Treatment of Acute Migraine Headache in Children

Migraine is common in children and is one of the most common etiologies of headache leading
to emergency room presentation of children [1-3]. Despite the high prevalence, there have
been few pediatric studies of the acute treatment of migraine headache. Anti-dopaminergic
medications such as metoclopramide are often considered first line medications in the
emergency room treatment of acute migraine [personal communication with Children's Hospital
of Philadelphia Emergency Department physicians], but only two pediatric studies guide this
clinical management. One was a retrospective, uncontrolled, descriptive study [4] and one
was a prospective, double-blind study that compared an anti-dopaminergic medication to a
different medication but did not include a control group [5]. More rigorous studies are
needed to determine whether commonly utilized anti-dopaminergic medications are efficacious.

We will perform a prospective, randomized, double-blind placebo controlled study of the
acute treatment of pediatric migrainous headache with metoclopramide.

Primary Objective The primary objective of the study is to determine whether metoclopramide
added to standard care [intravenous (iv) hydration, darkened room] is superior to placebo
and standard care in resolving acute migraine headache intensity within two hours in
children aged 8 to 18 years presenting to the emergency department (ED).

Secondary Objectives:

1. Determine whether metoclopramide added to standard care (iv hydration, darkened room)
is superior to placebo and standard care in resolving acute migraine headache intensity
within one hour in children aged 8 to 18 years presenting to the emergency department.

2. Determine whether metoclopramide added to standard care (iv hydration, darkened room)
is superior to placebo and standard care in resolving acute migraine headache intensity
at 24 hours in children aged 8 to 18 years presenting to the emergency department.

Study Design:

The study is a prospective, randomized, double-blind, placebo-controlled study of
metoclopramide versus placebo. Subjects may receive up to two doses of study medication one
hour apart.

Children who present to the emergency department with migraine headache based on
International Classification of Headache Disorders (ICHD) criteria will be eligible for
enrollment. A standard assessment form will be sued to ensure children meet ICHD criteria.
Children will then be randomized to receive either metoclopramide or placebo (intravenous
fluid injection). Both patients and the study investigator performing assessments will be
blind as to group assignment, while the Emergency Department physician will be aware of
group assignment (acting as the pharmacist) so that if problems arise they can be evaluated
and treated as clinically indicated. Assessment of headache and associated features will
occur at one hour. If the child is not headache free, they will receive a second dose of
either metoclopramide or placebo. If they received metoclopramide initially the second dose
will be metoclopramide, and if they received placebo initially the second dose will be
placebo. Assessment of headache and associated features will occur again at two hours. This
marks the primary endpoint, as our primary objective is to determine whether metoclopramide
is superior to placebo in making patients headache free at two hours.

Headache recurrence will be assessed at 24 hours.

Subject Population:

Children will be recruited from the Emergency Department. Consent and assent will be
obtained as described in the protocol.

Number of Subjects:

All subjects will be recruited from the Emergency Department of a single institution. Sample
size calculation suggests we will need 44 subjects for analysis.

Study Duration The total duration of the study is one day for each subject. The maximum time
spent in the Emergency Department will be six hours. We expect subject enrollment to take
approximately six months.

Study Phases:

1. Screening Phase: Upon presentation to the Emergency Department, patients diagnosed with
migrainous headache based on International Classification of Headache Disorders
criteria will be considered for enrollment. If they meet inclusion and exclusion
criteria they will be consented/assented and enrolled in the study.

2. Basic Information Collection Basic demographic information, medical history,
psychological/psychiatric history past headache history, and information regarding the
current headache will be gathered.

3. Double-Blind Study Subjects will be randomized to receive metoclopramide or placebo in
a double blind study. Baseline headache and associated symptom data will be gathered.
Assessments will be performed at one hour and two hours. The two hour assessment is the
primary endpoint. If the headache has not resolved, the cross-over will occur. Children
who received metoclopramide initially will receive a placebo injection and, if needed,
a second injection one hour later. Children who received placebo initially will receive
metoclopramide and, if needed, a second injection one hour later. Headache assessments
will be performed one and two hours after the cross-over.

4. Follow-up Phase Patients will rate their headache intensity and associated symptoms at
one day in order to assess for recurrence.

Efficacy Evaluations:

Efficacy will be judged hourly after each medication (or placebo administration). Efficacy
in reducing headache intensity will be judged on a 0-10 point numerical rating scale. The
primary measure of efficacy will be headache freedom (rating of zero). Secondary measures
will be improvement in headache intensity that is clinically relevant (6 point improvement)
or improvement that is measurable (3 point improvement), improvement in associated symptoms
(based on a 4 point categorical scale), or improvement in disability (based on a 4 point
categorical scale).

Safety Evaluations:

All subjects entered in the study will be included in safety analysis. The frequency and
descriptions of all adverse events will be summarized. Any serious adverse events will be
described in detail.

Statistical And Analytic Plan:

Based on prior studies, we estimate a metoclopramide efficacy of 80% and placebo rate of
35%. Sample size and power calculations using an alpha value of 0.05 and power of 0.8
demonstrate that we will need to enroll 44 patients in the study. Subjects who drop out due
to need for faster rescue medication will be maintained in the analysis which will be
performed in an intent-to-treat manner.

Inclusion Criteria:

1. Males or Females age 8-18 years

2. Girls 11 years or older must have a negative urine/serum pregnancy test.

3. Diagnosis of pediatric migrainous headache. The criteria for pediatric migraine
headache based on the most recent ICHD criteria are listed below. The requirement of
5 attacks (A) will not be required for this study, this making the diagnosis
migrainous headache. As described elsewhere in the protocol, this change is required
to make the study applicable to ED patients who require treatment before five attacks
have occurred.

Exclusion Criteria:

1. Evidence that headache is due to a secondary underlying disorder based on history or
physical examination.

2. Pregnant or lactating females.

3. Any investigational drug use within 30 days.

4. Known to have a contraindication to metoclopramide or valproic acid such as
pregnancy, liver disease, hematologic disease, or metabolic disease.

5. Have used metoclopramide (or other antidopaminergic medications) or valproic acid
within two days of presentation.

6. Severe developmental disorders or mental retardation if insufficient information can
be obtained to make a clear diagnosis of migraine or judge headache severity.

7. If patients re-present to the ED, they can not be re-enrolled.