Guidelines for Pediatric Migraine Clinical Trial Design Released

Andrew D. Hershey, MD, PhD, the Endowed Chair and Director of Neurology, professor of Pediatrics and Neurology, and director of the Headache Center at Cincinnati Childrens Hospital Medical Center

Andrew D. Hershey, MD, PhD

The International Headache Society (IHS) has released new guidelines for the preventive treatment of migraine in children and adolescents, focusing on issuing a number of recommendations to address what it determined to be the major challenges with clinical trials in this population.¹

Authored by Ishaq Abu-Arafeh, MBBS, DM; Andrew D. Hershey, MD, PhD; Hans-Christoph Diener, MD, PhD; and Cristina Tassorelli, MD, PhD, the strategies included seek to provide a modern, uniform, and evidence-based approach to the design, conduct, and reporting of well-controlled clinical trials. Ultimately, they wrote, “these guidelines should be consulted and used in designing and conducting clinical trials of preventive treatments in children and adolescents with migraine.”

Although this is the first time this guideline was developed, all told, the statement mirrors that of the IHS guidelines for adults, though they address the challenges which are unique to pediatric patient populations.

“It is not only important to properly diagnose, but these guidelines also address how to design and implement studies so that we are the most likely to achieve scientifically sound and comparable studies,” Hershey, the Endowed Chair and director of neurology, professor of pediatrics and neurology, and director of the Headache Center at Cincinnati Children’s Hospital Medical Center, told NeurologyLive.

The recommendations include a number of prerequisites that should be met, including the use of change in headache frequency (as measured by headache days or migraine days) and 50% responder rate (as measured by migraine days) as the only primary end points, with the non-used end point being used secondarily. Trials should have a minimum of 28 days for baseline and a minimum of 12 weeks for treatment periods and are recommended to be parallel-group in design.

Hershey and colleagues recommended a number of secondary end points to use as well, including maximum headache intensity (measured by a 4-point scale) and headache hours per 28 days. The frequency of migraine aura and other outcomes may also be considered, they wrote, but these “need to be defined prior to trial initiation.”

The group recommended dosing for treatments to mirror what is known with regard to pharmacokinetics and pharmacodynamics, as well as results from trials in adults as a guide for phase 2 trials. For phase 3 trials, up to 2 doses are acceptable to be administered to participants, while dosing in trials of migraine devices and non-pharmaceutical products should be adjusted to match individual participants’ stage of development.

“Research into the treatment of children and adolescents with migraines are being standardized so that the future studies can be compared and the appropriate treatments utilized,” Hershey explained. He and colleagues wrote that the development of these guidelines was a process which included discussions among a number of committees, roundtable deliberations with lay people and the pharmaceutical industry, and open consultation with the IHS membership on the final draft.

The guidelines, they wrote, “have the potential to influence multiple factors in the preventive treatment of pediatric patients with migraine.” They are certainly welcomed for physicians like Christina Szperka, MD, a pediatric neurologist and director of the Pediatric Headache Program at Children’s Hospital of Philadelphia.

In August 2018, Szperka told NeurologyLive that one of the biggest steps in the pediatric migraine space was the fact that for preventive treatment, the field is just “getting there” in terms of understanding how to design trials properly.

“From an acute therapy standpoint, it seems like that’s really been worked out, but it seems like we need to do either a placebo lead-in or a crossover design to maximize the chance that you’ll find the benefit, if it really exists,” she said. She explained that in pediatrics, the CHAMP trial, despite being positive in its findings, “didn’t split out from placebo and that made us question, ‘OK, how are we doing this?’”

“We’re still pretty far out, I think, from the point of actually getting substantial data. Now having said that, most of what we’ve done in pediatrics, historically, has been off-label because it’s only in the past 15 years with the different changes in the laws that there have been pediatric trials,” Szperka said.

The full guidelines were published in Cephalagia.

REFERENCE

1. Abu-Arafeh I, Hershey AD, Diener HC, Tassorelli C. Guidelines of the International Headache Society for controlled trials of preventive treatment of migraine in children and adolescents, 1^st edition. Cephalagia. 2019;0(0):1-14. doi: 10.1177/0333102419842188. Published online April 4, 2019.