The Childhood and Adolescent Migraine Prevention Study

Study Overview
=================
Brief Summary
-----------------
The purpose of this research study is to test two medicines for migraine prevention in children and adolescents.

Detailed Description
-----------------
The purpose of this research study is to test two medicines for migraine prevention in children and adolescents. The investigators want to see if amitriptyline and/or topiramate are better than placebo (sugar pill) in reducing headache frequency in children and adolescents ages 8 to 17 with migraines. At this time, there are no FDA approved medicines approved in the US for the prevention treatment of migraine headaches in children and adolescents.

Official Title
-----------------
Amitriptyline and Topiramate in the Prevention of Childhood Migraine

Conditions
-----------------
Migraine, Migraine Disorders, Headache

Intervention / Treatment
-----------------
* Drug: Amitriptyline
* Drug: Topiramate
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Migraine with or without aura (International Classification of Headache Disorders, 2nd Edition (ICHD-II) or chronic migraine (ICHD-II revised) Migraine frequency based upon prospective headache diary of 28 days must be ≥ 4. Migraine frequency defined as any migraine during one day in the 28 day baseline period (1) PedMIDAS Disability Score > 10, indicating at least mild disruption in daily activities and < 140, indicating extreme disability that may require more comprehensive, multi-component therapy Females or males 8-17 years, inclusive Migraine frequency is defined as the period from the onset to the stop time of painful migraine symptoms not to exceed 24 hours with the clock starting at midnight. If painful symptoms last longer than 24 hours, this is considered a new and distinct migraine headache. If painful symptoms recur within 24 hours of initial onset, this is considered part of the initial migraine episode and would be counted as one migraine. Exclusion Criteria: Continuous migraine defined as an unrelenting headache for a 28 day period Weight less than 30 kg or greater than 120 kg Unwilling to avoid taking non-specific acute medication such as NSAIDS (e.g., ibuprofen), more than 3 times per week, or migraine specific acute medications such as triptans more than 6 times per month Currently taking other prophylactic anti-migraine medication within a period equivalent to 2 weeks of that medication before entering the screening phase, or the use of Botulinum toxin (Botox®) within 3 months of entering the screening phase Subjects who have previously failed an adequate trial of AMI or TPM for prophylaxis of at least 3 months duration at doses recommended for migraine relief because of lack of efficacy or adverse events(2) Current use of disallowed medications/products: opioids, antipsychotics, antimanics, barbiturates, benzodiazepines, muscle relaxants, sedatives, tramadol, nutraceuticals, SSRIs, or SSNRIs Known history of allergic reaction or anaphylaxis to AMI or TPM Abnormal findings on ECG at baseline, particularly lengthening of the QT interval greater than or equal to 450 msec Subject is pregnant or has a positive pregnancy test Subject is sexually active and not using a medically acceptable form of contraception Diagnosis of epilepsy or other neurological diseases History of kidney stones Inability to swallow pills after using behavioral techniques if indicated between screening visit and baseline visit (3) Present psychiatric disease as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV) (e.g. psychosis, bipolar disorder, major depression, generalized anxiety disorder), alcohol or drug dependence, or documented developmental delays or impairments (e.g., autism, cerebral palsy, or mental retardation) that, in the opinion of the site investigator, would interfere with adherence to study requirements or safe participation in the trial Any and all other diagnoses or conditions which in the opinion of the site investigator, that would prevent the patient from being a suitable candidate for the study or interfere with the medical care needs of the study subject (2)Previously failed an adequate trial of AMI or TPM is defined as: dosage of 1mg/kg/day of AMI or 2 mg/kg/day of TPM; trial of at least 3 months duration; efficacy of having at least a 50% decrease in migraine frequency in response to drug therapy; or unable to tolerate taking the medication due to treatment-related side effects. (3)Subjects who cannot swallow pills at the time of the screening visit will be given a training session using behavioral techniques. Upon return for baseline visit, if the subject continues to be unable to swallow pills, the subject will be excluded from the study.

Ages Eligible for Study
-----------------
Minimum Age: 8 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Amitriptyline<br>Drug to be administered twice daily. | Drug: Amitriptyline<br>* Amitriptyline will be administered twice daily at home during the 8-week titration period followed by a 16 week maintenance phase of the highest tolerated dose. The morning dose is a placebo pill. Dosing of amitriptyline will be weight-based.<br>|
| Active Comparator: Topiramate<br>Drug to be administered twice daily. | Drug: Topiramate<br>* Topiramate will be administered twice daily at home during the 8-week titration period followed by a 16 week maintenance phase of the highest tolerated dose. Dosing of topiramate will be weight-based.<br>|
| Placebo Comparator: Placebo<br>To be administered twice daily. | Drug: Placebo<br>* Placebo will be administered twice daily at home during the 8-week titration period followed by a 16 week maintenance period.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number (Percentage) of Participants Reporting a ≥ 50% Reduction in Headache Days | The primary endpoint was a ≥ 50% reduction in headache frequency from the 28 days (4 weeks) baseline period prior to randomization to the last 28 days (4 weeks) of the trial. Headache frequency was defined as the number of days with headache for a given four week 28 day (4 week) period. A headache day was defined as any day during which any headache occurs within a 24 hour period, starting and ending at midnight. For each participant, the primary endpoint involved a determination of whether a 50% or greater reduction in headache frequency was observed during the last 4 weeks of active treatment as compared with the headache frequency during the 4-week baseline period. Results were compared across the three treatment groups. | 4 week baseline period and last 4 weeks of the 24-week trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Absolute Headache Disability Score on PedMIDAS | The PedMIDAS scale which evaluated the impact of headaches in school, home, play, and social activities, is comprised of six items that pertain to days missed in various activities over the past 90 days. Questions were answered by the youth in consultation with their parents and reviewed by study staff. The PedMIDAS scale was administered at baseline (covering the three months prior to enrollment) and at the 24-week endpoint visit (the end of the maintenance period, covering three months of enrollment). A total PedMIDAS score (sum of items 1-6) was used in this trial. Scores range from 0-240; with a score of 0-10 indicating no disability, 11-30 mild disability, 31-50 moderate disability, and more than 50 severe disability in daily activities. The main outcome measure for this comparison will be the difference in the baseline and endpoint (24 week) PedMIDAS total scores for: Amitriptyline vs. Placebo Topiramate vs. Placebo Amitriptyline vs Topiramate | baseline and 24 week endpoint | 
| Change in Number of Headache Days | This outcomes measure examines whether the rate of absolute number of headache days, per 28 day period, differs between treatment groups over time. This was assessed longitudinally based on the actual number of headache days from the 28 days prior to randomization to the last 28 days of this 24 week trial. The change in absolute headache days was compared between: Amitriptyline vs. placebo Topiramate vs. placebo Amitriptyline vs. Topiramate | 4 week baseline period and last 4 weeks of the 24-week trial | 
| Tolerability, as Indicated by the Number (Percentage) of Participants That Completed the 24-week Treatment Phase | To assess tolerability, the percentage of subjects who complete the entire 24-week treatment period will be estimated in each of the three groups. | 24 weeks | 
| Occurrence of Treatment Emergent Serious Adverse Events | To determine if amitriptyline or topiramate differ from placebo on the occurrence of treatment emergent serious adverse events. | 24 weeks of the trial | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pediatric, Children, Adolescent, Headache, Migraine