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

Patients and Methods

Ethical Considerations

The study was performed in accordance with the Declaration of Helsinki. An Institutional Review Board (IRB; study centers in the US) or Ethics Committee (study centers in Europe) approved the final study protocol, including any amendments made. Before initiation of the study, written informed consent was obtained from each patient's parent or legal guardian and written assent obtained from each patient; these were obtained before screening procedures for eligibility commenced (ie, before the start of the run-in period).

Study Design and Procedures

The TEENZ Study was a global, multicenter, double-blind, randomized, parallel group, placebo-controlled, comparison of 3 dosage strengths of zolmitriptan nasal spray vs placebo (delivered in an identical device) in the treatment of adolescent (ages 12 to 17 years) migraine (Fig. 1). The study was conducted at 153 study centers in the US, Latin America, and Europe between October 2010 and October 2013 and reported on Clinicaltrials.gov in September 2010 (NCT01211145). The majority of participating centers were Departments of Neurology, Neuropsychiatry or Pediatrics, Headache Centers, Children's Hospitals or Clinical Research Institutes; some were Family Care Centers. Patient recruitment was organised by each clinic and, when used, advertising was approved by the relevant IRB/Ethics Committees.

Figure 1.

Study design included a placebo challenge period followed by randomization to zolmitriptan nasal spray 5, 2.5, 0.5 mg, or placebo.

Patients were enrolled at Visit 1, and eligible patients entered a 30-day placebo challenge run-in period, during which a single migraine headache was to be treated with 1 dose of single-blind placebo. Patients were instructed to treat the first headache of moderate or severe pain intensity and to complete a paper diary capturing the headache intensity (rated as severe, moderate, mild, or none), the presence of bilateral headache, other associated symptoms and adverse events (AEs), and their ability to perform normal activities. Diary entries were recorded prior to treatment with study drug, and at 15 minutes and 1, 2, 3, 4, and 24 hours after treatment. If, after 2 hours, the migraine headache had not responded (ie, reduced to a pain intensity of mild or none), the patient was permitted to use approved rescue medication(s). Any subsequent migraine episodes during the run-in period were treated with standard acute migraine medication. Patients who had not treated a migraine headache with blinded placebo during the 30-day run-in period were considered screen failures.

At Visit 2, patients who met all conditions for randomization, including a lack of response to placebo during the run-in period, were randomized to receive one of three double-blinded doses of zolmitriptan nasal spray (5, 2.5, or 0.5 mg) or matching placebo in a 5:3:3:5 ratio according to a computer-generated randomization scheme. Patients were to treat a single migraine with this dose and to complete the symptoms diary as described above, recording headache pain intensity, AEs, and medications taken.

Patients had approximately 10 weeks to complete treatment; those who had not treated a migraine within 4 weeks of randomization returned for an interim visit to review instructions.

After treating a single migraine headache or at 10 weeks after randomization (if no migraine had been treated), patients returned to the study site for a final visit (Visit 3). At this visit, the nasal spray device was returned, patient diaries were returned and reviewed, and end-of-study assessments were performed.

Standard safety assessments included laboratory assessment of vital signs, 12-lead electrocardiogram (ECG) results and physical examination; these were conducted at the screening/enrollment and final visits. The Columbia-Suicide Severity Rating Scale (C-SSRS) was administered at Visits 1, 2, and 3. AEs were collected at all visits, including the run-in and placebo-challenge periods.

Patients could discontinue from the study for any of the following reasons: voluntary discontinuation by the patient or the parent/legal guardian (who was at any time free to discontinue the patient's participation in the study, without prejudice to further treatment); severe noncompliance to the study protocol (as judged by the investigator and/or AstraZeneca); incorrect enrollment; patient lost to follow-up; clinically significant or serious AE that was not consistent with continuation in the study; other safety reasons (as judged by the investigator, particularly if the patient became pregnant); a worsening of the condition under investigation; inability to comply with the restrictions on the use of concomitant medications; and inability to tolerate the assigned dose of study drug.

Inclusion and Exclusion Criteria

Enrollment was restricted to adolescent patients of ages 12 to 17 years, who would not turn 18 years of age within 10 weeks after randomization.

Patients were required to have an established diagnosis of migraine with or without aura, as defined by IHS in the second edition of the International Classification of Headache Disorders (ICHD-II) or its revision, ICHD-IIR. The patient's history of usual migraine-type was recorded at Visit 1 as "with aura," "without aura," or "both with and without aura." Furthermore, the patient's history of migraine was to have been at least 1 year, with a minimum of 2 migraine attacks, considered moderately/severely disabling, per month. The original inclusion criteria also required the patient to have had a history of usual untreated attack duration of ≥4 hours for any 3-month period prior to screening and a history of migraine attacks occurring at intervals of >24 hours apart. In June 2012, the protocol was amended to allow patients with a history of ≥3 hour headache duration to be recruited, to enable the planned sample size to be reached, and to complete the study.

In addition, patients were required to be able to distinguish between migraine and nonmigraine headaches, understand and comply with all study procedures, and be capable of keeping and using the patient diary. Female patients were required to have a pregnancy test, with those in a sexual relationship counselled on effective birth control.

Patients were excluded from the study for any of the following reasons: participation in another clinical study within 30 days of screening for this study; any medical condition with major increase of risk with exposure to zolmitriptan nasal spray; a history of basilar, ophthalmoplegic or hemiplegic migraine headache or any potentially serious neurological condition associated with headache; unacceptable adverse experience following previous use of any 5HT1B/1D agonist drug; evidence of ischemic heart disease, arrhythmia or accessory conduction pathway disorders (eg, Wolff-Parkinson-White syndrome); history, symptoms, or significant risk factors of/for ischemic heart (eg, silent ischemia, angina, myocardial infarction) or other cardiovascular disease, including coronary vasospasm, cardiac accessory conduction pathways, arrhythmias, cerebrovascular syndromes (eg, stroke) or peripheral vascular disease; any clinically significant abnormality indicated in the patient's medical history, physical examination, clinical chemistry, hematology, or urine drug screen; diagnosis or suspicion of drug-induced or chronic daily headaches within 1 year; frequent nonmigraine headache days (≥14 per month) in the 3 months before screening; uncontrolled hypertension; use of monoamine oxidase A (MAO-A) inhibitors, methysergide, methylergonovine or cimetidine in the 2 weeks before randomization or a selective serotonin reuptake inhibitor (SSRI) 4 weeks before randomization; any recent history of abuse (in the previous year) of alcohol or other drugs, including drugs for the acute treatment of headache; any serious condition (eg, severe hepatic impairment) which, in the opinion of the investigator, would present a risk to the patient participating in the study; clinically relevant nasopharyngeal abnormality. Pregnant or breast-feeding females were also excluded from the study, as were those who responded to placebo challenge during the run-in period.

Objectives and Outcome Measures

The primary objective of the study was to compare the efficacy of zolmitriptan nasal spray 5, 2.5, and 0.5 mg with placebo in the acute treatment of migraine headache in adolescents, ages 12 to 17 years, as measured by the primary outcome variable of pain-free status 2 hours post-treatment.

Secondary efficacy endpoints included: pain-free status at 15 minutes and at 1, 3, 4, and 24 hours post-treatment; headache response (ie, moderate or severe headache improving to mild or no pain) at 15 minutes and at 1, 2, 3, 4, and 24 hours post-treatment; sustained headache response at 2 hours (defined as headache response at 1 hour that is maintained [ie, without a return to moderate or severe pain] at 2 hours with no use of rescue medication prior to the 2-hour assessment); presence/resolution of associated symptoms of photophobia, phonophobia, nausea, or vomiting at 15 minutes and at 1, 2, 3, 4, and 24 hours post-treatment; incidence/time to use of rescue medication up to 24 hours post-treatment; ability to perform normal activities at 15 minutes and at 1, 2, 3, 4, and 24 hours post-treatment; headache recurrence 2 to 24 hours post-treatment; bilateral headache at 15 minutes and at 1, 2, 3, 4, and 24 hours post-treatment; intensity of pain increased by movement at 15 minutes and at 1, 2, 3, 4, and 24 hours post-treatment. In addition, the study aimed to assess the safety and tolerability of zolmitriptan nasal spray.

Statistical Analysis

A comprehensive statistical analysis plan was finalized prior to database lock and unblinding of the data. The safety analysis set included all randomized and treated patients who provided post-treatment safety data, classified according to the treatment actually received. Analysis of all safety and tolerability variables were performed using the safety analysis set. The full analysis set (FAS) included all randomized and treated patients who provided post-treatment efficacy data, classified according to randomized treatment, that is, all evaluable patients. The analysis of all efficacy variables was performed using the FAS.

The primary variable of pain-free status at 2 hours post treatment was to be analyzed using a logistic regression model with 2-hour pain-free status as the response variable including treatment and center as fixed factors in the model. For the primary analysis, last observation carried forward (LOCF) methods were used to derive the pain-free status at 2 hours (ie, the corresponding status at 2 hours or, if missing, the last nonmissing postbaseline pain-free status carried forward).

For the primary efficacy comparison of pain-free status at 2 hours post-treatment between the zolmitriptan 5 mg and placebo groups, a sample size of 250 patients per group was planned as it would provide 80% power to detect a clinically relevant difference in proportions/rates of 0.11 between groups (assuming pain-free rates of 0.30 and 0.19, respectively, and a significance level of 0.05). Using a 5:3:3:5 randomization to placebo, zolmitriptan 0.5, 2.5, and 5 mg, a total of 800 evaluable patients was planned.

To protect against the higher placebo response rates observed in other studies, an interim sample size re-estimation analysis of blinded pain-free status data similar to that described by Friede and Kieser[16] was planned to occur after approximately one-third of the planned patients had treated a migraine headache with randomized treatment. Based on the results of this analysis, the sample size could have increased up to a maximum of 1036 evaluable patients. After the sample size re-estimation analysis, an interim futility analysis was also planned to examine unblinded 2-hour pain-free response data and to identify and discontinue randomization to any zolmitriptan doses unlikely to demonstrate statistically significant improvements over placebo at study conclusion. A difference in 2-hour pain-free rate of 0.055 (ie, 5.5%) or less between a zolmitriptan nasal spray dose and placebo was defined as providing evidence of futility for that dose.

All statistical comparisons were conducted using 2-sided tests at the 5% level of significance. For the primary analysis of pain-free status at 2 hours, a step-down approach was used to control for multiple statistical comparisons for each zolmitriptan nasal spray dose vs placebo. All zolmitriptan comparisons to placebo were conducted according to this step-down procedure, regardless of whether any dose met the futility criteria at the interim analysis. The odds ratio (OR) and its 95% confidence interval (CI) were calculated for each comparison. The robustness of the primary outcome result was examined using sensitivity analyses of observed cases (OC) and worst-case endpoints, as well as by post hoc subgroup analyses. Secondary endpoint comparisons were tested at the 5% significance level without multiplicity correction.

Descriptive statistics and graphs were used to summarize efficacy and safety variables. Number of patients, mean, median, standard deviation (SD) and ranges were reported for continuous variables, frequencies, and percentages for categorical variables.

Safety variables included AEs, laboratory assessments, vital signs, 12-lead ECG results, physical examination results and Columbia-Suicide Severity Rating Scale (C-SSRS). Unless otherwise specified, safety analyses were performed using only the OC data of the safety analysis set. No formal statistical testing was planned for safety data.

All statistical analyses were conducted using SAS (Version 8.2 or above).

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