Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

Transcription

1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: SUMB2003 Title: A double-blind, randomised, placebo-controlled study to compare the efficacy and safety of oral sumatriptan (25mg, 50mg and 100mg) in the acute treatment of migraine in adolescents. Rationale: The study was designed to assess the comparative efficacy and tolerability of sumatriptan in the acute treatment of migraine in adolescent subjects using the same assessments that have been used in sumatriptan studies in adults. Phase: Phase II Study Period: 3 March 1995 to 4 March Study Design: Randomised, double-blind, placebo-controlled, three attack, out-patient study. Centres: 62 active centres in 7 countries: Belgium (2), Canada (16), Denmark (4), France (3), Israel (4), Sweden (11), UK (22). Indication: Acute migraine with and without aura. Treatment: Subjects who had treated up to three migraine attacks with their normal migraine medication were then randomised to one of the following on a per attack basis using a randomisation ratio of 2:2:2:1: Group A, triptan 25 mg initial treatment (sumatriptan 25 mg for recurrence) Group B, triptan initial treatment (sumatriptan for recurrence) Group C, triptan 100 mg initial treatment (sumatriptan 100 mg for recurrence) Group D, Placebo initial treatment (sumatriptan for recurrence). Subjects could treat recurrence with the second tablet if they had successfully responded to the first dose of study medication within 4 hours and did not take rescue medication, and experienced a significant worsening of their headache (i.e. to moderate or severe pain, grade 2/3) within 4-24 hours post first-dose. The second dose for treatment of recurrence was the same as the treatment used for the first dose, except where placebo was used for the initial treatment. In this case subjects received 50mg sumatriptan for the treatment of recurrence Objectives: The primary objectives were to compare the efficacy, safety and tolerability of oral sumatriptan (25mg, 50mg and 100mg) with placebo in the acute treatment of migraine in subjects aged years. Primary Outcome/Efficacy Variable: The primary efficacy variable was the number of subjects who obtained headache relief (grade 2 or 3 [moderate or severe] to grade 0 or 1 [no or mild pain) at 120 minutes after administration of the first dose of study medication for the first attack. Secondary Outcome/Efficacy Variable(s): The secondary efficacy variables were: headache relief at 120 minutes after first dose (attacks 2 and 3); headache relief at 30, 45, 60 and 240 minutes after first dose (attacks 1, 2 and 3); time to first relief (attacks 1, 2 and 3), time to first relief (attacks 1, 2 and 3) shifts in headache severity grade at 30, 45, 60, 120 and 240 minutes after first dose (attacks 1, 2 and 3); headache relief 120 minutes after first dose (attacks 1, 2 and 3) by migraine type, duration between attack and treatment, and gender; headache severity grades pre-treatment and at 30, 45, 60, 120 and 240 minutes after first dose (attacks 1, 2 and 3); presence or absence of nausea, vomiting and photophobia and/or phonophobia and subjects ability to undertake normal activities pre-treatment and at 30, 45, 60, 120 and 240 minutes post-first dose and 30, 60 and 120 minutes post-second dose (attacks 1, 2 and 3); use of rescue medication within 24 hours of first dose (attacks 1, 2 and 3); headache recurrence (worsening to grade 2 or 3 from 4-24 hours following initial headache relief at 4 hours post first dose) between 4 and 24 hours after first dose (attacks 1, 2 and 3); headache relief for recurrent headache at 30, 60 and 120 minutes after second dose (attacks 1, 2 and 3); subject s global rating of study treatment at each attack. Statistical Methods: All hypothesis tests were performed at the two-sided 5% significance level. The Mantel-Haenszel chi-square test without continuity correction was used in the analysis of headache relief at each time point and for each attack. Due to the small number of subjects in each centre, centres in each country were pooled and the analysis adjusted for country. Odds ratios and 95% confidence intervals (CI) for headache relief were obtained for each dose of sumatriptan compared with placebo. Similar analyses were performed for headache relief at 120 minutes stratified by migraine type, duration between attack and treatment, and gender, without stratification by country. Percentages were calculated based on the number of non-missing responses for each endpoint. The number of subjects randomised was greater than the number planned for treatment in order to account for randomised subjects who would withdraw from the study before treating a migraine attack. The safety population comprised all subjects who were randomised and who treated at least one attack with study medication. The intent-totreat (ITT) population comprised all subjects who were randomised, who treated the attack with study treatment and who some evaluable data for each attack. 1

2 Study Population: Males and nonpregnant females using adequate contraception (if sexually active) were eligible if they were between 12 and 17 years of age (inclusive), had at least a 6-month history of migraine with or without aura as defined by the 1988 International Headache Society criteria, had 1 to 6 attacks per month of moderate (grade 2) or severe (grade 3) intensity, in either of the two months prior to study entry, were able to distinguish migraine attacks as discrete attacks from other headaches, and were able to understand and complete diary cards. Subjects were excluded if they had hypertension (supine diastolic blood pressure 90 mmhg and/or systolic blood pressure 140 mmhg treated or untreated); history of or confirmed or suspected medical condition predisposing to cardiovascular disease; history of congenital heart disease; cardiac arrhythmias requiring medication; confirmed or suspected coronary disease; history of Raynaud s Disease/Syndrome; history suggestive of cerebrovascular disease (including stroke or epilepsy); impaired hepatic or renal function; basilar or hemiplegic migraine; tension-type headache with a frequency of 10 episodes per month in either of the 2 months prior to screening. Other exclusion criteria included abuse of opiate analgesics or other psychotropic drugs, alcohol or solvents; current or history in the previous year of ergotamine abuse; use of migraine prophylactic medication containing ergotamine or derivatives; use of a monoamine oxidase inhibitor, selective serotonin reuptake inhibitor or lithium within 2 weeks of study entry; known hypersensitivity to study drug; participation in a clinical trial within the month prior to entry or planned or current participation in any other clinical trial during the course of this study; any severe concurrent medical condition. triptan Placebo (+ ) 25 mg (+ 25 mg) (+ ) 100 mg (+100 mg) Number of Subjects: Planned, N Randomised, N Completed, n (%) 36 (72) 62 (65) 69 (68) 63 (63) Number Subjects Withdrawn, n (%) 14 (28) 33 (35) 33 (32) 37 (37) Withdrawn due to Adverse Events, n (%) 1 (2) 1 (1) 2 (2) 5 (5) Withdrawn due to Lack of Efficacy, n (%) Withdrawn for Other Reasons, n (%) 13 (26) 32 (34) 31 (31) 32 (32) Demographics N (ITT population) Females: Males 27: 14 43: 30 44: 36 42: 37 Mean Age, years (SD) 14.2 (1.63) 13.9 (1.50) 14.2 (1.68) 14.0 (1.61) Caucasian, n (%) 39 (95) 70 (96) 77 (96) 75 (95) Primary Efficacy Results: (ITT Population) Headache relief at 120 minutes post first dose triptan (Attack 1) Placebo (n=41) 25 mg (n=73) (n=80) 100 mg (n=79) N, headache Grade 2 or 3 and data Headache relief, n (%) 20 (59) 26 (50) 36 (55) 34 (50) Treatment comparison, odds ratio vs placebo NA % CI NA 0.297, , , p-value NA Secondary Outcome Variable(s): (ITT Population) Headache relief at 120 minutes post first dose triptan (Attack 2): Placebo (n=29) 25 mg (n=60) (n=62) 100 mg (n=60) Headache relief, n (%) 12 (46) 29 (62) 30 (59) 28 (61) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.715, , , Headache relief at 120 minutes post first dose triptan (Attack 3): Placebo (n=22) 25 mg (n=52) (n=44) 100 mg (n=43) N, headache Grade 2 or 3 and data Headache relief, n (%) 10 (56) 21 (49) 20 (54) 19 (53) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.283, , , Other Secondary Outcome Variable(s) by Attack: triptan 2

3 Attack 1 (ITT Population) Placebo (n=41) 25 mg (n=73) (n=80) 100 mg (n=79) Headache relief at 30, 45, 60 and 240 minutes post first dose : 30 min: N, headache Grade 2 or 3 and data Headache relief, n (%) 8 (22) 9 (16) 5 (7) 8 (11) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.301, , , min: N, headache Grade 2 or 3 and data Headache relief, n (%) 13 (36) 12 (23) 10 (15) 17 (24) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.236, , , min: N, headache Grade 2 or 3 and data Headache relief, n (%) 14 (40) 19 (37) 17 (27) 26 (37) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.399, , , min: N, headache Grade 2 or 3 and data Headache relief, n (%) 18 (56) 26 (58) 41 (64) 43 (66) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.404, , , Shifts in headache severity Pre-treatment severity Severity at 30 minutes None Mild Moderate Severe Not Mild Moderate Severe Not None Mild Moderate Severe Not None Mild Moderate Severe Not Pre-treatment severity Severity at 45 minutes 3

4 None Mild Moderate Severe Not Mild Moderate Severe Not None Mild Moderate Severe Not None Mild Moderate Severe Not Pre-treatment severity Severity at 60 minutes None Mild Moderate Severe Not Mild Moderate Severe Not None Mild Moderate Severe

5 Not None Mild Moderate Severe Not Pre-treatment severity Severity at 120 minutes None Mild Moderate Severe Not Mild Moderate Severe Not None Mild Moderate Severe Not None Mild Moderate Severe Not Pre-treatment severity Severity at 240 minutes None Mild Moderate Severe Not

6 Mild Moderate Severe Not None Mild Moderate Severe Not None Mild Moderate Severe Not Time to first relief after first dose: N, headache Grade 2 or 3 and data Headache relief within 4 hours, n (%) 26 (68) 37 (61) 49 (68) 50 (68) Median time to first relief (minutes) for subjects obtaining relief within 4 hours Headache relief at 120 min post first dose by migraine type: Migraine without aura, N N, headache Grade 2 or 3 and data Headache relief, n (%) 16 (64) 15 (52) 23 (55) 24 (59) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.200, , , Migraine with aura, N N, headache Grade 2 or 3 and data Headache relief, n (%) 4 (44) 11 (48) 13 (54) 10 (37) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.238, , , Headache relief at 120 minutes post first dose by duration between attack and treatment: Duration 4 hours, N N, headache Grade 2 or 3 and data Headache relief, n (%) 19 (61) 23 (53) 31 (53) 32 (52) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.283, , , Duration >4 hours, N N, headache Grade 2 or 3 and data Headache relief, n (%) 1 (33) 3 (38) 4 (57) 2 (33) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.064, , NA Headache relief at 120 minutes post first dose by gender: Males, N N, headache Grade 2 or 3 and data Headache relief, n (%) 7 (54) 11 (58) 19 (68) 15 (48) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.278, , , Females, N

7 N, headache Grade 2 or 3 and data Headache relief, n (%) 13 (62) 15 (45) 17 (45) 19 (51) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.167, , , Headache severity grades pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Pre-treatment headache severity n=40 n=73 n=80 n=79 0. Absent 1 (3) 0 2 (3) 1 (1) 1. Mild 1 (3) 12 (16) 6 (8) 4 (5) 2. Moderate 29 (73) 47 (64) 51 (64) 52 (66) 3. Severe 9 (23) 14 (19) 21 (26) 22 (28) Headache severity at 30 minutes n=39 n=67 n=74 n=75 0. Absent 1 (3) 0 2 (3) 0 1. Mild 8 (21) 12 (21) 7 (9) 12 (16) 2. Moderate 21 (54) 39 (58) 44 (59) 42 (56) 3. Severe 9 (23) 14 (21) 21 (28) 21 (28) Headache severity at 45 minutes n=38 n=62 n=73 n=76 0. Absent 0 1 (2) 1 (1) 1 (1) 1. Mild 14 (37) 15 (24) 12 (16) 18 (24) 2. Moderate 17 (45) 36 (58) 38 (52) 31 (41) 3. Severe 7 (18) 10 (16) 22 (30) 26 (34) Headache severity at 60 minutes n=37 n=62 n=69 n=76 0. Absent 3 (8) 6 (10) 7 (10) 9 (12) 1. Mild 12 (32) 18 (29) 13 (19) 19 (25) 2. Moderate 15 (41) 27 (44) 32 (46) 24 (32) 3. Severe 7 (19) 11 (18) 17 (25) 24 (32) Headache severity at 120 minutes n=35 n=62 n=73 n=73 0. Absent 10 (29) 12 (19) 15 (21) 16 (22) 1. Mild 10 (29) 21 (34) 25 (34) 19 (26) 2. Moderate 12 (34) 22 (35) 15 (21) 22 (30) 3. Severe 3 (9) 7 (11) 18 (25) 16 (22) Headache severity at 240 minutes n=33 n=56 n=70 n=69 0. Absent 12 (36) 19 (34) 23 (33) 28 (41) 1. Mild 7 (21) 15 (27) 23 (33) 18 (26) 2. Moderate 9 (27) 15 (27) 11 (16) 15 (22) 3. Severe 5 (15) 7 (13) 13 (19) 8 (12) Presence of Nausea pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Nausea at Pre-treatment, n (%) a 16 (40) 39 (56) 40 (51) 41 (53) Nausea at 30 minutes, n (%) a 16 (41) 35 (54) 33 (46) 34 (47) Nausea at 45 minutes, n (%) a 13 (34) 27 (44) 33 (46) 38 (52) Nausea at 60 minutes, n (%) a 8 (22) 27 (44) 29 (43) 40 (56) Nausea at 120 minutes, n (%) a 7 (20) 22 (35) 26 (37) 32 (46) Nausea at 240 minutes, n (%) a 5 (15) 16 (29) 22 (32) 22 (33) Presence of Vomiting pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Vomiting at Pre-treatment, n (%) a 2 (5) 5 (7) 2 (3) 6 (8) Vomiting at 30 minutes, n (%) a 0 3 (5) 2 (3) 3 (4) Vomiting at 45 minutes, n (%) a 1 (3) 1 (2) 4 (6) 4 (6) Vomiting at 60 minutes, n (%) a 2 (6) 3 (5) 0 6 (8) Vomiting at 120 minutes, n (%) a 3 (9) 3 (5) 2 (3) 5 (7) Vomiting at 240 minutes, n (%) a 3 (9) 5 (9) 3 (5) 5 (8) Presence of Photophobia/phonophobia pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Photophobia/phonophobia at Pre-treatment, n (%) a 30 (75) 56 (77) 58 (73) 54 (69) Photophobia/phonophobia at 30 minutes, n (%) a 29 (74) 51 (77) 56 (76) 52 (71) Photophobia/phonophobia at 45 minutes, n (%) a 26 (68) 44 (70) 50 (68) 47 (64) Photophobia/phonophobia at 60 minutes, n (%) a 23 (62) 39 (63) 41 (59) 42 (56) Photophobia/phonophobia at 120 minutes, n (%) a 15 (43) 29 (47) 32 (44) 37 (51) 7

8 Photophobia/phonophobia at 240 minutes, n (%) a 15 (45) 16 (29) 22 (32) 26 (38) Undertaking normal activity pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Unable at Pre-treatment, n (%) a 27 (66) 56 (77) 52 (65) 50 (64) Unable at 30 minutes, n (%) a 23 (59) 50 (77) 51 (69) 44 (60) Unable at 45 minutes, n (%) a 20 (53) 47 (77) 49 (67) 46 (62) Unable at 60 minutes, n (%) a 17 (47) 43 (70) 42 (61) 38 (51) Unable at 120 minutes, n (%) a 14 (40) 32 (52) 45 (63) 39 (55) Unable at 240 minutes, n (%) a 15 (45) 20 (36) 29 (41) 28 (42) Use of rescue medication within 24 hours of first dose: Subjects who took rescue from 0-4 hours post dose, 4 (10%) 5 (7%) 6 (8%) 3 (4%) n(%) Subjects who took rescue from 4-24 hours post dose, 12 (29%) 19 (26%) 20 (25%) 15 (19%) n(%) Subjects rescue-free 0-24 hours post-first dose, n (%) 26 (63) 48 (67) 54 (68) 61 (77) Rescue-free 0-24 hours treatment comparison, odds NA ratio vs placebo 95% Confidence Interval (CI) NA 0.487, , , Headache recurrence 4-24 hours after first dose: N, improved at 4 hours and data Recurrence, n (%) 3 (21) 6 (27) 10 (32) 9 (26) Headache relief in recurrent headache at 30, 60 and 120 minutes post second dose: Subjects who had recurrence, n Subjects who took second treatment for recurrence, n N with pre-treatment grade 2 or Headache relief at 30 minutes, n (%) a 1 (33) 1 (17) 1 (17) 1 (14) Headache relief at 60 minutes, n (%) a 1 (33) 2 (33) 4 (67) 3 (43) Headache relief at 120 minutes, n (%) a 1 (33) 3 (60) 6 (100) 6 (86) Presence of Nausea pre-treatment and at 30, 60 and 120 minutes after second dose: Nausea at Pre-treatment, n (%) a 2 (67) 3 (50) 1 (14) 5 (63) Nausea at 30 minutes, n (%) a 1 (33) 3 (50) 1 (14) 5 (71) Nausea at 60 minutes, n (%) a 1 (33) 4 (67) 1 (14) 5 (71) Nausea at 120 minutes, n (%) a 0 4 (80) 0 2 (29) Presence of Vomiting pre-treatment and at 30, 60 and 120 minutes after second dose: Vomiting at Pre-treatment, n (%) a Vomiting at 30 minutes, n (%) a Vomiting at 60 minutes, n (%) a 0 1 (17) 0 0 Vomiting at 120 minutes, n (%) a (14) Presence of Photophobia/phonophobia pre-treatment and at 30, 60 and 120 minutes after second dose: Photophobia/phonophobia at Pre-treatment, n (%) a 2 (67) 6 (100) 4 (57) 4 (57) Photophobia/phonophobia at 30 minutes, n (%) a 2 (67) 5 (83) 2 (29) 3 (43) Photophobia/phonophobia at 60 minutes, n (%) a 1 (33) 4 (67) 1 (14) 3 (43) Photophobia/phonophobia at 120 minutes, n (%) a 1 (33) 3 (60) 0 2 (29) Undertaking normal activity pre-treatment and at 30, 60 and 120 minutes after second dose: Unable at Pre-treatment, n (%) a 2 (67) 5 (83) 4 (57) 4 (50) Unable at 30 minutes, n (%) a 2 (67) 4 (67) 5 (71) 4 (57) Unable at 60 minutes, n (%) a 2 (67) 4 (67) 5 (71) 3 (43) Unable at 120 minutes, n (%) a 1 (33) 2 (50) 1 (14) 0 Subjects global rating of study treatment: Did not work, n (%) a 12 (31) 12 (18) 13 (18) 17 (23) Poor, n (%) a 9 (23) 8 (12) 19 (27) 11 (15) Fair, n (%) a 5 (13) 17 (26) 9 (13) 14 (19) Good, n (%) a 8 (21) 21 (32) 27 (38) 22 (30) Excellent, n (%) a 5 (13) 8 (12) 3 (4) 9 (12) a Percentages based on number of subjects with data. Other Secondary Outcome Variable(s) by Attack: triptan 8

9 Attack 2 (ITT Population) Placebo (n=29) 25 mg (n=60) (n=62) 100 mg (n=60) Headache relief at 30, 45, 60 and 240 minutes post first dose: 30 min: N, headache Grade 2 or 3 and data Headache relief, n (%) 2 (7) 8 (16) 3 (5) 10 (20) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.513, , , min: N, headache Grade 2 or 3 and data Headache relief, n (%) 8 (30) 14 (29) 9 (16) 14 (29) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.378, , , min: N, headache Grade 2 or 3 and data Headache relief, n (%) 12 (44) 20 (43) 13 (24) 22 (48) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.402, , , min: N, headache Grade 2 or 3 and data Headache relief, n (%) 15 (63) 30 (67) 39 (78) 32 (80) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.305, , , Shifts in headache severity Pre-treatment severity Severity at 30 minutes None Mild Moderate Severe Not None Mild Moderate Severe Not None Mild Moderate Severe Not None Mild Moderate Severe Not Pre-treatment severity Severity at 45 minutes 9

10 Moderate Severe Not None Mild Moderate Severe Not None Mild Moderate Severe Not None Mild Moderate Severe Not Pre-treatment severity Severity at 60 minutes Moderate Severe Not None Mild Moderate Severe Not None Mild Moderate Severe

11 Not None Mild Moderate Severe Not Pre-treatment severity Severity at 120 minutes Moderate Severe Not None Mild Moderate Severe Not None Mild Moderate Severe Not None Mild Moderate Severe Not Pre-treatment severity Severity at 240 minutes Moderate Severe Not None

12 Mild Moderate Severe Not None Mild Moderate Severe Not None Mild Moderate Severe Not Time to first relief after first dose: N, headache Grade 2 or 3 and data Headache relief within 4 hours, n (%) 18 (62) 37 (70) 40 (68) 38 (70) Median time to first relief (minutes) for subjects obtaining relief within 4 hours Headache relief at 120 min post first dose by migraine type: Migraine without aura, N N, headache Grade 2 or 3 and data Headache relief, n (%) 8 (47) 21 (66) 26 (62) 21 (62) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.645, , , Migraine with aura, N N, headache Grade 2 or 3 and data Headache relief, n (%) 4 (44) 7 (50) 4 (44) 7 (58) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.224, NA 0.294, Headache relief at 120 minutes post first dose by duration between attack and treatment: Duration 4 hours, N N, headache Grade 2 or 3 and data Headache relief, n (%) 12 (48) 22 (56) 27 (60) 27 (63) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.508, , , Duration >4 hours, N N, headache Grade 2 or 3 and data Headache relief, n (%) 0 7 (88) 3 (50) 1 (33) Treatment comparison, odds ratio vs placebo NA NA NA NA 95% Confidence Interval (CI) NA NA NA NA Headache relief at 120 minutes post first dose by gender: Males, N N, headache Grade 2 or 3 and data Headache relief, n (%) 4 (36) 11 (55) 12 (63) 15 (79) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.466, , , Females, N

13 N, headache Grade 2 or 3 and data Headache relief, n (%) 8 (53) 18 (67) 18 (56) 13 (48) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.476, , , Headache severity grades pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Pre-treatment headache severity n=29 n=60 n=62 n=60 0. Absent 0 1 (2) 1 (2) 1 (2) 1. Mild 0 6 (10) 2 (3) 5 (8) 2. Moderate 17 (59) 39 (65) 39 (63) 40 (67) 3. Severe 12 (41) 14 (23) 20 (32) 14 (23) Headache severity at 30 minutes n=27 n=56 n=58 n=57 0. Absent 1 (4) 3 (5) 0 1 (2) 1. Mild 1 (4) 9 (16) 5 (9) 12 (21) 2. Moderate 16 (59) 36 (64) 33 (57) 29 (51) 3. Severe 9 (33) 8 (14) 20 (34) 15 (26) Headache severity at 45 minutes n=27 n=55 n=57 n=54 0. Absent 2 (7) 3 (5) 1 (2) 4 (7) 1. Mild 6 (22) 15 (27) 9 (16) 13 (24) 2. Moderate 13 (48) 29 (53) 27 (47) 24 (44) 3. Severe 6 (22) 8 (15) 20 (35) 13 (24) Headache severity at 60 minutes n=27 n=52 n=55 n=52 0. Absent 4 (15) 8 (15) 4 (7) 7 (13) 1. Mild 8 (30) 15 (29) 10 (18) 18 (35) 2. Moderate 10 (37) 24 (46) 27 (49) 17 (33) 3. Severe 5 (19) 5 (10) 14 (25) 10 (19) Headache severity at 120 minutes n=26 n=52 n=54 n=52 0. Absent 7 (27) 15 (29) 15 (28) 19 (37) 1. Mild 5 (19) 16 (31) 17 (31) 11 (21) 2. Moderate 11 (42) 16 (31) 13 (24) 16 (31) 3. Severe 3 (12) 5 (10) 9 (17) 6 (12) Headache severity at 240 minutes n=24 n=49 n=53 n=45 0. Absent 8 (33) 23 (47) 27 (51) 26 (58) 1. Mild 7 (29) 11 (22) 15 (28) 10 (22) 2. Moderate 7 (29) 8 (16) 7 (13) 4 (9) 3. Severe 2 (8) 7 (14) 4 (8) 5 (11) Presence of Nausea pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Nausea at Pre-treatment, n (%) a 15 (52) 23 (40) 24 (39) 29 (48) Nausea at 30 minutes, n (%) a 9 (35) 20 (37) 27 (47) 28 (50) Nausea at 45 minutes, n (%) a 9 (35) 19 (36) 24 (44) 25 (47) Nausea at 60 minutes, n (%) a 10 (37) 15 (30) 21 (39) 25 (49) Nausea at 120 minutes, n (%) a 6 (32) 13 (25) 17 (33) 21 (40) Nausea at 240 minutes, n (%) a 5 (21) 10 (21) 10 (19) 8 (18) Presence of Vomiting pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Vomiting at Pre-treatment, n (%) a (7) 1 (2) Vomiting at 30 minutes, n (%) a 0 1 (2) 3 (5) 1 (2) Vomiting at 45 minutes, n (%) a 0 2 (4) 3 (6) 0 Vomiting at 60 minutes, n (%) a 0 1 (2) 4 (8) 2 (4) Vomiting at 120 minutes, n (%) a (12) 3 (6) Vomiting at 240 minutes, n (%) a 0 2 (4) 2 (4) 0 Presence of Photophobia/phonophobia pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Photophobia/phonophobia at Pre-treatment, n (%) a 21 (72) 48 (80) 45 (73) 39 (66) Photophobia/phonophobia at 30 minutes, n (%) a 20 (74) 42 (76) 42 (72) 34 (61) Photophobia/phonophobia at 45 minutes, n (%) a 15 (56) 40 (74) 37 (65) 28 (52) Photophobia/phonophobia at 60 minutes, n (%) a 15 (56) 36 (71) 32 (57) 23 (45) Photophobia/phonophobia at 120 minutes, n (%) a 12 (46) 24 (46) 19 (36) 16 (30) 13

14 Photophobia/phonophobia at 240 minutes, n (%) a 8 (33) 21 (43) 14 (26) 9 (20) Undertaking normal activity pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Unable at Pre-treatment, n (%) a 18 (56) 39 (66) 36 (58) 31 (52) Unable at 30 minutes, n (%) a 17 (63) 30 (58) 32 (58) 32 (56) Unable at 45 minutes, n (%) a 14 (52) 29 (57) 29 (54) 33 (61) Unable at 60 minutes, n (%) a 11 (41) 23 (48) 29 (55) 27 (53) Unable at 120 minutes, n (%) a 7 (27) 20 (41) 26 (51) 21 (40) Unable at 240 minutes, n (%) a 4 (17) 16 (34) 19 (38) 15 (34) Use of rescue medication within 24 hours of first dose: Subjects who took rescue from 0-4 hours post dose 2 (7%) 2 (3%) 2 (3%) 2 (3%) Subjects who took rescue from 4-24 hours post dose 11 (38%) 12 (20%) 13 (21%) 9 (15%) Subjects rescue-free 0-24 hours post-first dose, n (%) 18 (62) 47 (78) 48 (77) 50 (83) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.861, , , Headache recurrence 4-24 hours after first dose: N, improved at 4 hours and data Recurrence, n (%) 3 (25) 8 (33) 8 (26) 5 (19) Headache relief in recurrent headache at 30, 60 and 120 minutes post second dose: Subjects who had recurrence, n Subjects who took second treatment for recurrence, n N with pre-treatment grade 2 or Headache relief at 30 minutes, n (%) a 0 2 (29) 0 2 (50) Headache relief at 60 minutes, n (%) a 1 (33) 3 (50) 0 1 (33) Headache relief at 120 minutes, n (%) a 2 (67) 5 (100) 4 (80) 1 (33) Presence of Nausea pre-treatment and at 30, 60 and 120 minutes after second dose: Nausea at Pre-treatment, n (%) a 2 (67) 2 (25) 3 (50) 0 Nausea at 30 minutes, n (%) a 2 (67) 2 (25) 4 (67) 1 (25) Nausea at 60 minutes, n (%) a 2 (67) 2 (29) 2 (40) 1 (33) Nausea at 120 minutes, n (%) a 2 (67) 0 1 (20) 0 Presence of Vomiting pre-treatment and at 30, 60 and 120 minutes after second dose: Vomiting at Pre-treatment, n (%) a (17) 0 Vomiting at 30 minutes, n (%) a Vomiting at 60 minutes, n (%) a Vomiting at 120 minutes, n (%) a (20) 0 Presence of Photophobia/phonophobia pre-treatment and at 30, 60 and 120 minutes after second dose: Photophobia/phonophobia at Pre-treatment, n (%) a 2 (67) 8 (100) 4 (67) 3 (60) Photophobia/phonophobia at 30 minutes, n (%) a 2 (67) 6 (75) 4 (67) 3 (75) Photophobia/phonophobia at 60 minutes, n (%) a 1 (33) 4 (57) 4 (80) 2 (67) Photophobia/phonophobia at 120 minutes, n (%) a 1 (33) 1 (17) 1 (20) 1 (50) Undertaking normal activity pre-treatment and at 30, 60 and 120 minutes after second dose: Unable at Pre-treatment, n (%) a 3 (100) 8 (100) 4 (67) 3 (60) Unable at 30 minutes, n (%) a 2 (67) 6 (75) 4 (67) 2 (50) Unable at 60 minutes, n (%) a 1 (33) 4 (57) 4 (80) 1 (33) Unable at 120 minutes, n (%) a 1 (33) 0 1 (20) 0 Subjects global rating of study treatment: Did not work, n (%) a 7 (26) 10 (17) 9 (16) 9 (15) Poor, n (%) a 5 (19) 10 (17) 9 (16) 7 (12) Fair, n (%) a 5 (19) 7 (12) 14 (25) 11 (19) Good, n (%) a 7 (26) 22 (38) 17 (30) 21 (36) Excellent, n (%) a 3 (11) 9 (16) 7 (13) 11 (19) a Percentages based on number of subjects with data. Other Secondary Outcome Variable(s) by Attack: triptan Attack 3 (ITT Population) Placebo (n=22) Headache relief at 30, 45, 60 and 240 minutes post first dose: 25 mg (n=52) (n=44) 100 mg (n=43) 14

15 30 min: N, headache Grade 2 or 3 and data Headache relief, n (%) 3 (14) 5 (10) 7 (17) 2 (5) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.121, , , min: N, headache Grade 2 or 3 and data Headache relief, n (%) 6 (30) 12 (25) 11 (27) 7 (18) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.204, , , min: N, headache Grade 2 or 3 and data Headache relief, n (%) 8 (40) 13 (28) 12 (31) 13 (36) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.198, , , min: N, headache Grade 2 or 3 and data Headache relief, n (%) 10 (63) 27 (64) 28 (80) 26 (72) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.326, , , Shifts in headache severity Pre-treatment severity Severity at 30 minutes None Moderate Severe Not Mild Moderate Severe Not None Moderate Severe Not Mild Moderate Severe Not Pre-treatment severity Severity at 45 minutes None

16 Moderate Severe Not Mild Moderate Severe Not None Moderate Severe Not Mild Moderate Severe Not Pre-treatment severity Severity at 60 minutes None Moderate Severe Not Mild Moderate Severe Not None Moderate Severe Not

17 Mild Moderate Severe Not Pre-treatment severity Severity at 120 minutes None Moderate Severe Not Mild Moderate Severe Not None Moderate Severe Not Mild Moderate Severe Not Pre-treatment severity Severity at 240 minutes None Moderate Severe Not Mild Moderate Severe Not

18 None Moderate Severe Not Mild Moderate Severe Not Time to first relief after first dose: N, headache Grade 2 or 3 and data Headache relief within 4 hours, n (%) 13 (62) 30 (60) 34 (79) 27 (68) Median time to first relief (minutes) in subjects obtaining relief within 4 hours Headache relief at 120 min post first dose by migraine type: Migraine without aura, N N, headache Grade 2 or 3 and data Headache relief, n (%) 7 (54) 18 (55) 15 (58) 12 (50) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.280, , , Migraine with aura, N N, headache Grade 2 or 3 and data Headache relief, n (%) 3 (60) 2 (22) 5 (45) 7 (58) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.018, , , Headache relief at 120 minutes post first dose by duration between attack and treatment: Duration 4 hours, N N, headache Grade 2 or 3 and data Headache relief, n (%) 9 (60) 18 (46) 18 (58) 17 (53) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.170, , , Duration >4 hours, N N, headache Grade 2 or 3 and data Headache relief, n (%) 1 (33) 1 (50) 2 (33) 1 (50) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.034, NA 0.034, Headache relief at 120 minutes post first dose by gender: Males, N N, headache Grade 2 or 3 and data Headache relief, n (%) 4 (50) 14 (70) 10 (53) 10 (59) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.428, , , Females, N N, headache Grade 2 or 3 and data Headache relief, n (%) 6 (60) 7 (30) 10 (56) 9 (47) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.063, , ,

19 Headache severity grades pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Pre-treatment headache severity n=22 n=52 n=44 n=43 0. Absent 1 (5) 0 1 (2) 0 1. Mild 0 2 (4) 0 3 (7) 2. Moderate 11 (50) 35 (67) 29 (66) 21 (49) 3. Severe 10 (45) 15 (29) 14 (32) 19 (44) Headache severity at 30 minutes n=22 n=50 n=43 n=42 0. Absent 1 (5) Mild 3 (14) 6 (12) 8 (19) 3 (7) 2. Moderate 8 (36) 30 (60) 21 (49) 21 (50) 3. Severe 10 (45) 14 (28) 14 (33) 18 (43) Headache severity at 45 minutes n=21 n=49 n=42 n=41 0. Absent 2 (10) 2 (4) 1 (2) 1 (2) 1. Mild 5 (24) 10 (20) 10 (24) 6 (15) 2. Moderate 8 (38) 24 (49) 21 (50) 16 (39) 3. Severe 6 (29) 13 (27) 10 (24) 18 (44) Headache severity at 60 minutes n=21 n=48 n=40 n=39 0. Absent 2 (10) 7 (15) 4 (10) 2 (5) 1. Mild 7 (33) 6 (13) 8 (20) 11 (28) 2. Moderate 8 (38) 21 (44) 19 (48) 14 (36) 3. Severe 4 (19) 14 (29) 9 (23) 12 (31) Headache severity at 120 minutes n=19 n=44 n=38 n=36 0. Absent 4 (21) 9 (20) 10 (26) 9 (25) 1. Mild 6 (32) 13 (30) 10 (26) 10 (28) 2. Moderate 6 (32) 16 (36) 9 (24) 13 (36) 3. Severe 3 (16) 6 (14) 9 (24) 4 (11) Headache severity at 240 minutes n=17 n=42 n=36 n=38 0. Absent 5 (29) 21 (50) 20 (56) 21 (55) 1. Mild 6 (35) 6 (14) 8 (22) 7 (18) 2. Moderate 2 (12) 9 (21) 5 (14) 7 (18) 3. Severe 4 (24) 6 (14) 3 (8) 3 (8) Presence of Nausea pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Nausea at Pre-treatment, n (%) a 12 (57) 26 (50) 15 (35) 23 (53) Nausea at 30 minutes, n (%) a 13 (62) 25 (51) 13 (31) 26 (62) Nausea at 45 minutes, n (%) a 12 (57) 22 (46) 14 (34) 22 (54) Nausea at 60 minutes, n (%) a 10 (48) 20 (43) 16 (41) 23 (59) Nausea at 120 minutes, n (%) a 4 (21) 13 (30) 11 (29) 15 (42) Nausea at 240 minutes, n (%) a 4 (24) 10 (24) 9 (25) 9 (24) Presence of Vomiting pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Vomiting at Pre-treatment, n (%) a 3 (14) 2 (4) 1 (2) 4 (9) Vomiting at 30 minutes, n (%) a 0 2 (4) 0 3 (7) Vomiting at 45 minutes, n (%) a 1 (5) 3 (6) 1 (3) 1 (2) Vomiting at 60 minutes, n (%) a 0 3 (6) 1 (3) 1 (3) Vomiting at 120 minutes, n (%) a 0 1 (2) 0 4 (11) Vomiting at 240 minutes, n (%) a 0 2 (5) 0 2 (5) Presence of Photophobia/phonophobia pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Photophobia/phonophobia at Pre-treatment, n (%) a 15 (68) 40 (77) 33 (75) 37 (86) Photophobia/phonophobia at 30 minutes, n (%) a 14 (67) 36 (73) 31 (72) 35 (83) Photophobia/phonophobia at 45 minutes, n (%) a 11 (52) 31 (63) 31 (74) 33 (80) Photophobia/phonophobia at 60 minutes, n (%) a 11 (55) 27 (56) 27 (68) 27 (69) Photophobia/phonophobia at 120 minutes, n (%) a 7 (39) 21 (48) 16 (42) 15 (42) Photophobia/phonophobia at 240 minutes, n (%) a 5 (29) 14 (33) 11 (31) 10 (26) Undertaking normal activity pre-treatment and at 30, 45, 60, 120 and 240 minutes post first dose: Unable at Pre-treatment, n (%) a 18 (82) 32 (63) 27 (63) 38 (88) Unable at 30 minutes, n (%) a 15 (71) 30 (61) 24 (57) 38 (90) 19

20 Unable at 45 minutes, n (%) a 12 (60) 25 (52) 26 (63) 33 (80) Unable at 60 minutes, n (%) a 10 (50) 23 (49) 23 (58) 29 (74) Unable at 120 minutes, n (%) a 9 (50) 17 (40) 18 (47) 17 (49) Unable at 240 minutes, n (%) a 5 (31) 13 (32) 15 (42) 15 (41) Use of rescue medication within 24 hours of first dose: Subjects who took rescue from 0-4 hours post dose 0 2 (4%) 2 (5%) 2 (5%) Subjects who took rescue from 4-24 hours post dose 6 (27%) 8 (15%) 5 (11%) 7 (16%) Subjects rescue-free 0-24 hours post-first dose, n (%) 16 (73) 42 (81) 37 (84) 34 (79) Treatment comparison, odds ratio vs placebo NA % Confidence Interval (CI) NA 0.389, , , Headache recurrence 4-24 hours after first dose: N, improved at 4 hours and data Recurrence, n (%) 1 (13) 4 (17) 4 (17) 2 (10) Headache relief in recurrent headache at 30, 60 and 120 minutes post second dose: Subjects who had recurrence, n Subjects who took second treatment for recurrence, n N with pre-treatment grade 2 or Headache relief at 30 minutes, n (%) a 1 (100) Headache relief at 60 minutes, n (%) a 1 (100) 2 (50) 2 (50) 1 (50) Headache relief at 120 minutes, n (%) a 1 (100) 2 (50) 3 (75) 1 (50) Presence of Nausea pre-treatment and at 30, 60 and 120 minutes after second dose: Nausea at Pre-treatment, n (%) a 0 3 (75) 1 (25) 2 (100) Nausea at 30 minutes, n (%) a 0 2 (50) 0 1 (50) Nausea at 60 minutes, n (%) a 0 1 (25) 0 1 (50) Nausea at 120 minutes, n (%) a 0 1 (25) 0 1 (50) Presence of Vomiting pre-treatment and at 30, 60 and 120 minutes after second dose: Vomiting at Pre-treatment, n (%) a (50) Vomiting at 30 minutes, n (%) a Vomiting at 60 minutes, n (%) a Vomiting at 120 minutes, n (%) a Presence of Photophobia/phonophobia pre-treatment and at 30, 60 and 120 minutes after second dose: Photophobia/phonophobia at Pre-treatment, n (%) a 0 3 (75) 3 (75) 1 (50) Photophobia/phonophobia at 30 minutes, n (%) a 0 3 (75) 2 (50) 1 (50) Photophobia/phonophobia at 60 minutes, n (%) a 0 2 (50) 0 1 (50) Photophobia/phonophobia at 120 minutes, n (%) a 0 2 (50) 0 1 (50) Undertaking normal activity pre-treatment and at 30, 60 and 120 minutes after second dose: Unable at Pre-treatment, n (%) a 1 (100) 3 (75) 3 (75) 1 (50) Unable at 30 minutes, n (%) a 1 (100) 3 (75) 3 (75) 1 (50) Unable at 60 minutes, n (%) a 0 3 (75) 2 (50) 0 Unable at 120 minutes, n (%) a 0 3 (75) 1 (25) 0 Subjects global rating of study treatment: Did not work, n (%) a 7 (33) 9 (17) 7 (17) 4 (10) Poor, n (%) a 4 (19) 11 (21) 4 (10) 7 (18) Fair, n (%) a 6 (29) 11 (21) 10 (24) 9 (23) Good, n (%) a 3 (14) 15 (29) 12 (29) 17 (43) Excellent, n (%) a 1 (5) 6 (12) 9 (21) 3 (8) a Percentages based on number of subjects with data. Safety Results: ITT Population Adverse events (AEs) and serious adverse events (SAEs) were collected at each visit throughout the study and summarised as those occurring post-dose according to the dose at event. On therapy AEs were those which occurred within 24 hours of the initial treatment. Place bo Place bo + 25 mg 25 mg + 25 mg + 50 mg 100 mg 100 mg mg 20

21 N Most Frequent Adverse Events n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) On-Therapy Subjects with any AE(s), n (%) 16 (19) 11 (39) 43 (30) 8 (17) 37 (24) 3 (9) 49 (33) 6 (19) Nausea & vomiting 4 (5) 3 (11) 13 (9) 2 (4) 15 (10) 0 10 (7) 0 Musculoskeletal pain (1) 0 2 (1) 0 7 (5) 0 Dizziness 0 1 (4) 7 (5) 0 5 (3) 0 5 (3) 0 Headaches 2 (2) 1 (4) 1 (<1) 0 2 (1) 0 4 (3) 0 Malaise & fatigue 3 (4) 0 5 (3) 2 (4) 1 (<1) 0 4 (3) 1 (3) Ear nose & throat infections 0 2 (7) 2 (1) 0 1 (<1) 0 3 (2) 0 Numbness (<1) 0 2 (1) 0 2 (1) 0 Burning/stinging sensation (1) 0 2 (1) 0 Tingling (2) 0 1 (<1) 1 (3) 2 (1) 1 (3) Fractures (1) (1) 0 Blindness & low vision 1 (1) 0 1 (<1) (1) 0 Viral respiratory infections (<1) 0 4 (3) 0 1 (<1) 0 Hypnagogic effects 2 (2) (1) 1 (3) 1 (<1) 1 (3) Gastrointestinal signs & symptoms 1 (1) (<1) 0 1 (<1) 0 Gastrointestinal discomfort & pain 1 (1) 0 1 (<1) 1 (2) 0 1 (3) 1 (<1) 0 Skin rashes 1 (1) 0 1 (<1) (<1) 0 Feeling strange (1) Temperature regulation disturbances 1 (1) 0 1 (<1) Upper respiratory inflammation 1 (1) (3) Pharyngitis 1 (1) Disorders of thirst & fluid intake 1 (1) Feeding problems 1 (1) Hyposalivation 1 (1) (<1) Colitis 1 (1) Diarrhea 1 (1) Asthma 1 (1) (2) Pneumonia 1 (1) Urinary frequency 1 (1) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Placebo Placebo + 25 mg 25 mg + 25 mg mg 100 mg mg N Subjects with nonfatal (<1) 1 (2) 1 (<1) 0 2 (1) 0 AE(s), n (%) n (%) [related] n (%) [related] n (%) [related] n (%) [related] n (%) [related] n (%) [related] n (%) [related] Worsening asthma (<1) [0] Worsening eczema (<1) [0] Concussion of the (2) [0] brain Nausea (<1) [0] Left foot fracture (<1) [0] 0 Overdose of ponstan (<1) [0] 0 Overdose of paracetamol Subjects with fatal SAEs, n (%) (<1) [0] n (%) [related] 21

22 Conclusion: See publication below. Publications: Rothner D, Asgharnejad M. Tolerability of sumatriptan tablets in the acute treatment of migraine in adolescent patients: A review of data from clinical trials. EUR. J. NEUROL. 1999;6 SUPPL. 3:106. (Meeting Abstract) Date Updated: 06-Sep