2016 Winner of the ASRA Chronic Pain Grant: Effectiveness of OnabotulinumtoxinA (Botox®) in Pediatric Patients Experiencing Migraines: A Randomized, Double-Blinded, Placebo Crossover Study in the Pediatric Pain Population
While many chronic pain conditions are manageable, migraine pain can be devastating. Migraine episodes are unpredictable in onset and duration and profoundly debilitating for sufferers. Recently, onabotulinumtoxinA (OBTA) was approved for the prophylaxis of adult migraine symptoms by the United States Food and Drug Administration (FDA), which has dramatically altered the way pain physicians approach migraine pain.
“Treatment for pediatric head pain is an extrapolation from all that we have learned about adult headaches combined with what we have learned from working with children in pain.”
Most adults who suffer with migraines have their first headache during childhood or adolescence. Although many preventative agents appear to be safe for use in children, none are currently FDA approved for that age group (apart from topiramate, which achieved on-label status in 2014). As a result, despite experiencing significant disability, the vast majority of children who present to their physician with migraine headaches do not receive prophylactic therapy. A 2003 study published in JAMA found that health care costs, work-related disability for parents, and lost educational opportunities for children lead to an annual economic impact in the United States of approximately $36 billion, because of both direct medical costs and lost productivity into adulthood.
Thus, treatment for pediatric head pain is an extrapolation from all that we have learned about adult headaches combined with what we have learned from working with children in pain. Pediatric pain medicine historically has its own challenges, largely suffering from underassessment and treatment paradigms extrapolated from adult literature that may not work as well in the pediatric population. Current clinical studies, when able to demonstrate efficacy, may not demonstrate safety, or vice versa. In the case of pediatric migraines, the best current treatment recommends involves nonsteroidal anti-inflammatory drugs, acetaminophen, and antiemetics.
The significance of this study is to evaluate the efficacy of OBTA (sold commercially as Botox®) for the treatment and prophylaxis of pediatric migraine in a randomized, double-blinded, placebo crossover study. No trials currently exist in literature studying OBTA for efficacy and/or safety for indication of pediatric migraine, although significant contributions have been made by retrospective case series over the past 10 years.,[7–10] Additional historical and longitudinal interest for the design of this study comes from the principal investigator's (PI) extensive use of off-label OBTA to treat refractory pediatric migraine over the past five years.
We had impressive anecdotal evidence: Patients who presented with refractory migraines who were treated with OBTA in the PI's clinical practice saw a substantial reduction in migraine days and migraine duration. In some cases, this meant a significant improvement in school attendance and daily functional status, and the effect seemed to persist over longitudinal treatments. In preparation for proposal of the prospective study, we went back and more formally assessed the treatment effect of OBTA for refractory pediatric migraine and found strong evidence in support of its use; the manuscript based on this work is currently under review for publication.
Looking at our historical off-label data, we realized we had an ideal candidate to investigate for ASRA's goal of identification of novel applications of existing therapeutics. Moreover, the findings from this trial may benefit an understudied pain population with the longterm aim of obtaining a new FDA indication to “on-label” status. The proposal also carries policy and legislative impact by fulfilling the federal initiative to design and conduct trials in the pediatric pain population within the confines of the Best Pharmaceuticals for Children Act (BPCA) of 2002. The goal of the BPCA program is to improve pediatric therapeutics through preclinical and clinical drug trials that lead to drug labeling changes.
Because we intended to formally study an off-label use of OBTA, we had to submit an Investigational New Drug (IND) application to the FDA prior to institutional review board (IRB) approval. The FDA was very responsive to our application and, after some minor revisions, approved our application. However, we then discovered that botulinum toxin is classified as an agent of chemical warfare in the United States and labeled as a bioterrorism agent. Because of this, the National Institutes of Health confirmed that our study falls under the United States Government Policy for Institutional Oversight of Life Sciences Dual Use Research of Concern (DURC), and we were subjected to additional review to confirm that our study is not a threat to national security. Finally, on March 1, 2017, our IRB allowed us to proceed under protocol HS 2016-3108.
Applications of botulinum toxin A have been shown to be generally safe in the pediatric population for indications—such as localized or segmental spasticity disorders, bladder hypertonicity, and vestibular migraine in patients as young as 2 years of age, although the majority of the class I and II studies included abobotulinumtoxinA (trade name Dysport®). With the encouraging data presented at the 14th Congress of the International Headache Society (held in 2009 in Philadelphia, PA) for adults with chronic migraines, the PREEMPT Data,[5-6] and the experiences of several retrospective case series, further exploration is reasonable for the potential role for OBTA in the management of chronic migraine in the pediatric population.
The study itself has three specific aims:
Aim 1: To test whether OBTA is superior to placebo in reducing headache frequency, intensity, and pediatric migraine-related disability (efficacy).
Aim 2: To evaluate the incidence of adverse events of OBTA administration in children ages 8–17 (safety, tolerability).
Aim 3: To evaluate whether OBTA can contribute to reduction in preventive and rescue medication, emergency room and hospital admissions, and health care costs (hospital and pharmacy resource utilization).
The study's goal is to provide an overall framework so that primary and secondary outcomes are easily defined, measurable, and validated as an acceptable means to gauge clinical success and longitudinally assess response.
Of note, given the existing evidence of efficacy in available scientific data (adult and retrospective pediatric) and personal experience in the pediatric population, the PI did not consider it reasonable to prolong withholding of OBTA for the purpose of study. Thus, a desirable study design minimized the placebo control period while still allowing for comparison of OBTA to a control group. After consideration of the alternatives, an AB/BA crossover design was selected as the best option. The influence of confounding covariates was reduced because each crossover patient served as his or her own control. A 4-week baseline prior to treatment would act as a no-treatment control in comparison to the treatment and placebo. In an attempt to demonstrate superiority of the study drug over conservative medical management, we did not exclude patients on preventive or abortive migraine medication. Following the crossover period, all patients will proceed to an open-label treatment phase with OBTA.
We have begun our journey to deliver better relief to children in pain, and we, as investigators and physicians, have gathered new insight into the success of nontraditional thinking for sustainable pain relief in this vulnerable population. More specifically, we discovered that the general pediatric community as well as patients and families welcomed this experimental and investigational option more warmly than traditional methods of treating migraine pain— reminding us why we physicians continually pursue research so enthusiastically. We learned (through a very arduous process) that performing clinical trials in the pediatric population—even more so in the pediatric pain population—is trenched with bureaucratic protocols and processes; however, based on our early data, it was well worth the struggle. Ultimately, our overriding rationale is to demonstrate efficacy, tolerability, and safety of OBTA for pediatric migraine, thereby potentially hastening the lengthy process to evaluate OBTA for approval in the pediatric population. The most urgent goals for pharmaceutical innovation are the development of pathomechanism-based antimigraine drugs and personalized therapy tailored to children and adolescents experiencing migraines.
We wholeheartedly thank ASRA and the Committee on Research for its generous support, guidance, and enthusiasm in supporting the study of migraine pain in children. We thank our team for its endless commitment and late-night meetings, as well as our patients for taking the journey with us towards discovery. We hope our work will be a springboard for future physicians to develop a contribution to pediatric migraine, and we welcome all opportunities for collaboration.
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