Migraine Therapeutics in Adolescents

Abstract

OBJECTIVES To conduct a systematic review and analysis of trial data submitted to the US Food and Drug Administration (FDA) to identify possible causes for the failure of pediatric trials of triptans for treatment of migraines. DATA SOURCE The FDA website for drug information and published literature. STUDY SELECTION All pediatric efficacy and pharmacokinetics trial data of drugs used for abortive treatment of migraine submitted to the FDA from January 1, 1999, through December 31, 2011. MAIN OUTCOME MEASURES Patient demographic baseline characteristics, inclusion and exclusion criteria, trial designs, efficacy end points, and pharmacokinetic profiles were analyzed and compared across drug products. RESULTS We analyzed data for sumatriptan succinate nasal spray and zolmitriptan, eletriptan hydrobromide, almotriptan malate, and rizatriptan benzoate tablets. Seven efficacy trials had a randomized, double-blinded, placebo-controlled, parallel-group trial design. In 4 trials, patients were required to have a history of migraine attacks lasting at least 4 hours. High response rates for placebo were observed in all trials, with pain relief at 2 hours ranging from 53% to 57.5%. Nonrandomization of patients with an early placebo response design was used in the rizatriptan trial in 2011. Compared with the rizatriptan trial conducted in 1999, the 2011 rizatriptan trial reduced the placebo response rate by 6% for headache freedom at the 2-hour posttreatment end point owing to study design. The pharmacokinetic profiles between adolescents and adults were statistically similar. CONCLUSIONS High placebo response rates are consistent across all trials and may represent the principal challenge in pediatric trials of drugs for abortive treatment of migraine. Enrichment with selection of subjects with long-lasting migraine attacks is not sufficient to overcome high placebo response rates. Another enrichment strategy, the nonrandomization of patients with an early placebo response, successfully reduces the high placebo response rate for rizatriptan and is a trial design that should be considered for future pediatric trials of abortive migraine therapeutics.

Primary Endpoints in Pediatric Efficacy Trials Submitted to the US FDA

“…9 This may be because of differences between the 2 populations in the natural history (eg, migraine), 10 in the pathophysiology, or in the symptomatology (eg, heart failure) 11 of the disease or condition under study. Furthermore, the adult endpoint may not be suitable to measure in certain pediatric age subgroups because of differences in performance capacity.…”

Pain and placebo in pediatrics: A comprehensive review of laboratory and clinical findings

“…Placebo research, defined as the investigation of the mechanisms underlying suggestive and conditioned healing processes [14], has been mostly done in adults and it remains unclear how and to what extent children form placebo effects [9; 77]. On one hand, there is evidence from clinical studies that placebo responses are present in a variety of pediatric conditions including Attention-deficit hyperactivity disorder (ADHD) [65], asthma [5], atopic dermatitis [67], seasonal allergic conjunctivitis [51]; autism [38], depression [12], epilepsy [60], functional gastrointestinal conditions [66], chronic fatigue syndrome [62], hypertension [68], migraine [69], and syncope [64]. On the other hand, it is important to understand whether the placebo mechanisms that have been explored so far are uniquely important for adults as opposed to children.…”

Advances in Pediatric Pharmacology, Therapeutics, and Toxicology

“…A systematic analysis of trial data submitted to the FDA for approval as acute treatment of migraine attacks in the pediatric population was assessed to identify causes of study failures [69]. Clinical trial data for sumatriptan succinate, zolmitriptan, eletriptan hydrobromide, almotriptan malate, and rizatriptan benzoate were included in the analysis.…”

“…Clinical trial data for sumatriptan succinate, zolmitriptan, eletriptan hydrobromide, almotriptan malate, and rizatriptan benzoate were included in the analysis. A high placebo response rate was reported across trials: 53–57.5% for pain relief at 2 hours [69]. The authors emphasized the benefit of using a double randomization strategy whereby patients with an early placebo response are not included in a second randomization phase.…”

“…The authors emphasized the benefit of using a double randomization strategy whereby patients with an early placebo response are not included in a second randomization phase. This strategy was used for rizatriptan and resulted in a 6% reduction in the placebo response rate compared with a previous trial [69]. …”