Study population and design
Male or female subjects, aged 18–65 years, with a current history of migraine with or without aura, according to IHS criteria, and with at least one migraine attack per month for 6 months prior to entering the study, were eligible for participation in the study [
7].
Patients with uncontrolled hypertension, cardiac, vascular, liver and renal impairment, or any other severe or disabling medical condition could not be enrolled. Individuals with history of alcohol or analgesic or psychotropic drug abuse, known hypersensitivity to study drugs, previous inadequate response to at least two triptans, currently using ergotamine (and its derivatives) or MAO-inhibitors, or suffering from headaches that have been lasting for >6 days, were excluded as well. Pregnant women, breast-feeding mothers, and women with childbearing potential having a positive or missing pregnancy test were not eligible.
Written informed consent was obtained from all patients prior to their inclusion in the study. The study was approved by the Independent Institutional Review Boards of the study centers.
The study had a multicenter, randomized, double-blind, cross-over design, and included 14 Italian centers (
Appendix 1). Each patient received F 2.5 mg or Z 2.5 mg in a randomized sequence. After treating three episodes of migraine in not >3 months with the first treatment, the patient had to switch to the other treatment. After treating three episodes of migraine in not >3 months with the second treatment, each patient was asked to assign preference to one of the treatments according to a questionnaire with a preference score graded from 0 to 5 on a 10-cm scale.
Subjects were instructed to treat at least three migraine episodes occurring in not >3 months and to come for the second visit and to take one dose of study medication as early as possible after the onset of migraine attack. If insufficient relief had been obtained after 2 h, patients were allowed to take a second dose of study medication, with a maximum daily intake of two doses. In case of insufficient relief 1 h after the intake of the second dose of the study medication, patients were allowed to take a rescue medication (excluding other triptans, ergotamine or its derivatives).
During the study use of concomitant medications, occurrence of adverse events (from diary), blood pressure, and heart rate were regularly checked, and a physical and neurological examination performed. A headache diary was dispensed with study medication.
Data analysis
The primary study endpoint was the between-treatment comparison of the direction and average strength of preference at the end of the study, measured on a scale from 0 to 5. The hypothesis was that a superiority of one treatment against the other had to occur in the presence of a difference of +1.0 with a standard deviation of 2.375. Considering a two-tailed test with a 0.05 significance level and an 80.7% power, the estimated number of patients to be randomized was 120 (including a 25% of drop-outs), 60 for each treatment group.
The intention-to-treat population (ITT, all patients treating at least one attack in each treatment period and completing the preference questionnaire) was the study primary analysis population, while the per-protocol population was the confirmatory analysis.
Secondary study endpoints were quantified according to IHS Guidelines [
7] (1) pain-free (PF) episodes at 2 h (absence of migraine 2 h after intake of one dose of study drug and without any rescue medication), (2) recurrence (migraine occurring within 48 h after a period without migraine), (3) sustained pain-free (SPF) episodes within 48 h (migraine attack which is PF at 2 h, does not recur and does not require the use of rescue medication or a second study drug dose within 48 h), and (4) pain-relief (PR) episodes at 2 h (defined as a decrease in migraine intensity from severe or moderate to mild or none). Consistency of recurrence, defined as patients having at least two or three recurrences over three attacks, was also assessed.
Safety analysis was applied to all randomized patients, by calculating the incidence of adverse events and changes in vital signs during the study.
Preference scores were compared between treatment groups by analysis of variance, while logistic regression analysis was used for testing the difference in the proportion of patients with preference for one of the two drugs. Secondary endpoints were compared between groups by generalized estimating equation analysis. The level of statistical significance was kept at 0.05 throughout the whole study.