A $12 million NIH award to Cincinnati Children’s provides much-needed relief to the sorely underfunded study of pediatric migraine headaches.

Migraines affect more than 6 million children and adolescents in the United States and cause them to miss nearly 130,000 days of school every two weeks.

“Pediatric migraine is one of the five most prevalent childhood disorders in the United States,” says neurologist Andrew Hershey, MD, PhD. “The negative impact of migraines on overall quality of life is similar to childhood cancer, heart disease and rheumatic disease. The economic effects for children, families, and society are estimated at more than $30 billion per year in the United States.”

Yet there are no FDA-approved medications to prevent childhood migraines and no evidence based studies of treatment.

Hershey and Scott Powers, PhD, plan to change that with the help of a $12 million award from the National Institute of Neurological Disorders and Stroke.

The two will lead a study involving 40 sites nationwide, comparing the effectiveness of amitriptyline and topiramate, the two most frequently prescribed medicines for preventing childhood migraines.

The study will compare which drug is superior for reducing migraine frequency and disability, estimate how well each drug is tolerated and determine specific safe dosing levels for children.

A Huge Boost To Headache Research

After years of woeful neglect from research funders, the NIH boosts its commitment to headache research by 20 percent with this single project.

Convincing the NIH of the need for such research took Hershey and Powers three years of work, but they agree it was well worth the effort.

“Determining the optimal first-line prevention medication will have a transformational impact on the field,” says Powers, a psychologist in our Division of Behavioral Medicine and director of the Office for Clinical and Translational Research at Cincinnati Children’s.

“The results of this trial will help ensure that early, effective treatment for millions of children with migraine can be based on sound evidence.”

Current Practice Varies Widely

Hershey and Powers have an interest in learning which treatment works better for reasons beyond the grant. They have co-directed the Headache Center at Cincinnati Children’s for the last 14 years.

Part of building the case for their study was a nationwide survey of doctors who cared for children with severe chronic headaches. They found that doctors prescribed topiramate and amitriptyline most frequently, but dosing ranges varied widely.

Months of Preparation Needed

The study will recruit 675 children, ages 8 to 17, over the next five years. Enrollment will begin in summer 2012 at some sites, with all 40 centers expected to be up and running within a year.

Before the clinical trial can begin, the investigators will need nearly six months to build the supporting infrastructure: contracts, IRB protocol approvals, setting up the database, and more.

One crucial component is data collection. In addition to the $12 million to Cincinnati Children’s for clinical coordination, the project has awarded $5.8 million to the University of Iowa to serve as the data-coordinating center. Biostatistician Christopher Coffey, PhD, an expert in building and managing research databases, will oversee the center.

“These large-scale grants separate the clinical aspect from the data so that there’s no potential conflict of interest and we can get true results,” Hershey says.

“We’re doing an FDA-based, state-of-the-art pharmaceutical trial,” Powers adds. “We have to conduct this exactly according to industry standards.”

Amitriptyline or Topiramate?

Amitriptyline was developed in 1961 to treat depression but has long been used to prevent headaches. Topiramate is a newer medication used to treat epilepsy and approved for migraines in adults. Neither drug has been rigorously studied for use in children.

“The central problem in pediatric headache medicine is the lack of placebo-controlled clinical trials and comparative effectiveness studies of preventive medication therapy,” says Hershey.

This study will be double-blind and placebo-controlled. For every five children enrolled, two will be on amitriptyline, two on topiramate and the fifth on placebo.

Neither patient nor doctor will know who gets what.

“The only people who will know will be the medical monitor, who monitors for safety, the data coordinating center and the pharmacy. In the event of a serious adverse reaction, the data has to be reported within FDA-prescribed guidelines,” Powers says.

What They Expect

Powers’ and Hershey’s experience is that treatment with a preventive medication over a period of months usually lessens the frequency of headaches or stops them altogether, something they can now put the rigors of science behind.

“Our premise is that we think we can bend the trajectory of disease,” Powers says. “Maybe if we treat the disease effectively in childhood, we won’t end up having a 40-year-old female headache sufferer who’s never really been adequately treated, has co-morbid conditions because of it and has lost out on education and social life.”

Funding Based on Results

In keeping with the nature of NIH “U” awards, which are large, multisite cooperative agreements, the agency has so far given only $7 million of the $12 million promised to Cincinnati Children’s.

“It’s a five-year award but they’ve given us three years’ worth of money. We have to perform to get the last two years,” Powers says. “We feel some pressure with the benchmarks, but we should. If someone is going to trust you with that level of investment, you need to deliver.”