Efficacy and Tolerability of Zolmitriptan Nasal Spray for the Treatment of Acute Migraine in Adolescents

Results of a Randomized, Double-blind, Multi-center, Parallel-group Study (TEENZ)

Paul Winner, DO; Viktor Farkas, MD; Helena Štillová, MD; Brian Woodruff, MD; Charlie Liss, MS; Stefan Lillieborg, MD; Shane Raines, Ms

Disclosures

Headache. 2016;56(7):1107-1119. 

In This Article

Discussion

High placebo response rates have consistently been observed in previous studies of adolescent migraine, and have necessitated the use of enrichment strategy trial designs in order to reliably demonstrate efficacy.[11–15] Enrichment factors studied have included requirements for the typical duration of an untreated migraine, the length of time since diagnosis of migraines, lack of response during a placebo run-in period, and exclusion of patients with rapid migraine resolution.

A recent review of 7 triptan trials in adolescents suggested that enrichment designs that include only patients with long-lasting migraines are insufficient to overcome high placebo response rates, and recommended designs that utilize placebo challenge prior to randomization to reduce placebo response rates.[12] One of these trials, a randomized, controlled trial using orally administered almotriptan, demonstrated a significant headache response with reduced frequency of associated symptoms at the 2-hour time point in adolescent patients; however, with no statistically significant benefit in pain-free rate at any time point. The parallel-group design enriched the study population by requiring patients to have a longer duration of headaches than typical for this age group, while requiring a prospective 30-day lead-in period to ensure patients met all entry criteria prior to randomization.[14] In a placebo-controlled, parallel-group trial that also used enrichment to eliminate placebo responders before randomisation, a statistically significant treatment effect of orally administered rizatriptan was demonstrated at the 2-hour time point using pain-free status as the primary endpoint (30.6% vs 22.0%),[15] less than the 11% clinically relevant difference the study was designed to detect. A placebo challenge/cross-over design was used in a previous study of zolmitriptan 5 mg nasal spray, and demonstrated efficacy in adolescents aged 12–18 years old (Study NCT00617695).[13] As the primary endpoint was met and the drug was well tolerated, zolmitriptan nasal spray was subsequently approved for adolescent use in the European Union. Recently, on the basis of the current study, zolmitriptan nasal spray was approved by the US Food and Drug Administration (FDA) for use in adolescents. This approval, in addition to the currently available oral medications of rizatriptan, almotriptan, and the combination of sumatriptan/naproxen, provides an alternative route of administration for North American adolescents, particularly those who experience concomitant nausea or vomiting with migraine attacks.

The study sought to confirm the therapeutic efficacy of zolmitriptan 5 mg in adolescent patients. To enrich the trial population, patients were required to have a history of prolonged headache duration (≥4 hours in 98% of all randomized patients) and to have failed to respond to the placebo challenge prior to randomization. Pain-free response at 2 hours was chosen as the primary variable for this study, as this provides a more accurate prediction of satisfaction with treatment and health-related quality of life than does the 2-hour headache response.[17] Furthermore, this variable is recommended by the International Headache Society (IHS) as the primary measure of efficacy for randomized controlled acute migraine trials.[18]

The study demonstrated the superiority of zolmitriptan 5 mg nasal spray relative to placebo in reducing pain associated with adolescent migraine as measured by the IHS-recommended primary end-point of pain-free status 2 hours after treatment. The robustness of the primary outcome result was also supported by sensitivity analyses of observed case data. Secondary analyses also supported the therapeutic benefit of zolmitriptan 5 mg nasal spray; it was more effective than placebo in achieving pain-free status at 3 and 4 hours (Fig. 3), and this resulted in statistically significant improvements in the proportion of patients able to perform normal activities from 3 to 24 hours (all P ≤ .010).

At the interim analysis, zolmitriptan 2.5 and 0.5 mg nasal spray doses met the futility criteria so randomization to those treatment arms was discontinued. However, the 2.5 mg dose, despite being declared futile demonstrated some benefit over placebo as measured by the primary endpoint although the difference did not reach statistical significance. Furthermore, significant improvements were observed for the 2.5 mg dose vs placebo with regard to several of the secondary endpoints, in particular clinically important improvements at 2 hours in photophobia and phonophobia, and the ability to perform normal activities.

A limitation of this study is that randomization to the lower doses was stopped at the interim analysis, and therefore, no conclusive evidence of efficacy or lack of efficacy could be provided for the 2.5 mg nasal spray dose in adolescent migraineurs. A second limitation is that sequential hypothesis testing was not performed for secondary analyses. Although the P values presented have not been corrected for multiplicity, several of the comparisons would have survived a more conservative adjustment. For example, even under the most conservative Bonferroni procedure across all secondary analyses (which would require a P value of < .002 for significance), 5 mg zolmitriptan was statistically superior to placebo in pain-free status at 2, 3, and 4 hours.

In an attempt to mitigate the high placebo-response rates that have been observed in other migraine studies, the placebo challenge was performed prior to randomization. Despite this prospective placebo challenge, 17% of randomized patients treated with placebo were still pain-free at 2 hours. This observed placebo-response rate is similar to that reported in other adolescent trials using enrichment designs.[13,15] Cohort characteristics in this trial resemble those of prior adolescent migraine trials, including female predominance, headache frequency and severity, and the incidence of accompanying disturbances (eg, nausea, photophobia, phonophobia). A relatively high incidence of bilateral headache (52%), another feature typical of adolescent migraine, was also observed.

Tolerability data agreed broadly with those of prior trials of zolmitriptan in both adults and adolescents. A transient, unusual taste, recorded as dysgeusia, frequently accompanied nasal instillation of active drug. No new safety signals emerged in this single-dose treatment trial.

In conclusion, zolmitriptan 5 mg nasal spray demonstrated superior efficacy compared with placebo for the primary efficacy endpoint of pain-free status 2 hours after treatment, a clinically relevant end-point as patients prefer to be pain-free rather than just somewhat better. The efficacy of the 5 mg dose was supported by the majority of secondary efficacy endpoints. Zolmitriptan nasal spray was well-tolerated in the acute treatment of adolescent migraine. Most commonly reported AEs were consistent with those previously reported in adult and adolescent populations. Zolmitriptan is currently the only FDA-approved triptan formulation for nasal administration with evidence of treatment benefits (ie, pain-free rates) in adolescent migraineurs.

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