Abstract
In this open phase-II clinical tolerability trial 17 neurologists enrolled a total of 112 patients and instructed them to administer a maximum of two doses of intranasal alniditan, a 5-HT1B/D receptor agonist, for the treatment of three consecutive migraine attacks of moderate to severe intensity. A second dose of the trial medication was allowed within 1–24 h after the first administration. At 1 h after intranasal administration, 70/103 (68%) patients had responded to treatment (reduction from severe or moderate headache before treatment to mild or no headache) after their first migraine attack, 65/94 (69%) after their second and 52/75 (71%) after their third. In 187/270 (69%) of all attacks, patients were considered responders at 1 h. The median time to onset of effect was 30 min. The migraine headache recurred in 44% (attack 1), 55% (attack 2) and 44% (attack 3) after 4–5 h. Sixty-eight per cent of the patients reported nasal irritation, 19% taste disturbance and 44% throat irritation. Alniditan 2 mg, administered via the intranasal route, was effective in relieving migraine headaches in over two-thirds of the patients at 1 h.
Introduction
Alniditan, a 5-HT1B/D receptor agonist with no significant binding at the 5-HT1F receptor, was developed for use in the treatment of acute migraine attacks (1). Alniditan is the first nonindole, nonergolide benzopyran derivative within the group of 5-HT1B/D receptor agonists (2). It has a similarly high affinity for 5-HT1B and 5-HT1D serotonin receptors in radioligand binding studies (3) but differs from other sumatriptan successors in that it has very little affinity for 5-HT1F receptors (4). In studies with cloned human 5-HT1B receptors heterologously expressed at high densities, alniditan and sumatriptan are full agonists for the inhibition of forskolin-stimulated cAMP accumulation (3). However, compared with sumatriptan, alniditan has a significantly higher affinity for both cloned human 5-HT1D and 5-HT1B receptors. Animal studies support this observation as alniditan attenuates neuropeptide release significantly more than sumatriptan (5). It has been suggested that alniditan might have an improved profile of side-effects since only slight effects on coronary, mesenteric, renal arterial blood flow and contraction on cerebral arteries have been observed (5, 6).
Although most widely used, oral treatment of an acute migraine attack may be unsatisfactory for several reasons. Patients with migraine often experience nausea or vomiting, rendering the oral intake of drugs difficult or even impossible. In addition, gastric stasis, which often occurs during a migraine attack, may hamper a good and reliable gastrointestinal absorption and may thus reduce the efficacy, or slow down the onset of effect, of orally taken medicines. The intranasal route of administration is a good alternative to circumvent these problems. This way of application was also chosen for sumatriptan (7–11). Furthermore, intranasally administered anti-migraine medication may have a more rapid onset of action than orally administered drugs.
A double-blind randomized two-way cross-over trial has been completed in which the tolerability and safety of two subsequent intranasal administrations of 2 mg or 4 mg of alniditan in a chitosan formulation, with 2 h between doses, was investigated in 12 healthy subjects (12). Many subjects reported a short-lasting mild to moderate nasal irritation, without a clear relationship between the dose administered and the frequency or severity of nasal irritation. None of the subjects reported these adverse events as unacceptable. Previous trials in healthy subjects showed that an intranasal dose of 2 mg alniditan yielded approximately the same maximum plasma concentration as a subcutaneous dose of 0.8 mg alniditan (13–16). In a double-blind, placebo-controlled dose-finding trial (17) using subcutaneous doses from 0.8 mg to 1.4 mg, the response rate at 1 h was 73% with the 0.8 mg dose; 39% of the patients had a complete relief of headache at 1 h, whilst migraine headache recurred within 24 h in 45% of the responders at 2 h.
As no dose-finding trial using the intranasal formulation had yet been performed at the time of this trial, a 2-mg intranasal dose was expected to yield sufficiently high response rates, comparable with a 0.8-mg subcutaneous dose. The objectives of the phase II trial were to assess the overall acceptability and to evaluate the tolerability of the intranasal route of administration of alniditan in patients with acute migraine attacks. The dose to be evaluated was 2 mg alniditan in a chitosan formulation.
Patients and methods
This was an open phase II trial consisting of a screening visit, a treatment period and a follow-up visit. The trial was performed in accordance with the Declaration of Helsinki and its subsequent revisions. Ethics committee approval was obtained at each participating centre and the patients gave their informed consent to participate in the trial. Inclusion criteria were: migraine with or without aura, as defined by the International Headache Society diagnostic criteria (18), at least a 6-month history of 1–6 migraine attacks per month, age between and including 18–65 years of age, and good health and physical condition as determined by medical history, physical examination, vital signs and ECG. Exclusion criteria were the same as in other clinical trials with triptans (7–11).
Patients were instructed to administer a maximum of two doses for the treatment of one migraine attack. The first intranasal dose had to be administered when the intensity of the headache of the migraine attack was moderate or severe. Patients were allowed to use a second dose of the trial medication within 1–24 h after the first administration if no or insufficient pain relief was obtained after the first dose or if headache recurred within 1–24 h after initial response to the first intranasal administration. Patients who did not wish to use the second dose of the trial medication were allowed to use the attack treatment they used habitually (but not ergot derivatives or sumatriptan) from 2 h after the first dose administration. Patients recorded all data related to the treatment of the migraine attacks in a diary.
The use of any medication for the acute treatment of the migraine attack before the first trial drug administration and until 2 h after the last trial drug administration was forbidden. From 2 h after the last trial drug administration, the patients were allowed to take their usual attack treatment. From 24 h after the last trial drug administration the usual attack treatment including ergot derivatives or sumatriptan was allowed. At the screening visit, the patient's history, previous therapy, and the essential features of his/her migraine, were recorded. In women of childbearing potential a urine pregnancy test was performed.
Headache intensity and associated symptoms were scored by the patient during the treatment of the subsequent migraine attacks by means of a 4-point scale (none, mild, moderate or severe) immediately before trial drug administration and at 30-min intervals thereafter until 2 h. The various effectiveness parameters measured were: number of responders at 1 h, number of patients with complete relief at 1 h, number of patients with 24 h complete relief, onset of effect, duration of effect in responders, and the use of rescue medication.
Statistics
A patient was defined as ‘evaluable’ if the trial drug had been administered and all required assessments had been made up to and including the follow-up visit. This trial intended, with 90% power, to discriminate with an acceptance proportion of 40%. According to the ‘Fleming’s single stage procedure' (19), 52 evaluable patients are required in order to test with α= 0.05 (one-sided). An intent-to-treat analysis was performed, i.e. all screened patients with at least one post-baseline primary efficacy datum, regardless of their compliance with the protocol, were included in the analysis (unless no treatment data were available at all). All statistical tests were interpreted at the 5% significance level (2-tailed). Descriptive statistics were calculated for each of the demographic and other baseline parameters. Descriptive statistics were also calculated for each of the efficacy parameters (headache intensity and associated symptoms) and tabulations were made.
Results
The trial was run from 1 August 1995 to 7 March 1996. Seventeen neurologists screened a total of 116 patients, four of whom had no treatment data. Demographic and other baseline data were, hence, available for 112 patients. Two treated patients had no efficacy data. Hence, 110 were included in the intent-to-treat analysis of the efficacy data. Two other treated patients had no diary data and are not included in the diary analysis. For the safety analysis, 112 patients were included. There were 18 dropouts in total, mainly because of inefficacy (n = 10), adverse events (n = 6) and lost to follow-up (n = 2). A total of 12 patients had only one attack treated, 21 patients had two attacks treated and 75 had three attacks treated. There were five patients with missing data in their diary for the first attack, two patients for the second and two patients for the third attack. A total of 23 patients were considered as major protocol violators, the most frequently reported reason being the forbidden use of rescue medication (n = 13), followed by application of the trial drug when headache was still mild (n = 9).
The majority (88%) of the 112 patients in this trial were female, and their ages ranged from 18 to 63 years (median 41 years). The migraine headache was usually severe in the majority (82%) of cases and migraine attacks recurred in 67%. Usual anti-migraine medication was reported by all but four patients, the most frequently reported one being sumatriptan (47 cases).The current migraine attack was initiated by an aura in 29% of the attacks and the median time between onset of attack and application of the trial medication was 1 h 45 min.
Response was defined as a reduction of headache from moderate or severe to mild or absent. One hour after the intranasal administration, 70/103 (68%) responded to treatment at the first attack, 65/94 (69%) at the second attack and 52/73 (71%) at the third attack. Table 1 gives the change in headache severity from before the attack to 1 h after intranasal administration. Time to onset of effect was 35 min in all three attacks, with a 95% CI of 0.27–0.43 min. A second dose was required in less than half of the cases as can also be seen in Table 1; 32/103 (31%) of the patients had complete headache relief (i.e. reduction of headache intensity from moderate/severe to none) at 1 h after the first attack, 32/94 (34%) after the second and 28/73 (38%) after the third attack. In 45/270 (17%) of the attacks treated with one dose, the patients remained headache-free for at least 24 h. The median time (min–max) between application of the trial medication and onset of the effect was 30 min for all three attacks.
Response at 1 h (reduction from moderate/severe to mild/no headache) and use of a second dose of medication
The migraine attack recurred in approximately half of the responders: in 44% (attack 1), 55% (attack 2) and 44% (attack 3). The median duration (h:min; min–max) of the effect in responders, i.e. the time between the onset of response and recurrence of headache, was 4:59 (0:00–21:10) for attack 1, 4:30 (0:30–21:16) for attack 2 and 4:03 (0:00–19:35) for attack 3. After the first attack and its treatment, 39/103 (38%) patients reported the use of rescue medication. The numbers and percentages for the second and third attack were 40/94 (42%) and 29/73 (39%); i.e. for 108/270 (40%) of the attacks treated, the use of rescue medication was reported. The incidence of phonophobia was reduced from 53–63% to 14–21% and of photophobia from 54–65% to 15–21% from before the attack to 1 h after treatment.
Tolerability and safety
A total of 73/108 (68%) patients reported nasal irritation, with a median duration (min–max) of 20 min (1–1440). Only one patient dropped out because of nasal irritation; 20/108 (19%) patients reported taste disturbance, with a median duration of 20 min (10–3600); 47/108 (43.5%) reported throat irritation, with a median duration of 22.5 min (1–120). A total of 96/112 (86%) patients experienced one or more adverse events in the course of the trial. An application site reaction was reported by 77 patients (69% of the total population). Other frequently reported adverse events were head pressure and fatigue (14 instances, 13%, each), and paraesthesia and nausea (10 instances, 9%, each).There were no serious adverse events.
Discussion
This open safety and efficacy study showed that 2 mg intranasal alniditan is effective 1 h after application. The results are comparable with the intanasal application of sumatriptan (6). Due to the fact that a placebo group was not included, a comparison with other trials of triptans is difficult. Patients treated their migraine attack within 2 h after start, and onset of effect was reported after 30 min. The primary objectives of this trial were to assess the tolerability of the intranasal administration of alniditan 2 mg in patients with migraine attacks. The trial medication and route of administration were to be considered acceptable by 62% of the patients and they would use the drug again if it were commercially available. Patients particularly appreciated the ease of use and the speed of pain relief. The main reasons for not using the trial medication were inefficacy and adverse events. The incidence of adverse events was consistent over the three attacks: some 80% reported adverse events, mainly application site reactions. Nasal irritation was reported by two-thirds of the patients, but it was usually short-lived, subsided spontaneously within half an hour and only once resulted in discontinuation of the trial.
Although it was not the main objective of the present trial to gather efficacy data, encouraging results were obtained: the response rate at 1 h after intranasal administration of alniditan 2 mg (i.e. approximately 70%) was consistent over the three attacks and consistent with results obtained with subcutaneous administration of alniditan 0.8 mg (17). Recurrence of headache was reported by about half of the patients. This could indicate that the dose administered (2 mg) was too low in this sample with a rather long average duration of their migraine attack.
In conclusion, alniditan 2 mg, administered via the intranasal route, was effective in relieving migraine headaches in over two-thirds of the patients at 1 h. A majority of patients were moderately or very satisfied with the amount and speed of pain relief, and with the ease of use of the trial medication.
Footnotes
Acknowledgements
The study was performed with a grant from the Janssen Research Foundation, Beerse, Belgium.