Official Title: “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 in children. Despite this, few studies have investigated the treatment of acute migraine headache in the emergency room. We propose a prospective, double-blind, placebo-controlled, cross-over study of metoclopramide versus placebo in the treatment of acute migraine headache with open-label rescue using valproic acid. The primary outcome will be the number of patients who are pain free at two hours. The use of a standardized rescue medication will provide exploratory data for possible future trials.

Clinical experience is that many children do not experience headache relief with first line medications such as metoclopramide or experience rapid recurrence of headache. Prior data has demonstrated that many children with headache have co-morbid anxiety, depression or other psychological co-morbidities. There has been little investigation of these psychological co-morbidities in children with migraine headache although clinical experience and limited investigations suggest that when these co-morbidities are addressed some children with refractory headache improve. We prose a descriptive study of these co-morbidities in children presenting with acute migraine, and a comparison of medication efficacy among children with and without psychological co-morbidity.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Efficacy Study

Study Primary Completion Date: January 2009

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 ER treatment of acute migraine (personal communication with CHOP ED 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. Clinical experience suggests that some children do not experience headache relief with first line medications such as metoclopramide or experience rapid recurrence of headache [5]. Commonly used rescue medications include valproic acid, steroids, or dihydroergotamine, but there is little data to guide treatment of these children. Prior data has demonstrated that many children with headache have co-morbid anxiety, depression or other psychological co-morbidities. There has been little investigation of these psychological co-morbidities in children with migraine headache although clinical experience and limited investigations suggest that when these co-morbidities are addressed some children with refractory headache improve.

We propose a prospective, randomized, double-blind, placebo controlled, cross-over study of the acute treatment of pediatric migrainous headache with metoclopramide. We propose a prospective descriptive study of the effectiveness of valproic acid in children with migrainous headache that continues after treatment with metoclopramide. We propose a study of the proportion of children who present with acute migraine headache who also have psychological co-morbidities, and an evaluation of the influence of these co-morbidities on response to pharmacologic treatment. The full objectives and methodology is described in the appropriate sections below.

Primary Objective The primary objective of the study is to 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 two hours in children aged 8 to 18 years presenting to the emergency department.

Secondary Objectives:

1. Determine whether metoclopramide is superior to placebo in reducing headache intensity by a clinically relevant amount (Reduction in headache from either Moderate (5 -7) or Severe (8 - 10) to either Mild 1- 4) or None (0).

2. Determine whether metoclopramide is superior to placebo in reducing headache intensity by any measurable amount (3 point reduction in headache intensity on a 0-10 point numerical rating scale, which corresponds to a one level drop in disability).

3. Determine whether metoclopramide is superior to placebo in improving migraine symptoms associated with headache (such as nausea, photophobia, and phonophobia).

4. Determine whether metoclopramide is superior to placebo in reducing "migraine free" which is a combined measure of pain free, disability free, and associated symptom free.

5. Determine whether metoclopramide is superior to placebo in reducing headache recurrence at 1 day and 1 week.

6. Describe the percent of children who have not responded to metoclopramide who do respond to a specific rescue medication (valproic acid).

7. Describe the occurrence of psychological co-morbidity (anxiety and depression) in children presenting with acute migraine headache.

8. Determine whether children with psychological co-morbidity have less response to pharmacological treatment.

Study Design:

The study is a prospective, randomized, double-blind, placebo-controlled, cross-over treatment study of metoclopramide versus placebo. Subjects may receive up to 2 doses of study medication 1 hour apart.

Children who present to the CHOP ED with migraine headache based on 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 (IV fluid injection). Both patients and the study investigator performing assessments will be blind as to group assignment, while the ED 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 2 hours. A this point, if headache is not resolved, patients will cross-over.

If the child had received placebo initially, they will receive metoclopramide. If headache has not resolved 1 hour after metoclopramide administration the child will receive a second dose of metoclopramide. If the child had received metoclopramide initially, they will receive placebo. If headache has not resolved 1 hour after metoclopramide administration the child will receive a second dose of metoclopramide. Headache intensity and associated features will be assessed at one and two hours after administration or metoclopramide or placebo.

If children are not headache free after completing the study describe above, having received treatment with metoclopramide either initially or after first receiving placebo, they will receive rescue medication (valproic acid). Headache intensity and associated features will be assessed two hours after valproic acid administration.

Headache recurrence will be assessed at one and seven days.

While in the ED, children and parents will complete psychological assessment instruments.

This data will be used to describe the percent of children who have psychological co-morbidity and will be used to compare treatment efficacy in those with and without psychological co-morbidity.

Subject Population:

Children will be recruited from the CHOP ED. Consent and assent will be obtained as described in the protocol.

Number of Subjects:

All subjects will be recruited from CHOP. Sample size calculation suggests we will need 44 subjects for analysis.

Study Duration The total duration of the study is 7 days for each subject. The maximum time spent in the ED will be 6 hours. We expect subject enrollment to take approximately 6 months.

Study Phases:

1. Screening Phase: Upon presentation to the ED, patients diagnosed with migrainous headache based on ICHD 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. Un-blinded Rescue Study Patients who require further treatment after the cross-over component of the study described above will receive rescue medication (valproic acid).

There will be no comparison or placebo group. They will rate their headache intensity and associated symptoms at specific timepoints (one and two hours) after receiving rescue medication. Response to valproic acid will be described.

5. Follow-up Phase Patients will rate their headache intensity and associated symptoms at 1 and 7 days in order to assess for recurrence.

6. Psychological Assessment Study While in the ED, patients will complete psychological assessment instruments to determine the incidence of co-morbidity and whether co-morbidity affects response to medication.

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.

Intervention(s) in this Clinical Trial

• Drug: Metoclopramide
  • Intravenous bolus administration.

Primary Measures

• The primary endpoint will be a change in NRS score from baseline value to zero at two hours. Thus, the primary endpoint is headache resolution at two hours.
  • Time Frame: 2 hours
    Safety Issue?: No

Secondary Measures

• The change in NRS score from baseline value to zero at one hour for headache intensity.
  • Time Frame: 2 hours
    Safety Issue?: No
• The change in NRS score by 6 points from baseline to 2 hour value for headache intensity.
  • Time Frame: 2 hours
    Safety Issue?: No
• The change in NRS score by 3 points from baseline to 2 hour value for headache intensity.
  • Time Frame: 2 hours
    Safety Issue?: No
• The change in NRS score by 6 points from baseline to 2 hour value for associated symptoms.
  • Time Frame: 2 hours
    Safety Issue?: No
• The change in NRS score for "Migraine Free" category which is change in NRS score for headache intensity and associated symptoms from baseline to two hour value.
  • Time Frame: 2 hours
    Safety Issue?: No
• The change in NRS score from two hour measurement to follow-up at 1 day and 7 days
  • Time Frame: 1 day
    Safety Issue?: No
• The percent of children who have not responded to metoclopramide who do respond to rescue medication (valproic acid).
  • Time Frame: 6 hours
    Safety Issue?: No
• The change in NRS score from baseline to zero at one hour for headache intensity.
  • Time Frame: 1 hour
    Safety Issue?: No
• The change in NRS score from baseline to zero at two hours for headache intensity/
  • Time Frame: 2 hours
    Safety Issue?: No
• The change in NRS score by 6 points from baseline to 2 hour value for headache intensity.
  • Time Frame: 2 hours
    Safety Issue?: No
• The change in NRS score by 3 points from baseline to 2 hour value for headache intensity.
  • Time Frame: 2 hours
    Safety Issue?: No
• The change in NRS score by 6 points from baseline to 2 hour value for associated symptoms
  • Time Frame: 2 hours
    Safety Issue?: No
• The percent of children with psychological co-morbidity (anxiety and depression) presenting with acute migraine headache.
  • Time Frame: 0
    Safety Issue?: No
• The percent of children who become headache free at two hours with and without psychological comorbidity.
  • Time Frame: 2 hours
    Safety Issue?: No

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 ICDH 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 8 Years

Maximum Age for this Clinical Trial: 18 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Children's Hospital of Philadelphia

Overall Clinical Trial Officials and Contacts

Donald Younkin, MD Principal Investigator Children's Hospital of Philadelphia  

Overall Contact: Nicholas S Abend, MD 215-590-1719 abend@email.chop.edu

Information obtained from ClinicalTrials.gov on September 04, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00355394

Study ID Number: 2006-4-4755

ClinicalTrials.gov Identifier: NCT00355394

Health Authority: United States: Institutional Review Board