Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: 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.: SUMA3006 Title: An open-label study to evaluate the long-term safety, tolerability and efficacy of sumatriptan nasal spray in the acute treatment of multiple migraine attacks in adolescent migraineurs (12-17 years of age). Rationale: At the time of this study, there were no prescription drugs approved in the United States for the treatment of migraine in subjects under 18 years of age. The nasal formulation of sumatriptan was available for treatment of migraine in the adult population, and was considered to be an appropriate route for treatment of migraine in adolescent subjects. This study was undertaken to evaluate the safety and tolerability of sumatriptan in the acute treatment of migraine in adolescents over a 12 month period. Phase: III Study Period: 2 December 1997 to 1 December Study Design: An open-label, 12-month, multi-attack, outpatient study. Centres: 46 active centres in the United States. Indication: Acute migraine with or without aura. Treatment: Subjects received sumatriptan nasal spray to treat all migraine attacks with headache severity of moderate to severe over a 12-month period. All subjects were to be started on the dose but could be titrated up or down (to 20 mg or, respectively) at the investigator s discretion in order to improve efficacy or tolerability. If the subject obtained relief (mild or no pain [a headache severity score of 1 or 0]) at 120 minutes after dosing and the migraine pain returned to moderate or severe (headache severity score of 2 or 3) within 2 to 24 hours after the initial dose, a second dose of sumatriptan was permitted to treat recurrence. A 24-hour headache-free period was required before treating a new attack, at least 2 hours must have elapsed between any two doses of sumatriptan, and no more than 2 doses could be taken during any 24-hour period. Objectives: The primary objective of this study was to evaluate the safety and tolerability of sumatriptan nasal spray in the long-term treatment (up to 12 months) of multiple migraine attacks in adolescent migraineurs (12-17 years of age) as measured by the occurrence and severity of adverse events (AEs). Primary Outcome/Efficacy Variable: Safety. Secondary Outcome/Efficacy Variable(s): Secondary efficacy variables were the proportion of attacks where the subject had headache relief (reduction in headache severity from moderate or severe [2 or 3] at baseline to mild or no pain [1 or 0]) 2 hours after the first dose of sumatriptan by dose; the proportion of attacks where the subject was pain free (reduction in headache severity from moderate or severe [2 or 3] at baseline to no pain [0]) 2 hours after the first dose of sumatriptan by dose; the proportion of attacks with recurrence of pain (headache relief within 2 hours followed by a return of moderate or severe [2 or 3] pain within 2-24 hours after the first dose) and time to recurrence within 2-24 hours after the first dose of sumatriptan by dose; the proportion of attacks which required use of rescue medication (either a second dose of sumatriptan or other acute migraine medication) within 24 hours after the first dose of sumatriptan by dose; the proportion of subjects who switched to each of the and doses, and the proportion who switched back to the dose; the mean and median number of treatment doses used on a per attack basis for each dose; the proportion of subjects with headache relief 2 hours after the first dose of sumatriptan by dose and attack number. All secondary endpoints were analysed for all attacks treated, and also by first and second 6 months of treatment. Statistical Methods: No formal statistical analysis was performed. The number of subjects enrolled was greater than the number of subjects required (300 subjects with 6 months of evaluable data and 100 subjects with 12 months of evaluable data) in order to account for enrolled subjects who would withdraw from the study before completing 6 or 12 months of treatment. The Intent-to-Treat (ITT) population included all subjects who treated at least one migraine attack with study treatment and had evaluable efficacy data. The safety population included all subjects who treated at least one migraine attack with study treatment. 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 2 to 8 moderate to severe migraine attacks per month in each of the previous 2 months (60 days) prior to screening; had a typical migraine attack duration of about 4 hours or more (untreated or unsuccessfully treated); 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 1

2 card; were able to, and their parent or guardian was able to, read and write English; and had completed SUMA3005 (after a protocol amendment subjects could be enrolled despite not participating in study SUMA3005). Subjects were excluded if they had uncontrolled hypertension at screening (systolic pressure of 140mmHg or diastolic pressure of 90mmHg in a non-migrainous state); a history of congenital heart disease; confirmed or suspected cardiovascular disease (angina pectoris, history of myocardial infarction or documented silent ischemia) or Prinzmetal s angina; confirmed or suspected medical conditions predisposing to cardiovascular and cerebrovascular diseases including systemic lupus erythematosus, Kawasaki disease, homozygous sickle cell anaemia, 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 a monoamine oxidase inhibitor in the 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 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. Subjects who were in but failed to follow and/or complete study SUMA3005 were also excluded. Number of Subjects: Planned, N 300 Entered, N 518 Completed, n (%) 189 (36) Total Number Subjects Withdrawn, n (%) 329 (64) Withdrawn due to Adverse Events, n (%) 22 (4) Withdrawn due to Lack of Efficacy, n (%) 24 (5) Withdrawn for Other Reasons, n (%) 286 (55) Demographics N (safety population) 437 Females: Males 231: 206 Mean Age, years (SD) 14.1 (1.65) Caucasian, n (%) 397 (91) Primary Efficacy Results: See safety results below. Secondary Outcome Variable(s): (ITT population) Headache relief at 2 hours Attacks with relief overall, n/n (%) 16/23 (70) 1480/1938 (76) 905/1261 (72) Attacks with relief first 6 months, n/n (%) 8/13 (62) 1055/1438 (73) 435/612 (71) Attacks with relief second 6 months, n/n (%) 8/10 (80) 425/500 (85) 470/649 (72) Headache free at 2 hours Attacks with relief overall, n/n (%) 11/23 (48) 829/1938 (43) 502/1261 (40) Attacks with relief first 6 months, n/n (%) 4/13 (31) 570/1438 (40) 245/612 (40) Attacks with relief second 6 months, n/n (%) 7/10 (70) 259/500 (52) 257/649 (40) Recurrence 2-24 hours after first dose Overall, attacks with recurrence, n/n (%) 0/16 181/1480 (12) 133/905 (15) Mean time to recurrence (sd) (6.05) (7.75) First 6 months, attacks with recurrence, n/n (%) 0/8 151/1055 (14) 64/435 (15) Mean time to recurrence (sd) (6.35) (8.36) Second 6 months, attacks with recurrence, n/n (%) 0/8 30/425 (7) 69/470 (15) Mean time to recurrence (sd) (4.19) (7.22) Use of rescue medication within 24 hours Overall, attacks with rescue medication not including a 2 nd dose, n/n (%) 5/23 (22) 292/1938 (15) 275/1261 (22) 2

3 Overall, attacks with rescue medication or 2 nd dose, n/n (%) First 6 months, attacks with rescue medication not including a 2 nd dose, n/n (%) First 6 months, attacks with rescue medication or 2 nd dose, n/n (%) Second 6 months, attacks with rescue medication not including a 2 nd dose, n/n (%) Second 6 months, attacks with rescue medication or 2 nd dose, n/n (%) 6/23 (26) 472/1938 (24) 402/1261 (32) 3/13 (23) 250/1438 (17) 142/612 (23) 4/13 (31) 394/1438 (27) 204/612 (33) 2/10 (20) 42/500 (8) 133/649 (20) 2/10 (20) 78/500 (16) 198/649 (31) (N=437) Dose titration to to to No. subjects (%) 5 (1) 3 (<1) 220 (50) 6 (1) Reason: tolerability, n (%) 5 (1) (1) Reason: efficacy, n (%) 0 2 (<1) 218 (50) 0 Reason: other, n (%) 0 1 (<1) 2 (<1) 1 (<1) Doses used per attack to Overall, mean doses per attack Overall, median doses per attack First 6 months, mean doses per attack First 6 months, median doses per attack Second 6 months, mean doses per attack Second 6 months, median doses per attack Headache relief at 2 hours, by attack number Attack 1, n/n (%) 1/2 (50) 296/420 (70) 2/3 (67) Attack 2, n/n (%) 0/2 236/327 (72) 36/47 (77) Attack 3, n/n (%) 2/3 (67) 172/242 (71) 51/77 (66) Attack 4, n/n (%) 2/2 (100) 128/163 (79) 71/111 (64) Attack 5, n/n (%) 3/3 (100) 98/124 (79) 87/114 (76) Attack 6, n/n (%) 2/2 (100) 74/101 (73) 76/103 (74) Attack 7, n/n (%) 1/2 (50) 69/77 (90) 69/96 (72) Attack 8, n/n (%) 1/2 (50) 55/66 (83) 58/85 (68) Attack 9, n/n (%) 1/1 (100) 52/59 (88) 46/73 (63) Attack 10, n/n (%) 1/1 (100) 36/51 (71) 38/60 (63) Attack 11, n/n (%) 1/1 (100) 35/42 (83) 35/55 (64) Attack 12, n/n (%) 1/1 (100) 34/38 (89) 34/45 (76) Attack 13, n/n (%) 0/1 28/33 (85) 31/38 (82) Attack 14, n/n (%) 0/0 23/27 (85) 26/34 (76) Attack 15, n/n (%) 0/0 23/24 (96) 25/34 (74) Attack 16, n/n (%) 0/0 14/18 (78) 22/32 (69) Attack 17, n/n (%) 0/0 13/15 (87) 27/29 (93) Attack 18, n/n (%) 0/0 12/13 (92) 20/25 (80) Attack 19, n/n (%) 0/0 12/12 (100) 17/25 (68) Attack 20, n/n (%) 0/0 7/9 (78) 20/24 (83) Attack 21, n/n (%) 0/0 7/8 (88) 15/18 (83) Attack 22, n/n (%) 0/0 8/8 (100) 12/15 (80) Attack 23, n/n (%) 0/0 5/7 (71) 11/14 (79) Attack 24, n/n (%) 0/0 6/6 (100) 7/13 (54) Attack 25, n/n (%) 0/0 4/5 (80) 8/11 (73) Attack 26, n/n (%) 0/0 3/4 (75) 7/10 (70) Attack 27, n/n (%) 0/0 3/5 (60) 7/8 (88) 3

4 Attack 28, n/n (%) 0/0 3/3 (100) 5/7 (71) Attack 29, n/n (%) 0/0 2/3 (67) 4/6 (67) Attack 30, n/n (%) 0/0 2/3 (67) 4/5 (80) Attack 31, n/n (%) 0/0 3/3 (100) 5/5 (100) Attack 32, n/n (%) 0/0 3/3 (100) 4/5 (80) Attack 33, n/n (%) 0/0 1/2 (50) 4/4 (100) Attack 34, n/n (%) 0/0 0/2 2/4 (50) Attack 35, n/n (%) 0/0 2/2 (100) 4/4 (100) Attack 36, n/n (%) 0/0 2/2 (100) 4/4 (100) Attack 37, n/n (%) 0/0 1/2 (50) 2/4 (50) Attack 38, n/n (%) 0/0 2/2 (100) 2/4 (50) Attack 39, n/n (%) 0/0 1/1 (100) 2/3 (67) Attack 40, n/n (%) 0/0 1/1 (100) 1/2 (50) Attack 41, n/n (%) 0/0 1/1 (100) 1/2 (50) Attack 42, n/n (%) 0/0 0/1 1/1 (100) Attack 43, n/n (%) 0/0 1/1 (100) 1/1 (100) Attack 44, n/n (%) 0/0 1/1 (100) 1/1 (100) Attack 45, n/n (%) 0/0 1/1 (100) 0/0 Safety Results: Safety Population Adverse events (AEs) and serious adverse events (SAEs) were recorded from the time of administration of the first dose of study medication until the final visit. Most Frequent Adverse Events On-Therapy n (%) n (%) n (%) No. of treated attacks, N Attacks with any AE(s), n (%) 9 (38) 765 (39) 472 (37) No. of subjects, N Subjects with any AE(s), n (%) 3 (43) 286 (66) 126 (64) Disturbances of sense of taste 1 (14) 190 (44) 73 (37) Ear, nose and throat infections 1 (14) 24 (6) 13 (7) Vomiting 1 (14) 24 (6) 7 (4) Nausea 0 21 (5) 5 (3) Nasal signs and symptoms 0 19 (4) 6 (3) Throat and tonsil discomfort and pain 0 16 (4) 4 (2) Burning/stinging sensation 0 14 (3) 7 (4) Headaches 0 13 (3) 6 (3) Migraines 0 13 (3) 2 (1) Dizziness 0 12 (3) 9 (5) Viral ear, nose and throat infections 1 (14) 7 (2) 6 (3) Paraesthesia 0 6 (1) 6 (3) Acne and folliculitis 0 2 (<1) 6 (3) Muscle cramps and spasms 1 (14) 0 0 Serious Adverse Events On-Therapy n (%) [n considered by the investigator to be related to study medication] Subjects with non-fatal SAEs, n (%) 0 8 (2) 0 n (%) [related] n (%) [related] n (%) [related] Exacerbation of migraine 0 2 (<1) [0] 0 Acute migraine 0 1 (<1) [0] 0 Cerebrovascular accident 0 1 (<1) [1] 0 Exacerbation of asthma 0 1 (<1) [0] 0 Facial nerve disorder 0 1 (<1) [1] 0 Fiorinal abuse 0 1 (<1) [0] 0 4

5 Lobar pneumonia 0 1 (<1) [0] 0 Numbness 0 1 (<1) [1] 0 Persistent migraine 0 1 (<1) [0] 0 Psychiatric depression 0 1 (<1) [0] 0 Status asthmaticus 0 1 (<1) [0] 0 Substance abuse 0 1 (<1) [0] 0 Violent behaviour 0 1 (<1) [0] 0 Subjects with fatal SAEs, n (%) Conclusion: See publication below. Publications: Rothner AD, Winner P, Nett R, et al. One-year tolerability and efficacy of sumatriptan nasal spray in adolescents with migraine: Results of a multicenter, open-label study. Clinical Therapeutics 2000;22(12): Long-term use of imitrex0 nasal spray in an adolescent patient population. P. Winner, A. D. Rothner D. Lewis R. Nett M. Asgharnejad A. Laurenza R. Austin M. Peykamian. 5th Congress of the European Federation of Neurological Societies (EFNS) 10/14/2000 Copenhagen; Denmark Date Updated: 08-Aug