Treatment of migraine attacks with subcutaneous sumatriptan: first placebo-controlled study

W Hester Visser1 Michel D Ferrari1, Evelyn M Bayliss2, Susan Ludlow2, Alison J Pilgrim2 for the Subcutaneous Sumatriptan International Study Group*

Department of Neurology1, University Hospital Leiden, The Netherlands; Glaxo Group Research Ltd2, Greenford, Middlesex, UK *

For listing of principal investigators, see Appendix.

Cephalalgia

Visser WH, Ferrari MD, Bayliss EM, Ludlow S, Pilgrim AJ. Treatment of migraine attacks with subcutaneous sumatriptan: first placebo-controlled study. Cephalalgia 1992;12:308-13. Oslo. ISSN 0333-1024 The results of the very first large-scale placebo-controlled dose-response trial with the novel selective 5-hydroxytryptamine1-like (5HT1-like) receptor agonist sumatriptan are presented. We studied the efficacy and tolerability of subcutaneous injections of 1 mg, 2 mg and 3 mg of sumatriptan in alleviating migraine attacks in a double-blind, placebo-controlled, parallel-group, multicentre clinical trial. Six-hundred and ninety patients were randomized and 685 received study medication. At 30 min, reduction of headache severity to mild or none (primary efficacy endpoint) was achieved in 22.% (95% CI: 15-28%) of placebo-treated patients and in 39% (CI: 31-46%) of patients treated with 1 mg sumatriptan, 44% (CI: 36-51%) treated with 2 mg sumatriptan and 55% (CI: 48-63%) treated with 3 mg sumatriptan. Differences from placebo were 17% (CI: 8-27%) for 1 mg sumatriptan, 22% (CI: 13-32%) for 2 mg sumatriptan and 34% (CI: 24-44%) for 3 mg sumatriptan (p < 0.001 for all three comparisons). Other migraine symptoms were also more effectively treated by sumatriptan than by placebo. Subsequently, an open-label 3 mg dose subcutaneous sumatriptan was given to partial or non-responders. Thirty minutes after this open dose the response rate to sumatriptan had improved to between 70 and 80%. Adverse events after sumatriptan were minor and short-lived. We conclude that subcutaneous sumatriptan is well tolerated in doses up to 3 + 3 mg and may rapidly abort migraine attacks. • Acute treatment of migraine, clinical study, migraine, sumatriptan, 5-HT agonist Michel D Ferrari, Department of Neurology, University Hospital Leiden, PO Box 9600, 2300 RC Leiden, The Netherlands. Received 28 May 1992, accepted I June 1992

Migraine is one of the most frequent neurological disorders (1). Up to 15% of the population may suffer from recurrent debilitating attacks of severe or moderately severe headache associated with anorexia, nausea, vomiting and/or photo/phonophobia (2-6). Typically, but not necessarily, the headache is unilateral, pulsating and aggravated by routine physical activity (6). Attacks may last 4-72 h and are sometimes preceded or associated with transient focal neurological symptoms (aura) (6). Current pharmacological treatment attempts either to provide symptomatic relief during an attack or to reduce attack frequency (7). Response rates, however, are generally low and side effects are often prominent (7-9). The marked global variation in treatment strategy for migraine clearly reflects the lack of superiority of any individual drug in the past (7-10). The pathophysiology of migraine is not well understood, but serotonin (5-hydroxytryptamine, 5-HT) as well as activation of the "trigemino-vascular system" is believed to play a pivotal role in the development of the headache and associated symptoms (11-15). Sumatriptan is a selective 5-HT1-like receptor agonist (13, 16). Its pharmacology and potential role in the treatment of the migraine attack have been reviewed and emphasized (13, 16-18). Preliminary open-label studies have indicated that sumatriptan was an effective and well-tolerated treatment for migraine when given by the intravenous ( 19, 20), subcutaneous (21) or oral route (20). Here, we present the results of the very first large-scale randomized, double-blind, placebo-con-trolled, dose-response clinical trial on the efficacy and tolerability of 1-6 mg sc sumatriptan. The primary efficacy endpoint was the relief of headache within 30 min. Although this trial has already been superseded in the literature by more recent trials testing the efficacy and tolerability of higher doses of subcutaneous sumatriptan (22, 23), we believe the present trial is important because of historical reasons, the methodology used, the scale of the trial (685 patients), the dose-response relation and the instructive aspects for succeeding trials. This study adds safety and efficacy data to the literature on 523 patients treated with subcutaneous sumatriptan and 172 patients treated with placebo during a migraine attack. Preliminary results of the interim analysis have been published previously (24).

Methods

Selection of patients The study was carried out between I June 1988 and 31 May 1989 in 42 centres in hospital neurology departments, specialist pain clinics and physicians' offices in six European countries. We included 690 male and female patients aged 18 to 60 years who met the criteria of the International Headache Classification Committee for mi-graine (6), either with aura (classical migraine) or without aura (common migraine), and who had a migraine history of at least one year with an average frequency of 1-6 (moderately) severe migraine attacks per month. We excluded patients who had a history of ischaemic heart disease, renal, hepatic or cardiac impairment, epilepsy, hypertension (ò160/95), significant psychiatric illness, and women who were pregnant, lactating or not using adequate contraceptive measures. We also excluded patients who regularly required or abused opiate analgesics, ergotamine (ò 1 mg daily for ò 3 months) or other drugs. In addition, on the study day we excluded patients who had used ergot or morphine containing preparations within 24 h and analgesics within 6 h. The use of prophylactic therapy, provided it did not contain ergotamine, was allowed. Study design and treatments All patients underwent a pre-study screen to determine eligibility and presented to the clinic at the time of a migraine attack. Those with moderate or severe headache (grades 2 or 3 on a 0-3 rating scale, see below) which was not already improving were clinically assessed and equal numbers of patients were randomly allocated to four treatment groups to receive a subcutaneous injection of either placebo or 1 mg, 2 mg or 3 mg sumatriptan. If after 30 min the patient still had a grade 2 or 3 headache, an open subcutaneous injection of 3 mg sumatriptan could be given. Rescue medication, not containing ergotamine or dihydroergotamine, was allowed at 60 min after the first injection. Patients remained at the clinic for at least 120 min after the first injection and returned 24 h later for control blood samples. The trial was conducted in accordance with the Declaration of Helsinki. The approval of an Ethics Committee at each centre and witnessed informed consent were obtained from each patient prior to the trial. Study medication Sumatriptan was supplied as ampoules of isotonic solution containing 1 ml of 2, 4 or 6 mg/ml GR43175C base as the succinate salt. Placebo was supplied as matching 1 ml ampoules containing isotonic saline solution. The drug was given as a 0.5 ml subcutaneous injection. Evaluation of efficacy Patients rated headache severity as 3 = severe, 2 = moderate, 1 = mild, 0 = none. Functional disability was rated as 3 = requiring bedrest, 2 = working ability severely impaired, 1 = working ability slightly impaired, 0 = able to work/function normally. The presence or absence of associated symptoms (nausea, vomiting, photo/phonophobia), and the use of rescue medication were also recorded. The primary clinical efficacy endpoint was the number of patients who obtained relief of headache from grade 3 or 2 to grade 1 or 0 at 30 min. Secondary efficacy endpoints were: the number of patients who needed a second injection at 30 min, the change in functional disability and relief of nausea, vomiting and photo/phonophobia and use of rescue medication. The effect of attack duration prior to treatment and migraine type (with or without aura) on response to study drug were also examined. Evaluation of safety and tolerability Heart rate, blood pressure and electrocardiograms (ECG) were recorded before and at 10, 20, 30, 60 and 120 min after the first injection, and, if the patient had received a second injection at 30 min, also at 40 and 50 min. At the same intervals blood samples were taken for plasma assay of sumatriptan. Haematology and blood biochemistry parameters were measured pre-treatment, at 120 min and, where possible, 24 h post-treatment. Adverse events were recorded throughout the treatment and patients were asked to report any untoward symptoms following the injection(s). Power calculations and randomization Sample size calculations were based on predicted headache relief rates (reduction from grade 3 or 2 to grade 1 or 0) as seen in pilot studies, i.e. 30% for placebo, 35%, 55% and 80% for 1 mg, 2 mg and 3 mg subcutaneous sumatriptan, respectively. For detecting at least a 25% difference in headache relief rate between sumatriptan 2 mg and placebo and between sumatriptan 3 mg and 2 mg with 90% power at the two-sided 5% significance level, 100 patients per treatment group were required. A computer-generated randomization code was used to allocate patients in block sizes of four. Complete blocks were allocated to centres and patients were entered in ascending sequential order of patient number at each centre.

Statistical analysis Improvement of headache, other symptoms and functional disability and the number of patients requiring a second injection at 30 min were analysed using the Mantel-Haenszel chi-squared test without continuity correction. The effect of migraine type and duration of attack prior to treatment on headache relief were analysed using the Mantel-Haenszel approach and also assessed using a logistic regression model. Homogeneity of treatment differences across country was assessed using the Breslow-Day test. A chi-square test for trend was undertaken to determine whether efficacy was dose-related. The incidence of adverse events was compared using either the Mantel-Haenszel test or Fisher's exact test as appropriate. Results

Patient population Six hundred and ninety patients (92% Caucasian) were randomized and 685 received the first dose of study medication. Table 1 gives the numbers and the demographic and clinical characteristics of the patients in each treatment group. There were no significant differences between the treatment groups at entry into the study. Deviations from the protocol Thirteen patients were excluded from the efficacy analysis because of the following: mild headache (grade 1) on presentation (n = 4); ergotamine treatment within previous 24 h (n = 1); incorrect dose of sumatriptan (n = 1); open treatment less than 30 min after the first injection (n = 1); incorrect diagnosis (n = 1); no study-medication taken (n = 4) and open treatment with overdose (n = 1). These last two groups were also excluded from the analysis of safety according to dose; data from the patient who received an overdose were reviewed separately. Thus the efficacy analysis was carried out on 677 patients and safety analysis on 685 patients. A further 52 patients deviated from the protocol, but these deviations were considered unlikely to have influenced the primary efficacy analysis: in 21 patients the second injection was given later than 30 min after the first injection and in the remaining 31 patients the deviations from the protocol occurred after 30 min. Efficacy

Headache relief at 30 min Figure 1 shows the proportion of patients (and 95% CI) in whom headache severity was improved from severe or moderate (grade 3 or 2) to mild or none (grade 1 or 0) at 30 min. By that time 17% (95% CI 8% to 27%) more patients had improved with 1 mg sumatriptan, 22% (95% CI 13% to 32%) with 2 mg sumatriptan and 34% (95% CI 24% to 44%) with 3 mg sumatriptan than with placebo (p < 0.001 for all three comparisons versus placebo). The number of patients who were improved increased significantly with increasing dose (p < 0.002; chi-square test for trend). Complete resolution of pain was obtained at 30 min by 5% of placebo-treated patients, 9% of patients treated with 1 mg Table 1. Demographic and clinical characteristics of the study population and details of attacks treated (patients grouped according to first injection). Placebo 1 mg 2 mg 3 mg Number* of patients 172 (25%) 170 (25%) 171 (25%) 172 (25%) Sex Male 37 22%) 38 (22%) 41 (24%) 49 (28%) Female 135 (78%) 132 (78%) 130 (76%) 123 (72%) Mean age (y) (SD) 39 (10) 41 (11.) 40 (11) 39 (10) Frequency of attacks 1-3/month 87 (51%) 86 (50%) 96 (56%) 86 (50%) 4-6/month 62 (36%) 64 (35%) 53 (31%) 61 (35%) >6/month 22 (13%) 20 (12%) 22 (13%) 25 (15%) Use of prophylaxis 57 (33%) 51 (30%) 56 (33%) 56 (33%) Type of attack treated With aura 44 (26%) 36 (21%) 40 (23%) 42 (24%) Without aura 128 (74%) 134 (79%) 131 (77%) 130 (76%) Attack duration before treatment 4 h 116 (67%) 122 (72%) 116 (68%) 121 (70%) Median 358 384 338 400 * And percentage of the total population; other percentages are of the total number in the relevant treatment group.

sumatriptan and by 14% treated with 2 mg or 3 mg sumatriptan respectively. Effect of migraine type and attack duration prior to treatment There were no statistically significant differences in relative response rates (odds ratio) obtained in migraineurs with or without aura. Respective response rates were 20% and 22% for placebo, 36% and 39% for sumatriptan 1 mg, 35% and 47% for sumatriptan 2 mg, and 45% and 59% for sumatriptan 3 mg. Likewise, no significant differences in relative response rates (odds ratio) were found between patients who were treated early in the attack (within the first 4 h) and those who were treated later. Respective response rates were 29% and 18% for placebo, 38% and 39% for sumatriptan 1 mg, 49% and 42% for 2 mg and 66% and 51% for sumatriptan 3 mg. Nausea, vomiting, photo/phonophobia Sumatriptan was significantly more effective than placebo in relieving nausea, vomiting and photo/ phonophobia. Pre-treatment, 93% to 96% of the patients in the four treatment groups had at least one of these symptoms; at 30 min 39% of the patients treated with 1 mg sumatriptan, 40% with 2 mg and 46% with 3 mg were free of these symptoms, compared to 26% of the placebo-treated patients (p < 0.005 for all comparisons vs placebo). Functional disability Pre-treatment, 84 to 86% of the patients in the four treatment groups were severely functionally disabled or required bedrest. At 30 min, 43% of the patients treated with 1 mg sumatriptan, 50% with 2 mg and 62% with 3 mg were able to function normally or were only mildly impaired, compared to 32% of the placebo-treated patients (p < 0.001 for all comparisons vs placebo and p < 0.005 for 3 mg vs 2 mg and 1 mg). Need for second subcutaneous injection at 30 min Open treatment with 3 mg sumatriptan was given to 60% of the patients treated with 1 mg sumatriptan, 54% with 2 mg and 45% with 3 mg, compared to 79% of the placebo-treated patients (p < 0.001 for all comparisons vs placebo). The number of patients requiring the second injection significantly decreased as the initial dose of sumatriptan increased (p = 0.006; chi-square trend test). Headache improvement beyond 30 min In those patients who did not require a second subcutaneous injection, headache severity continued to improve beyond 30 min. The mean headache severity grade dropped from 2.3-2.6 pre-treatment to 0.8-0.9 at 30 min, 0.4-0.7 at 60 min and 0.2-0.5 at 120 min. Effect of open treatment with 3 mg sc sumatriptan at 30 min Patients who still had headache grade 2 or 3 at 30 min received open treatment with 3 mg subcutaneous sumatriptan. Thirty minutes after this injection, headache was improved to grade 1 or 0 in 99/132 (75%) of the patients initially treated with placebo, 51/93 (55%) of those initially treated with 1 mg sumatriptan, 47/87 (54%) with 2 mg and 40/ 67 (60%) with 3 mg. At 60 min 667 patients were evaluated: 264 patients who had received only the first double-blind treatment and 403 who had also received a second open label injection with 3 mg sumatriptan. Response rates at 60 min ranged from 70% to 80%. Looking at the effect of the second injection of 3 mg sumatriptan only, improvement was 58% in patients initially treated with placebo and 31%, 29% and 24% in those patients initially treated with 1 mg, 2 mg and 3 mg subcutaneous sumatriptan, respectively (Fig. 2). Other medication was taken from 60 min onward by 15% to 25% of the patients. Tolerability and safety

Adverse events were experienced by 38% of the patients receiving sumatriptan compared with 15%

Table 2. Most frequently reported adverse events as proportion of patients receiving the treatment. Placebo Sumatriptan only one or two doses No. of treated patients n = 34 n = 651 Injection site reaction 3% 16% Nausea/vomiting 3% 3% Flushing 0% 2.5% Warm/hot sensation 3% 4.5% Feeling of heaviness 3% 7% Pressure sensation 3% 2% Paraesthesia 3% 1% Tingling 3% 2%

who received placebo. The most frequently occurring adverse events are listed in Table 2. All adverse events resolved spontaneously and were generally of short duration (10-30 min) and mild in nature. There were no deaths or other serious adverse events. The incidence of events graded as severe was not related to dose of sumatriptan. No patient withdrew because of an adverse event. There were no consistent changes in blood parameters, heart rate, blood pressure or ECG. Discussion

The present study was the first controlled study on the efficacy of subcutaneous sumatriptan and one of the largest clinical trials in migraine. The results largely confirmed the expectations set by earlier open trials (19-21) and established that subcutaneous sumatriptan is a rapid, effective and well tolerated acute treatment for migraine attacks. At 30 min, 55% of the patients who were treated with 3 mg subcutaneous sumatriptan had improved compared to only 22% of those who were treated with placebo. By extrapolating the observed dose-response relation and the efficacy found following an additional subcutaneous injection with 3 mg sumatriptan, it could be predicted that 6 mg subcutaneous sumatriptan would relieve headache in about 80% of the patients at 60 min. This has indeed been confirmed in subsequent controlled trials (22, 23). The primary assessment of efficacy was chosen as improvement of headache from moderate or severe to mild or none. This was considered to represent a clinically relevant response and avoided the difficulty some patients may have, shortly after a severe headache, in distinguishing between a mild residual headache and complete absence of pain. However, sumatriptan was also effective in ameliorating the associated sympoms of the migraine attack, returning patients to normal functioning and reducing the use of escape medication. Following subcutaneous injection, rapid and con-. sistent peak-plasma levels of sumatriptan are achieved (16, 20, 21), while drug administration problems caused by nausea and vomiting are avoided. Sumatriptan was effective in alleviating headache, nausea and vomiting even when taken late in the attack, in contrast to drugs such as ergo-famine, which is generally believed to be effective only when taken early in the attack (7-9). This gives the advantage that the use of sumatriptan could be postponed until the patient is sure that she is suffering from a migraine attack. In countries in

which sumatriptan is already on the market, including The Netherlands and the UK, self-administration of sumatriptan with a subcutaneous auto-injector device (in analogy to subcutaneous self-administration of insulin by diabetics) is well accepted and effective. Sumatriptan, in doses up to a total of 6 mg, was well tolerated but associated with more adverse events than placebo treatment. These, however, were mostly of a minor nature and short-lived. A few minor ECG changes were seen but the incidence was similar in the sumatriptan and placebo-treated groups. Furthermore, ECG changes have been observed during migraine attacks (27-29); we therefore consider a causal relationship to sumatriptan treatment to be unlikely. An interesting aspect of our study is the low placebo response compared to earlier clinical trials in migraine, in which it is not unusual to encounter placebo response rates up to 45-50% (7). This may have been due to the strict inclusion and evaluation criteria used in our trial. In conclusion, subcutaneous sumatriptan in doses up to a total of 6 mg is an effective and well-tolerated acute treatment for migraine attacks. Appendix

The principal clinical investigators were as follows: Canada: MJ Gawel, Toronto; DV Doell, Montreal, Quebec; RF Nelson, Ottawa; JI McEwen, Vancouver; J Ahuja, Ottawa, Ontario; DCN Howse, Kingston, Ontario; J Ducharme, Quebec; BA Anderson, Winnipeg, Manitoba; WEM Pryse-Phillips, St John's Newfoundland; Beveridge, Toronto, Ontario; RW Del Grande, London, Ontario; SR Bloyd, Hamilton, Ontario; JF Dreyer, London, Ontario; France: N Brion, Versailles; P Dano, Marseille; Israel: E Melamed, Petah Tikva; D Harel, Haifa; Y Goldhammer, Tel Hashomer; Reches, Jerusalem; The Netherlands: MD Ferrari, Leiden; MAM Bomhof, Breda; HJG Kok, Den Helder; JW Hartman, Rotterdam; LAH Hogenhuis, Sittard; Switzerland: H Ludin, Bern; H Kaeser, Basel; BW Weder, St Gallen; West Germany: J Brand, Königstein/Tatmus; A Doenicke, Munich; M Trybe, Berg-mannshiel, Bochum; V Lueben, Giessen; V Pfaffenrath, Munich; J Meyer, Minden; W Tolksdorf, Aachen, H Taneri, Duisburg; KH Grotemeyer, Münster; HD Langhor, Fulda; W Paulus, München; R Enkelmann, St Goar/Rhein; R Leeser, Bad Mergentheim, Loeffelstelzen; Schimek, Giengen/BR; G Sehhati-Chafai, Bremen. References

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