The Childhood and Adolescent Migraine Prevention Study

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.

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

1. 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

- 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.