J Neurol (1991) 238:$62-$65
Journal of
Neurology © Springer-Verlag I991
Clinical experience with oral sumatriptan: a placebo-controlled, dose-ranging study J. P. Patten, for the Oral Sumatriptan Dose-defining Study Group Farnham Road Hospital, Farnham Road, Guildford~ United Kingdom
Summary. A double-blind, placebo-controlled nmlticentre study was carried out to evaluate the efficacy and tolerability of 100,200 and 300 mg sumatriptan, a selective 5-hydroxytryptamine (5-HT)rlike receptor agonist, given in an oral dispersible form in the acute treatment of migraine attacks. A total of 1130 patients were recruited from 51 centres in eight countries and the efficacy results are presented from an interim analysis of 538 cases. Tolerability was evaluated in 227 patients. At 2h, an improvement in headache severity from moderate or severe to mild or none was reported by 67% of patients who received 100mg sumatriptan, 75% receiving 200mg and 69% of patients receiving 300 mg sumatriptan, compared with 22% of patients who received placebo (P < 0.001 all doses sumatriptan vs placebo). Adverse events were generally mild and transient, and appeared to be doserelated; the adverse event profile of 100 mg sumatriptan was similar to that of placebo. Overall, nausea/vomiting and "bitter taste" were the most common complaints. The proportion of patients withdrawn due to adverse events was similar in the placebo and 100 mg sumatriptan treatment groups (2% and 3%, respectively). It is concluded that 100mg sumatriptan given orally is well tolerated with an anti-migraine efficacy comparable to that provided by the two higher doses. Key words: Sumatriptan - Oral administration - Acute therapy - Migraine
Introduction Sumatriptan, a selective 5-hydroxytryptamine (5-HT)Ilike receptor agonist, has been shown to be effective in the acute treatment of migraine. Early studies employing an intravenous formulation indicated possible benefits in patients suffering from migraine [1]. Subcutaneous administration of sumatriptan was later found to produce complete relief in up to 80% of patients studied [2].
A dispersible oral tablet formulation of sumatriptan has been developed and preliminary open studies, using doses between 70 and 280 mg, provided good tolerability results and relief of headache comparable to that associated with the intravenous treatment [5]. Although the data were obtained from a relatively small number of patients and studies were not placebo-controlled, these results were sufficiently encouraging for larger-scale studies to be carried out. The purpose of the present study was, therefore, to compare the efficacy of oral sumatriptan (100, 200 or 300 mg) with that of placebo in the treatment of acute migraine attacks. The safety and tolerability of sumatriptan at each dose was also evaluated in order to identify the optimum dose for use in future studies. This communication presents the efficacy and tolerability results from a planned interim analysis of the study.
Patients and methods The study followed a double-blind, randomized, placebocontrolled, parallel-group design and involved 51 centres in Austria, Belgium, Finland, France, The Netherlands, Sweden, Federal Republic of Germany and the United Kingdom. The inclusion criteria for the study required that patients had at least a 12-month history of migraine with aura (classical migraine) or migraine without aura (common migraine) in accordance with the International Headache Society classification [3]. All patients were aged between 18 and 60 years, and suffered an average of between one and six moderate or severe attacks per month. All use of prophylactic migraine therapy was stopped at least 2 weeks before starting the study medication. Exclusion criteria comprised pregnancy or lactation, hypertension, ischaemic heart disease or any other serious illness, and ergotamine/opiate abuse. Informed consent was obtained from all patients before entry. After the initial screen, patients were either randomized to receive placebo, or 100,200 or 300 mg sumatrip-
$63 tan in dispersible tablets. The randomization allocated two patients to placebo for every three allocated to each of the three active treatment groups. Patients were provided with supplies of blinded study medication sufficient to treat up to three attacks. They were instructed to treat at the earliest sign of a migraine attack provided 48 h had elapsed since previous study treatment. If symptoms were not adequately relieved at 2h, non-ergotamine-containing medication was permitted as rescue. Diary cards were provided on which patients were asked to record details of the migraine before treatment and the subsequent response to study drug. Headache was rated on a four-point scale: 0, 1, 2, 3,
no pain mild pain moderate pain severe pain
During the run-in period of 2 - 6 weeks patients practised using the diary card while treating their migraines with their normal medication. Patients were required to visit the clinic each month for assessment of their progress. On these occasions heart rate and blood pressure were measured and blood samples taken for laboratory analysis. Any adverse events that occurred during the study were also noted. They remained in the study until three migraines had been treated with study drug or 3 months had elapsed. The principal efficacy end-point was the number of patients who experienced a reduction in headache severity from grade 3 or 2 (severe/moderate) to grade 0 or 1 (none/mild) at 2 h after taking the study drug. Data from the first attack treated formed the basis of the main analysis since only then were patients naive to treatment. Not all patients treated a second or third attack, so analysis of attack i avoided self-selection on the basis of successful earlier treatment.
Statistics All pairwise comparisons were made using the MantelHaenszel chi-square test at the 5% significance level.
Results
A total of 1130 patients were recruited to the study. Of the 624 patients who had treated one attack at the time of the interim analysis, 538 had moderate or severe headache before treatment and were, therefore, eligible for the efficacy evaluation. Tolerability was assessed in the 227 patients whose case record forms had been returned at that time.
Efficacy of treatment A comparison of the percentage of patients in each group with no headache or only mild headache at 2 h is shown in Fig. 1. A reduction in headache severity from grade 3 or 2 to grade 1 or 0 was r e p o r t e d by 95/142 (67%) patients in the 100mg sumatriptan treatment group,
100
(n= 538)
80
(n= 142)
(n= 141)) ~-
(n= 155)
60
~ 40 e~
(n= 101)
20 [
0
100 mg Placebo
200 mg Sumatriptan
300 mg
Fig. 1. Efficacy of oral sumatriptan in the acute treatment of migraine: percentage of patients with no or mild headache 2h after treatment with 100 mg, 200 mg, or 300 mg sumatriptan or placebo Table 1. Percentage incidence of adverse event experienced by 227 migraine patients treated orally with placebo, or 100,200 or 300 mg sumatriptan Treatment
Event
100mg sumatripPlacebo tan (n=42) (n=69)
Chest symptoms Heaviness/pressure/ warmth Tingling/prickling Drowsiness/sedation Nausea/vomiting Bitter taste Total
200mg sumatriptan (n=56)
300mg sumatriptan (n=60)
0
1
4
13
5 0 1 4 7
4 10 3 9 7
16 1 4 14 9
10 3 6 13 22
17
34
48
67
105/140 (75%) receiving 200mg sumatriptan and 107/155 (69%) treated with 300 mg sumatriptan. This compared with 22/101 (22%) patients in the placebo group. All three sumatriptan treatment groups showed a statistically significant (P < 0.001) benefit compared with placebo, but there were no significant differences in headache relief between the sumatriptan groups. A worsening of migraine headache was noted in only one patient in each of the 100 mg and 200 mg sumatriptan groups, three in the 300 mg sumatriptan group and five in the placebo group.
Tolerability of treatment The placebo control and each of the three doses of oral sumatriptan were generally well tolerated during the study. The main categories of adverse events reported and the percentage of patients reporting these events are shown in Table 1. Overall, 14.3% of patients who took placebo reported adverse events. These included bitter taste from the trial medication, and feelings of heaviness, warmth or pressure. One patient in the placebo group withdrew from the study because of adverse events.
$64 Table 2. Proportion of patients who reported adverse events, total number of adverse event reports, and patient withdrawals due to adverse events following oral treatment with 100, 200, or 300 mg sumatriptan or placebo Treatment
Event
Placebo (n=42)
100 mg sumatriptan (n=69)
No. patients with adverse events No. adverse events No. patients withdrawn
6 (14.3%) 10 1 (2%)
26 (37.7%) 46 2 (3%)
200 mg sumatriptan (n=46)
300 mg sumatriptan (n=60)
27 (48.2%) 48 7 (13%)
41 (68.3%) 70 11 (t8%)
In the sumatriptan treatment groups, both the proportion of patients reporting adverse events and the total number of adverse events increased with increasing dose (Table 2). However, in all three groups the adverse events reported were generally mild and transient in nature. Taste disturbance due to the tablet was more noticeable in the 300 mg treatment group (22%) than in the 100mg and 200mg treatment groups (7% and 9%, respectively). Other reports included nausea/vomiting and chest symptoms such as pain and pressure in the chest, and tightness of the throat. Heaviness in the limbs, pressure in the head and a warm sensation in the face, nose and head were also noted, and some patients experienced prickling, tingling or numbness in the face and limbs. Although the incidence of adverse events appeared to be dose-related, in several cases (e.g. bitter taste, heaviness/warmth/pressure, chest symptoms), the 100 mg sumatriptan treatment group did not differ significantly from placebo (Table 1). The percentage of patients withdrawn due to adverse events was similar in the placebo group (2%) and 100 mg sumatriptan treatment group (3%), but was higher in the 200 mg and 300 mg sumatriptan groups (13% and 18%, respectively) (Table 2).
Discussion Currently available acute treatments for migraine include non-steroidal anti-inflammatory drugs, ergotamine, dihydroergotamine and phenothiazines. Prophylactic therapy is recommended particularly for patients with more frequent attacks, and [3-adrenergic receptor blockers or 5-HT2 antagonists are commonly used. Sumatriptan, a novel 5-HTl-like agonist, has been shown to be effective when given either intravenously and subcutaneously for the acute treatment of migraine [1, 2, 5, 6]. In the present study, the oral dispersible tablet formulation of sumatriptan was further explored as an acute treatment for migraine with or without aura in a large-scale multicentre study of over 1000 patients. In the absence of any objective measurement of response in migraine, the primary end-point of efficacy was
evaluated as the percentage of patients with a reduction in self-rated headache severity from moderate or severe to mild or no headache within 2 h of taking the medication. Like many other painful but self-limiting conditions, migraine is recognized as having a high and variable placebo response rate. It was, therefore, essential to include a placebo group in this randomized study in order to evaluate properly the true efficacy of sumatriptan. The placebo response rate seen (just over 20%) was relatively low, probably reflecting the very strict patient selection criteria employed in the study and the strict definition of an effective response [41. In all three sumatriptan treatment groups the proportion of patients with effective relief of migraine was significantly higher than in the placebo group. No apparent differences were observed between the three sumatriptan treatment groups, indicating that a 100 mg oral dose is capable of producing similar migraine relief to that achieved with the two higher sumatriptan doses studied. Compliance and accuracy in completing the diary card were excellent; over 96% of cards were completed correctly. This may have been because patients were given a detailed explanation of how to complete the diary card and were required to practise using it before entering the randomized phases of the study. Sumatriptan was generally well-tolerated and the adverse events experienced by patients were mostly mild and transient. The number of patients withdrawn due to adverse events and the incidence (but not the nature) of adverse events appeared to be dose-related. Taste disturbance was one of the most common adverse events and was particularly noticeable in the 300 mg sumatriptan treatment group (22% of patients) compared with the 100 mg and 200 mg groups (7% and 9%, respectively). With the exception of nausea and tingling sensations, the adverse events profile was very similar in the placebo and the 100 mg sumatriptan groups. From both the efficacy and tolerability results, it appears that the 100mg sumatriptan offered the best risk/benefit ratio in the treatment of acute migraine attacks. As mentioned previously, these results represent an interim assessment from a large-scale ongoing study. In addition to the primary efficacy end-point and tolerability evaluation described here, the full study will report on secondary end-points including the absolute changes in headache grade, the relief of associated symptoms such as nausea, vomiting and photophobia and the use of rescue medication. The effect of migraine type (common versus classical) and the duration of attack prior to treatment will also be reported. In addition, full safety data on the total population of 1130 patients will be analysed. It is concluded that oral sumatriptan given as dispersible tablets was both effective and well-tolerated as acute treatment for migraine with or without aura. Data from the full study population of more than 1100 migraine sufferers are expected to provide further confirmation of these interim results. On the basis of these findings, the 100 mg oral dose of sumatriptan would appear to offer the optimal balance between efficacy and tolerability in the acute treatment of migraine.
$65
References
Appendix
1. Doenicke A, Brand J, Perrin VL (1988) Possible benefit of GR43175, a novel 5-HTl-like agonist, for the treatment of severe migraine. Lancet I: 1309-1311 2. Ferrari M, Bayliss EM, Ludlow S, Pilgrim AJ (1989) Subcutaneous GR43175 in the treatment of acute migraine: An international study. Cephalalgia 9 (suppl 10) : 348 3. Headache Classification Committee of the International Headache Society (1989) Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8 (suppl 7) : 19-28 4. Olesen J, Tfelt-Hansen P (1988) Methodology of clinical trials in migraine. In: Capildeo R, Orgogozo J-M (eds) Methodology in clinical trials in neurology. Macmillan, London, pp 85-109 5. Perrin VL, Farkkila M, Gosguen J, Doenicke A, Brand J (1989) Overview of initial clinical studies with intravenous and oral sumatriptan in acute migraine. Cephalalgia 9 (suppl 9) : 63-72 6. Tfelt-Hansen P, Brand J, Dano P, Doenicke A, Findley LJ, Invensen HK, Melchart D, Sahlender HM (1989) Early clinical experience with subcutaneous sumatriptan in acute migraine: an overview. Cephalalgia 9 (suppl 9) : 73-77
The Publication Committee of the Oral Sumatriptan Dose-defining Study Group consisted of the following: Dr. C. Dahl6f, Sahlgrenska Sjukhuset, Gothenborg, Sweden; Dr. C. Edwards (Cardiovascular Medicine and Migraine) Glaxo Group Research Ltd, Greenford, United Kingdom; Ms S.Ludlow (Medical Statistics) Glaxo Group Research Ltd, Greenford, United Kingdom; Dr. P. Winter (Cardiovascular Medicine and Migraine) Glaxo Group Research Ltd, Greenford, United Kingdom; Dr. M. Tansey (Cardiovascular Medicine and Migraine) Glaxo Group Research Ltd, Greenford, United Kingdom. The participating investigators in the Oral Sumatriptan Dosedefining Study in the eight countries were as follows: Austria, Prof. Ott, Prof. Ladurner, Prof. Wessely, and Dr. Klingerl; Belgium, Dr. Schoenen, Dr. van den Berghe, Dr. van zan Dijke, Dr. Louis, Dr. Jacquy, Dr. Burton, Dr. Laterre, and Dr. Decarne; Federal Republic of Germany, Dr. Kempf, Dr. Hartung, Dr. Krause, Dr. Drillisch, and Prof. Hildebrandt; Finland, Dr. Junes, Dr. Kangasniemi and Prof. Rinne; France, Prof. Henry, Dr. Viader, Dr. Roullet, Prof. Bousser, and Prof. Goasguen; The Netherlands, Prof. Ansink; Sweden, Dr. Andersson, Dr. Behring, Prof.Boivie, Dr. Dahl6f, Dr. Hedman, Dr. Hindfelt, Dr. Kinnmann, Dr. Landin, Dr. Muhr, Prof. Persson, and Dr. Riman; United Kingdom, Dr. Critchley, Dr. Millac, Dr. Ferguson, Dr. McKeran, Dr. Lyons, Dr. Mortimer, Dr. Cumming, Dr. Corston, Dr. Gibson, Dr. Bamford, Dr. Newman, Dr. Mortimer and Dr. Wilkinson.
Journal of
Neurology © Springer-Verlag I991
Clinical experience with oral sumatriptan: a placebo-controlled, dose-ranging study J. P. Patten, for the Oral Sumatriptan Dose-defining Study Group Farnham Road Hospital, Farnham Road, Guildford~ United Kingdom
Summary. A double-blind, placebo-controlled nmlticentre study was carried out to evaluate the efficacy and tolerability of 100,200 and 300 mg sumatriptan, a selective 5-hydroxytryptamine (5-HT)rlike receptor agonist, given in an oral dispersible form in the acute treatment of migraine attacks. A total of 1130 patients were recruited from 51 centres in eight countries and the efficacy results are presented from an interim analysis of 538 cases. Tolerability was evaluated in 227 patients. At 2h, an improvement in headache severity from moderate or severe to mild or none was reported by 67% of patients who received 100mg sumatriptan, 75% receiving 200mg and 69% of patients receiving 300 mg sumatriptan, compared with 22% of patients who received placebo (P < 0.001 all doses sumatriptan vs placebo). Adverse events were generally mild and transient, and appeared to be doserelated; the adverse event profile of 100 mg sumatriptan was similar to that of placebo. Overall, nausea/vomiting and "bitter taste" were the most common complaints. The proportion of patients withdrawn due to adverse events was similar in the placebo and 100 mg sumatriptan treatment groups (2% and 3%, respectively). It is concluded that 100mg sumatriptan given orally is well tolerated with an anti-migraine efficacy comparable to that provided by the two higher doses. Key words: Sumatriptan - Oral administration - Acute therapy - Migraine
Introduction Sumatriptan, a selective 5-hydroxytryptamine (5-HT)Ilike receptor agonist, has been shown to be effective in the acute treatment of migraine. Early studies employing an intravenous formulation indicated possible benefits in patients suffering from migraine [1]. Subcutaneous administration of sumatriptan was later found to produce complete relief in up to 80% of patients studied [2].
A dispersible oral tablet formulation of sumatriptan has been developed and preliminary open studies, using doses between 70 and 280 mg, provided good tolerability results and relief of headache comparable to that associated with the intravenous treatment [5]. Although the data were obtained from a relatively small number of patients and studies were not placebo-controlled, these results were sufficiently encouraging for larger-scale studies to be carried out. The purpose of the present study was, therefore, to compare the efficacy of oral sumatriptan (100, 200 or 300 mg) with that of placebo in the treatment of acute migraine attacks. The safety and tolerability of sumatriptan at each dose was also evaluated in order to identify the optimum dose for use in future studies. This communication presents the efficacy and tolerability results from a planned interim analysis of the study.
Patients and methods The study followed a double-blind, randomized, placebocontrolled, parallel-group design and involved 51 centres in Austria, Belgium, Finland, France, The Netherlands, Sweden, Federal Republic of Germany and the United Kingdom. The inclusion criteria for the study required that patients had at least a 12-month history of migraine with aura (classical migraine) or migraine without aura (common migraine) in accordance with the International Headache Society classification [3]. All patients were aged between 18 and 60 years, and suffered an average of between one and six moderate or severe attacks per month. All use of prophylactic migraine therapy was stopped at least 2 weeks before starting the study medication. Exclusion criteria comprised pregnancy or lactation, hypertension, ischaemic heart disease or any other serious illness, and ergotamine/opiate abuse. Informed consent was obtained from all patients before entry. After the initial screen, patients were either randomized to receive placebo, or 100,200 or 300 mg sumatrip-
$63 tan in dispersible tablets. The randomization allocated two patients to placebo for every three allocated to each of the three active treatment groups. Patients were provided with supplies of blinded study medication sufficient to treat up to three attacks. They were instructed to treat at the earliest sign of a migraine attack provided 48 h had elapsed since previous study treatment. If symptoms were not adequately relieved at 2h, non-ergotamine-containing medication was permitted as rescue. Diary cards were provided on which patients were asked to record details of the migraine before treatment and the subsequent response to study drug. Headache was rated on a four-point scale: 0, 1, 2, 3,
no pain mild pain moderate pain severe pain
During the run-in period of 2 - 6 weeks patients practised using the diary card while treating their migraines with their normal medication. Patients were required to visit the clinic each month for assessment of their progress. On these occasions heart rate and blood pressure were measured and blood samples taken for laboratory analysis. Any adverse events that occurred during the study were also noted. They remained in the study until three migraines had been treated with study drug or 3 months had elapsed. The principal efficacy end-point was the number of patients who experienced a reduction in headache severity from grade 3 or 2 (severe/moderate) to grade 0 or 1 (none/mild) at 2 h after taking the study drug. Data from the first attack treated formed the basis of the main analysis since only then were patients naive to treatment. Not all patients treated a second or third attack, so analysis of attack i avoided self-selection on the basis of successful earlier treatment.
Statistics All pairwise comparisons were made using the MantelHaenszel chi-square test at the 5% significance level.
Results
A total of 1130 patients were recruited to the study. Of the 624 patients who had treated one attack at the time of the interim analysis, 538 had moderate or severe headache before treatment and were, therefore, eligible for the efficacy evaluation. Tolerability was assessed in the 227 patients whose case record forms had been returned at that time.
Efficacy of treatment A comparison of the percentage of patients in each group with no headache or only mild headache at 2 h is shown in Fig. 1. A reduction in headache severity from grade 3 or 2 to grade 1 or 0 was r e p o r t e d by 95/142 (67%) patients in the 100mg sumatriptan treatment group,
100
(n= 538)
80
(n= 142)
(n= 141)) ~-
(n= 155)
60
~ 40 e~
(n= 101)
20 [
0
100 mg Placebo
200 mg Sumatriptan
300 mg
Fig. 1. Efficacy of oral sumatriptan in the acute treatment of migraine: percentage of patients with no or mild headache 2h after treatment with 100 mg, 200 mg, or 300 mg sumatriptan or placebo Table 1. Percentage incidence of adverse event experienced by 227 migraine patients treated orally with placebo, or 100,200 or 300 mg sumatriptan Treatment
Event
100mg sumatripPlacebo tan (n=42) (n=69)
Chest symptoms Heaviness/pressure/ warmth Tingling/prickling Drowsiness/sedation Nausea/vomiting Bitter taste Total
200mg sumatriptan (n=56)
300mg sumatriptan (n=60)
0
1
4
13
5 0 1 4 7
4 10 3 9 7
16 1 4 14 9
10 3 6 13 22
17
34
48
67
105/140 (75%) receiving 200mg sumatriptan and 107/155 (69%) treated with 300 mg sumatriptan. This compared with 22/101 (22%) patients in the placebo group. All three sumatriptan treatment groups showed a statistically significant (P < 0.001) benefit compared with placebo, but there were no significant differences in headache relief between the sumatriptan groups. A worsening of migraine headache was noted in only one patient in each of the 100 mg and 200 mg sumatriptan groups, three in the 300 mg sumatriptan group and five in the placebo group.
Tolerability of treatment The placebo control and each of the three doses of oral sumatriptan were generally well tolerated during the study. The main categories of adverse events reported and the percentage of patients reporting these events are shown in Table 1. Overall, 14.3% of patients who took placebo reported adverse events. These included bitter taste from the trial medication, and feelings of heaviness, warmth or pressure. One patient in the placebo group withdrew from the study because of adverse events.
$64 Table 2. Proportion of patients who reported adverse events, total number of adverse event reports, and patient withdrawals due to adverse events following oral treatment with 100, 200, or 300 mg sumatriptan or placebo Treatment
Event
Placebo (n=42)
100 mg sumatriptan (n=69)
No. patients with adverse events No. adverse events No. patients withdrawn
6 (14.3%) 10 1 (2%)
26 (37.7%) 46 2 (3%)
200 mg sumatriptan (n=46)
300 mg sumatriptan (n=60)
27 (48.2%) 48 7 (13%)
41 (68.3%) 70 11 (t8%)
In the sumatriptan treatment groups, both the proportion of patients reporting adverse events and the total number of adverse events increased with increasing dose (Table 2). However, in all three groups the adverse events reported were generally mild and transient in nature. Taste disturbance due to the tablet was more noticeable in the 300 mg treatment group (22%) than in the 100mg and 200mg treatment groups (7% and 9%, respectively). Other reports included nausea/vomiting and chest symptoms such as pain and pressure in the chest, and tightness of the throat. Heaviness in the limbs, pressure in the head and a warm sensation in the face, nose and head were also noted, and some patients experienced prickling, tingling or numbness in the face and limbs. Although the incidence of adverse events appeared to be dose-related, in several cases (e.g. bitter taste, heaviness/warmth/pressure, chest symptoms), the 100 mg sumatriptan treatment group did not differ significantly from placebo (Table 1). The percentage of patients withdrawn due to adverse events was similar in the placebo group (2%) and 100 mg sumatriptan treatment group (3%), but was higher in the 200 mg and 300 mg sumatriptan groups (13% and 18%, respectively) (Table 2).
Discussion Currently available acute treatments for migraine include non-steroidal anti-inflammatory drugs, ergotamine, dihydroergotamine and phenothiazines. Prophylactic therapy is recommended particularly for patients with more frequent attacks, and [3-adrenergic receptor blockers or 5-HT2 antagonists are commonly used. Sumatriptan, a novel 5-HTl-like agonist, has been shown to be effective when given either intravenously and subcutaneously for the acute treatment of migraine [1, 2, 5, 6]. In the present study, the oral dispersible tablet formulation of sumatriptan was further explored as an acute treatment for migraine with or without aura in a large-scale multicentre study of over 1000 patients. In the absence of any objective measurement of response in migraine, the primary end-point of efficacy was
evaluated as the percentage of patients with a reduction in self-rated headache severity from moderate or severe to mild or no headache within 2 h of taking the medication. Like many other painful but self-limiting conditions, migraine is recognized as having a high and variable placebo response rate. It was, therefore, essential to include a placebo group in this randomized study in order to evaluate properly the true efficacy of sumatriptan. The placebo response rate seen (just over 20%) was relatively low, probably reflecting the very strict patient selection criteria employed in the study and the strict definition of an effective response [41. In all three sumatriptan treatment groups the proportion of patients with effective relief of migraine was significantly higher than in the placebo group. No apparent differences were observed between the three sumatriptan treatment groups, indicating that a 100 mg oral dose is capable of producing similar migraine relief to that achieved with the two higher sumatriptan doses studied. Compliance and accuracy in completing the diary card were excellent; over 96% of cards were completed correctly. This may have been because patients were given a detailed explanation of how to complete the diary card and were required to practise using it before entering the randomized phases of the study. Sumatriptan was generally well-tolerated and the adverse events experienced by patients were mostly mild and transient. The number of patients withdrawn due to adverse events and the incidence (but not the nature) of adverse events appeared to be dose-related. Taste disturbance was one of the most common adverse events and was particularly noticeable in the 300 mg sumatriptan treatment group (22% of patients) compared with the 100 mg and 200 mg groups (7% and 9%, respectively). With the exception of nausea and tingling sensations, the adverse events profile was very similar in the placebo and the 100 mg sumatriptan groups. From both the efficacy and tolerability results, it appears that the 100mg sumatriptan offered the best risk/benefit ratio in the treatment of acute migraine attacks. As mentioned previously, these results represent an interim assessment from a large-scale ongoing study. In addition to the primary efficacy end-point and tolerability evaluation described here, the full study will report on secondary end-points including the absolute changes in headache grade, the relief of associated symptoms such as nausea, vomiting and photophobia and the use of rescue medication. The effect of migraine type (common versus classical) and the duration of attack prior to treatment will also be reported. In addition, full safety data on the total population of 1130 patients will be analysed. It is concluded that oral sumatriptan given as dispersible tablets was both effective and well-tolerated as acute treatment for migraine with or without aura. Data from the full study population of more than 1100 migraine sufferers are expected to provide further confirmation of these interim results. On the basis of these findings, the 100 mg oral dose of sumatriptan would appear to offer the optimal balance between efficacy and tolerability in the acute treatment of migraine.
$65
References
Appendix
1. Doenicke A, Brand J, Perrin VL (1988) Possible benefit of GR43175, a novel 5-HTl-like agonist, for the treatment of severe migraine. Lancet I: 1309-1311 2. Ferrari M, Bayliss EM, Ludlow S, Pilgrim AJ (1989) Subcutaneous GR43175 in the treatment of acute migraine: An international study. Cephalalgia 9 (suppl 10) : 348 3. Headache Classification Committee of the International Headache Society (1989) Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8 (suppl 7) : 19-28 4. Olesen J, Tfelt-Hansen P (1988) Methodology of clinical trials in migraine. In: Capildeo R, Orgogozo J-M (eds) Methodology in clinical trials in neurology. Macmillan, London, pp 85-109 5. Perrin VL, Farkkila M, Gosguen J, Doenicke A, Brand J (1989) Overview of initial clinical studies with intravenous and oral sumatriptan in acute migraine. Cephalalgia 9 (suppl 9) : 63-72 6. Tfelt-Hansen P, Brand J, Dano P, Doenicke A, Findley LJ, Invensen HK, Melchart D, Sahlender HM (1989) Early clinical experience with subcutaneous sumatriptan in acute migraine: an overview. Cephalalgia 9 (suppl 9) : 73-77
The Publication Committee of the Oral Sumatriptan Dose-defining Study Group consisted of the following: Dr. C. Dahl6f, Sahlgrenska Sjukhuset, Gothenborg, Sweden; Dr. C. Edwards (Cardiovascular Medicine and Migraine) Glaxo Group Research Ltd, Greenford, United Kingdom; Ms S.Ludlow (Medical Statistics) Glaxo Group Research Ltd, Greenford, United Kingdom; Dr. P. Winter (Cardiovascular Medicine and Migraine) Glaxo Group Research Ltd, Greenford, United Kingdom; Dr. M. Tansey (Cardiovascular Medicine and Migraine) Glaxo Group Research Ltd, Greenford, United Kingdom. The participating investigators in the Oral Sumatriptan Dosedefining Study in the eight countries were as follows: Austria, Prof. Ott, Prof. Ladurner, Prof. Wessely, and Dr. Klingerl; Belgium, Dr. Schoenen, Dr. van den Berghe, Dr. van zan Dijke, Dr. Louis, Dr. Jacquy, Dr. Burton, Dr. Laterre, and Dr. Decarne; Federal Republic of Germany, Dr. Kempf, Dr. Hartung, Dr. Krause, Dr. Drillisch, and Prof. Hildebrandt; Finland, Dr. Junes, Dr. Kangasniemi and Prof. Rinne; France, Prof. Henry, Dr. Viader, Dr. Roullet, Prof. Bousser, and Prof. Goasguen; The Netherlands, Prof. Ansink; Sweden, Dr. Andersson, Dr. Behring, Prof.Boivie, Dr. Dahl6f, Dr. Hedman, Dr. Hindfelt, Dr. Kinnmann, Dr. Landin, Dr. Muhr, Prof. Persson, and Dr. Riman; United Kingdom, Dr. Critchley, Dr. Millac, Dr. Ferguson, Dr. McKeran, Dr. Lyons, Dr. Mortimer, Dr. Cumming, Dr. Corston, Dr. Gibson, Dr. Bamford, Dr. Newman, Dr. Mortimer and Dr. Wilkinson.
