoxinA in the first treatment and saline placebo in the second.Both groups will then receive OnabotulinumtoxinA in the last two treatments. There will be one treatment at the beginning of each 12 week block, meaning 4 treatments over the 48 week study period total. Progress check-ups will occur every 6 weeks during the study. Randomization will be via selection of sealed envelope.
Placebo (Saline): The BA subject group will receive saline and then Onabotulinumtoxin. A.Both groups will then receive OnabotulinumtoxinA in the last two treatments. There will be one treatment at the beginning of each 12 week block, meaning 4 treatments over the 48 week study period total. Progress check-ups will occur every 6 weeks during the study. Randomization will be via selection of sealed envelope. | 6 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Open-Label Period | Lost to Follow-up | 0 | 0 | 2 | 0 |
| Open-Label Period | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Cross-Over: OnabotulinumtoxinA, Then Saline Placebo | Cross-Over: Saline Placebo, Then OnabotulinumtoxinA | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 9 Participants | 6 Participants | 15 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 6 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 8 Participants | 5 Participants | 13 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 6 | 0 / 9 | 0 / 3 |
| other Total, other adverse events | 0 / 9 | 0 / 6 | 0 / 9 | 0 / 3 |
| serious Total, serious adverse events | 0 / 9 | 0 / 6 | 0 / 9 | 0 / 3 |
Outcome results
Primary
Frequency of Migraines
The frequency of migraines in days.
Time frame: Baseline (4 weeks) and 12 weeks post each, respective intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline Period | Control | Frequency of Migraines | 28 days |
| Botox Period | Frequency of Migraines | 20 days |
| Placebo Period | Frequency of Migraines | 28 days |
p-value: 0.038Wilcoxon signed-rank test
Primary
Intensity of Migraines
Median intensity of migraines based on 0-10 Pain Numeric Rating Score (NRS). The higher the score, the more intense the pain.
Time frame: Baseline (4 weeks) and 12 weeks post each, respective intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline Period | Control | Intensity of Migraines | 8 units on a scale |
| Botox Period | Intensity of Migraines | 5 units on a scale |
| Placebo Period | Intensity of Migraines | 7 units on a scale |
p-value: 0.047Wilcoxon signed-rank test)
Primary
Migraine Duration, in Hours
Duration of migraines in hours.
Time frame: Baseline (4 weeks) and 12 weeks post each, respective intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline Period | Control | Migraine Duration, in Hours | 24 hours |
| Botox Period | Migraine Duration, in Hours | 10 hours |
| Placebo Period | Migraine Duration, in Hours | 24 hours |
p-value: 0.148Wilcoxon signed-rank test)
Primary
Pediatric Migraine Disability Score (PedMIDAS)
Pediatric Migraine Disability Score consists of 6 questions: 3 addressing school attendance and functioning, and 3 evaluating participation in events outside of school. The questionnaire is based on the patient's recall of the previous 3 months. The questionnaire produces a raw score (0-10, 11-30, 31-50, \>50) corresponding to a disability grade with increasing severity (little to non, mild, moderate, and severe) which was coded (1, 2, 3, and 4).
Time frame: Baseline (4 weeks) and 12 weeks post each, respective intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline Period | Control | Pediatric Migraine Disability Score (PedMIDAS) | 4 score on a scale |
| Botox Period | Pediatric Migraine Disability Score (PedMIDAS) | 3 score on a scale |
| Placebo Period | Pediatric Migraine Disability Score (PedMIDAS) | 4 score on a scale |
p-value: 0.047Wilcoxon signed-rank test)
Secondary
Concomitant Headache Medications
Number of concomitant headache medications taken
Time frame: Baseline (4 weeks) and 12 weeks post each, respective intervention
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline Period | Control | Concomitant Headache Medications | 3 number taken |
| Botox Period | Concomitant Headache Medications | 1 number taken |
| Placebo Period | Concomitant Headache Medications | 2 number taken |
p-value: 0.64Wilcoxon signed-rank test)
Secondary
Difficulty Sleeping
Subject reported having difficulty sleeping
Time frame: Baseline (4 weeks) and 12 weeks post each, respective intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Baseline Period | Control | Difficulty Sleeping | 12 Participants |
| Botox Period | Difficulty Sleeping | 5 Participants |
| Placebo Period | Difficulty Sleeping | 11 Participants |
p-value: 0.82McNemar
Secondary
Duration of Benefit
The duration of benefit in weeks
Time frame: Baseline (4 weeks) and 12 weeks post each, respective intervention
Population: No data collected from participants at 4-week baseline in order to act as the control.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline Period | Control | Duration of Benefit | 4 weeks |
| Botox Period | Duration of Benefit | 0 weeks |
p-value: <0.001Wilcoxon signed-rank test)
Secondary
Emergency Department (ED) Visits
Subject visited an Emergency Department
Time frame: Baseline (4 weeks) and 12 weeks post each, respective intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Baseline Period | Control | Emergency Department (ED) Visits | 8 Participants |
| Botox Period | Emergency Department (ED) Visits | 2 Participants |
| Placebo Period | Emergency Department (ED) Visits | 3 Participants |
p-value: 0.039McNemar
Secondary
Functionality Improvement
Improvement of functionality as determined by their Pediatric Migraine Disability Score (PedMIDAS). The PedMIDAS consists of 6 questions: 3 addressing school attendance and functioning, and 3 evaluating participation in events outside of school. The questionnaire is based on the patient's recall of the previous 3 months. The questionnaire produces a raw score (0-10, 11-30, 31-50, \>50) corresponding to a disability grade with increasing severity (little to non, mild, moderate, and severe) which was coded (1, 2, 3, and 4).
Time frame: Baseline (4 weeks) and 12 weeks post each, respective intervention
Population: Baseline acted as control so no data for Functionality Improvement collected from participants at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline Period | Control | Functionality Improvement | 1 score on a scale |
| Botox Period | Functionality Improvement | 0 score on a scale |
p-value: 0.002Wilcoxon signed-rank test)
Secondary
Home School
Subject is home schooled full-time.
Time frame: Baseline (4 weeks) and 12 weeks post, respective intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Baseline Period | Control | Home School | 2 Participants |
| Botox Period | Home School | 2 Participants |
| Placebo Period | Home School | 2 Participants |
p-value: 0.016McNemar
Secondary
Hospital Admissions
Admission to hospital
Time frame: Baseline (4 weeks) and 12 weeks post each, respective intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Baseline Period | Control | Hospital Admissions | 8 Participants |
| Botox Period | Hospital Admissions | 0 Participants |
| Placebo Period | Hospital Admissions | 2 Participants |
p-value: 0.006McNemar
Secondary
School Plan Enrollment
Subject is enrolled in a school plan such as IEP, 504 plan, or similar modified school schedule.
Time frame: Baseline (4 weeks) and 12 weeks post each, respective intervention
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Baseline Period | Control | School Plan Enrollment | 11 Participants |
| Botox Period | School Plan Enrollment | 10 Participants |
| Placebo Period | School Plan Enrollment | 10 Participants |
p-value: 0.18McNemar
Other Pre-specified
Duration of Migraine | Open-Label Period
Duration of migraine in hours during the open-label period (2 additional rounds of onabotulinumtoxinA) as compared to the cross-over period.
Time frame: 24-48 weeks post-baseline period
Population: After the unblinding visit, 11 subjects elected to continue with the open-label period and were scheduled to receive two additional rounds of OBTA treatment (2 were lost to follow up). 4 subjects elected to receive standard of care (1 discontinued intervention).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline Period | Control | Duration of Migraine | Open-Label Period | 24 hours |
| Botox Period | Duration of Migraine | Open-Label Period | 6 hours |
| Placebo Period | Duration of Migraine | Open-Label Period | 24 hours |
Other Pre-specified
Frequency of Migraines | Open-label Period
The frequency of migraines during the open-label period (2 additional rounds of onabotulinumtoxinA) as compared to the cross-over period.
Time frame: 24-48 weeks post-baseline period
Population: 15 subjects completed the cross-over period. Of those 15, 11 continued Botox (2 lost to follow-up), and 4 elected conservative management (1 discontinued intervention)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline Period | Control | Frequency of Migraines | Open-label Period | 28 days |
| Botox Period | Frequency of Migraines | Open-label Period | 20 days |
Other Pre-specified
Intensity of Migraines | Open-Label Period
Intensity of migraines during the the open-label period (2 additional rounds of onabotulinumtoxinA) as compared to the cross-over period. Intensity based on 0-10 Pain Numeric Rating Score (NRS). The higher the score, the more intense the pain.
Time frame: 24-48 weeks post-baseline period
Population: 15 subjects completed the cross-over period. Of those 15, 11 continued Botox (2 lost to follow-up), and 4 elected conservative management (1 discontinued intervention)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline Period | Control | Intensity of Migraines | Open-Label Period | 8 units on a scale |
| Botox Period | Intensity of Migraines | Open-Label Period | 5 units on a scale |
| Placebo Period | Intensity of Migraines | Open-Label Period | 6 units on a scale |
Other Pre-specified
Pediatric Migraine Disability Score (PedMIDAS) | Open-Label Period
The PedMIDAS the open-label period (2 additional rounds of onabotulinumtoxinA) as compared to the cross-over period. The PedMIDAS consists of 6 questions: 3 addressing school attendance and functioning, and 3 evaluating participation in events outside of school. The questionnaire is based on the patient's recall of the previous 3 months. The questionnaire produces a raw score (0-10, 11-30, 31-50, \>50) corresponding to a disability grade with increasing severity (little to non, mild, moderate, and severe) which was coded (1, 2, 3, and 4).
Time frame: 24-48 weeks post-baseline period
Population: After the unblinding visit, 11 subjects elected to continue with the open-label period and were scheduled to receive two additional rounds of OBTA treatment (2 were lost to follow up). 4 subjects elected to receive standard of care (1 discontinued intervention).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Baseline Period | Control | Pediatric Migraine Disability Score (PedMIDAS) | Open-Label Period | 4 score on a scale |
| Botox Period | Pediatric Migraine Disability Score (PedMIDAS) | Open-Label Period | 3 score on a scale |
| Placebo Period | Pediatric Migraine Disability Score (PedMIDAS) | Open-Label Period | 4 score on a scale |