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

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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.: SUMA3005 Title: A double-blind. placebo-controlled, parallel group study to evaluate three dose levels (5mg, 10mg and 20mg) of sumatriptan nasal spray in the acute treatment of a single migraine attack in adolescent migraineurs (12-17 years of age). Rationale: At the time of this study, no drugs had been approved in the United States of America (USA) for the treatment of migraine in subjects under 18 years of age. Sumatriptan had been proven to be an effective treatment for many adults with migraine. For adolescent subjects, the subcutaneous route of sumatriptan administration could be unacceptable because of fear or dislike of injections, and oral administration could be inappropriate because of the longer onset of action in a younger population with a shorter duration of attack and the chance of gastrointestinal symptoms including nausea and vomiting. Therefore, it was considered that the nasal route of sumatriptan administration could be the most appropriate for treating acute migraine in adolescents. Phase: III Study Period: 30 October 1997 to 21 January Study Design: A double-blind, placebo-controlled, randomized, parallel group, dose-ranging, single attack, outpatient study. Centers: 46 active centers in the USA. Indication: Acute migraine with and without aura. Treatment: Subjects were randomised (1:1:1:1) to receive sumatriptan 5mg, 10mg or 20mg, or placebo as a nasal spray to treat a single migraine attack with headaches of moderate to severe (grade 2 or 3) intensity. Study medication was to be administered into one nostril within 6 hours of onset of the migraine to be treated. Headache relief was assessed on a 4-point scale where 0 = none (no pain), 1 = mild (a little or small headache), 2 = moderate (a medium headache, not really bad) and 3 = severe (a really bad headache) If the subject obtained headache relief (mild or no pain i.e. grade 1 or 0) at 120 minutes and then the migraine returned to moderate or severe pain (recurrence) within 2 to 24 hours after the initial dose, a second, identical, blinded dose was permitted as treatment for the recurrence of migraine. Objectives: The primary objective was to compare the rate of headache relief (defined as a reduction in headache severity from a baseline score of 3 or 2 to a score of 1 or 0) at 2 hours post-dose following the use of sumatriptan nasal spray 20mg with that of placebo in the acute treatment of migraine in adolescents. Primary Outcome/Efficacy Variable: The primary efficacy variable was the comparison of the proportion of subjects with headache relief at 2 hours post first dose (post-dose) in the treatment of an acute migraine following use of sumatriptan nasal spray 20mg versus (vs) placebo. Secondary Outcome/Efficacy Variable(s): The secondary efficacy variables were: the proportion of subjects with headache relief at 2 hours post-dose following use of sumatriptan nasal spray 10mg and 5mg versus (vs) placebo and the between treatment comparisons (20mg vs 10mg, 20mg vs 5mg, 10mg vs 5mg); the proportion of subjects with headache relief at 15, 30 and 60 minutes post-dose; the proportion of subjects who were pain-free (defined as a reduction from Grade 3 or 2 to Grade 0) at 15, 30, 60 and 120 minutes post-dose; presence/absence of the associated symptoms of nausea (sick to my stomach/feel like throwing up), vomiting (throwing up or puking), photophobia (light bothers or hurts me/my eyes) and phonophobia (noise bothers or hurts me/my ears) at 15, 30, 60 and 120 minutes post-dose; recurrence of migraine pain ( incidence of and time to ) within 2 to 24 hours post-dose; use of rescue (a second dose of study drug or other acute migraine medication) taken within 24 hours post-dose; headache relief at 120 minutes post-dose summarized by subgroup factors (demographics, migraine history and baseline characteristics). Statistical Methods: All statistical tests were presented using 2-sided p-values. The Cochran-Mantel-Haenszel test, adjusted for center effects, was used to compare treatment groups with respect to the proportion of subjects who had headache relief, were pain free and who had associated symptoms (apart from vomiting) at 15, 30, 60 and 120 minutes post-dose, and those subjects who took rescue medication within 24 hours post-dose; due to the very small number of events, vomiting was assessed using Fisher s Exact test, without any adjustment for center. For each of the parameters listed above, a logistic regression model was used to test for a linear trend across dose levels at each observed timepoint. The Mantel-Haenzsel estimate of the odds ratios between each treatment comparison was calculated and summarized. No formal statistical comparisons were performed on the headache recurrence data. The number of subjects randomized was greater than the number planned for treatment in order to account for randomized subjects who would withdraw from the study before treating a migraine attack. All subjects receiving at least 1 dose of study medication were included in the safety population. Subjects who took the 1

2 study medication and returned a completed diary card were included in the intent-to-treat (ITT) population; the ITT population was the primary population used for efficacy analyses. Study Population: Male and nonpregnant female subjects using adequate contraception were eligible if they were between 12 and 17 years of age (inclusive); had a diagnosis of migraine with or without aura as defined by the 1988 International Headache Society criteria; had at least a 6-month history of moderate or severe migraine attacks, sufficient to establish a definitive diagnosis of migraine; had failed or responded inadequately to 1 over the counter or prescription medication for the acute treatment of migraine; had a typical migraine attack duration of about 4 hours or more (untreated or unsuccessfully treated); had between 2 and 8 (inclusive) moderate or severe migraine attacks per month in each of the two months prior to entry into the study (the minimum requirement for 2 attacks per month could be waived during the summer/non-school months where headache frequency in adolescents is typically decreased as long as the subject had a clear history of at least 2 attacks per month during the remainder of the year); were able to distinguish migraine attacks from other headaches (i.e. tension headaches) and between mild, moderate, and severe pain; were able to understand and complete the diary card; were able to, and their parent or guardian was able to, read and write English; and were able and willing to properly use the nasal spray. Subjects were excluded if they had uncontrolled hypertension at screening (systolic pressure of 140mmHg or diastolic pressure of 90mmHg in a nonmigrainous state); a history of congenital heart disease; confirmed or suspected cardiovascular disease (angina pectoris, history of myocardial infarction or documented silent ischemia) or Printzmetal s angina; confirmed or suspected medical conditions predisposing to cardiovascular and cerebrovascular diseases including systemic lupus erythematosus, Kawasaki disease, homozygous sickle cell anemia, or recurrent syncope; cardiac arrhythmias requiring medication; atherosclerotic disease; a history of cerebrovascular pathology including stroke; a history of Raynaud s syndrome; a current history of epilepsy; basilar or hemiplegic migraine; a history of tension-type headache on 15 days per month in either of the 2 months (60 days) before screening; impaired hepatic or renal function; or were likely, in the investigator s opinion, to have unrecognized cardiovascular or cerebrovascular disease. Other exclusion criteria included evidence of alcohol, drug, or substance abuse within the last year, evidence of ergotamine abuse within the last 3 months; known hypersensitivity to, intolerance of, or contraindication to the use of sumatriptan or any other 5- hydroxytryptamine (5HT1) receptor agonists; use of ergotamine containing drugs, and ergotamine derivatives, within the 24 hours before or after study treatment; use of sumatriptan or any 5HT1 agonist within 24 hours before or after study treatment; use of any acute medication for migraine, including opiate or simple analgesics and anti-emetics, within 6 hours before or 2 hours after study treatment; use of a monoamine oxidase inhibitor for at least 2 weeks before screening or during the study; use of selective serotonin reuptake inhibitors at any time during the course of the study; participation in an investigational drug trial within 4 weeks preceding the study or plans to participate in another drug or device trial during the current study; and any concurrent medical condition which could affect the interpretation of efficacy and safety data, or which otherwise contraindicated participation in a clinical trial with a new chemical entity. Number of Subjects: Planned, N Randomized, N Completed, n (%) 131 (79) 126 (77) 132 (80) 117 (73) Total Number Subjects Withdrawn, n (%) 35 (21) 37 (23) 32 (20) 43 (27) Withdrawn due to Adverse Events, n (%) Withdrawn due to Lack of Efficacy, n (%) Not applicable Not applicable Not applicable Not applicable Withdrawn for Other Reasons, n (%) 35 (21) 37 (23) 32 (20) 43 (27) Demographics N (Safety) Females: Males 65: 66 63: 65 73: 60 61: 57 Mean Age, years (standard deviation [sd]) (1.62) (1.72) (1.64) (1.58) White, n (%) 119 (91) 117 (91) 119 (89) 107 (91) Primary Efficacy Results: (ITT population) (N=130) Headache relief at 120 minutes post-dose: Subjects with Grade 2/3 headache at baseline, n (%) 130 (100) 117 (100) Subjects with headache relief at 120 minutes, (n %) 69 (53) 74 (63) Treatment comparison, p-value Secondary Outcome Variables: (ITT population) (N=130) (N=127) (N=117) (N=117) 2

3 Headache relief at 15, 30, 60 and 120 minutes post-dose: Subjects with Grade 2/3 headache at 130 (100) 127 (100) 133 (100) 117 (100) baseline, n (%) Headache relief, n (%) At 15 minutes 11 (8) 14 (11) 18 (14) 20 (17) At 30 minutes 33 (25) 32 (25) 44 (33) 39 (33) At 60 minutes 53 (41) 60 (47) 74 (56) 66 (56) At 120 minutes 69 (53) 84 (66) 85 (64) 74 (63) Headache relief at 120 minutes post-dose by baseline and demographic factors: Sex Female, n (%) 31 (48) 41 (66) 44 (60) 37 (61) Male, n (%) 38 (58) 43 (66) 41 (68) 37 (66) Race White, n (%) 63 (53) 76 (66) 77 (65) 66 (62) Black, n (%) 2 (40) 3 (75) 5 (56) 3 (75) Asian, n (%) (100) 0 American hispanic, n (%) 4 (67) 4 (80) 2 (50) 3 (60) Other, n (%) 0 1 (100) 0 2 (100) Age years, n (%) 41 (55) 56 (72) 59 (69) 44 (63) years, n (%) 28 (50) 28 (57) 26 (54) 30 (64) Body mass index <20, n (%) 20 (47) 23 (58) 41 (73) 31 (70) 20 to <25, n (%) 30 (57) 38 (67) 29 (56) 25 (57) 25 to <30, n (%) 12 (55) 14 (82) 10 (56) 14 (70) 30 to <35, n (%) 4 (67) 7 (64) 3 (75) 3 (43) 35 or more, n (%) 3 (50) 2 (100) 2 (67) 1 (50) Tanner score-females Stage I, n (%) (100) 1 (100) Stage II, n (%) 1 (33) 3 (75) 6 (86) 8 (80) Stage III, n (%) 5 (56) 2 (29) 8 (57) 4 (44) Stage IV, n (%) 10 (38) 18 (78) 16 (64) 13 (59) Stage V, n (%) 14 (58) 15 (63) 11 (50) 11 (61) Tanner score-males Stage I, n (%) 2 (67) 6 (75) 5 (71) 7 (88) Stage II, n (%) 11 (69) 7 (70) 13 (76) 12 (57) Stage III, n (%) 4 (40) 8 (62) 8 (80) 6 (67) Stage IV, n (%) 11 (48) 13 (65) 8 (73) 5 (83) Stage V, n (%) 8 (67) 7 (58) 6 (43) 4 (44) Menarchal status Potentially able to bear children, n (%) 29 (51) 39 (68) 35 (56) 29 (57) Premenarche, n (%) 2 (29) 2 (40) 9 (82) 8 (80) Time from onset to first dose (hours) 0 to <2, n (%) 47 (56) 48 (68) 54 (70) 49 (64) 2 to <4, n (%) 14 (48) 27 (73) 24 (59) 17 (65) 4+, n (%) 8 (47) 9 (47) 7 (47) 8 (57) Migraine history With aura, n (%) 10 (59) 8 (62) 5 (42) 10 (63) Without aura, n (%) 44 (47) 58 (65) 61 (63) 53 (60) With and without aura, n (%) 15 (75) 18 (72) 19 (79) 11 (85) Average migraine attack duration 4-8 hours, n (%) 32 (52) 33 (60) 42 (69) 33 (69) >8 hours, n (%) 37 (54) 51 (71) 43 (60) 41 (59) Sumatriptan use None, n (%) 41 (55) 53 (67) 54 (68) 42 (65) 3

4 Any formulation, n (%) 28 (52) 28 (62) 30 (59) 32 (62) Oral 100mg, n (%) 0 1 (100) 0 0 Oral 50mg, n (%) 5 (50) 10 (63) 9 (60) 7 (50) Oral 25mg, n (%) 19 (54) 17 (71) 22 (61) 21 (66) Subcutaneous, n (%) 3 (38) 3 (50) 3 (38) 4 (40) Intranasal, n (%) 1 (50) 4 (67) 2 (50) 1 (33) Other 5HT1 agonists, n (%) 5 (50) 6 (75) 3 (60) 8 (89) Proportion of pain-free subjects at 15, 30, 60 and 120 minutes post-dose: Headache-free, n (%) At 15 minutes 1 (1) At 30 minutes 3 (2) 3 (2) 4 (3) 5 (4) At 60 minutes 12 (9) 8 (6) 17 (13) 16 (14) At 120 minutes 32 (25) 30 (24) 44 (33) 42 (36) Presence/absence of associated symptoms at 15, 30, 60 and 120 minutes post-dose: Presence of nausea, n (%) At baseline 51 (39) 58 (46) 65 (49) 60 (51) At 15 minutes 52 (40) 58 (46) 59 (44) 52 (44) At 30 minutes 42 (32) 42 (33) 46 (35) 47 (40) At 60 minutes 36 (28) 29 (23) 27 (20) 34 (29) At 120 minutes 33 (25) 26 (20) 23 (17) 24 (21) Presence of vomiting, n (%) At baseline 6 (5) 4 (3) 5 (4) 9 (8) At 15 minutes 2 (2) 3 (2) 9 (7) 6 (5) At 30 minutes 3 (2) 6 (5) 8 (6) 6 (5) At 60 minutes 3 (2) 6 (5) 11 (8) 8 (7) At 120 minutes 6 (5) 9 (7) 6 (5) 6 (5) Presence of photophobia, n (%) At baseline 117 (90) 111 (87) 110 (83) 98 (84) At 15 minutes 109 (84) 101 (80) 103 (77) 91 (78) At 30 minutes 91 (70) 87 (69) 90 (68) 72 (62) At 60 minutes 76 (58) 64 (50) 71 (53) 58 (50) At 120 minutes 62 (48) 48 (38) 57 (43) 42 (36) Presence of phonophobia, n (%) At baseline 108 (83) 104 (82) 100 (75) 90 (77) At 15 minutes 94 (72) 90 (71) 91 (68) 72 (62) At 30 minutes 79 (61) 79 (62) 70 (53) 54 (46) At 60 minutes 66 (51) 50 (39) 54 (41) 42 (36) At 120 minutes 57 (44) 36 (28) 44 (33) 29 (25) Recurrence of migraine pain within 2 to 24 hours post-dose: Subjects with headache relief at 2 hours, n Subjects with recurrence of headache, n (%) 14 (20) 15 (18) 17 (20) 12 (16) Time to recurrence [hours], median (range) 3.8 ( ) a 4.9 ( ) b 8.8 ( ) 4.9 ( ) Use of rescue medication within 24 hours post-dose: Subjects taking rescue medication, n (%) 43 (33) 27 (21) 29 (22) 30 (26) Subjects taking second dose of study 51 (39) 37 (29) 40 (30) 37 (32) medication or rescue medication, n (%) Based on data from 13 subjects. Based on data from 14 subjects. Safety Results: (Safety Population) All adverse events (AEs) and serious adverse events (SAEs) occurring from the time of the subject s first dose of study medication until the subject completed an exit visit were reported. AE s were reported based on the randomized dose group (i.e., regardless of whether the subject took one or two doses). (+ placebo) (N=131) (+ 5mg) (N=128) (+ 10mg) (+ 20mg) (N=118) 4

5 Most Frequent Adverse Events n (%) n (%) n (%) n (%) On-Therapy Subjects with any AE(s) 53 (40) 55 (43) 65 (49) 65 (55) Disturbance of sense of taste 2 (2) 24 (19) 40 (30) 31 (26) Nausea 22 (17) 16 (13) 9 (7) 25 (21) Vomiting 11 (8) 10 (8) 15 (11) 12 (10) Photophobia 3 (2) 3 (2) 3 (2) 3 (3) Migraines 11 (8) 2 (2) 2 (2) 3 (3) Paresthesia 2 (2) 0 2 (2) 3 (3) Headaches 1 (<1) 1 (<1) 0 3 (3) Gastrointestinal discomfort and pain 0 1 (<1) 3 (2) 2 (2) Phonophobia 1 (<1) 2 (2) 2 (2) 2 (2) Throat and tonsil discomfort and pain 1 (<1) 2 (2) 0 2 (2) Dizziness 2 (2) 0 2 (2) 1 (<1) Ear, nose and throat infections 2 (2) 0 2 (2) 1 (<1) Other pressure/tightness 2 (2) 0 1 (<1) 0 Chest symptoms 0 2 (2) 0 0 Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] (+ placebo) (N=131) (+ 5mg) (N=128) (+ 10mg) (+ 20mg) (N=118) Subjects with non-fatal SAEs, n (%) 1 (<1) n (%) [related] n (%) [related] n (%) [related] n (%) [related] Exacerbation of migraine 1 (<1) [0] Peripheral tingling 1 (<1) [0] Flushing 1 (<1) [0] Burning sensation: face 1 (<1) [0] Subjects with fatal SAEs, n (%) Conclusion: See publication below. Publications: Winner, Paul et al. A Randomized, Double-Blind, -Controlled Study of Sumatriptan Nasal Spray in the Treatment of Acute Migraine in Adolescents. Pediatrics Vol.106 No.5 November 2000; Date Updated: 26-Jul